Clin Tox

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Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
PREFACE
The significant health impact of deliberate and accidental poisonings resulting from exposures to thousands
of drugs, chemicals, and environmental toxins has led to the development of Medical Toxicology as an
important medical specialty. In the United States, this development was formalized when the American
Board of Medical Specialties recognized Medical Toxicology as a specialty area of practice in 1992. Medical
toxicologists provide inpatient and outpatient consultation services in hospitals and clinics, provide direct
care for poisoned patients in inpatient toxicology units, and offer clinical expertise to laypeople and health
care providers requesting assistance from poison centers. As well, primary care providers and critical care
specialists also render care to poisoned patients and thus must have a working knowledge of toxicology.
Our goal has been to provide students, residents, and practitioners with an authoritative, affordable textbook
of medical toxicology, one whose format allows easy access to clinical information. Nurses, pharmacists,
and other health care providers will also find this book to be a helpful training and reference source. The
initial chapters examine broad clinical topics, including variations in advanced life support and airway
management necessitated by different poisonings. Section II focuses on the evaluation and treatment of
patients with specific signs and symptoms, as well as toxicologic problems encountered in specific organ
systems. The third section presents information on commonly encountered drugs and toxins in a
standardized format. Emphasis has been placed on clinical presentation and treatment, and the
standardized format and tables make this information more readily accessible to the busy practitioner. As
often occurs with attempts at uniformity, not every chapter could be fitted to a rigid structure, especially those
covering multiple drugs or toxins. In these cases, the format was modified appropriately. Concise addenda
cover therapeutic drug dosages, laboratory values, pertinent legal issues, and helpful Internet sites.
Contributors to this textbook represent a diverse group of practitioners of toxicology with varied expertise.
We appreciate their hard work and patience during the writing and editing processes and are grateful for the
sharing of their knowledge. I (M.D.F) commend my co-editors, whose labors resulted in a more
standardized, readable text.
We also thank the staff of W.B. Saunders Company, including Editors Judy Fletcher and Stephanie Donley
and Developmental Editors Beth Hatter and Arlene Chappelle. Their constant attention to our editorial needs
and timelines got us past many hurdles and to our goal. We are grateful for the work of the many staff
assistants, secretaries, and librarians who assisted with secretarial and bibliographic chores. Finally, this
project could not have been completed without the support of our families, partners, and friends, who
tolerated lost weekends and late evenings—thank you for your understanding.
MARSHA D. FORD, KATHLEEN A. DELANEY, L OUIS J. LING , TIMOTHY ERICKSON
Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

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CLINICAL TOXICOLOGY
Marsha D Ford, M.D., FACEP, FACMT

Director, Division of Toxicology
Assistant Chairman, Department of Emergency Medicine
Director, Carolinas Poision Center, Carolinas Medical Center, Charlotte, North Carolina
Clinical Associate Professor of Emergency Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North
Carolina
Kathleen A Delaney, M.D., FACP, FACEP, ABMT

Professor, Division of Emergency Medicine, University of Texas-Southwestern Medical Center
Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas
Louis J. Ling, M.D., FACEP, FACMT

Professor and Director, Emergency Medicine Program, University of Minnesota Medical School
Medical Direcotr, Hennepin Regional Poison Center
Associate Medical Director for Medical Education, Hennepin County Medical Center, Minneapolis, Minnesota
Timothy Erickson, M.D., FACEP, FACMT

Associate Professor of Emergency Medicine
Director, Division of Clinical Toxicology
Residency Director, Program in Emergency Medicine, University of Illinois, Chicago, Illinois
Dedication
For our patients, whose lives are entrusted to us and to whom we owe intelligent, informed medical care
and
In memory of Francis M. “Nick” Nichols, Jr., my revered mentor; for my early teachers at the New York City
Poison Center, who nourished my love of toxicology; for my colleagues at Carolinas Medical Center and
Carolinas Poison Center, who support, challenge, and continuously teach me; and for my family, friends, and
partner, whose love and caring sustain me
M. D. FORD
To all my students, from whom I continue to learn
K. A. DELANEY
To the staff of the Hennepin Regional Poison Center, for teaching me toxicology; my parents, Rose and
Joseph Ling, for teaching me about caring; and to my family, Amanda, Ali, Eric, and Beth, for teaching me
about life. Special thanks to the authors and my fellow editors, who share their wisdom, time, experience, and
patience
L. J. LING
To Valerie, Camille, Isabelle, Celeste, Julian, and my parents, brothers, and sisters; my mentors, colleagues,
and residents in Emergency Medicine; the Toxikon Consortium faculty and fellows, along with special thanks
to Paracelsus
T. ERICKSON
W.B. Saunders Company
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Library of Congress Cataloging-in-Publication Data
Clinical Toxicology/Marsha D. Ford.—[et al.]—1st ed.
p.cm.
ISBN 0–7216–5485–1
1. Poisoning—Treatment.2. Toxicology.3. Toxicological emergencies. I. Ford, Marsha D.[DNLM: 1.

Poisoning—therapy.2. Poisons 3. Toxins.QV 601 C641 2001]
00-029712
RA1211.C587 2001515.9—dc21
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CLINICAL TOXICOLOGY
ISBN 0-7216-5485-1
Copyright © 2001 by W.B. Saunders Company
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Last digit is the print number: 9 8 7 6 5 4 3 2 1


CONTRIBUTORS
Cynthia K. Aaron, M.D., F.A.C.E.P., F.A.C.M.T.

Assistant Professor, Emergency Medicine, University of Massachusetts Medical School;
Director, Toxicology Services, University of Massachusetts Medical Center, Worcester, Massachusetts
Organophosphates and Carbamates
Jawaid Akhtar, M.B.B.S.

Assistant Professor, Department of Emergency Medicine, University of Pittsburgh School of Medicine;
Attending Physician, Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh,
Pennsylvania
Salicylates
Timothy E. Albertson, M.D., Ph.D., F.A.C.M.T., F.A.C.E.P.

Professor of Medicine, Pharmacology/Toxicology and Anesthesiology, University of California, Davis School of
Medicine;
Executive Medical Director, California Poison Control System;
Chief, Division of Pulmonary and Critical Care Medicine;
Chief, Pulmonary Division, Northern California VA Hospital and Clinics, Davis, California
Pulmonary Abnormalities
Roblee P. Allen, M.D.

Associate Professor of Clinical Medicine, Division of Pulmonary and Critical Care Medicine, University of
California, Davis, School of Medicine;
Medical Director, Laser/Bronchoscopy Lab;
Medical Director, Medical Specialties, ICU;
Co-Director, Lung Transplant/Volume Reduction Program, UC Davis Medical Center, Sacramento, California
Deborah L. Anderson, Pharm.D.

Director, Hennepin Regional Poison Center, Hennepin County Medical Center, Minneapolis, Minnesota
Camphor and Mothballs
Anthony Anker, M.D., F.A.C.E.P.

Attending Physician, Emergency Department, Rogue Valley Medical Center, Medford, Oregon
Hepatic Failure; Acetaminophen
Beth A. Baker, M.D., M.P.H.

Director of Occupational and Environmental Medicine, Senior Partner, Medical and Toxicology Consulting,
Hennepin County Medical Center, Minneapolis, Minnesota
Metal Fume Fever
Theodore Bania, M.D.
Assistant Professor of Clinical Medicine, College of Physicians and Surgeons, Columbia University;
Director, Division of Toxicology, and Assistant Director of Research, St. Luke's–Roosevelt Hospital Center, New
York, New York
Thallium and Other Metals
Marc J. Bayer, M.D., F.A.C.E.P., A.B.M.T.

Medical Director, Connecticut Poison Control Center, Vice Chair, Department of Traumatology and Emergency
Medicine;
Chief, Division of Toxicology, University of Connecticut School of Medicine, Avon, Connecticut
Inhalation: Gases with Immediate Toxicity; Inhalation: Gases with Delayed Toxicity
Tareg A. Bey, M.D., F.A.C.E.P.

Assistant Professor of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical
School;
Assistant Director, Medical Toxicology Fellowship, University of Texas Southwestern Medical Center, Dallas,
Texas
Seizures
Kathleen Birnbaum, Pharm.D., C.S.P.I.

Poison Specialist II, University of New Mexico, Albuquerque, New Mexico
Carbamazepine
Robert A. Bitterman, M.D., J.D., F.A.C.E.P.

Director of Risk Management and Managed Care, Department of Emergency Medicine, Carolinas Medical
Center, Charlotte, North Carolina
Appendix B, Patient Refusal of Treatment: Legal Issues; Appendix C, Interhospital Transfer Principles—EMTALA
G. Randall Bond, M.D., F.A.C.M.T.

Professor, Departments of Pediatrics and Emergency Medicine, University of Cincinnati College of Medicine;
Medical Director, Drug and Poison Information Center, Cincinnati, Ohio
Black Widow Spider Envenomation
Jeffrey Brent, M.D., Ph.D., F.A.C.M.T., F.A.C.E.P.

Associate Clinical Professor of Medicine, Surgery, and Pediatrics, University of Colorado School of Medicine;
Toxicology Associates, Denver, Colorado
Cardiovascular Instability Caused by Drugs or Chemicals; Serotonin Reuptake Inhibitors, Newer
Antidepressants, and the Serotonin Syndrome
Keith K. Burkhart, M.D., F.A.C.M.T., F.A.C.E.P.

Associate Professor of Medicine and Pharmacology, The Pennsylvania State University School of Medicine;
Medical Director, Central Pennsylvania Poison Center, The Milton S. Hershey Medical Center, Hershey,
Pennsylvania
Anticoagulant Rodenticides
E. Martin Caravati, M.D., M.P.H., F.A.C.E.P.

Professor, Division of Emergency Medicine, University of Utah School of Medicine;
Associate Medical Director, Utah Poison Control Center, Salt Lake City, Utah
Insecticides: Pyrethrins, Pyrethroids, Organochlorines; Insecticides: N,N-Diethyl-3-methylbenzamide (DEET)
Edward W. Cetaruk, M.D.

Attending Faculty, Rocky Mountain Poison Center, Denver;
Attending Physician, Department of Emergency Medicine, Swedish Hospital Medical Center, Englewood,
Colorado
Vitamins
Calvin Chiang, M.D.

Department of Emergency Medicine, Strong Memorial Hospital, University of Rochester, Rochester, New York
Withdrawal Syndromes
William K. Chiang, M.D.

Assistant Professor of Clinical Surgery/Emergency Medicine, New York University School of Medicine;
Assistant Director, Emergency Department, Bellevue Hospital Center, New York;
Medical Director, Hudson Valley Poison Control Center, Sleepy Hollow, New York
Mercury
Rachel L. Chin, M.D., F.A.C.E.P.

Assistant Clinical Professor of Surgery, University of California, San Francisco;
Attending in Emergency Services, San Francisco General Hospital, San Francisco, California
Antivirals
Peter A. Chyka, Pharm.D.

Professor, Department of Pharmacy Practice and Pharmacoeconomics, and Associate Professor, Department of
Physical Therapy, University of Tennessee, College of Medicine;
Executive Director, Southern Poison Center, Memphis, Tennessee
Androgenic-Anabolic Steroids
John J. Cienki, M.D., F.A.C.E.P.

Consultant, Florida Poison Information Center–Miami;
Attending Emergency Physician, Jackson Memorial Hospital, Miami Beach, Florida
Nonanticoagulant Rodenticides
James E. Cisek, M.D., F.A.C.M.T., F.A.C.E.D.

Associate Professor, Emergency Medicine, Medical College of Virginia School of Medicine;
Medical Director, Virginia Poison Center, Richmond, Virginia
Polychlorinated Biphenyls and Related Substances
Cathleen Clancy, M.D., F.A.C.E.P.
Clinical Assistant Professor, University of Maryland School of Pharmacy, Baltimore, Maryland;
Clinical Instructor, Georgetown University Medical Center, Washington, DC;
Medical Toxicologist, Adjunct Assistant Professor, George Washington University Medical Center, Washington,
DC;
Medical Director, Maryland Poison Center, Baltimore, Maryland;
Attending Physician, Department of Emergency Medicine, Georgetown University Medical Center, Washington,
DC;
Medical Toxicologist, National Capital Poison Center, Washington, DC
Plants: Central Nervous System Toxicity
Richard F. Clark, M.D., F.A.C.M.T., F.A.C.E.P.

Associate Professor of Medicine, University of California, San Diego, School of Medicine;
Director, UCSD Division of Medical Toxicology;
Medical Director, San Diego Division, California Poison Control System, UCSD Medical Center, San Diego,
California
Nitroprusside; Rattlesnakes and Other Crotalids; Scorpion Envenomation
Jack C. Clifton II, M.D.

Assistant Professor, Department of Pediatrics, Rush Medical College;
Toxicology Fellow, Toxikon Consortium;
Cook County Hospital, University of Illinois, Rush-Presbyterian-St. Luke's Medical Center;
Attending Physician, Pediatric Emergency Department, Rush Children's Hospital, Rush-Presbyterian-St. Luke's
Medical Center, Chicago, Illinois
Acid Ingestion
David M. Cosentino, M.D., F.A.C.E.P.

Clinical Instructor, Department of Emergency Medicine, University of Florida Health Sciences Center,
Jacksonville;
Attending Physician, Orange Park Medical Center, Orange Park, Florida
Inhalation: Gases with Delayed Toxicity
Megan C. Cosentino, M.D.

Department of Emergency Medicine, University of Florida Health Sciences Center, Jacksonville, Florida
Inhalation: Gases with Delayed Toxicity
Sandra A. Craig, M.D.

Clinical Instructor, Department of Emergency Medicine, University of North Carolina at Chapel Hill, School of
Medicine;
Associate Residency Director, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North
Carolina
Radiology
Merilyn J. Crittenden, R.N., C.S.P.I.

Certified Specialist in Poison Information, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North
Carolina
Appendix F, Internet Resources
Barbara Insley Crouch, Pharm.D., M.S.P.H.

Associate Professor (Clinical), Department of Pharmacy Practice, College of Pharmacy, University of Utah;
Director, Utah Poison Control Center, Salt Lake City, Utah
Insecticides: Pyrethrins, Pyrethroids, Organochlorines; Insecticides: N,N-Diethyl-3-methylbenzamide (DEET)
Colleen O'Neil Davis, M.D., F.A.A.P.

Departments of Emergency Medicine and Pediatrics, Strong Memorial Hospital, University of Rochester,
Rochester, New York
Focused Physical Examination/Toxidromes
Kathleen A. Delaney, M.D., F.A.C.P., F.A.C.E.P., A.B.M.T.

Professor, Division of Emergency Medicine, University of Texas Southwestern Medical Center;
Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas
Initial Approach to the Poisoned Patient; Fluids and Electrolytes; Acid-Base Disturbances in the Poisoned
Patient; Central Nervous System Depression; Central Nervous System Agitation; Disorders of Thermoregulation:
Hyperthermia and Hypothermia; Anticholinergics and Antihistamines (H1 Antagonists); Cyanide; Antiseptics,
Disinfectants, and Sterilizing Agents
Francis J. De Roos, M.D., F.A.C.E.P.

Assistant Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine;
Attending Physician, Department of Emergency Medicine, Hospital of the University of Pennsylvania,
Philadelphia, Pennsylvania
Neuroleptics; Plants: Gastrointestinal Toxicity
J. Ward Donovan, M.D., F.A.C.E.P., F.A.C.M.T.

Center for Emergency Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
Salicylates
Suzanne Doyon, M.D.

Medical Director, Maryland Poison Center, School of Pharmacy, Baltimore, Maryland
Antimalarials
Brent R. Ekins, Pharm.D.

Assistant Professor of Clinical Pharmacy, University of the Pacific School of Pharmacy, Stockton;
Assistant Clinical Professor of Pharmacy, University of California, San Francisco, School of Pharmacy;
Director, California Poison Control System, Fresno Division, Fresno, California
Paraquat and Diquat
Janet Eng, D.O., F.A.C.O.E.P.

Attending Physician, Emergency Medicine, and Medical Toxicologist, Michigan State University Emergency
Medicine Residency, Ingham Regional Medical Center, Lansing, Michigan
Arsenic
Kristin M. Engebretsen, Pharm.D.

Associate Clinical Professor, University of Minnesota College of Pharmacy, Minneapolis;
Clinical Toxicologist, Emergency Medicine, Regions Hospital, St. Paul, Minnesota
Caffeine and Related Nonprescription Sympathomimetics
Timothy Erickson, M.D., F.A.C.E.P., F.A.C.M.T.

Associate Professor, Emergency Medicine;
Director, Division of Clinical Toxicology;
Residency Director, Program in Emergency Medicine, University of Illinois at Chicago College of Medicine,
Chicago, Illinois
Anticancer and Other Cytotoxic Drugs
Susan E. Farrell, M.D., F.A.A.E.M.

Instructor, Department of Medicine, Harvard Medical School;
Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Benzodiazepines
Fun H. Fong Jr., M.D., F.A.C.E.P.

Assistant Medical Director, Emory Adventist Hospital, Smyrna, Georgia
Radiation
Show H. Fong, Ph.D.

Senior Health Physicist, Atlanta, Georgia
Radiation
Marsha D. Ford, M.D., F.A.C.E.P., F.A.C.M.T.

Director, Division of Toxicology;
Assistant Chairman, Department of Emergency Medicine;
Director, Carolinas Poison Center, Charlotte;
Clinical Associate Professor of Emergency Medicine, University of North Carolina at Chapel Hill School of
Medicine, Chapel Hill, North Carolina
Initial Approach to the Poisoned Patient; Opioids; Ethylene Glycol and Methanol; Isopropanol; Alkali Ingestions
Gregory G. Gaar, M.D., F.A.C.E.P.

Clinical Associate Professor of Pediatrics, University of South Florida College of Medicine;
Co–Medical Director, Florida Poison Information and Toxicology Resource Center;
Tampa General Healthcare, Tampa, Florida
Valproate and Selected Newer Anticonvulsants; Coral Snakes
Richard J. Geller, M.D., M.P.H., F.A.C.M.T.

Assistant Clinical Professor, Emergency Medicine, University of California, San Francisco, School of Medicine,
San Francisco;
Medical Director, Fresno Division, California Poison Control System;
Clinical Director, Emergency Department, Fresno Community Hospital and Medical Center, Fresno, California
Paraquat and Diquat
Laurie Beth Gesell, M.D.

Assistant Professor, Emergency Medicine;
Director, Division of Hyperbaric Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
Ethanol
Leon M. Gussow, M.D., A.B.M.T.

Senior Attending Physician, Department of Emergency Medicine;
Toxicology Consultant, Toxikon Consortium, Illinois Poison Center, Cook County Hospital, Chicago, Illinois
Inhalants of Abuse; Lacrimating Agents: Tear Gases and Pepper Spray
Fred P. Harchelroad Jr., M.D., F.A.C.M.T., F.A.C.E.P.

Associate Professor, Emergency Medicine, MCP Hahnemann School of Medicine;
Director, Medical Toxicology Treatment Center, Allegheny General Hospital, Pittsburgh, Pennsylvania
Ergot Alkaloids
Carson R. Harris, M.D., F.A.C.E.P.

Assistant Professor of Clinical Emergency Medicine, Senior Staff Physician and Director of Toxicology,
University of Minnesota Medical School;
Consultant, Hennepin Regional Poison Center, Minneapolis, Minnesota
Caffeine and Related Nonprescription Sympathomimetics
Sandra Haynes, M.D.

Assistant Professor of Surgery and Emergency Medicine, New York Hospital/Bellevue Hospital Center, New
York, New York
Isoniazid and Other Antituberculous Drugs
Fred M. Henretig, M.D., F.A.C.M.T.

Professor of Pediatrics and Emergency Medicine, University of Pennsylvania School of Medicine;
Director, Section of Clinical Toxicology, Children's Hospital of Philadelphia;
Medical Director, Poison Control Center, Philadelphia, Pennsylvania
Clonidine and Central-Acting Antihypertensives
Glendon C. Henry, M.D.

Medical Director, Harlem Hospital, New York, New York
Isoniazid and Other Antituberculous Drugs
John A. Henry, M.D., R.R.C.P., F.F.A.E.M.

Professor of Accident and Emergency Medicine, Imperial College School of Medicine, St. Mary's Hospital,
London, England
Amphetamines
Robert S. Hoffman, M.D., F.A.C.M.T., F.A.C.E.P.

Assistant Professor of Clinical Surgery and Emergency Medicine, New York University School of Medicine;
Director, New York City Poison Center, New York, New York
Peripheral Neuropathy; Cocaine
Judd E. Hollander, M.D., F.A.C.E.P.

Associate Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine;
Clinical Research Director, Department of Emergency Medicine, Hospital of the University of Pennsylvania,
Cocaine
Rivka S. Horowitz, M.D., Ph.D.

Clinical Assistant Professor of Medicine, Brown University School of Medicine, Providence, Rhode Island;
Attending Physician, Emergency Department, Lawrence and Memorial Hospital, New London, Connecticut
Aromatic Hydrocarbons
Susan Hou, M.D.

Staff Physician, Loyola University Medical Center, Maywood, Illinois
Extracorporeal Removal of Drugs and Toxins
Mary Ann Howland, Pharm.D., D.A.B.A.T., F.A.A.C.T.

Clinical Professor of Pharmacy, St. John's University College of Pharmacy;
Consultant, New York City Poison Control Center, Bellevue Hospital Emergency Department, New York, New
York
Herbals and Other Dietary Supplements; Theophylline
Daniel O. Hryhorczuk, M.D., M.P.H., F.A.C.M.T.

Chief, Section of Clinical Toxicology, Cook County Hospital, and the Toxikon Consortium;
Professor of Occupational Medicine, University of Illinois;
Director, Great Lakes Center for Occupational and Environmental Health and Safety, Chicago, Illinois
Arsenic
William Kerns II, M.D., F.A.C.E.P., A.C.M.T.

Emergency Medicine and Medical Toxicology, Carolinas Medical Center, Charlotte, North Carolina
Beta-adrenergic Receptor Antagonists
J. Fergus Kerr, M.B.B.S., M.P.H., F.A.C.E.M.

Clinical Toxicologist, Austin and Repatriation Medical Centre, Melbourne, Victoria, Australia
Household Cleaning Products
Christopher Keyes, M.D.

Associate Professor, Division of Emergency Medicine, The University of Texas Southwestern Medical Center;
Medical Director, North Texas Regional Poison Control Center, Dallas, Texas
Psychoactive Drugs
Daniel E. Keyler, Pharm.D.

Professor, Clinical Pharmacy, University of Minnesota College of Pharmacy;
Clinical and Research Toxicologist and Co-Director, Toxicology Research, Hennepin County Medical Center and
Minneapolis Medical Research Foundation, Minneapolis, Minnesota
Cyclic Antidepressants
Mark Kirk, M.D., F.A.C.M.T.

Assistant Clinical Professor, Indiana University School of Medicine;
Director, Medical Toxicology Fellowship, Medical Advisory, Indianapolis Fire Department Hazardous Materials
Team;
Indiana Poison Center, Emergency Medicine and Trauma Center, Clarian/Methodist Hospital, Indianapolis,
Indiana
Managing Patients with Hazardous Chemical Contamination
Wendy Klein-Schwartz, Pharm.D., M.P.H.

Associate Professor, Department of Pharmacy Practice and Science, University of Maryland School of
Pharmacy;
Coordinator of Research and Education, Maryland Poison Center, Baltimore, Maryland
Plants: Central Nervous System Toxicity
Kurt C. Kleinschmidt, M.D., F.A.C.E.P.

Assistant Professor of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical
Center, Associate Medical Director, Emergency Department, Parkland Memorial Hospital, Dallas, Texas
Fluids and Electrolytes; Opioids
Jeffrey A. Kline, M.D.

Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina
Calcium Channel Antagonists
Paul Kolecki, M.D.

Assistant Professor, Department of Surgery, Division of Emergency Medicine, Jefferson Medical College of
Thomas Jefferson University;
Consultant, Philadelphia Poison Control Center, Philadelphia, Pennsylvania
Central Nervous System Depression
Gideon Koren, M.D., F.A.C.M.T.

Department of Pediatrics, Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario,
Canada
Special Considerations in the Pregnant Patient
Michael J. Kosnett, M.D., M.P.H., F.A.C.E.P., F.A.C.M.T.
Associate Clinical Professor of Medicine, Division of Clinical Pharmacology and Toxicology, University of
Colorado School of Medicine, Denver, Colorado
Lead
Edward P. Krenzelok, Pharm.D.

Professor of Pharmacy and Pediatrics, University of Pittsburgh School of Medicine;
Director, Pittsburgh Poison Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Poison Centers; Household Cleaning Products
Ken Kulig, M.D., F.A.C.M.T., F.A.C.E.P.

Associate Clinical Professor, Division of Emergency Medicine and Trauma, Department of Surgery, University of
Colorado School of Medicine;
Director, Porter Regional Toxicology Center;
Chairman, Department of Medicine, Porter Adventist Hospital, Denver, Colorado
Gastrointestinal Decontamination
Jerrold B. Leikin, M.D., F.A.C.P., F.A.C.E.P., D.A.B.M.T., F.A.C.M.T.

Professor of Medicine, Rush Medical College;
Associate Medical Director, Rush Emergency Services, Rush–Presbyterian–St. Luke's Medical Center, Chicago,
Illinois
Extracorporeal Removal of Drugs and Toxins; Poison Centers; Hydrogen Sulfide
Erica L. Liebelt, M.D., F.A.A.P., F.A.C.M.T.

Assistant Professor, Department of Pediatrics, Johns Hopkins University School of Medicine;
Attending, Pediatric Emergency Department, and Medical Toxicologist, Johns Hopkins Hospital, Baltimore,
Maryland
Sedative-Hypnotics
Christopher H. Linden, M.D., F.A.C.M.T., F.A.C.E.P.

Associate Professor, Department of Emergency Medicine, Division of Medical Toxicology, University of
Massachusetts Medical School, Worcester, Massachusetts
Digitalis Glycosides
Louis J. Ling, M.D., F.A.C.E.P., F.A.C.M.T.

Professor and Director, Emergency Medicine Program, University of Minnesota Medical School;
Medical Director, Hennepin Regional Poison Center;
Associate Medical Director for Medical Education, Hennepin County Medical Center, Minneapolis, Minnesota
Pine Oil and Turpentine
Toby Litovitz, M.D., F.A.C.M.T., F.A.C.E.P.

Clinical Professor, Emergency Medicine, The George Washington University School of Medicine;
Director, National Capital Poison Center, Washington, DC
Button Batteries
David Malkevich, M.D.
Department of Emergency Medicine, Lincoln Medical and Mental Health Center, Bronx, New York
Lithium
Richard L. Manka, M.D.

Assistant Professor of Ophthalmology, University of Minnesota Medical School;
Faculty Staff, Hennepin County Medical Center, Minneapolis, Minnesota
Ocular Abnormalities
Gregory P. Marelich, M.D.

Assistant Clinical Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of
California, Davis, School of Medicine, Davis, California
Thomas G. Martin, M.D., M.P.H., F.A.C.M.T., F.A.A.C.T., F.A.C.E.P.

Associate Professor, Department of Medicine, Division of Emergency Medicine, University of Washington;
Director, University of Washington Medical Toxicology Service, Seattle, Washington
Advanced Life Support in the Poisoned Patient (TOX ACLS)
Nancy J. Matyunas, Pharm.D.

Adjunct Instructor, Department of Pharmacology and Toxicology, University of Louisville School of Medicine;
Managing Director, Kentucky Poison Center, Louisville, Kentucky
Nicotine Poisoning
Susan M. Maynard, Ph.D.

Director of Chemistry and Toxicology Laboratories, Carolinas Medical Center, Charlotte, North Carolina
Drugs and Toxins: Therapeutic and Toxic Levels
Patrick E. McKinney, M.D., F.A.C.M.T., F.A.C.E.P.

Assistant Professor, Department of Emergency Medicine, College of Pharmacy, and Medical Director, New
Mexico Poison Center, University of New Mexico, Albuquerque, New Mexico
Carbamazepine; Phenytoin
Kenneth McMartin, Ph.D.

Professor, Department of Pharmacology, Louisiana State University Health Sciences in Shreveport, Shreveport,
Louisiana
Ethylene Glycol and Methanol
William J. Meggs, M.D., F.A.C.E.P.

Professor, Department of Emergency Medicine, East Carolina University School of Medicine;
Chief of Toxicology, Pitt County Memorial Hospital, Greenville, North Carolina
Hypersensitivity Reactions; Hymenoptera
M. John Mendelsohn, M.D.
Attending Physician and Toxicologist, Falmouth Hospital, Falmouth, Massachusetts
Monoamine Oxidase Inhibitors
Timothy J. Meredith, M.D.

Professor of Medicine and Pathology, Vanderbilt University School of Medicine;
Director, Center for Clinical Toxicology, Vanderbilt University Medical Center, Nashville, Tennessee
Hydrofluoric Acid
Brent Morgan, M.D.

Assistant Professor of Emergency Medicine, Emory University School of Medicine;
Assistant Medical Director, Georgia Poison Center, Atlanta, Georgia
Renal Failure
Michael F. Murphy, M.D., F.R.C.P.C.

Associate Professor, Emergency Medicine and Anaesthesia, Dalhousie University;
Staff, Emergency Medicine and Anaesthesia, Health Sciences Centre, Halifax, Nova Scotia, Canada
Airway Management in the Poisoned Patient
Lindsay M. Murray, M.B.B.S., F.A.C.E.M.

Senior Lecturer in Emergency Medicine, University of Western Australia;
Emergency Physician and Clinical Toxicologist, Sir Charles Gaironer Hospital, Perth, Western Australia,
Australia
Colchicine
Sean Patrick Nordt, Pharm.D.

Assistant Clinical Professor of Medicine, University of California, San Diego, School of Medicine;
Assistant Director, San Diego Division, California Poison Control System, UCSD Medical Center, San Diego,
California
Rattlesnakes and Other Crotalids
Sven A. Normann, Pharm.D.

Clinical Associate Professor, Pharmacy Practice;
Director, Working Professional Pharm.D. Program, College of Pharmacy, University of Florida, Gainesville;
Consultant, Florida Poison Information Center, Tampa General Hospital, Tampa, Florida
Valproate and Selected Newer Anticonvulsants; Coral Snakes
Kent R. Olson, M.D.

Clinical Professor of Medicine, Pediatrics and Pharmacy, University of California at San Francisco, School of
Medicine, San Francisco, California
Smoke Inhalation
Janis M. Orlowski, M.D.

Executive Dean and Associate Professor, Rush Medical College;
Associate Vice President, Rush Medical Center, Chicago, Illinois
Extracorporeal Removal of Drugs and Toxins
Harold H. Osborn, M.D., F.A.C.E.P.

Emergency Physician, New Rochelle, New York
Heparin; Lithium
Kevin C. Osterhoudt, M.D.

Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine;
Consultant Toxicologist, The Poison Control Center and The Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania
Methemoglobinemia
John D. Osterloh, M.D., M.S., F.A.C.M.T.

Professor of Pathology, University of New Mexico School of Medicine;
Medical Director of Chemico-Pathology/Toxicology, University of New Mexico Health Sciences Center and
Tricore Laboratories, Albuquerque, New Mexico
Laboratory Testing in Emergency Toxicology
Edward J. Otten, M.D., F.A.C.M.T.

Professor, Emergency Medicine and Pediatrics;
Director, Division of Toxicology, University of Cincinnati College of Medicine, Cincinnati, Ohio
Ethanol
Wesley B. Palatnick, M.D., F.R.C.P.C., A.B.E.M., A.B.M.T.

Head, Section of Emergency Medicine;
Associate Professor, Department of Family Medicine, University of Manitoba Faculty of Medicine;
Medical Director, Emergency Program, Health Sciences Centre, Winnipeg Hospital Authority, Winnipeg,
Manitoba, Canada
Metaldehyde
Mary E. Palmer, M.D., F.A.C.E.P.

Fellow in Medical Toxicology, New York City Poison Control Center, New York, New York;
Emergency Medicine Physician, University of Rykjavik, Iceland;
Arlington Hospital, Arlington, Virginia
Herbals and Other Dietary Supplements
Frank P. Paloucek, Pharm.D., A.B.A.T.

Clinical Associate Professor, Department of Pharmacy Practice;
Adjunct Assistant Professor, Department of Emergency Medicine, University of Illinois at Chicago College of
Medicine, Chicago, Illinois
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Maria Pelucio, M.D., F.A.C.E.P.
Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina
Appendix E: Drugs and Antidote Dosages
Paul R. Pentel, M.D.

Professor of Medicine and Pharmacology, University of Minnesota Medical School;
Chief, Division of Clinical Pharmacology and Toxicology, Hennepin County Medical Center, Minneapolis,
Minnesota
Cyclic Antidepressants
Jeanmarie Perrone, M.D., F.A.C.E.P.

Assistant Professor, Department of Emergency Medicine, University of Pennsylvania School of Medicine;
Attending Physician, and Co-Director, Division of Toxicology, Emergency Department, Hospital of the University
of Pennsylvania, Philadelphia, Pennsylvania
Selective Beta-Adrenergic Agonists
Rebecca Perry, D.O.

Assistant Clinical Professor, Department of Emergency Medicine, Wright State University School of Medicine,
Dayton, Ohio
Insulin
Scott D. Phillips, M.D., F.A.C.P., F.A.C.M.T.

Associate Clinical Professor, Department of Medicine, Division of Clinical Pharmacology and Toxicology,
University of Colorado School of Medicine;
Rocky Mountain Poison and Drug Center, University of Colorado Health Sciences Center;
Attending Physician, Porter Adventist Hospital, Littleton Adventist Hospital, Denver Health Medical Center, and
University Hospital, Denver, Colorado
Drug Testing in the Workplace
Michael Policastro, B.A.

Senior Medical Student, Wright State University School of Medicine, Dayton, Ohio
Oral Hypoglycemic Agents; Insulin
Katherine M. Prybys, D.O.

Assistant Professor, Emergency Medicine, University of Maryland Medical School, Baltimore, Maryland
Ethanol
Roy A. Purssell, M.D.

Assistant Professor, Department of Surgery, University of British Columbia Faculty of Medicine;
Head, Department of Emergency Medicine, and Medical Consultant, Drug and Poison Information Center–British
Columbia, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada
Antihypertensives
Lawrence W. Raymond, M.D., Sc.M.

Clinical Professor of Family Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill;
Attending Physician, Carolinas Medical Center, Charlotte, North Carolina
Glycol Ethers and Diethylene Glycol
David J. Roberts, M.D.

Clinical Associate Professor, University of Minnesota Medical School;
Senior Consultant, Hennepin Regional Poison Center;
Staff Emergency Physician and Toxicology Consultant, North Memorial Medical Center, Minneapolis, Minnesota
Plants: Cardiovascular Toxicity
George C. Rodgers Jr., M.D., Ph.D., F.A.C.M.T.

Professor of Pediatrics and Pharmacology and Toxicology, University of Louisville School of Medicine;
Medical Director, Kentucky Poison Center, Louisville, Kentucky
Nicotine Poisoning
S. Rutherfoord Rose, Pharm.D.

Clinical Assistant Professor, Department of Emergency Medicine, University of North Carolina at Chapel Hill
School of Medicine;
Director, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North Carolina
Pharmacokinetics and Toxicokinetics; Appendix A, Acute Nontoxic Exposures
Brett Roth, M.D., F.A.C.E.P.

Assistant Professor, University of Texas Southwestern Medical Center;
Director of Inpatient Toxicology Service, Parkland Memorial Hospital, Dallas, Texas
Smoke Inhalation
Anna M. Rouse, RPh, C.S.P.I.

Assistant Director, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North Carolina
Appendix E, Drugs and Antidote Dosages
Kevin O. Rynn, Pharm.D., A.B.A.T.

Clinical Assistant Professor, Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Jay L. Schauben, Pharm.D.

Clinical Professor, College of Pharmacy, and Department of Emergency Medicine, College of Medicine,
University of Florida;
Director, Florida Poison Information Center;
Director, Clinical Toxicology Service, Shands Jacksonville, Jacksonville, Florida
Muscle Relaxants
Nicola Schiebel, M.D.

Emergency Medicine, University of Alberta, Edmonton, Alberta, Canada
Barbiturates
Robert Schneider, M.D., F.A.C.E.P., F.A.C.S.
Associate Director of Clinical Operations, Department of Emergency Medicine, Carolinas Medical Center,
Charlotte, North Carolina
Airway Management in the Poisoned Patient
Sandra M. Schneider, M.D., F.A.C.E.P.

Professor and Chair, Department of Emergency Medicine, University of Rochester School of Medicine, Strong
Memorial Hospital, Rochester, New York
Mushrooms
Dirk C. Schrader, M.D.

Emergency Department, Athens Regional Medical Center, Athens, Georgia
Radiation
Charles M. Seamens, M.D., F.A.C.E.P.

Assistant Professor, Emergency Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
Hydrofluoric Acid
Donna L. Seger, M.D., F.A.C.E.P.

Assistant Professor of Medicine and Emergency Medicine, Vanderbilt University School of Medicine;
Fellowship Director and Chief, Medical Toxicology Service, Vanderbilt University Medical Center;
Medical Director, Middle Tennessee Poison Center, Nashville, Tennessee
Hydrofluoric Acid
Suzanne M. Shepherd, M.S., M.D., F.A.C.E.P.

Associate Professor and Program Director, Residency Training Program in Emergency Medicine, University of
Pennsylvania School of Medicine;
Education Director, Penn Travel Medicine, and Attending Physician, Hospital of the University of Pennsylvania,
Plants: Gastrointestinal Toxicity; Scombroid, Ciguatera, and Other Seafood Intoxications; Plant Poisoning:
Berries
Kathleen Shilalukey, M.B., Ch.B., B.Sc.

Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, the Hospital for
Sick Children, Toronto, Ontario, Canada
Special Considerations in the Pregnant Patient
William H. Shoff, M.D., F.A.C.E.P.

Assistant Professor, University of Pennsylvania School of Medicine;
Director, Penn Travel Medicine, and Attending Physician, Hospital of the University of Pennsylvania,
Scombroid, Ciguatera, and Other Seafood Intoxications; Plant Poisoning: Berries
Marco L.A. Sivilotti, M.D., M.Sc., F.R.C.P.C., F.A.C.E.P.
Fellow, Medical Toxicology, Assistant Professor, Emergency Medicine, University of Massachusetts Medical
School;
Instructor, Emergency Medicine, Harvard Medical School, Worcester, Massachusetts
Alkali Ingestions
Frank Smeeks, M.D.

Attending Emergency Physician, Grace Hospital, Morganton, North Carolina
Oral Hypoglycemic Agents
Susan C. Smolinske, Pharm.D.

Assistant Professor, Department of Pediatrics, Wayne State University College of Medicine;
Managing Director, Children's Hospital of Michigan, Regional Poison Control Center, Detroit, Michigan
Laxatives
Vincent C. Speranza, Pharm.D.

Assistant Director, Florida Poison Information and Toxicology Resource Center, Tampa General Hospital,
Tampa, Florida
Valproate and Selected Newer Anticonvulsants
Karl A. Sporer, M.D., F.A.C.E.P., F.A.C.P.

Associate Clinical Professor, University of California, San Francisco, School of Medicine;
Attending Physician, San Francisco General Hospital, San Francisco, California
Antidysrhythmics
Christine M. Stork, Pharm.D.

Assistant Professor, Department of Emergency Medicine and Department of Medicine, Section of Clinical
Pharmacology, Upstate Medical University;
Director, Central New York Poison Control Center, University Hospital, Syracuse, New York
Theophylline
Young-Jin Sue, A.B., M.D.

Clinical Assistant Professor of Pediatrics, Albert Einstein College of Medicine;
Attending Physician, Pediatric Emergency Services, Montefiore Medical Center, Bronx, New York
Antiseptics, Disinfectants, and Sterilizing Agents
Milton Tenenbein, M.D., F.A.C.M.T.

Professor of Pediatrics, Pharmacology and Medicine, University of Manitoba Faculty of Medicine;
Director, Emergency Services, Children's Hospital;
Director, Manitoba Poison Control Centre, Children's Hospital, Winnipeg, Manitoba, Canada
Iron; Thyroid Hormones
Christian Tomaszewski, M.D.

Assistant Clinical Professor, Department of Emergency Medicine, University of North Carolina–Chapel Hill
School of Medicine;
Director, Hyperbaric Medicine, Division of Medical Toxicology, Department of Emergency Medicine, Carolinas
Medical Center, Charlotte, North Carolina
Carbon Monoxide; Aquatic Envenomations
Andrew R. Topliff, M.D.

Consultant, Hennepin Regional Poison Center, Minneapolis, Minnesota
Ergot Alkaloids; Camphor and Mothballs; Pine Oil and Turpentine
Richard T. Tovar, M.D., F.A.C.E.P.

Assistant Clinical Professor, Medical College of Wisconsin, Milwaukee;
Chief of Staff, Oconomowoc Memorial Hospital, Oconomowoc, Wisconsin
Halogenated Hydrocarbons
John F. Tucker, M.D.

Clinical Assistant Professor, Medical College of Wisconsin;
Chief of Emergency Medicine, St. Luke's Medical Center, Milwaukee, Wisconsin
Aliphatic Hydrocarbons; Halogenated Hydrocarbons
Brent van Hoozen, M.D.

Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California,
Davis, School of Medicine, Davis, California
Susi Vassallo, M.D., F.A.C.E.P., F.A.C.M.T.

Clinical Assistant Professor of Emergency Medicine/Surgery, New York Hospital, Bellevue Medical Center;
Consultant, New York City Poison Control Center, New York, New York
Essential Oils
Larissa Velez-Daubon, M.D.

Fellow, Medical Toxicology, Clinical Instructor, Division of Emergency Medicine, University of Texas
Southwestern Medical School, Dallas, Texas
Central Nervous System Agitation
Ingrid Vicas, M.D.C.M., F.R.C.P.C., A.B.E.M., D.A.B.M.T.

Clinical Associate Professor (Pharmacology and Therapeutics) (Internal Medicine), Family Medicine, University
of Calgary Faculty of Medicine;
Director, Poison and Drug Information Service–Calgary; Calgary, Alberta, Canada
Barbiturates
Michael Wahl, M.D., F.A.C.E.P.

Clinical Instructor, University of Illinois at Chicago College of Medicine;
Attending Physician, Department of Emergency Medicine, Illinois Masonic Medical Center;
Medical Director, Illinois Poison Center, Chicago, Illinois
Anticancer and Other Cytotoxic Drugs
Michael Wainscott, M.D., F.A.C.E.P.

Associate Professor, Division of Emergency Medicine, and Emergency Medicine Residency Director,
Southwestern Medical School, Dallas, Texas
Opioids
Frank G. Walter, M.D., F.A.C.E.P., F.A.C.M.T.

Associate Professor of Surgery, Division of Emergency Medicine, Section of Medical Toxicology, University of
Arizona College of Medicine;
Director, Medical Toxicology Fellowship, and Director of Clinical Toxicology, University Medical Center, Tucson,
Arizona
Seizures
Richard Y. Wang, D.O., F.A.C.M.T., F.A.C.E.P.

Assistant Professor, Department of Medicine, Brown University School of Medicine;
Director, Division of Medical Toxicology, Rhode Island Hospital, Providence, Rhode Island
Hematologic Abnormalities
Gary S. Wasserman, D.O., F.A.A.P., F.A.C.M.T., F.A.A.C.T.

Professor of Medicine, Department of Pediatrics, University of Missouri–Kansas City School of Medicine;
Chief, Section of Medical Toxicology;
Director, Poison Control Center, The Children's Mercy Hospital, Kansas City, Missouri
Brown Recluse and Other Necrotizing Spiders
William A. Watson, Pharm.D.

Clinical Professor, Department of Surgery, University of Texas Medical School at San Antonio;
Managing Director, South Texas Poison Center, The University of Texas Health Science Center, San Antonio,
Texas
Pharmacokinetics and Toxicokinetics; Disulfiram
Paul M. Wax, M.D., F.A.C.M.T., F.A.C.E.P.

Associate Professor, Emergency Medicine, University of Rochester;
Associate Medical Director, Fingerlakes Regional Poison Control Center;
Attending Physician, Emergency Department, Strong Memorial Hospital, Rochester, New York
Focused Physical Examination/Toxidromes; Withdrawal Syndromes
Alan L. Weiner, M.D.

Medical Toxicologist, Connecticut Poison Control Center, University of Connecticut School of Medicine,
Farmington, Connecticut
Inhalation: Gases with Immediate Toxicity
Suzanne R. White, M.D., F.A.C.E.P.

Associate Professor of Pediatrics and Emergency Medicine, Wayne State University School of Medicine;
Medical Director, Regional Poison Control Center, Children's Hospital of Michigan; Detroit, Michigan
Laxatives; Botulism; Food Poisoning
Lena C. Williams, R.N., B.S.N.

Director, North Texas Regional Poison Control Center, Dallas, Texas
Psychoactive Drugs
Saralyn R. Williams, M.D.

Assistant Clinical Professor of Medicine, University of California, San Diego, School of Medicine, San Diego,
California
Nitroprusside
Leslie R. Wolf, M.D., A.C.M.T.

Associate Professor, Toxicology Coordinator, Department of Emergency Medicine, Wright State University
School of Medicine, Dayton, Ohio
Oral Hypoglycemic Agents; Insulin


FOREWORD
A great textbook appeals to numerous suitors. The pupil, from medical student to pundit, desires an
understanding of the fundamentals of the discipline. The clinician appreciates a commonsense-driven
approach to patient care. The academician seeks in-depth, state-of-the-art knowledge on the subject,
ranging from pathophysiology to management principles. All enjoy an organized, consistent, and scholarly
approach to learning.
Clinical Toxicology by Ford and colleagues appeals to each. The first 15 chapters are devoted to general
management and cover a breadth of topics, each from the perspective of “what's different for the patient with
suspected overdose?” To wit, how does one assess and stabilize the generic poison patient? What are the
particulars of managing the airway? Are adjustments in advanced life support peculiar to this population?
What are the axioms of gastrointestinal decontamination and extracorporeal removal techniques? What are
the idiosyncrasies of laboratory and radiologic evaluation? How should the pregnant patient be handled
differently?
For the pragmatic clinician, there are 13 “approach to” chapters. These provide a cogent thought process for
the physician confronted with specific clinical scenarios. Critical care disciplines such as toxicology and
emergency medicine often require rapid decision-making based on limited clinical information. Patients are
frequently categorized as fitting a particular scenario or toxidrome. Based upon this, the care provider
maneuvers through a relevant differential diagnosis and prescribed management schemata, then reacts as
the case unfolds. These 13 chapters proceed in precisely this manner, handling presentations such as CNS
depression, CNS agitation, seizures, methemoglobinemia, and pulmonary abnormalities. Each chapter gives
consideration to initial stabilization, relevant differential entities, examination and laboratory findings,
definitive treatment, and patient disposition.
The “toxins in depth” chapters, 101 in number, are just that. Within each is discussion of epidemiology,
pharmacokinetics, pathophysiology, clinical presentation including specific situations, general and toxin-
specific treatment, laboratory analysis, differential considerations, disposition, and sequelae.
Of considerable advantage to the reader, all chapters are consistently organized, well tabulated, and fully
annotated.
Finally, there are six “addenda” chapters intended to serve as easy-to-use resources. These include quick
references on therapeutic and toxic levels of drugs and toxins as well as dosages for therapeutic drugs and
antidotes. Three give perspective on increasingly germane aspects of care. One reviews toxicology-related
Internet resources; two offer clear perspective on the medicolegal aspects common to toxicology patients.
In sum, Clinical Toxicology is a carefully formulated text that meets the needs of a wide range of health care
providers, teachers, and scientists. Its editors are experienced and expert in the domain of toxicology. And,
for the sake of the reader, great care has been taken to consistently arrange and cogently and clearly
describe the information.
JOHN M ARX, Chairman, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North
Carolina, Editor-in-Chief, Rosen's Emergency Medicine, 5th ed.


Section I – GENERAL MANAGEMENT PRINCIPLES
Chapter 1 – Initial Approach to the Poisoned Patient
Marsha Ford Kathleen A. Delaney
INTRODUCTION
The initial approach to the poisoned patient should focus on six major areas: (1) resuscitation and
stabilization; (2) history and physical examination, including evaluation for a specific toxidrome; (3)
appropriate decontamination of the gastrointestinal tract, skin, and eyes; (4) judicious use of laboratory tests,
electrocardiograms, and radiographic studies; (5) administration of specific antidotes, if indicated; and (6)
utilization of enhanced elimination techniques for selected toxins. These topics are covered in detail in
selected general management chapters as well as in chapters that deal with specific toxins. This chapter
provides a rapid overview of these six areas.


RESUSCITATION AND STABILIZATION
The first priorities in the management of seriously poisoned patients are the same as with all patients. The
patency of the airway must be ensured, followed by assistance of breathing and support of circulation.
Cardiac monitoring, pulse oximetry, and intravenous access should be established as indicated by the
patient’s clinical condition. Airway management should focus on correcting hypoxia and respiratory acidosis
and avoiding pulmonary aspiration. Acidemia due to respiratory depression can exacerbate the toxicity of
drugs, such as cyclic antidepressants and salicylates. Certain toxic conditions can pose problems in the
performance of standard airway management techniques. For example, severe upper airway injury that
occurs following a caustic ingestion may preclude routine endotracheal intubation, necessitating surgical
management of the airway. The use of succinylcholine for rapid-sequence intubation can result in prolonged
paralysis in patients with organophosphate toxicity.[5] Routine ventilator settings may be grossly inadequate
for the patient with severe metabolic acidosis who requires significant respiratory compensation. Similarly,
standard advanced cardiac life support (ACLS) protocols may be inadequate or inappropriate for
resuscitation of poisoned patients with life-threatening cardiac dysrhythmias or cardiac arrest. Standard
ACLS doses of atropine are inadequate for organophosphate-induced cholinergic symptoms. The use of
procainamide is contraindicated for ventricular dysrhythmias caused by cyclic antidepressants and other
myocardial sodium channel–blocking agents. Intravenous calcium can be lifesaving in a patient poisoned
with hydrofluoric acid, a calcium channel–blocking agent, or magnesium. Sodium bicarbonate may be
lifesaving in resuscitation of the patient poisoned with cyclic antidepressants or salicylates. Variations in
these methods of management are discussed in Chapters 2 and 3 .
In patients with altered mental status, administration of naloxone, dextrose, and thiamine should be
considered, while flumazenil should be administered cautiously in cases of benzodiazepine overdose with
significant respiratory depression. [3]


HISTORY AND PHYSICAL EXAMINATION
The history provides critical information in the assessment of the patient with suspected overdose. A history
of medications potentially available to a patient or a history of chronic medical illnesses in members of the
household gives clues to classes of medications available. Accurate identification of ingestants is particularly
important in the patient exposed to agents that have delayed onset of toxic effects, such as acetonitrile,
which is metabolized to cyanide, or monoamine oxidase inhibitors. The physical examination gives important
clues to both the severity and the cause of poisoning. Vital sign and mental status abnormalities are
important signs of the severity of toxicity and may also suggest the class of toxin involved. Examples include
the respiratory depression of barbiturate or opioid poisoning and the tachycardia and hypertension of
poisoning with sympathomimetic agents. Characteristic “toxidromes” indicate the presence of agents with
cholinergic, anticholinergic, sympathomimetic, and opioid effects. Less specific findings, such as nystagmus,
myoclonus, asterixis, and tremor, also suggest various toxins. Characteristic odors suggest the presence of
toxins, such as cyanide (almond odor) or ethchlorvynol (vinyl odor).


DECONTAMINATION
Administration of activated charcoal is the primary method of gastrointestinal decontamination, and it should
be administered within 1 hour of toxin ingestion whenever possible. Multiple doses of activated charcoal may
be beneficial in patients ingesting life-threatening amounts of carbamazepine, dapsone, phenobarbital,
quinine, theophylline, [2] and other toxins. Multiplying digital-to-analog converter (MDAC) may also be
beneficial in situations of large acute ingestions of substances such as salicylates, where gastric emptying
may be delayed. Limited indications for the use of orogastric lavage, nasogastric suction, and whole-bowel
irrigation exist, and these are discussed in Chapter 5 . Syrup of ipecac is used rarely in the prehospital
setting, and virtually never in hospitals. The use of cathartics has never been shown to alter clinical
outcome. However, their overzealous or inappropriate use has been associated with significant morbidity
and mortality, and their routine use is no longer recommended.[1]
Dermal decontamination is best accomplished with copious amounts of water. However, the use of water on
skin contaminated with metallic sodium, metallic potassium, or phosphorus (white, yellow) may result in
further skin injury owing to heat generation and explosive injury. Irrigation of phenol burns with low molecular
weight polyethylene glycol is effective. [4] Other therapies, such as topical calcium salts for hydrofluoric acid
burns, may be indicated following initial water decontamination. Ocular decontamination can be
accomplished with water or normal saline irrigation.


DIAGNOSTIC TESTING
The results of routine toxicology screens seldom add useful information about the toxins involved that has
not already been gleaned from the history, and assessment of signs and symptoms. Additionally, the results
of screens may be inaccurate. Many toxic agents are not detected on routine screening, while false-positive
results are commonly reported. Unlike broad toxicology screens, serum concentrations of specific drugs are
useful in guiding management. A list of the agents in which quantitative serum levels reflect the severity of
poisoning and guide management can be found in Table 7–8 .
Other tests, such as serum electrolytes, calculated anion gap, glucose, arterial blood gases, serum
creatinine, and liver function tests, can assist in the indirect evaluation of the end-organ effects of a toxin.
They may also aid in the diagnosis of specific agents. The toxic differential diagnosis of an anion gap
acidosis is found in Chapter 11 . Electrocardiograms should be obtained in patients ingesting toxins known
to produce cardiac dysrhythmias or conduction delays, or in significantly poisoned patients as an aid to the
diagnosis of an unknown toxin. Routine radiographs may be indicated to evaluate potential adverse effects
of toxins, such as pulmonary injury due to inhalation of chlorine gas or aspiration of a hydrocarbon. Routine
abdominal radiographs may be unreliable for evaluation of toxins thought to be radiopaque. A thoughtful
discussion of their utility can be found in Chapter 8 .


ANTIDOTES
Specific antidotes exist for a few toxins. These are listed in Table 1–1 . Specific indications for antidote use
and dosing can be found in the chapters dealing with individual toxins and in Appendix E .
Table 1-1 -- Antidotes and Indications for Use

Antidote Indication for Use
Antivenom (equine)
Crotalid (Crotalidae Crotalids: Rattlesnakes (Crotalus spp. and Sistrurus spp.), cottonmouth
polyvalent antivenin) (Agkistrodon spp.), copperhead (Agkistrodon spp.)
Elapid Eastern (Micrurus fulvius fulvius) and Texas (Micrurus fulvius tenere) coral snakes
Antivenom (Fab) * Crotalids
Antivenom, latrodectus
Black widow spider (Latrodectus spp.)
(equine)
Antivenom, loxosceles
Brown recluse spider (Loxosceles reclusa)
(rabbit)
Antivenom, scorpion (goat) Scorpions (Centruroides spp.)
Botulinum antitoxin
Clostridium botulinum
(equine)
Calcium channel antagonists
Hydrofluoric acid
Calcium Hyperkalemia (except cardiac glycosides)
Hypermagnesemia
Hypocalcemia (e.g., ethylene glycol)
Calcium disodium edetate Lead
Cyanide antidote kit: Cyanide
Amyl nitrite
Sodium nitrite
Thiosulfate
Deferoxamine Iron
Ackee fruit (hypoglycin)
Insulin
Dextrose
Sulfonylureas
Other (e.g., salicylates, pentamidine)
Digoxin
Digoxin-specific antibody Digitalis

fragments (Fab) Other cardiac glycosides, e.g., bufodienalides (Bufo toads)
Oleander
Arsenic
Dimercaprol Lead
Mercury
Diethylene glycol
Ethylene glycol
Ethanol
Methanol
Experimental: sodium monofluoroacetate
Benzodiazepines
Flumazenil
Venlafaxine
Folic acid/tetrahydrofolic Methanol

acid (leucovorin) Methotrexate
Ethylene glycol
Fomepizole
Methanol
Beta-adrenergic receptor antagonists
Glucagon
Carbon monoxide
Hyberbaric oxygen Experimental: carbon tetrachloride
Cyanide, hydrogen sulfide
Methylene blue Methemoglobin-producing agents
Acetaminophen
N-Acetylcysteine
Experimental: carbon tetrachloride, chloroform, pennyroyal oil
Naloxone, nalmefene,
Opioids
naltrexone
Anticholinergic agents, e.g., diphenhydramine, Jimsonweed (Datura spp.),
Physostigmine
scopalamine
Pralidoxime Organophosphates
Protamine Heparin
Ethylene glycol (theoretical efficacy)
Pyridoxine Isoniazid
Monomethylhydrazine mushrooms (Gyrometra esculenta)
Myocardial sodium channel blockers, e.g., cyclic antidepressants, cocaine,
norpropoxyphene, class Ia and Ic antidysrhythmics, piperidine phenothiazines
(thioridazine, mesoridazine)
Sodium bicarbonate
Altered tissue distribution/enhanced elimination: chlorophenoxy herbicides,
chlorpropamide, formic acid (methanol), methotrexate, phenobarbital, salicylates
Neutralization: inhaled chlorine gas, hydrogen chloride, phosgene
Arsenic
Succimer Lead
Mercury
Vitamin K Anticoagulants, e.g., warfarin, long-acting anticoagulant rodenticides
* Experimental, not yet approved.
Enhanced Elimination
Important methods for enhancing toxin elimination involve manipulations of urine pH, with subsequent
increased urinary excretion of certain toxins; and extracorporeal removal via hemodialysis and charcoal
hemoperfusion. Urinary alkalinization through parenteral administration of sodium bicarbonate enhances the
elimination of weak acids, such as salicylates, phenobarbital, chlorpropamide, chlorophenoxy herbicides,
formic acid, and methotrexate. Urinary acidification, previously used for drugs such as phencyclidine and
amphetamines, is no longer recommended owing to complications associated with metabolic and urinary
acidosis.
Hemodialysis is the primary extracorporeal method for increasing the elimination of ethylene glycol, glycolic
acid, methanol, lithium, and salicylates. It is used rarely to remove isopropanol, ethanol, metformin, and
bromide and to clear theophylline if charcoal hemoperfusion is unavailable. Charcoal hemoperfusion
removes theophylline more effectively than hemodialysis and also will enhance the elimination of
phenobarbital. A more thorough discussion of these techniques and indications for their use can be found in
Chapter 6 .


REFERENCES
1. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical
Toxicologists: Position statement: Cathartics. J Toxicol Clin Toxicol 1997; 35:743.
2. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical
Toxicologists: Position statement and practice guidelines on the use of multi-dose activated charcoal in the
treatment of acute poisoning. J Toxicol Clin Toxicol 1999; 37:731.
3. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness: Controversies in the use of
a ‘coma cocktail.’. JAMA 1995; 274:562.
4. Hunter DM, Timerding BL, Leonard RB, et al: Effects of isopropyl alcohol, ethanol and polyethylene
glycol/industrial methylated spirits in the treatment of acute phenol burns. Ann Emerg Med 1992; 21:1303.
5. Selden BS, Curry SC: Prolonged succinylcholine-induced paralysis in organophosphate insecticide

poisoning. Ann Emerg Med 1987; 16:215.


Chapter 2 – Airway Management in the Poisoned Patient
Michael F. Murphy Robert Schneider
When and how to manage the airway is fundamental to the management of a patient suffering a toxicologic
exposure. Little is written specifically addressing airway management in the poisoned patient, aside from
highlighting its importance. Issues to be considered in managing the airway of the poisoned patient are, for
the most part, no different than those for any other patient requiring intubation. However, the poisoned
patient may present unique clinical situations that demand a customized approach. Examples include
drug:drug interactions, substances that lead to physical distortion of the airway, and profound physiologic
compromise as a result of the exposure.
AIRWAY MANAGEMENT
When and how to manage the airway are challenges that must be individualized on a case-by-case basis.
The decision to actively and definitively manage the airway is ordinarily straightforward. The indications
generally fall into the following categories:
• Failure to maintain reasonable gas exchange
• Failure to maintain a patent airway
• Failure to adequately protect the airway against aspiration (which may be especially problematic in the
toxicologic patient prone to vomiting)
• To provide a route for pulmonary toilette
• To facilitate patient and symptom control
However, timing the intubation is not quite so straightforward. The pace of change in each clinical situation is
an important dimension affecting the timing of the intubation. For instance, it is well recognized that the pace
of deterioration in cyclic antidepressant overdose is often rapid, motivating intubation earlier rather than
later. Therefore, one must anticipate with some degree of certainty that intubation will ultimately be required
and act to secure the airway in an appropriate manner.
All things being equal, rapid sequence intubation (RSI) is the preferred method of intubation because it
produces the highest success rate coupled with the lowest complication rate. However, before embarking on
an RSI course the following points must be addressed:
• Am I certain that I can intubate this patient?
• If intubation fails, will I be able to maintain airway support with a bag and mask?
• What central nervous system, cardiovascular, and ventilatory reserve does the patient have?
• What drug:drug interactions and adverse drug reactions need I consider in the RSI sequence?
The ability to successfully intubate any patient is never a certainty. However, it is possible to predict with
some accuracy those patients in whom the possibility of failure is significant. If one predicts that failure is a
significant possibility the patient should not be paralyzed until an evaluation indicates that success is likely.
The Difficult Intubation
Anticipating the difficult intubation and selecting the appropriate technique to secure the airway reduces the
incidence of failed intubation. Successful application of these principles is predicated on (1) recognizing and
predicting the difficult intubation, (2) choosing the most appropriate technique and equipment for the
particular situation, and (3) possessing a comprehensive set of pharmacologic and manual skills.
The physician may be able to rapidly ascertain a prior history of airway management difficulty from
individuals accompanying the patient or from other sources (e.g., a Medic Alert bracelet). Some estimation
of degree of difficulty is possible from observation and simple maneuvers during the physical examination,
although the clinical situation may impose some limitations. It is important to appreciate that this evaluation
will fail to predict all difficult intubations and may predict difficulty when none exists.
Physical Examination of the Airway
Certain anatomic factors need to be considered in the evaluation of a difficult airway:

• C-spine mobility: C-spine immobilization of and by itself adds a dimension of difficulty to the airway
management scenario. It also affects the performance of Sellick’s maneuver because the application of
cricoid pressure has the potential to cause motion in the case of an unstable C-spine injury.
• Mouth opening: An adult with normal temporomandibular joint (TMJ) function should be able to open the
mouth to accommodate three to four fingers (3–4 cm), incisor to incisor, top to bottom. The physician
can check this distance if limited TMJ mobility is a concern and the clinical scenario permits. TMJ
involvement in the patient with rheumatoid arthritis may lead to limited mouth opening. Rheumatoid
arthritis also has the potential to produce atlantoaxial subluxation and instability.
• External dimensions: The mandible should be sufficiently large to accommodate a normal-sized tongue.
Patients with small mandibles have tongues that obstruct access to the airway during intubation. In the
adult, one should expect 3 to 4 fingerbreadths between the symphysis and the hyoid bone.
• Neck length and larynx position: The larynx descends in the neck from the C3–4 level in infancy to the
C5–6 level by the age of 8 or 9. A larynx that is higher may be more difficult to visualize at the time of
orotracheal intubation than one that is lower (e.g., in obese individuals or those with “short” necks.
Typically, one should be able to get two fingers between the top of the thyroid cartilage and the base of
the neck in a normal adult.
• Teeth: All false teeth, especially full upper or lower plates, should be removed before intubation. Large
upper incisors may obstruct visualization of the larynx. Protruding teeth reduce visualization and access
because they elongate the anteroposterior axis of the mouth. Jagged teeth may lacerate the balloon on
an endotracheal tube.
• Oral dimension: The airway may be difficult to intubate in patients with narrow facial features and high
arched palates. Access to the airway is limited because of the reduced space from side to side in the
mouth. In addition, the longer anteroposterior dimension limits the ability to visualize the larynx.
In addition to anatomic features that portend a difficult airway, illnesses and injuries that lead to upper airway
distortion may also lead to a failed intubation. Classic disorders include caustic and thermal upper airway
injuries ( Fig. 2–1 ); blunt and penetrating neck and facial injuries; upper airway neoplasms; upper airway
infections, such as epiglottitis, parapharyngeal and retropharyngeal abscesses, and Ludwig’s angina; and
angioedema.
Figure 2-1 This young man has suffered upper airway thermal trauma secondary to freon abuse. He was intubated via the
nasotracheal route, awake and in a sitting position. Concerns about swelling in the anterior oropharyngeal airway precluded intubation
via the oropharyngeal route.
In the event the intubating physician cannot be assured of success, awake intubation should be undertaken.
At some point in this process the physician may visualize sufficient airway structures to be reassured that
success is certain and revert to an RSI strategy.
Rapid Sequence Intubation
Frequently, poisoned patients have a decreased level of consciousness, impaired airway protective reflexes,
delayed gastric emptying, and a full stomach. In addition, management usually requires activated charcoal
administration and may necessitate gastric lavage, enhancing the risk of aspiration. There is some evidence
to suggest that gastric aspiration in the acute phase of the poisoning contributes substantially to a poor
outcome.[12]
It is clear that airway protection and the prevention of aspiration in the poisoned patient are primary
concerns, and ones for which RSI was specifically designed. A French study of 394 poisoned patients
intubated out of hospital found that sedation with any agent followed by neuromuscular blockade facilitated
intubation; only 3 of 46 (7 per cent) intubations were difficult. Similar results were obtained with propofol
sedation alone (8 per cent [1/12] difficult), whereas etomidate alone resulted in difficulty with 47 per cent
(17/36).[1] RSI is the use of medications and techniques to sedate/induce, paralyze, and prevent aspiration in
the course of endotracheal intubation. It also is designed to mitigate the adverse physiologic responses to
intubation.
Patients who are, or are predicted to be, imminently unable to protect the airway, as evidenced by their level
of consciousness or the absence of gag and swallowing reflexes, require active airway intervention. Patients
who are currently, or who imminently will be, marginally capable of protecting their airway and who are to be
given activated charcoal or lavaged should be intubated. The sequence is presented here and is
summarized in Table 2–1 .
Table 2-1 -- Simplified Schema for Rapid Sequence Intubation (RSI)

1. Evaluate the airway for degree of difficulty.
2. Attempt to maintain acceptable blood gas tensions:
a. Preoxygenate.
b. Assist ventilation if necessary.
3. Pretreat 3 minutes before intubation if possible.
a. Defasciculate with 10% of the paralyzing dose of a nondepolarizer drug
b. Fentanyl, 2–9 µg/kg
c. Lidocaine, 1.5 mg/kg
4. Induce and paralyze:
a. Etomidate, 0.3 mg/kg
b. Succinylcholine, 1.5 mg/kg
c. Vecuronium, 0.15 mg/kg
5. Minimize the risk of aspiration (e.g., Sellick’s maneuver)
Evaluate the Airway
Caution is essential with C-spine immobility, limited mouth opening, a big tongue, a high arched palate, buck
teeth, a receding chin, a thick neck, or an anatomically disrupted airway (e.g., blunt trauma to face, neck).
If there is time and there is concern that intubation may not be possible, the laryngoscope can be used to
ensure that the epiglottis can be visualized, indicating that orotracheal intubation is possible. Sedation of the
patient may be necessary to achieve this. In desperate situations this is not an option, but they are not the
norm.
Caustic ingestions may require visualization to determine the need for intubation, particularly in the patient
who is unable to swallow or is hoarse. Furthermore, this visualization may reveal hypopharyngeal burns that
may preclude endoscopy. [5][13] Flexible, fiberoptic nasopharyngoscopy may be the most appropriate method
of viewing the upper airway in these patients and should be a skill in the armamentarium of the physician
managing the airway.
Preoxygenate and Avoid Hypercapnea
A pulse oximeter is used and the patient is preoxygenated. This replaces the functional residual capacity of
the lung (30 mL/kg) with oxygen, providing a buffer when the patient is apneic during the RSI sequence.
Preoxygenation is done with three to five vital capacity breaths if the patient is cooperative or, alternatively,
with 3 to 5 minutes of tidal respiration of 100 per cent oxygen. In reality, this involves placing 100 per cent
oxygen on the patient as soon as it is apparent that intubation is a possibility.
The PaCO2 is usually not a significant concern (rises at 3 mm Hg/min when apneic) unless the patient has a
head injury, severe ventilatory failure, or poisoning with drugs such as cyclic antidepressants or salicylates,
in which worsening of the systemic acidosis could lead to rapid clinical deterioration. In these cases one
should (1) assist ventilation in synchrony with natural respirations and (2) gently “bag” the patient after apnea
has been induced with cricoid pressure applied (modified RSI). Ordinarily the patient is not “bagged” when
apneic to avoid inflating the stomach and increasing the risk of aspiration.
Nondepolarizer Pretreatment
Nondepolarizer pretreatment to abolish fasciculations secondary to succinylcholine is probably done for

cosmetic reasons only. Pretreatment is done 3 minutes before administration of succinylcholine. The dose is
10 per cent of paralyzing dose:
Pancuronium, 10 per cent of 0.1 mg/kg
D-Tubocurarine, 10 per cent of 0.5
mg/kg
Vecuronium, 10 per cent of 0.1 mg/kg
Rocuronium, 10 per cent of 0.6 mg/kg
Pretreatment and priming are not the same. Priming implies that a small (10 per cent) dose of a
nondepolarizer (pancuronium, vecuronium), given 3 to 5 minutes before a full paralyzing dose of the same
drug leads to a more rapid onset of paralysis (this may or may not be true). Pretreatment refers to the use of
a small dose of a nondepolarizer to abolish fasciculations due to the subsequent administration of
succinylcholine.
Attenuation of Adverse Cardiovascular and Intracranial Pressure Responses

The attenuation of adverse physiologic consequences of intubation, particularly hypertension, tachycardia,
and intracranial pressure elevation, may be of concern in the patient poisoned with sympathomimetics or
monoamine oxidase inhibitors, or those with cerebral edema from agents such as salicylates, ethylene
glycol, and methanol.
Drugs ( Table 2–2 ) are given 3 minutes before intubation (like pretreatment) to be optimally effective. This
procedure should not be performed in moribund and desperate situations. Medications that are used include
(1) the opioids fentanyl, 2 to 9 µg/kg, and alfentanil, 20 to 30 µg/kg; (2) lidocaine, 1.5 mg/kg (probably
effective for intracranial pressure, less so for blood pressure); and the ß-adrenergic receptor antagonists
esmolol, 1.5 mg/kg over 30 seconds (implies rock stable patient), and labetalol, 0.25 mg/kg over 2 minutes.
Table 2-2 -- Agents That Mitigate Hypertensive Responses to Endotracheal Intubation *

Class Drug Dose Comments
Significant decreased blood pressure if compromised
Thiopentone 1–5 mg/kg
cardiovascular reserve.
Midazolam 0.1–0.35 mg/kg Remember adrenal suppression with etomidate.
Sedative-
hypnotics Propofol 0.5–2 mg/kg
Etomidate 0.2–0.4 mg/kg
Methohexital 0.5–2.5 mg/kg
Dissociative
Ketamine 1–1.5 mg/kg 1 mg/kg if compromised hemodynamics.
agents
Beta-adrenergic
receptor Esmolol
antagonists Beta-adrenergic antagonists and calcium channel
Diltiazem antagonists are rarely, if ever, of use in emergent RSI.
Calcium channel Avoid if compromised cardiovascular reserve.
Verapamil
antagonists
Nicardipine
Lidocaine 1.5 mg/kg
Local anesthetics Questionable efficacy.
Mexilitine 3 mg/kg
Watch for decreased blood pressure!
Nitrates Nitroglycerin 1–4 µg/kg Causes cerebrovasodilatation and increased intracranial
pressure.
* Refer to the text for a discussion and dosing guidelines for opioids.
Postintubation surges in blood pressure and heart rate can be managed with the ß-adrenergic receptor
antagonists or intermittent bolus doses of thiopental, 1 to 2 mg/kg. This is especially important in the patient
with cerebral edema or with a concomitant head injury.
ß-Adrenergic receptor antagonists and thiopental are contraindicated in the poisoned patient who is
currently, or anticipated to be, hemodynamically unstable. Examples include patients poisoned with ß-
adrenergic receptor antagonists, calcium channel antagonists, digoxin, antihypertensives, antidysrhythmic
drugs, barbiturates, cyclic antidepressants, iron, and phenothiazines.
Small doses of nitrates (sodium nitroprusside and nitroglycerin, 1 µg/kg) have been used with some success
immediately before intubation to control the hypertensive response to intubation. However, cerebral
vasodilatation leads to increased cerebral blood flow and increased intracranial pressure.
Optimize Intubating Conditions
Preparations should include suctioning equipment, a selection of tubes, airways, stylets (routinely inserted in
an endotracheal tube for emergent intubation), a percutaneous transtracheal ventilator, and a formal
cricothyroidostomy kit. Other devices, such as Laryngeal Mask Airways, Combitubes, and Lightwands serve
as rescue devices in the event that intubation proves to be impossible.
Sedative hypnotics are often used to produce amnesia and obtund sensibilities and adverse physiologic
responses to intubation, such as tachycardia, hypertension, bronchospasm, and elevations in intracranial
pressure. In each case the need to use such agents must be balanced against the risks of using them. This
risk evaluation involves estimating the “reserve” of the cardiovascular and sympathetic nervous systems in
accommodating the additional cardiovascular and sympathetic depressant activities of these medications.
This is especially apropos in toxicology, in which the toxin may additionally compromise these systems (
Table 2–3 ).
Table 2-3 -- Drugs and Doses Used in the RSI Sequence to Produce Sedation *
Drug Light Sedation Deep Sedation Induction
PO: 0.5 mg/kg; max, 10 mg; may repeat 0.25 0.01–0.1 mg/kg IV titrated to 0.1–0.35
Midazolam mg/kg × 1; max total, 15 mg effect; no maximum mg/kg IV
IM: 0.1 mg/kg
0.2 mg/kg IV titrated to effect; no
Thiopentone N/A 3–5 mg/kg IV
maximum
Methohexital N/A 1–2 mg/kg IV
maximum
Propofol N/A 1–2 mg/kg IV
maximum
Etomidate N/A N/A 0.3 mg/kg IV
Pentobarbital IM: 2 mg/kg IM: up to 6 mg/kg N/A
1–1.5 mg/kg
N/A IV: 0.1–0.5 mg/kg
IV
Ketamine
IM: 1–4 mg/kg
PO: 4 mg/kg
* Caution is advised in the poisoned patient when sedative-hypnotic, opioid, neuroleptic, major tranquilizers, and other central nervous system
and cardiovascular active medications are already in the patient.
The following sedative hypnotic agents are used:

Thiopental, 1 to 5 mg/kg (1 mg/kg potentially unstable; 3 mg/kg probably stable; 5 mg/kg rock stable)
Midazolam, 0.1 to 0.3 mg/kg (0.1 mg/kg potentially unstable; 0.2 mg/kg probably stable; 0.3 mg/kg rock
stable)
Ketamine, 1 to 1.5 mg/kg (1 mg/kg unstable but alert, 1.5 mg/kg asthmatic)
Etomidate, 0.3 mg/kg (decrease the dose if hemodynamic instability is possible)
The neuromuscular blocker succinylcholine is given in a dose of 1.5 mg/kg intravenously or 3 mg/kg
intramuscularly ( Table 2–4 ). Onset is virtually immediate, with complete paralysis in 30 to 90 seconds.
Hyperkalemia may be seen in the presence of neuromuscular disorders, burns, crush injuries, and
rhabdomyolysis, although not usually in the acute phase.[9][14][15] It is possible to see as much as a 0.5-
mEq/L rise in potassium in normal individuals with succinylcholine. This increase may be an issue in
poisonings that lead to hyperkalemia, such as toxicity due to cardiac glycosides, hydrofluoric acid,
potassium-sparing diuretics, and high doses of penicillin. Atropine, 0.01 mg/kg (minimum, 0.1 mg), should
be administered routinely in children younger than the age of 5 years, in children younger than age 8 if
bradycardic, and in all patients with symptomatic bradycardia. A second dose of succinylcholine may
precipitate profound bradycardia at all ages.
Table 2-4 -- Neuromuscular Blocking Drugs Commonly Used in the Emergency Department
Class Drug Dose Comments
Contraindications:
Hyperkalemia
Globe trauma or glaucoma
Increased intracranial pressure
1.5
Depolarizer Succinylcholine
mg/kg Recent major burns, soft tissue
trauma
Spinal cord injuries with paraplegia
or quadriplegia
Muscular dystrophies
0.6
Rocuronium Rapid onset
mg/kg
0.2 “Prime” with 0.02 mg/kg 3 minutes
Vecuronium
mg/kg before endotracheal intubation
Nondepolarizers (pretreatment dose is 10% of
0.5
paralyzing dose given 3 minutes before Curare (dTc) Histamine release
mg/kg
intubation)
intubation) Class Drug Dose Comments
0.5
Atracurium Elimination neither renal nor hepatic
mg/kg
0.1
Pancuronium Moderate sympathomimetic effects
mg/kg
dTc = D-tubocurarine.
Vecuronium may be substituted at a dose of 0.15 mg/kg if succinylcholine is contraindicated. Its onset and
time to complete paralysis is slower than those of succinylcholine (1 to 2 minutes, depending on circulation
time).
Rocuronium, 0.6 mg/kg, may have a more rapid onset than vecuronium (comparable to succinylcholine), but
like vecuronium it has a duration of paralysis of 20 to 40 minutes before reversal is possible.
Minimize the Risk of Aspiration
Knowing that the patient has had no recent oral intake (NPO status) is not practical in the emergency
department.
Sellick’s maneuver (10 lb pressure to the cricoid ring unless there is a potentially unstable C-spine) is
applied.
Stomach contents are aspirated through a nasogastric tube if one is already in place. Then the tube is
removed (a tube left in place may interfere with the function of the gastroesophageal junction, increasing the
risk of regurgitation). Some authors, notably Sellick, do not believe that this is necessary. If an acute gastric
dilatation exists, some would advocate placing a nasogastric tube before RSI. This depends on how urgently
the endotracheal intubation must be performed and on the relative risk of passing a nasogastric tube.
An attempt is made to avoid “bagging” the patient throughout the sequence. If it must be done, then Sellick’s
maneuver is applied (modified RSI). Adequate suction should be readily available.
Cricoid pressure is not released until the tube is in the trachea and the endotracheal tube balloon is inflated.
If the esophagus has been intubated and the stomach inflated, the tube is left in place but moved to the left
side of the mouth and then the patient is reintubated (similar to the endotracheal obturator airway
technique). In the setting of low oxygen saturations, the patient should have the endotracheal tube removed
from the esophagus and subsequently should be “bagged.” However, the risk of aspiration can be reduced
by the following maneuvers:
1. Inflate the balloon maximally with the tube in the esophagus.
2. Press on the epigastrium to force gas and gastric contents out through the tube.
3. Deflate the balloon and remove the tube with suction ready.
4. “Bag” the patient.
When using drugs to facilitate intubation, remember the old adage: Don’t take anything away from the
patient that you cannot replace.


AIRWAY MANAGEMENT: SPECIFIC TOXICOLOGIC ISSUES
Adverse Drug Interactions
Medications are routinely used to facilitate airway management. These medications have the potential to
interact with the pharmacologic or physical effects of a toxin, leading to further patient compromise. The
most common interactions to be considered in toxicology include succinylcholine in organophosphate
poisoning, succinylcholine in situations in which hyperkalemia may be expected, and the use of medications
that compromise cardiovascular or ventilatory performance.
Succinylcholine is metabolized rapidly in the liver and plasma by the enzyme butyrylcholinesterase, also
known as pseudocholinesterase. Many conditions are associated with a decrease in serum
pseudocholinesterase levels, including liver disease, cocaine use,[11] and others. However, this ordinarily is
of little clinical significance because even profound decreases in serum activity produce a maximum
duration of paralysis in the 20- to 25-minute range.[14] However, the same cannot be said of patients
exposed to organophosphate compounds. Cases of paralysis lasting more than 3 hours have been
reported.[16] This prolonged paralysis can be problematic if the intubation is difficult or if the clinician wants
to observe for seizures. With organophosphate toxicity, consider using short-acting nondepolarizing drugs
such as vecuronium or rocuronium instead of succinylcholine.
Succinylcholine is known to produce life-threatening elevations in serum potassium in some clinical

conditions:
• Burned patients may be susceptible to excessive potassium release beginning 24 hours after the injury
and persisting for up to 2 years.[15] Although the magnitude of the hyperkalemic response in burn
patients does not correlate well with the magnitude of the burn, it is recommended that succinylcholine
be avoided in patients suffering burns exceeding 8 per cent body surface area.[15]
• Patients with extensive neuromuscular disorders, particularly denervation syndromes (spinal cord
lesions, progressive muscle wasting disorders), are known to be susceptible to exuberant potassium
release with succinylcholine.[9]
• Patients with severe intra-abdominal infections persisting longer than 1 week have also been reported to
have a hyperkalemic response to succinylcholine.[9]
Although succinylcholine produces little elevation of serum potassium levels in normal individuals (up to 0.5
mg/dL), it seems reasonable to avoid succinylcholine in situations in which hyperkalemia may exist, such as
cardiac glycoside poisoning or hydrofluoric acid exposure. Muscle cell membrane instability in any clinical
setting associated with rhabdomyolysis is likely a setup for hazardous potassium release with
succinylcholine. Rhabdomyolysis has been reported with toxicity due to sympathomimetics, phencyclidine,
doxylamine, heroin, and envenomation by scorpions, Latrodectus spiders, and crotalids.
Lidocaine can be safely used in patients with cocaine toxicity[18]( Table 2–5 ).
Table 2-5 -- Contraindications to RSI in the Poisoned Patient
Moribund patient, desperate situation in patient with no muscle tone
RSI not needed; can proceed with endotracheal intubation
Anatomically abnormal or disrupted airway
Caustic injury to the airway
Severe swelling
Contraindication to individual medications used in the sequence
Allergy
Lethal electrolyte disturbance
Severely compromised hemodynamics
Prolonged drug effect
Upper Airway Distortion
Caustic and thermal injuries to the upper airway are known to lead to complete airway obstruction and are
ordinarily managed aggressively in a controlled manner before an uncontrolled, emergency intubation is
precipitated by complete airway obstruction.[6][10] Hints that an aggressive approach is indicated in these
situations include (1) patient sitting up, leaning forward with the mandible protruded; (2) inability to swallow;
(3) “hot potato” voice; (4) stridor; and (5) hoarseness. Although hoarseness may indicate impending upper
airway obstruction, it does not possess nearly the strength of association that the previous four signs do.
These patients should be intubated using direct visualization; severe burns of the hypopharynx may
predispose to perforation during blind intubation attempts.[13]
Obstruction can also result from angioedema of the tongue and glottis with use of angiotensin-converting
enzyme inhibitors and with angiotensin II receptor antagonist drugs.[17][19] Life-threatening airway obstruction
has been reported from the bite of a pet rattlesnake to its owner’s tongue. This patient was nasotracheally
intubated for several days until the obstruction subsided.[8]
Paralysis to facilitate intubation in these situations should occur only if a high degree of certainty exists that
the intubation will be successful. An evaluation of the airway with the patient awake may deliver the required
degree of certainty. Alternatively, nasotracheal intubation may be attempted initially and be successful, as in
the case of the boy shown in Figure 2–1 .
Patient and Symptom Control
There are some very specific dilemmas that face the physician from time to time in the management of
poisoned patients in whom paralysis and intubation is considered. Examples include, but are clearly not
limited to
• The patient with violent or combative behavior producing a risk to health care personnel (e.g., from
anticholinergics, phencyclidine, sympathomimetics, and abrupt opioid withdrawal secondary to naloxone
administration)
• The patient with intermittent or intractable vomiting (e.g., in organophosphate or theophylline poisoning)
to the point that it interferes with management
• The patient with seizures refractory to pharmacologic management when the cycle of lactic acidosis,
hyperthermia, and muscle tissue damage exists (e.g., isoniazid or theophylline toxicity)
• The patient whose condition is rapidly deteriorating after cyclic antidepressant overdose
In each of these situations, paralysis and intubation may be a reasonable strategy. In general, the risk of
paralysis and intubation must be weighed carefully against the benefit. Material risks include failure to
intubate, airway injury attendant with the procedure, and aspiration. These risks are minimized if the
principles of airway management articulated earlier are adhered to, including careful airway evaluation,
facility with the skill of intubation, and adherence to the details of RSI.
Specific risks associated with the pharmacologic management of the intubation must be recognized.
Examples include the use of succinylcholine in status seizure patients in whom potassium release is a risk
or precipitation of cardiovascular collapse with the use of a sedative hypnotic (e.g., midazolam, etomidate,
thiopental) in a hypotensive patient. In a retrospective study of 167 patients poisoned with chloroquine,
prehospital cardiac arrest occurred in 25 patients; of the 9 patients not in arrest on arrival of prehospital
personnel, 7 had cardiac arrest immediately after administration of thiopental. [4] Administration of
intravenous diazepam was followed closely by asystole in two patients with salicylate toxicity.[2] The
diazepam may have led to respiratory acidosis, facilitating salicylate entry into the central nervous system.[7]
Ventilating the Poisoned Patient
The principles dictating how to ventilate the poisoned patient are no different than for any other patient. The
most fundamental issue to be addressed in determining minute ventilation is how much carbon dioxide
needs to be eliminated. Patients who are hypothermic or anesthetized have low metabolic rates and require
less minute ventilation than patients who are actively seizing or acidemic. This latter example is particularly
important to appreciate in toxicology, because acid-base status is often a concern. For example, it may be
necessary initially to ventilate a salicylate-toxic patient at two to three times the normal rate to compensate
for his or her metabolic acidosis. Failure to do this may result in a relative respiratory acidosis with increased
shift of salicylate into the central nervous system.[3] Factors guiding the amount of minute ventilation to
provide include the patient’s respiratory rate before intubation, knowledge about the particular poison,
laboratory investigations, end-tidal carbon dioxide monitoring, and others.


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12. Jay SJ, Johanson WG, Pierce AK: Respiratory complications of overdose with sedative drugs. Am Rev
Respir Dis 1975; 112:591.
13. Middelkamp JN, Cone AJ, Ogura JH, et al: Endoscopic diagnosis and steroid and antibiotic therapy of
acute lye burns of the esophagus. Laryngoscope 1961; 71:1354.
14. In: Miller RD, ed. Anesthesia, 4th ed. New York: Churchill Livingstone; 1994:427.
15. In: Miller RD, ed. Anesthesia, 4th ed. New York: Churchill Livingstone; 1994:472-473.
16. Selden BS, Curry SC: Prolonged succinylcholine-induced paralysis in organophosphate insecticide
poisoning. Ann Emerg Med 1987; 16:215.
17. Sharma PK, Yium JJ: Angioedema associated with angiotensin II receptor antagonist losartan. South
Med J 1997; 90:552.
18. Shih RD, Hollander JE, Burstein JL, et al: Clinical safety of lidocaine in patients with cocaine-associated
myocardial infarction. Ann Emerg Med 1995; 26:702.
19. Wang PK, Wang HW, Lin JK, et al: Late-onset life-threatening angioedema and upper airway
obstruction caused by angiotensin-converting enzyme inhibitor: Report of a case. Ear Nose Throat
J 1997; 76:404.


Chapter 3 – Advanced Life Support in the Poisoned Patient (TOX ACLS)
THOMAS G. MARTIN
INTRODUCTION
A basic tenet of medical toxicology is that most poisonings can be adequately managed with standard
supportive care. Standard supportive care for critically ill patients often follows the advanced cardiac life
support (ACLS) algorithms published by the American Heart Association (AHA).[20] The fact that most
poisonings respond adequately to conventional care may be true only because most poisonings are not very
severe. Evidence suggests that standard supportive care may not be adequate for critically ill poisoned
patients. The infrequent occurrence of severe life-threatening poisonings is a major obstacle to clinical
research in this area. Resuscitation recommendations for severe poisonings are based on data derived
primarily from small case series, complex case reports, and animal studies. Many basic questions have not
been well studied, and most remain unanswered. The purpose of this chapter is to introduce toxicology-
oriented (TOX) ACLS; that is, modifications of or additions to standard ACLS algorithms for critically ill
poisoned patients. The topics are discussed using a problem-oriented, rather than a toxin-oriented,
approach. When one manages a severe or unusual poisoning, a medical toxicologist or certified regional
poison information center should be consulted unless the physician is especially experienced with and
knowledgeable about these special cases.


BASIC LIFE SUPPORT
Airway Management
The fundamental principles of airway management also apply to poisoned patients (see Chapter 2 ).
Because poisoned patients can deteriorate rapidly, frequent reassessment of airway protection and
ventilation is necessary (see Chapter 2 ). Aspiration pneumonia is a common complication that may be
avoided with appropriate airway management. Ensuring an adequate airway and ventilation is basic life
support and ideally should begin during prehospital care. However, administration of opioid antagonists is
indicated prior to intubating patients with suspected drug-induced coma. Reversal of benzodiazepine
intoxication is more hazardous than reversal of opioid intoxication; therefore, the routine inclusion of
flumazenil in the “coma cocktail,” the protocol used in a comatose patient, is not recommended. When one
uses opioid or benzodiazepine antagonists, the recommended endpoint is arousal of the patient to the point
where intubation is not required, but not complete arousal. By titrating the dose of antagonist and leaving the
patient with some degree of residual sedation, acute withdrawal may be avoided.
Successful reversal of heroin-induced respiratory depression almost always occurs with total doses of less
than 2 mg of naloxone. Synthetic or semisynthetic opioid poisoning may be more resistant to opioid
antagonists. “China white” and other illicit fentanyl analogs are notoriously resistant to opioid antagonists. As
much as 10 mg of naloxone has been required for adequate reversal in rare cases. Titration to higher total
doses of opioid antagonists is indicated when an opioid overdose is strongly suspected and there has been
an inadequate response to the usual doses. In Emergency Medical Service (EMS) systems in which opioid-
poisoned patients are not permitted to sign out against medical advice in the field, application of restraints
prior to opioid reversal may be prudent. In some EMS systems, naloxone is administered intramuscularly
first, then intravenously. The intramuscular dose is more slowly absorbed and so reduces the risk of relapse.
Rapid-sequence intubation to prevent aspiration pneumonia is recommended prior to performing gastric
lavage on an obtunded or comatose patient.
Prolonged Resuscitation
In the usual ACLS cases, cardiopulmonary resuscitation (CPR) is terminated within 30 min unless signs of
viability of the central nervous system are present. One reason for this is that cerebral blood flow has been
shown to drop dramatically with prolonged CPR in animal models of cardiac arrest. However, recovery that
includes good neurologic outcome has been reported in cases of severe poisoning requiring prolonged CPR
that extended to periods of up to 3 to 5 hours. [88][99][108] One hypothesis is that the marked vasodilation
associated with many types of severe poisoning prevents the severe vasoconstriction seen in standard CPR
cases. Prolonged CPR is frequently warranted in poisoned patients who have had a witnessed cardiac
arrest.


ADVANCED LIFE SUPPORT
Hyperadrenergic States (Tachycardia and Hypertension)
Severe tachycardia may cause hypotension, high-output heart failure, or myocardial ischemia and infarction,
especially in susceptible populations. Synchronized cardioversion for hemodynamically significant
supraventricular tachycardia may be appropriate for patients with primary cardiac disease, but it should be
avoided in severely poisoned patients. Drug-induced, hemodynamically significant tachycardia is very likely
to recur after cardioversion, so rate control with pharmaceutical agents (specific antagonists when available)
is preferred. For example, physostigmine (Antilirium) is indicated for hemodynamically significant
tachycardia associated with pure anticholinergic poisoning.[86]
Benzodiazepines such as diazepam or lorazepam are generally safe and effective for chest pain,
hypertension, or tachycardia associated with drug-induced hyperadrenergic states. However, deep sedation
requiring respiratory assistance must be avoided. In experimental patients undergoing cardiac
catheterization, nitroglycerin and phentolamine have been shown to reverse cocaine-induced
vasoconstriction, whereas labetalol had no effect and propranolol worsened it.[9][11][68][69] Conventional
pharmacologic treatment of hypertension and chest pain may also be effective. In general, short-acting
agents are preferred because the hyperadrenergic effects may be short-lived or followed by cardiovascular
depression in severe poisonings.
The use of ß-adrenergic receptor antagonists for severe sympathomimetic poisonings is controversial. In
one case of acute cocaine toxicity, the use of propranolol (a nonselective ß2-adrenergic receptor antagonist)
was followed by worsened hypertension. In this case ß2-adrenergic receptor blockade may have led to
unopposed a-adrenergic receptor stimulation.[97] Esmolol and metoprolol (ß1- but not ß2-adrenergic receptor
antagonists) should not worsen hypertension and may be used to treat drug-induced tachycardia, but not
hypertension.[102] Esmolol has the advantage of a very short half-life, which allows its adverse effects to
disappear within minutes. Labetalol (a nonselective ß-adrenergic receptor antagonist with weak a-adrenergic
receptor antagonist properties and ß2-adrenergic receptor agonistic properties) has been reported to be
effective in case reports of cocaine toxicity and other hyperadrenergic states.[22][24][30][78] The ß-adrenergic
receptor antagonists must be used cautiously in drug-induced hyperadrenergic states, and a medical
toxicology consultation is warranted when one is uncertain of their appropriate indications or utilization.
Cardioversion and Defibrillation
Electrical cardioversion is appropriate for drug-induced, hemodynamically significant tachycardias and for
less severe cases that are refractory to pharmacologic therapy and overdrive pacing.
Bradycardias
In the ACLS bradycardia algorithm, atropine, pacing, dopamine, epinephrine, and isoproterenol are
recommended in sequence for hemodynamically significant or “symptomatic” bradycardia. In bradycardias
due to severe poisoning by digoxin, calcium channel antagonists, or ß-adrenergic receptor antagonists,
atropine may be ineffective even in high doses.[50][98][118]
In drug-induced, symptomatic bradycardia, many authors have cautioned that isoproterenol (a nonselective
ß-adrenergic receptor agonist) may induce or aggravate hypotension (ß2 effect) and ventricular dysrhythmias
(ß1 effect). However, such aggravation of hypotension or induction of dysrhythmias has been documented
only infrequently.[103] In fact, in massive ß-adrenergic receptor antagonist poisonings, very high-dose
isoproterenol therapy has been effective.[1][44][71][113] Isoproterenol appears to be indicated only in acute ß-
adrenergic receptor antagonist poisonings.
Drug-induced, symptomatic bradycardia refractory to atropine is an indication for cardiac pacing (electrical).
In some cases, short periods of external cardiac pacing may provide adequate support. When external
pacing is poorly tolerated or electrical capture is difficult to maintain, transvenous pacing is indicated.
Prophylactic transvenous pacemaker placement is not recommended because the catheter tip may trigger
ventricular dysrhythmias when the endocardium is irritable. When the pacemaker fails to capture,
repositioning the tip (under fluoroscopy if necessary) may regain capture. In very severe poisonings, the
myocardium may fail to capture, even when properly located and with the highest voltage settings.
In cases of drug-induced, hemodynamically significant bradycardia resistant to atropine and pacing,

vasopressors with greater ß-adrenergic receptor agonist activity are indicated ( Table 3–1 ). In cases
refractory to conventional therapy, more heroic measures may be indicated such as high-dose vasopressors
or circulatory assist devices (see the later section).
Table 3-1 -- Doses and Properties of Standard Vasopressor Agents

Drug Usual Dosage Alpha Beta
Dopamine (Intropin) 2.5–20 µg/kg/min ++ ++
Dobutamine (Dobutrex) 2–20 µg/kg/min + +++
Epinephrine (Adrenalin) 2–10 µg/min (0.1 to 1.0 µg/kg/min) ++ +++
Norepinephrine (Levophed) 0.5–30 µg/min (0.1 µg/kg/min) +++ ++
Initial: 100–180 µg/min +++ +
Phenylephrine (Neo-Synephrine)
Maintenance: 40–60 µg/min
In acute organophosphate or carbamate poisoning, successful management of severe cholinesterase

inhibition may require atropine in doses much greater than the maximum parasympatholytic dose of 2–3 mg
recommended in ACLS guidelines. The recommended adult starting dose for insecticide poisoning is 2–4
mg. In a case of severe insecticide poisoning, approximately 20 g of atropine over 24 h was required.[33]
Atropine cannot reverse the severe nicotinic effects seen with organophosphate insecticides (i.e., muscle
paralysis and fasciculations), and pralidoxime will be required.
Digoxin-specific Fab antibody fragments have been shown to be extremely effective therapy for severe
digoxin and cardiac glycoside poisoning. [2] Digoxin-induced, life-threatening ventricular dysrhythmias and
conduction blocks are appropriate indications for Fab antibody fragments. A high potassium level in digoxin
intoxication is a sign of severe potassium sodium ATPase blockade and is an indication for use of Fab
antibody fragments when other causes of hyperkalemia (e.g., renal failure) are unlikely.[8] Debatable
indications include very high (>10 ng/mL), steady-state (more than 8–10 hr after ingestion) digoxin levels
and very large ingested doses (>10 mg in adults). Digoxin levels drawn before a steady state is achieved are
not useful predictors of outcome. Patients with digoxin levels as high as 20 ng/mL drawn just hours after an
overdose may remain asymptomatic without therapy.
Ventricular Dysrhythmias (Tachycardia and Fibrillation)
Antidysrhythmics
Standard ACLS treatment of unstable, monomorphic ventricular tachycardia involves defibrillation,

epinephrine, lidocaine, bretylium, magnesium, procainamide, and sodium bicarbonate. Procainamide (a type
Ia antidysrhythmic) may exacerbate cardiovascular toxicity in poisonings by cyclic antidepressants because
of its similar antidysrhythmic properties, although there are no studies (in vitro or in vivo) of procainamide
use in poisoning by cyclic antidepressants. In some animal models, lidocaine exacerbated the cardiac or
central nervous system toxicity of cocaine,[4][21] but in other models lidocaine reduced toxicity.[35][39][72][120] In
cocaine users with chest pain, lidocaine was reportedly used frequently, and without adverse effects, to treat
ventricular dysrhythmias.[106] Earlier investigators suggested that phenytoin was indicated for ventricular
dysrhythmias due to cyclic antidepressant poisonings, but more recent investigators have questioned its
efficacy and safety.[13][83] Although bretylium tosylate has been recommended for refractory cases of drug-
induced ventricular tachycardia or fibrillation, there are few data to support its use. Magnesium has shown
conflicting results in a rat model of poisoning by a cyclic antidepressant, but it may also aggravate drug-
induced hypotension.[56][62] Magnesium was also effective in an animal model of epinephrine-induced
dysrhythmias.[82] In most types of drug-induced monomorphic ventricular tachycardia or fibrillation, lidocaine
is the antidysrhythmic of choice.
Certain acute poisonings are associated with elevated catecholamine levels (e.g., amphetamines,
methamphetamines, cocaine, cyclic antidepressants, caffeine, theophylline, monoamine oxidase inhibitors).
In poisonings in which high catecholamine levels are suspected, the role of epinephrine in the management
of refractory ventricular fibrillation is questionable. The current ACLS recommendation in these cases—to
avoid high-dose epinephrine therapy and to increase the interval between doses—seems prudent.
Furthermore, in such poisonings, ß-adrenergic receptor blockade may be beneficial for refractory ventricular
tachycardia or fibrillation.[7][28][29][111] The current ACLS recommendation of propranolol, 1 mg over 1 min,
for refractory ventricular fibrillation associated with hyperadrenergic poisonings may be excessive and may
lead to significant hemodynamic deterioration.
Torsades de pointes is a type of atypical (polymorphic) ventricular tachycardia characterized by a ventricular

axis that gradually swings between positive and negative values ( Fig. 3–1 ). The mechanism of drug-
induced torsades de pointes is not known with certainty but is believed to be delayed repolarization and
associated early after-depolarizations.[18] A prolonged QT interval is a sign of delayed repolarization.
Increased QT dispersion is a sign of abnormal repolarization and may be a more reliable indicator than QT
prolongation.[43] Torsades de pointes has been associated with both therapeutic and toxic drug exposures.
Many drugs have been implicated in torsades de pointes ( Table 3–2 ). Imperfect elimination of these drugs
due to renal or hepatic impairment (depending on route of elimination), specific hepatic enzyme inhibition
(e.g., imidazole antifungals such as ketoconazole or macrolide antibiotics such as erythromycin), or
hypothyroidism may predispose a patient to torsades de pointes. Correctable factors that increase the risk of
torsades de pointes include hypoxemia, hypokalemia, and hypomagnesemia.
Figure 3-1 Torsades de pointes. (From Chou T-C: Electrocardiography in Clinical Practice: Adult and Pediatric, 4th ed. Philadelphia,
WB Saunders, 1996, p 430.)
Table 3-2 -- Drugs Associated with Torsades de Pointes

Antihistamines
Astemizole, terfenadine, terodiline
Butyrophenones
Droperidol, haloperidol
Class Ia antidysrhythmics
Disopyramide, N-acetyl-procainamide (NAPA), procainamide, quinidine
Class III antidysrhythmics
Amiodarone, almokalant, sotalol
Metals
Antimony, arsenic
Macrolides
Erythromycin, clarithromycin, spiramycin
Organophosphates
Phenothiazines
Chlorpromazine, mesoridazine, thioridazine
Other
Adenosine, bepridil, cisapride, fluoride, ibutilide, pentamidine, pimozide, propafenone, quinine, vasopressin
Recommended treatments for drug-induced torsades de pointes include correcting risk factors as well as
providing electric and pharmacologic therapy. Magnesium has been recommended for polymorphic
ventricular tachycardia, even when magnesium levels in the blood are normal.[49][90][114] The AHA-
recommended loading dose of magnesium sulfate is 1–2 g over 1–2 min with a maintenance dose of 1 g/hr
titrated to rhythm suppression. The usual total magnesium dose needed to extinguish this rhythm is 4–6 g.
Adverse effects of magnesium include hypotension and respiratory depression. It is not yet known whether
these doses of magnesium are either effective or safe in critically poisoned patients. In experimental studies
of torsades de pointes, lidocaine has had mixed results.[3][15] Prehospital data suggest that polymorphic
ventricular tachycardia and monomorphic ventricular tachycardia respond to lidocaine.[10]
Pacing
Electric and pharmacologic cardiac pacing may be indicated in critically poisoned patients with asystole,
hemodynamically significant bradycardias, or torsades de pointes.[16][45][109][112] External electrical pacing is
quicker and easier and should be considered first.[48] Because external pacing is often painful for conscious
patients, makes it difficult to maintain capture for prolonged periods, and may interfere with patient care, it
should be replaced with internal pacing when time permits. Electrical (overdrive) pacing at rates up to
100–120 beats/min is usually effective in terminating torsades de pointes. Pharmacologic overdrive pacing
has been recommended with isoproterenol, as well. However, isoproterenol may aggravate the hypotension
or ventricular dysrhythmias associated with some acute poisonings.
Hypertonic Saline and Systemic Alkalinization
Type I antidysrhythmics (fast, inward sodium channel antagonists) decrease the influx of sodium during
phase 0 of the action potential in nonpacemaker myocytes. Subsequently, poisonings with sodium channel
antagonists (membrane stabilizing agents) result in a prolonged action potential and prolonged ventricular
conduction (an increased QRS interval), predisposing to monomorphic ventricular tachycardia. Modalities
such as hypertonic saline and systemic alkalinization have been shown to reverse these adverse
electrophysiologic effects and to prevent or terminate ventricular tachycardia secondary to many types of
poisoning caused by sodium channel blocking agents.[12] Hypertonic sodium bicarbonate provides both
hypertonic saline and systemic alkalinization and has been shown to be more beneficial than either modality
individually in several, though not in all, types of sodium channel antagonist toxicity. Beneficial effects of
hypertonic sodium bicarbonate have been reported in serious poisonings with sodium channel antagonists
such as cyclic antidepressants,[85][89][104] cocaine,[5][21] propranolol,[51] diphenhydramine,[17][25] type Ia[55]
and Ic[54][64] antidysrhythmics, and propoxyphene.[110] When used in severe poisonings, the goal is an
arterial pH of 7.50–7.55. Respiratory alkalosis can be used as a temporizing measure until the appropriate
degree of metabolic alkalosis can be attained with sodium bicarbonate. Systemic alkalinization can be
achieved by means of repetitive administration of 1–2 mEq/kg of sodium bicarbonate as needed to achieve
the desired arterial pH. This degree of alkalinization is maintained via a titrated infusion of an alkaline
solution (i.e., three ampules of sodium bicarbonate (150 mEq) and potassium chloride (30 mEq) in 850 mL
of D5W), although use of this constant infusion is now disputed.
Potassium
Hypokalemia is a risk factor for ventricular dysrhythmias and a well-recognized sequela of both
hyperadrenergic states and alkalinization. Hyperadrenergic states induce hypokalemia as a result of
excessive ß2-adrenergic receptor stimulation. Alkalinization induces hydrogen ions to leave the cells in
exchange for potassium, which enters the cells, causing an intracellular potassium shift. Potassium should
be supplemented during alkalinization to avoid the theoretic increased risk of ventricular dysrhythmias.
Accordingly, potassium chloride, 30–40 mEq, may be added to each liter of bicarbonate solution. Excessive
potassium administration (rate or amount) may result in significant myocardial depression and must be
carefully avoided. Even with normal potassium levels, potassium supplementation has been recommended
in torsades de pointes.[36]
Shock
Vasopressor Agents
Shock secondary to critical poisoning commonly results from decreases in intravascular volume, systemic
vascular resistance (SVR), myocardial contractility, or a combination of factors ( Table 3–3 ). Initial treatment
usually includes correction of clinically suspected hypovolemia and a fluid challenge. Cardiotoxic agents
often reduce a patient’s ability to handle aggressive volume loading, especially in those with underlying
cardiopulmonary disease. [6] Excess fluid therapy may result in fluid overload and iatrogenic congestive heart
failure, even in young and previously healthy patients. When shock persists despite initial volume loading, a
vasopressor is indicated. Many prefer to start with dopamine. Some of dopamine’s pressor effects are
indirect (it stimulates the release of norepinephrine stores), so it may not be effective when norepinephrine
stores are depleted such as in poisoning by a cyclic antidepressant or monoamine oxidase inhibitor.
Nonetheless, dopamine has been shown to be effective in mild to moderate poisoning by a cyclic
antidepressant.[115] In severe cases of cyclic antidepressant poisoning, dopamine may not be sufficient and
more potent vasopressors may be necessary.
Table 3-3 -- Typical Hemodynamic Findings in Shock

Type PAOP CO SVR
Drug-induced (typical)
Distributive ( vasodilation)
Cardiogenic ( contractility)
Hypovolemic
Obstructive
Spinal
PAOP, pulmonary artery occlusion pressure; CO, cardiac output; SVR, systemic vascular resistance.
Even though many forms of drug-induced shock are caused by decreased contractility and SVR, sometimes
increased SVR is encountered. Appropriate treatment varies depending upon whether shock is present with
high or low SVR. When drug-induced shock is unresponsive to correction of clinically suspected
hypovolemia and moderate-dose vasopressor therapy, Swan-Ganz central hemodynamic monitoring is
indicated to help guide more aggressive therapy. Once central hemodynamic monitoring has been
established, the first goal is to ensure adequate preload, as indicated by a pulmonary artery occlusion
pressure (PAOP) of 15–18 mmHg. When the POAP is < 18 mmHg, further volume therapy is warranted.
Once adequate preload has been attained, appropriate vasopressor selection and use of an inotrope are
guided by measured cardiac output (CO) and SVR. When CO is normal or elevated and SVR is decreased
(distributive shock), vasopressors with greater a-adrenergic effects are preferred (see Table 3–1 ). Because
dobutamine and isoproterenol decrease SVR, these agents may be ineffective or even deleterious when
used alone to treat distributive shock. When drug-induced distributive shock is refractory to standard
vasopressor therapy, high-dose vasopressor therapy is indicated.[27][42][47] Conventional dose limits for
vasopressors do not apply to drug-induced shock. The dose of vasopressor is titrated until the desired blood
pressure is attained or adverse effects such as ventricular dysrhythmias are observed. Some poisoned
patients can be adequately resuscitated only with doses of vasopressors that are far beyond the usual doses
used in nonpoisoned patients.
Inotropic Agents
In drug-induced shock characterized by a low CO and high SVR (cardiogenic-like shock) or low SVR (typical
drug-induced shock), inotropic agents may be required. Calcium, amrinone, glucagon, insulin, and
isoproterenol are inotropic agents commonly used in severely poisoned patients ( Table 3–4 ). Sometimes
more than one inotropic agent may be required.[75]121 These agents may increase contractility and CO, but
they may also decrease SVR. Often a concomitant vasopressor is required, especially in typical drug-
induced shock.[63]
Table 3-4 -- Inotropic Agents

Agents Usual Starting Dose
Amrinone 0.75–2.0 mg/kg SIVP
Calcium 1–3 g SIVP
Glucagon 5–10 mg IVP
GIK
Glucose (D50W) 1 g/kg
Insulin (regular) 1.5 U/kg
Potassium chloride 10 mEq
Isoproterenol 2–20 µg/min
SIVP, slow intravenous push.
Intravenous Calcium
Intracellular calcium plays an essential role in the coupling of excitation to mechanical contraction in both the
vascular smooth muscle and the heart. Conditions that result in lower cytoplasmic calcium concentrations
may impair contraction. Conversely, supplemental extracellular calcium can increase the strength of
contraction in these muscles. In cases of acute fluoride poisoning, calcium deficiency occurs due to the
binding of calcium with fluoride. Calcium channel antagonists (including magnesium) and ß-adrenergic
receptor antagonists impair calcium influx and intracellular calcium release. Although textbooks often state
that calcium is contraindicated in digoxin poisoning, there are few published reports to support this
statement. Calcium therapy has been shown to be beneficial for acute fluoride and calcium channel and ß-
adrenergic receptor antagonist poisonings. [41][73][80][98][116] However, the optimal dose and rate of
administration of intravenous calcium has not been established for these indications. A common practice is
to give up to 3 g of calcium chloride by means of slow intravenous (IV) administration. Marked reductions in
blood pressure and heart rate may occur with too rapid an administration of calcium intravenously.[14] The
treating physician should personally administer calcium at the bedside while monitoring heart rate and blood
pressure. The recommended rate of administration is 1 g/min or slower, depending on the cardiovascular
response. Calcium chloride is preferred to calcium gluconate because of higher concentrations of ionic
calcium in the chloride preparation.[119] Experimental and case report data suggest that total or ionized
serum calcium levels may be meaningless when intravenous calcium is administered for these indications.
High-dose (>3 g) calcium delivered intravenously should be considered experimental and should be
employed only as a last resort in acute poisonings.
Glucagon
Glucagon is a polypeptide hormone produced in the alpha cells of the pancreas. Glucagon’s beneficial
cardiac effects include increased contractility and heart rate. These cardiotonic effects result from
glucagon’s binding to nonadrenergic receptors, producing increased levels of cyclic adenosine 3',5'-
monophosphate (cAMP).[77] Increased cAMP levels enhance calcium uptake by the sarcoplasmic reticulum
and plasma membrane. Glucagon has been reported to reverse myocardial depression caused by many
types of poisonings, including ß-adrenergic receptor antagonists,[65][74] calcium channel antagonists,[23][46]
imipramine,[105] ouabain,[95] procainamide,[96] and quinidine.[94] In electrophysiologic studies in human
papillary muscle, glucagon has been shown to enhance the membrane responsiveness (increase the Vmax)
of phase 0 of the action potential.[92][93] Thus, there is a theoretic rationale for its possible effectiveness in
treating toxicity resulting from membrane-stabilizing or sodium-channel–blocking agents such as
imipramine, procainamide, and quinidine.
The recommended initial adult dose in acute poisonings is a 3–10 mg (0.05–0.15 mg/kg) IV bolus. The
duration of effect of glucagon has been estimated to be 20–30 min.[31] If one or more boluses are effective, a
glucagon infusion at 5–15 mg/hr is indicated as needed.[87][91] Use of the standard 0.2 per cent phenol
diluent may worsen myocardial depression when large amounts of glucagon are utilized.[19] D5W is the
recommended diluent when large doses of glucagon are given. Adverse effects of glucagon include
vomiting, hyperglycemia, and hypokalemia. Glucagon may be effective in mild to moderate poisonings, but it
is not always effective in very severe poisonings.
Type III Phosphodiesterase Inhibitors
Type III phosphodiesterase inhibitors are selective for heart and vascular smooth muscle. These inhibitors
increase cytoplasmic cAMP and ionic calcium (as does glucagon) and thereby enhance myocardial
contractility and vascular smooth muscle relaxation. Type III phosphodiesterase inhibitors consistently
increase cardiac output but inconsistently increase heart rate and blood pressure. Beneficial hemodynamic
effects have been reported when phosphodiesterase inhibitors were used in animal models of acute
poisoning caused by ß-adrenergic receptor antagonists,[76] calcium channel antagonists,[32] barbiturates,
bupivacaine, chloroquine, labetalol, procainamide, and cyclic antidepressants. Amrinone is a type III
phosphodiesterase inhibitor with a recommended dose of 0.75–2.0 mg/kg IV over 2–3 min, followed, if
effective, by an infusion of 5–15 µg/kg/min. The addition of a- or ß-adrenergic receptor agonists may be
required to increase SVR or heart rate, respectively. In very large doses, phosphodiesterase inhibitors may
be myocardial depressants and dysrhythmogenic, and the maximum safe and effective dose is not known
for cases of severe poisoning.
Insulin Pump or Glucose-Insulin-Potassium (GIK)
The positive inotropic properties of insulin have been recognized for many years. [101] Glucose was added to
prevent hypoglycemia, and potassium to avoid the associated hypokalemia; together, they are known by the
acronym GIK. GIK has been reported to counteract the negative inotropic effects of ß-adrenergic receptor
antagonists,[53][66][100][101] calcium channel antagonists,[52][57][59][61] ouabain, and halothane. The exact
mechanism by which insulin enhances inotropy is uncertain. Verapamil inhibits myocardial fatty acid uptake,
induces systemic insulin resistance, and blocks insulin release, which leads to myocardial nutrient
deprivation that contributes to clinically relevant negative inotropy.[58][60] In verapamil-poisoned animals,
insulin-induced increases in myocardial carbohydrate uptake were associated with positive inotropic
effects.[57] Insulin improves systolic and diastolic heart function (increased end-systolic elastance and
myocardial mechanical efficiency) during aerobic shock and accelerates in vivo myocardial lactate oxidation
without increasing glucose uptake.[59] Thus, insulin-glucose treatment increases myocardial contractile
function independent of increased sugar transport.
Although insulin or GIK therapy appears to enhance contractility, it may also decrease SVR. Because of its
vasodilatory properties, combination with a vasopressor may be necessary in critical poisonings. Sufficient
glucose and insulin must be given to stimulate myocardial glucose uptake and glycolysis. The recommended
initial dosages are dextrose 50 per cent, 1 g/kg; regular insulin, 1.5 U/kg; and potassium, 10 mEq. The initial
dose of insulin is followed by a constant infusion at 0.5–1.0 U/kg/hr with dextrose and potassium
supplementation as needed to avoid hypoglycemia and hypokalemia. The use of GIK is promising, but
further studies must be performed before it can be recommended as first-line therapy.
Circulatory Assist Devices
In fatal poisonings, death results from failure to maintain adequate perfusion of vital organs. Intra-aortic
balloon pumps (IABPs) and cardiopulmonary bypass circuits are circulatory assist devices that have been
used successfully in critical poisonings. Along with providing life support, these devices may enhance tissue
perfusion and thereby increase drug distribution and elimination. Circulatory assist devices may permit
hemodialysis and perfusion in patients who would otherwise be too hypotensive. Because these techniques
are expensive, require a large staff, and have significant associated morbidity, they should be employed only
in cases refractory to maximal medical supportive care. To be effective, they must be employed rapidly,
before the irreversible effects of severe shock have occurred. Agreement about the initiation criteria and
procedures for these techniques must be reached in advance with the appropriate cardiology and
cardiothoracic surgery services.
The most widely used circulatory assist device is the IABP. The IABP can be inserted in any critical care
area of a hospital, including the emergency department. A disadvantage of the IABP is the need for an
intrinsic cardiac rhythm for synchronization and optimal augmentation. Successful resuscitation with an IABP
has been reported for many types of severe poisonings, such as quinidine,[107] propranolol,[67] and
antihistamine[26] poisonings. Emergency cardiopulmonary bypass and extracorporeal life support do not
require an intrinsic rhythm to augment perfusion. Recent technologic advancements have made rapid
application through peripheral vessels possible in critical care areas of a hospital. Extracorporeal life support
has been utilized in successful resuscitations of patients with very severe poisonings, including poisoning by
verapamil, [40] propranolol[84] and cyclic antidepressants.[34][70][79][81] In some cases, the patient was
eventually weaned from the circuits and demonstrated good neurologic recovery.


BRAIN DEATH AND ORGAN DONATION CRITERIA
Electroencephalograms and neurologic examinations do not provide valid criteria for proof of brain death
during acute toxic encephalopathy and can be applied only when drug levels are no longer toxic. In the
presence of toxic drug levels, the only valid criterion for ascertaining brain death is the absence of cerebral
blood flow. Successful transplantation has been reported in cases of organ donation from victims of fatal
poisoning caused by acetaminophen, cyanide, methanol, and carbon monoxide.[38] However, failures
suspected to be the result of irreversible end-organ damage (direct or indirect) have also been reported. In
general, the overall success rate of transplantation from poisoned donors is comparable to that from
nonpoisoned donors.[37] Organ transplantation following a fatal poisoning by agents capable of severe end-
organ damage (e.g., carbon monoxide, cocaine, iron) is controversial but may be appropriate in donors who
are thoroughly evaluated.
SUMMARY
Utilization of standard AHA ACLS protocols for critically poisoned patients may not result in optimal
outcomes. In a small but significant proportion of cases, rapid administration of specific antidotes may result
in dramatic improvement. In critical poisonings that do not respond to conventional therapy, a more
toxicology-oriented type of ACLS (TOX ACLS) may be effective. Elements of TOX ACLS not usually
included in standard ACLS protocols include higher doses of standard drugs, nonstandard drugs (amrinone,
calcium, esmolol, glucagon, glucose-insulin-potassium (GIK), metoprolol, phenylephrine, physostigmine,
and sodium bicarbonate) and nonstandard techniques such as prolonged CPR and circulatory assist
devices. Proper application of TOX ACLS techniques requires basic understanding of the pathophysiology of
acute poisonings. In some cases in which resuscitation after a critical poisoning failed, organ donation has
been successful. Care of critically poisoned patients can be enhanced through consultation with a medical
toxicologist or a regional poison information center.


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Chapter 4 – Focused Physical Examination/Toxidromes
COLLEEN O’NEIL DAVIS PAUL M. WAX
Many toxic exposures cause characteristic physical findings that are detectable by a carefully focused
physical examination. This aspect of the evaluation of a poisoned patient is particularly important when a
reliable history cannot be obtained. In the case of a patient who is unresponsive or delirious, the physical
examination may provide the only clues to the presence of a toxin.
This chapter discusses characteristic clinical manifestations of toxins, including effects on vital signs, mental
status, pupils, skin, hair, oral cavity, and gastrointestinal tract. It also reviews the five common
“toxidromes”—constellations of physical findings that characterize poisoning with anticholinergic,
sympathomimetic, opioid, anticholinesterase, and sedative-hypnotic agents.[59] These hallmark physical
findings often prove invaluable during the early assessment of an overdosed patient, even when only a few
of the features of a specific toxidrome are present.
FOCUSED PHYSICAL EXAMINATION: VITAL SIGNS
The physical examination begins with a full set of vital signs which should be performed immediately upon
presentation to the emergency department. Pulse oximetry is a valuable “fifth vital sign” that may provide
valuable information.
Temperature
Exposure to various toxins can result in hyperthermia or hypothermia ( Tables 4–1 and 4–2 ). Accurate
measurement of the core temperature is essential in all patients with temperature disturbances. Because the
maximal temperature range for standard thermometers is 32°C to 43°C, special high- and low-recording
thermometers are needed to measure the core temperature in patients with suspected extreme temperature
abnormalities. Once the diagnosis of hyperthermia or hypothermia has been established, the core
temperature should be continuously monitored.
Table 4-1 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hyperthermia
Increased Heat Production
Excessive muscle activity and muscle tone
Amphetamines
Anticholinergics
Cocaine
Cyclic antidepressants
Lysergic acid diethylamide (LSD)
Methylenedioxymethamphetamine (MDMA), other designer amphetamines
Monoamine oxidase inhibitors (MAOIs)
Phencyclidine (PCP)
Strychnine
Withdrawal from ethanol and sedative-hypnotics
Uncoupling of oxidative phosphorylation
Arsenic
Dinitrophenol
Pentachlorophenol
Salicylates
Increased metabolic rate
Thyroid hormones
Decreased Heat Loss
Impaired sweating
Anticholinergics
Antihistamines
Phenothiazines
Vasoconstriction
Sympathomimetics
Amphetamines
Cocaine
Ephedrine
Phenylephrine
Phenylpropanolamine
Pseudoephedrine
Other
Malignant hyperthermia
Halothane
Succinylcholine
Neuroleptic malignant syndrome
Haloperidol
Fluphenazine
Trifluoperazine
Serotonin syndrome
Dextromethorphan–MAOI interaction
Meperidine–MAOI interaction
Selective serotonin reuptake inhibitor (SSRI)–MAOI interaction
SSRI overdose
Metal fume fever
Copper oxide fumes
Zinc oxide fumes
Hydrocarbon aspiration
Gasoline
Lamp oil
Table 4-2 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypothermia
Vasodilation
Ethanol
Phenothiazines
Impaired perception of cold
Carbon monoxide
Ethanol
Opioids
Sedative-hypnotics
Depressed hypothalamic/central nervous system function
Barbiturates
Ethanol
Opioids
Phenothiazines
Sedative-hypnotics
Substrate depletion
Ethanol
Insulin
Oral hypoglycemics
Decreased heat production or metabolic activity
Cyanide
Hydrogen sulfide
Organophosphates
Hyperthermia
Pathophysiology.
The thermoregulatory center in the hypothalamus maintains body temperature at a set-point of 37°C
(98.6°F) by regulating sweating, vasodilation, and shivering. [8] Hyperthermia occurs when the body
temperature has risen higher than the normal thermal set-point, whereas fever occurs when the thermal set-
point has been increased. Both hyperthermia and fever occur as consequences of drug overdose.
Elevation of body temperature in the setting of drug overdose may be due to increased heat production,
decreased heat loss, or fever related to the pyrogenic effects of drugs or their diluents. Mechanisms of
increased heat production include increased muscle activity or muscle tone, uncoupling of oxidative
phosphorylation, and increased metabolic rate. The ability to lose heat is adversely affected by impairment
of sweating, extreme vasoconstriction, and impairment of cardiac function. Pyrogens such as drugs,
bacteria, viruses, and fungi raise the thermal set-point in the preoptic area of the anterior hypothalamus,
causing fever.[46] Pyrogens are also released from endogenous sources by stimulation of neutrophils,
monocytes, and Kupffer cells.
Hyperthermia Associated with Drugs and Toxins.
Excessive heat production follows exposure to toxins that cause agitation, muscular hyperactivity, seizures,
and increased muscle tone. Common examples of drugs that do this include amphetamines,[27] cocaine,[58]
lysergic acid diethylamide (LSD), phencyclidine, cyclic antidepressants, antihistamines, monoamine oxidase
inhibitors (MAOIs), and strychnine.[10] Fatal hyperthermia has been associated with
methylenedioxymethamphetamine (MDMA) use and dancing at rave parties.[36] Tremors associated with
withdrawal from ethanol, barbiturates, and other sedative-hypnotics also increase temperature by this
mechanism.
Even therapeutic doses of drugs may cause an elevation of body temperature during heavy exercise,
infection, or exposure to a warm environment. Heat stress in the setting of therapeutic dosing of a-
adrenergic receptor agonists, including over-the-counter pseudoephedrine or phenylpropanolamine, has
resulted in life-threatening hyperthermia. [6][43] Impaired sweating due to the anticholinergic effects of
antihistamines, cyclic antidepressants, phenothiazines, and belladonna alkaloids may also cause significant
hyperthermia. Salicylates, dinitrophenol, and pentachlorophenol cause an increase in body heat production
by uncoupling oxidative phosphorylation. Overdose of exogenous thyroid hormone raises body temperature
by increasing the basal metabolic rate.
“Drug fever” typically occurs 7 to 10 days after initiation of a new drug, although it may have many patterns.
It resolves within 48 hours of discontinuing the medication and recurs withing a few hours of re-exposure.[52]
Penicillins, sulfonamides, salicylates, antihistamines, barbiturates, procainamide, quinidine, methyldopa,
phenytoin, isoniazid, allopurinol, and cimetidine are some of the more common drugs reported to cause drug
fever in therapeutic doses.
Other drug-induced etiologies of hyperthermia include malignant hyperthermia, neuroleptic malignant

syndrome (NMS), and serotonin syndrome. Malignant hyperthermia is a rare autosomal dominant disorder
associated with abnormal calcium regulation. It develops as a complication of general anesthesia with
inhaled agents such as halothane. Severe, sudden muscle rigidity precipitates extreme hyperthermia, with
tachycardia, acidosis, and hyperkalemia. NMS is seen following exposure to antipsychotic drugs that block
dopaminergic receptors and after withdrawal of dopaminergic agonists such as amantadine or
bromocriptine. The diagnosis of NMS is based on the presence of hyperthermia, increased muscle tone,
altered mental status, and autonomic dysfunction. Haloperidol, fluphenazine, and trifluoperazine are
common etiologic agents of this syndrome. Acute dystonias may be associated with elevated temperature as
well. The serotonin syndrome is most commonly associated with drug interactions between serotonergic
agents such as selective serotonin reuptake inhibitors (SSRIs) and MAOIs or lithium.[61] The notorious
combination of meperidine with an MAOI has resulted in life-threatening hyperthermia attributed to the
serotonin syndrome.[11]
Metal fume fever following exposure to zinc oxide and copper oxide fumes is postulated to be due to a
cytokine response.[9][48] Hyperthermia that occurs during the first 12 to 24 hours following hydrocarbon
exposure is due to a chemical pyrogenic response. This is distinguished from the fever caused by bacterial
superinfection, which typically develops after 24 to 48 hours.
Differential Diagnosis of Hyperthermia.
The differential diagnosis of hyperthermia includes environmental exposure (heat exhaustion, heatstroke);
increased motor activity due to psychosis, status epilepticus, chorea, and parkinsonism; and fever from
thyrotoxicosis or infection.
Hypothermia
Pathophysiology.
Hypothermia, defined as a core temperature less than 35°C, has multiple etiologies, particularly when
environmental exposure is mild.[19] Defenses against hypothermia include increased heat production by
shivering and metabolic activities, vasoconstriction to reduce heat loss to the environment, and behavioral
responses that include dressing and seeking shelter. Drugs and toxins induce hypothermia by causing
vasodilation, impairing behavioral responses to cold, depressing hypothalamic and central nervous system
(CNS) function, depleting substrates, and decreasing metabolic heat production.
Drug-Induced Hypothermia.
Ethanol, a common cause of toxin-related hypothermia, impedes shivering, causes vasodilation, depresses
the CNS, can cause hypoglycemia, and is a risk factor for trauma.[66] Drugs with prominent a-adrenergic
receptor antagonist properties, such as phenothiazines, potentiate hypothermia by inducing vasodilation.
Opioids, sedative-hypnotics, general anesthetics, phenothiazines, and carbon monoxide directly inhibit
hypothalamic function. Oral hypoglycemic agents and insulin cause hypothermia by depleting substrates
needed for thermogenesis. [42] Beta-adrenergic receptor antagonists interfere with the mobilization of
thermogenic substrates and inhibit the ability to maintain euthermia during cold stress.[56]
Differential Diagnosis of Hypothermia.
Infections, hypoglycemia, hypothyroidism, trauma, burns, and cachexia predispose to hypothermia. The very
young, very old, unconscious, immobile, and intoxicated are particularly susceptible. The term “urban
hypothermia” has been used to describe two different situations: (1) a syndrome of homelessness and
substance abuse that leads to exposure-related hypothermia, and (2) mild hypothermia occurring in elderly
urban dwellers who are reluctant to heat their homes because of the cost.[60] Hypothermia has been noted
as a presenting sign of shaken baby syndrome[54][76] and child abuse.[33] Hypothermia should be suspected
in every patient with coma.
Pulse
The heart rate is the product of competing influences that include the sympathetic and parasympathetic
nervous systems, core temperature, and endocrine function. Causes of tachycardia include sinus,
supraventricular, or ventricular mechanisms. Bradycardia may be due to direct depression of myocardial
pacemakers, reflex mechanisms, decreased central sympathetic outflow, parasympathomimetic effects,
CNS depressant effects, and severe membrane depressant effects.
Tachycardia
Drug-Induced Tachycardia.
Stimulants associated with an increased heart rate include amphetamines, caffeine, cocaine, ephedrine, and
other sympatholytics; phencyclidine; and theophylline ( Table 4–3 ). Withdrawal from ethanol, barbiturates,
and other sedative-hypnotic drugs increases the heart rate owing to enhanced noradrenergic stimulation.
Anticholinergics and antihistamines decrease parasympathetic tone by blocking muscarinic receptors,
inducing tachycardia. Poisoning with anticholinesterase agents such as organophosphate and carbamate
pesticides causes tachycardia through acetylcholine stimulation of sympathetic preganglionic nicotinic
receptors. Tachycardia may also be a compensatory response to bronchorrhea-induced hypoxemia. Drugs
and toxins that decrease peripheral resistance (calcium channel antagonists, ethanol, iron, nitrites, arsenic,
and salicylates) are associated with reflex tachycardia, as are agents that cause intravascular volume loss
from vomiting, diarrhea, or bleeding (iron, salicylates, colchicine). Agents that increase myocardial
sensitization to catecholamines, such as the halogenated hydrocarbons or chloral hydrate, may also
precipitate tachycardia. Thyroid hormones cause tachycardia by increasing the metabolic rate.
Table 4-3 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Tachycardia
Sympathomimetic–ß1-adrenergic receptor stimulation
Amphetamines
Caffeine
Cocaine
Methylenedioxymethamphetamine (MDMA), other designer amphetamines
Phencyclidine (PCP)
Theophylline
Withdrawal from ethanol, barbiturates, and sedative-hypnotics
Acetylcholine excess
Carbamates
Organophosphates
Therapeutic cholinesterase inhibitors (e.g., physostigmine, pyridostigmine, neostigmine)
Anticholinergic-muscarinic blockade
Antihistamines
Belladonna-containing plants
Lomotil (atropine and diphenoxylate)
Phenothiazines
Vasodilation
Arsenic
Disulfiram reactions
Ethanol
Iron
Nitrites
Phenothiazines
Volume loss
Antibiotics
Arsenic (acute)
Colchicine
Disulfiram-ethanol interaction
Iron
Mushrooms (e.g., Amanita phalloides)
Opioid withdrawal
Thallium
Theophylline
Increased metabolic rate
Thyroid hormones
Increased sensitivity to catecholamines
Halogenated hydrocarbons
Hypoxemia
Carbamates
Organophosphates
Prodysrhythmic
Amiodarone
Amphetamines
Arsenic
Caffeine
Chloral hydrate
Cocaine
Digitalis glycosides
Diphenhydramine
Flecainide
Phenothiazines
Procainamide
Quinidine
Thallium
Theophylline
Cellular asphyxia
Carbon monoxide
Cyanide
Hydrogen sulfide
Oxidizing agents
Sodium azide
A number of drugs and toxins can cause ventricular tachycardia or conduction disturbances such as Q-Tc
prolongation, which may precipitate atypical ventricular tachycardia, torsades de pointes, and ventricular
fibrillation. Excessive doses or drug interactions with certain antidysrhythmics such as quinidine and
procainamide may also result in tachycardia.
Differential Diagnosis of Tachycardia.
The nontoxic differential diagnosis of sinus tachycardia includes sympathetic stimulation due to psychiatric
disorders, volume depletion, fever or hyperthermia, hyperthyroidism, hypoxemia, vasodilation (in sepsis, for
example), and heart failure. In one study, an increase in core temperature of 1°C was associated with a
mean increase in heart rate of 8.5 beats per minute.[41] Conduction disturbances in the atria or ventricles
may result in supraventricular or ventricular tachycardias.
Bradycardia
Drug-Induced Bradycardia.
Sedative-hypnotics such as barbiturates cause bradycardia through their CNS depressant effects ( Table
4–4 ). Opioids and central a2 agonists such as clonidine, guanfacine, and imidazoline-containing eye
drops[28][50][55] cause bradycardia by decreasing central noradrenergic outflow from the locus ceruleus.
Alpha1-adrenergic receptor agonists such as phenylpropanolamine cause peripheral vasoconstriction and
hypertension that secondarily result in bradycardia mediated by baroreceptor reflexes. Group IA
antidysrhythmic agents such as procainamide cause bradycardia by blocking the sodium (fast) channels in
conduction tissue.
Table 4-4 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Bradycardia
Direct myocardial pacemaker depressant effects
Cardiac glycoside-containing plants (e.g., lily of the valley, oleander, foxglove) and toads
Digitalis
Reflex mechanisms
Alpha-adrenergic receptor agonists (phenylpropanolamine)
CNS depressants
Opioids
Sedative-hypnotics
Decreased sympathetic outflow
Clonidine
Guanabenz
Guanfacine
Imidazoline, topical
Methyldopa
Opioids
Cholinomimetic agents
Carbamates
Mushrooms containing muscarine (Clitocybe and Inocybe spp.)
Organophosphates
Physostigmine, other medicinal cholinesterase inhibitors
Antidysrhythmics—membrane depressant effects
Cyclic antidepressants (severe)
Encainide/flecainide (severe)
Quinidine/procainamide/disopyramide (severe)
Digoxin and plants that contain cardiac glycosides such as lily of the valley (Convallaria majalis), foxglove
(Digitalis purpurea), and oleander (Nerium oleander); ß-adrenergic receptor antagonists; and calcium
channel antagonists cause bradycardia by directly affecting myocardial conduction. The muscarinic effects
of organophosphates and carbamate insecticides may cause bradycardia. Aphrodisiacs such as “Rock
Hard” and “Love Shop,” intended for topical application, contain cardioactive toad venoms (bufadienolides)
that cause vomiting, bradycardia, and dysrhythmias when ingested. Significant toxicity has been reported
after licking or ingesting Cane and Colorado River toads.[12]
Differential Diagnosis of Bradycardia.
Increased intracranial pressure from mass lesions or cerebral edema may cause bradycardia and
hypertension as manifestations of the Cushing reflex. Myocardial depression by ischemia or hypoxia, or
myocardial conduction disturbances, may also be associated with bradycardia. Increased vagal tone of any
etiology also results in bradycardia.
Blood Pressure
Measurement of blood pressure should be done with a cuff that covers two thirds of the upper arm or leg.
Too small a cuff results in falsely elevated readings, and too large a cuff causes falsely depressed readings.
Hypertension
The major mechanism of drug- and toxin-induced hypertension is vasoconstriction ( Table 4–5 ).
Amphetamines and cocaine increase the availability of norepinephrine at a1-adrenergic receptors, resulting
in vasoconstriction and hypertension. Phenylpropanolamine[37][38] and phenylephrine are potent a1-
adrenergic receptor agonists that cause significant vasoconstriction and hypertension. Hypertension also
occurs in the early stages of a clonidine overdose owing to nonselective postsynaptic stimulation of
peripheral a1-adrenergic receptors. Ergot is also a powerful vasoconstrictor, and ingestion of ergot-
containing compounds sometimes results in hypertension. The MAOIs are among the most notorious agents
causing hypertension. MAOIs inhibit the breakdown of catecholamines, increasing the pool of
norepinephrine in the presynaptic sympathetic nerve terminal. Indirect-acting sympathomimetic agents and
foods that contain tyramine (e.g., Chianti wine, aged cheese, pickled herring, and chicken livers) release this
stored pool of norepinephrine, resulting in hypertensive crisis. Overdose of MAOIs or cyclic antidepressants
may be associated with hypertension that is followed by hypotension due to “washout” and depletion of
catecholamines. Chronic lead exposure has been associated with hypertension due to lead-induced
nephropathy or increased catecholamine levels.[14][65][69]
Table 4-5 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypertension
Vasoconstriction
Amphetamines
Clonidine (early intoxication)
Cocaine
Cyclic antidepressant overdoses (early)
Ephedrine
Ergot
Imidazolines (naphazoline, oxymetazoline, tetrahydrozoline)
Monoamine oxidase inhibitors
Nicotine
Phencyclidine
Phenylephrine
Phenylpropanolamine
Pseudoephedrine
Thyroid hormones
Withdrawal from ethanol, barbiturates, sedative-hypnotics
Nephropathy
Chronic lead exposure
Differential Diagnosis of Hypertension.
Nontoxic causes of hypertension, including renal disease, aldosteronism, pheochromocytoma, coarctation of

the aorta and thyrotoxicosis should be considered during evaluation of the patient.
Hypotension
Drug-induced hypotension is caused by hypovolemia, decreased peripheral vascular resistance, decreased
myocardial contractility, and dysrhythmias ( Table 4–6 ). Gastrointestinal fluid losses from vomiting or
diarrhea often contribute to hypotension but are seldom the sole cause. Treatment with ipecac and
cathartics such as sorbitol can lead to excessive volume losses. Antibiotics, organophosphates, carbamates,
iodine, laxatives and cathartics, lithium, and opioid withdrawal are some causes of drug-induced vomiting or
diarrhea. The etiology of hypotension due to arsenic and theophylline is multifactorial and includes
decreased systemic vascular resistance and hypovolemia. Gastrointestinal tract burns secondary to
ingestion of caustic agents such as strong alkalis, strong acids, or mercuric chloride can result in massive
fluid shifts that cause hypotension.
Table 4-6 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypotension
Decreased peripheral resistance—vasodilation
Alpha-adrenergic receptor antagonists (e.g., phenoxybenzamine, phentolamine, tolazoline, prazosin, terazosin,
yohimbine, indoramin)
Angiotensin-converting enzyme inhibitors
Arsenic
Caffeine
Clonidine, guanfacine, guanabenz, imidazolines (oral)
Ethanol
Iron
Isopropanol
Nitrates/nitrites
Nitroprusside
Opioids
Phenothiazines
Salicylates
Sedative-hypnotics
Theophylline
Trimethaphan
Decreased myocardial contractility
Iron
Hypovolemia or third spacing of intravascular volume
Antibiotics
Caustic injuries
Colchicine, other antimitotics
Coprinus-ethanol interaction
Iron
Lead
Lithium (diabetes insipidus)
Mercury salts
Mushrooms
Nicotine
Organophosphates/carbamates
Plants (e.g., pokeweed)
Rattlesnake envenomation
Theophylline (late)
Zinc phosphate
Other/unknown
Cyanide
High doses of CNS depressants such as barbiturates and opioids result in centrally mediated vasodilation,
which may lead to vasomotor collapse. Clonidine, guanfacine, and other central a2-adrenergic agonists
decrease sympathetic stimulation, which in turn decreases peripheral vascular resistance. A number of
antihypertensive agents such as nifedipine, nitroprusside, and prazosin are potent peripheral vasodilators.
Nitroglycerin, disulfiram-ethanol reactions, and phenothiazines also cause decreased peripheral resistance.
Overdoses of ß-adrenergic receptor antagonists and calcium channel antagonists such as verapamil and
diltiazem produce profound hypotension by their negative inotropic effects on cardiac function.[78] Calcium
channel antagonists also cause peripheral vasodilation. Cyclic antidepressants cause consequential
hypotension through impairment of myocardial contractility, as well as the a-adrenergic receptor antagonist
effects. The hypotension associated with severe iron poisoning is also multifactorial, a consequence of
hypovolemia, increased capillary permeability, decreased myocardial function, bradycardia, and
vasodilation.[75]
Differential Diagnosis of Hypotension.

Traumatic and spontaneous hemorrhage, spinal cord injury, sepsis, and myocardial ischemia are important
causes of hypotension that should be considered during the evaluation of a patient with circulatory
insufficiency.
Respiratory Rate
An evaluation of the rate and depth of respirations is a critical aspect of the physical examination. In the
past, many deaths due to drug overdose occurred because of untreated hypoventilation and apnea.
Although prehospital respiratory arrest is still a significant cause of morbidity and mortality, modern
approaches to airway management and ventilation, including judicious use of certain antidotes such as
naloxone, should limit the consequences of many cases of respiratory failure.
Tachypnea.
Tachypnea is defined as rapid breathing. Tachypnea is seen with toxins that cause metabolic acidosis,
directly stimulate the CNS, produce seizures, are aspirated, or cause noncardiogenic pulmonary edema (
Table 4–7 ). Cases of hydrocarbon aspiration often present with tachypnea. Salicylates, dinitrophenol,
pentachlorophenol, and theophylline increase the respiratory rate by directly stimulating the CNS. Agents
that cause metabolic acidosis such as ethylene glycol, methanol, phenformin, metformin, and salicylates
stimulate respiratory compensatory mechanisms for acidosis. Aspiration, restrictive lung disease, pleuritic
chest pain, cardiac tamponade, and congestive heart failure are among the many nontoxic causes of
tachypnea.
Table 4-7 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hyperventilation
(Tachypnea or Hyperpnea)
Stimulation of the central nervous system
Dinitrophenol
Nicotine (early)
Pentachlorophenol
Salicylates
Metabolic acidosis
Arsenic (acute)
Cyanide
Ethylene glycol
Hydrogen sulfide
Isoniazid
Iron
Ketoacidosis (alcoholic)
Methanol
Metformin
Nonsteroidal anti-inflammatory drugs (propionic acid class)
Paraldehyde
Phenformin
Sodium azide
Sodium monofluoroacetate
Toluene
Hyperadrenergic stimulation
Amphetamines
Cocaine
Aspiration of gastric contents
Hydrocarbons
Noncardiogenic pulmonary edema
Barbiturates
Cadmium
Carbon monoxide
Cocaine
Ethchlorvynol
Glutethimide
Opioids
Phosgene
Salicylates
Hypoxia
Carbon monoxide
Methemoglobin-producing drugs and toxins
Pulmonary edema—multiple drugs/toxins
Hyperpnea, a pattern of deep breathing, occurs with exercise, anxiety, and metabolic acidosis. Increased
intracranial pressure, myocardial infarction, hypoxia, and hypoglycemia also cause hyperpnea. At times,
salicylate intoxication may cause hyperpnea without tachypnea.
Pulmonary Edema.
Noncardiogenic pulmonary edema has been associated with heroin,[72] meperidine, methadone,[45]
barbiturates,[29] ethchlorvynol, cocaine,[17] and salicylates.[32][35] Leakage of pulmonary capillaries is the
postulated mechanism. Pulmonary edema in an otherwise healthy patient should raise the suspicion of an
overdose. Toxic gases such as phosgene, carbon monoxide, and the toxic components of smoke may also
cause noncardiogenic pulmonary edema.
Bradypnea.
Bradypnea, a decreased respiratory rate, results from CNS depression or ventilatory muscle failure.
Exposure to sedative-hypnotics, barbiturates, opioids, clonidine,[31] and alcohol causes respiratory
depression. Respiratory failure occurs as a result of muscle weakness following exposure to
organophosphates, carbamates,[51] neuromuscular blocking agents, strychnine, tetrodotoxin, venom from
elapids and the Mojave rattlesnake (Crotalus scutulatus scutulatus), and botulinum toxin ( Table 4–8 ).
Although increased intracranial pressure more commonly causes hyperpnea, it is also associated with
bradypnea.
Table 4-8 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Respiratory Depression
Depression of central respiratory drive
Barbiturates
Clonidine
Ethanol and other alcohols
Opioids
Sedative-hypnotics
Zolpidem
Respiratory muscle failure
Botulinum toxin
Coelenterate venom (Physalia, Chironex fleckeri)
Elapid venom (e.g., coral snake)
Ibuprofen (high doses, especially in children)
Mojave rattlesnake (Crotalus scutulatus scutulatus)
Neuromuscular blocking agents (e.g., succinylcholine, nondepolarizing drugs)
Nicotine (late)
Phenylbutazone
Poison hemlock (conine)
Strychnine
Tetrodotoxin (toxin found in puffer fish, blue-ringed octopus)
Pulse Oximetry
Maintenance of adequate oxygenation is fundamental to the management of poisoned or intoxicated

patients.[34][39] Pulse oximetry provides a continuous, noninvasive, painless, and relatively fast measure of
arterial hemoglobin oxygen saturation (SaO 2). [47] Most pulse oximeters measure only two forms of
hemoglobin (oxygenated and reduced) and do not accurately reflect the presence of abnormal forms of
hemoglobin such as carboxyhemoglobin, methemoglobin, and sulfhemoglobin.[80] The detection of
abnormal forms of hemoglobin requires the use of co-oximetry. Whereas pulse oximeters may record falsely
elevated amounts of oxyhemoglobin in patients with abnormal forms of hemoglobin, falsely decreased levels
of oxyhemoglobin are reported with agents that decrease the respiratory rate or cause pulmonary edema.
Any condition that reduces the strength of the arterial pulse may interfere with the measurement of the SaO 2.
This includes hypotension, hypothermia, vasoconstrictive drugs, or the placement of the oximeter sensor
distal to a blood pressure cuff or indwelling arterial line.[47] Patient movement also interferes with the
detection of the arterial pulse. This can be a problem with patients who are agitated or who require transport,
or with pediatric patients.


FOCUSED PHYSICAL EXAMINATION: NEUROLOGIC MANIFESTATIONS OF TOXINS
Altered Mental Status
Drugs and toxins commonly produce alteration of the mental status. Although agitated delirium and coma
may appear to be distinct presentations, they are more often manifestations of a continuum of CNS
depression, and many drugs cause both conditions. Sedative-hypnotic agents such as ethanol and
barbiturates cause an initial period of disinhibition manifested by excitement and agitation. Higher doses
lead to sedation and unresponsiveness. Many patients intoxicated with cocaine present with agitation or
delirium that is followed by marked lethargy, known as the “washed-out syndrome.” [73] The cyclic
antidepressants cause dose-related CNS excitation and depression.
Agitation and Delirium.
Anticholinergic agents, cocaine, amphetamines, ethanol, sedative-hypnotic withdrawal, and hypoglycemic

agents are among the most common precipitants of agitation and delirium ( Table 4–9 ). Toxic causes of
hypoglycemia include ingestion of akee fruit, ethanol, or sulfonylureas or use of insulin. Carbon monoxide,
cyanide, and simple asphyxiants cause hypoxia that leads to agitation and delirium. Acute lead intoxication
causes encephalopathy that may present as irritability in children.
Table 4-9 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Agitation and Delirium
Direct central nervous system stimulation
Amphetamines
Anticholinergics
Arsenic
Carbamazepine
Disulfiram reaction
Ethanol, sedative-hypnotic, barbiturate withdrawal
Lead
Lithium
Meperidine (normeperidine)
Methylphenidate
Nicotine
Nonsteroidal anti-inflammatory drugs (phenylbutazone, diclofenac, fenoprofen)
Organochlorines
Phenothiazines
Propoxyphene (norpropoxyphene)
Salicylates
Serotonin syndrome
Thallium
Theophylline
Hypoglycemic agents
Akee fruit
Insulin
Sulfonylureas
Antidysrhythmic agents
Lidocaine
Hypoxia-producing agents
Carbon monoxide
Cyanide
Simple asphyxiant hydrocarbons
Hallucinogens
Ibotenic acid, muscimol-containing mushrooms
Khat, methcathinone
Other psychoactive agents
Envenomations
Black widow spiders
Pit vipers
Scorpions
Other
Mefloquine
Quinine (cinchonism)
Sedation and Coma.
Sedation and coma in the setting of a toxic exposure are most commonly caused by global depression of the
CNS by drugs, hypoglycemia, or hypoxia ( Table 4–10 ). Agents that directly depress the CNS include
benzodiazepines, sedative-hypnotics, barbiturates, and alcohols. Agents such as ethanol and salicylates
induce hypoglycemia, which may contribute to the direct CNS depressant effects. Other toxic causes of CNS
depression include agents associated with cellular asphyxia such as cyanide, hydrogen sulfide, carbon
monoxide, and sodium azide; methemoglobinemia; anticholinergics; and acetylcholinesterase inhibitors.
Table 4-10 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Sedation and Coma
Hypoxia
Carbon monoxide
Cyanide
Hydrogen sulfide
Methemoglobin-producing drugs and toxins
Oxidants
Simple asphyxiants (methane, ethane, butane, propane)
Acetylcholinesterase inhibitors
Organophosphates
Central nervous system depression
Alcohols
Anticholinergics
Anticonvulsants (carbamazepine, phenytoin, valproic acid, ethosuximide)
Bromides
Clonidine, guanfacine, imidazolines
Lithium
Magnesium
Seizures.
Agitation, delirium, or sedation may also result from toxin-induced seizures, resulting in a prolonged postictal
state. Some toxins known to cause seizures include camphor,[26] cocaine,[24] cyclic antidepressants,[22]
hypoglycemics, isoniazid, lead, lidocaine,[21] lithium,[23] penicillin, phenothiazines, salicylates, and
theophylline[3] ( Table 4–11; see Chapter 18 for a more complete discussion). Seizures are the major toxic
effect of the potent cicutoxin found in water hemlock (Cicuta spp). Overdoses of anticonvulsants such as
carbamazepine are often associated with seizures.[77] Seizures caused by theophylline or isoniazid can be
very difficult to control.
Table 4-11 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Seizures
Central nervous system—various mechanisms
Amphetamines
Anticholinergics
Baclofen
Camphor
Carbamazepine
Chloroquine
Clonidine, other central a 2 agonists
Cocaine
Ethanol, sedative-hypnotic, barbiturate withdrawal
Insulin
Isoniazid
Lead
Lidocaine
Lindane
Lithium
Meperidine (normeperidine)
Organochlorines
Penicillin
Phencyclidine
Phenothiazines
Phenylbutazone (especially in children)
Propranolol
Quinine (cinchonism)
Quinolones (enoxacin, norfloxacin, ofloxacin)
Strychnine
Sulfonylureas
Theophylline
Water hemlock (cicutoxin)
Hypoglycemia
Akee fruit
Ethanol
Insulin
Salicylates
Sulfonylureas
Cerebral edema
Arsenic
Ethylene glycol
Lead
Methanol
Salicylates
Other
Cisplatin
Pyrimidine analogs (cytarabine, fluorouracil)
Vinblastine (intrathecal)
Laboratory Evaluation.
Serum chemistry determination, computed tomography of the head (head CT), and lumbar puncture may be
required to exclude metabolic, infectious, or structural etiologies of altered mental status in a poisoned
patient. A positive drug screen should not be interpreted as proving causality for a patient’s altered mental
status. A positive drug screen only confirms exposure to a particular drug during a recent period.
Differential Diagnosis.
Many patients are brought to the emergency department with altered mental status. Although a past history
of drug overdose, alcohol abuse, or psychiatric problems may tempt the physician to attribute the altered
mental status to a drug or toxin, other important causes of altered mental status or seizures need to be
considered. Differentiating delirium caused by a drug or toxin from other organic etiologies such as
encephalitis, head trauma, hypoglycemia, or hypoxemia is critical in order to expeditiously treat the
underlying condition. Although some acute psychiatric disorders that present with altered thought and
behavior may at times be confused with a drug-precipitated delirium, patients presenting with an altered
mental status due to a psychiatric etiology tend to maintain a clear sensorium, are able to attend, and do not
have the waxing and waning agitation commonly associated with organic disturbances.
A patient whose mental status is altered by drugs or toxins may also have associated traumatic injuries,
including diffuse axonal injury, cerebral contusion, or space-occupying lesions such as subdural or epidural
hematomas. Physicians should have a high index of suspicion for underlying closed head injuries in patients
with altered mental status.[64]
Pupils
Pupillary size may be particularly helpful in the evaluation of a toxic patient. Normal pupil size ranges
between 2.5 and 5.5 mm in diameter and varies with age.[5] Miosis is defined as a pupillary diameter of 2.5
mm or less. Mydriasis is defined as a pupillary diameter of 6 mm or greater. Actual pupil size results from a
balance between sympathetic and parasympathetic innervation. Sympathetic stimulation of a1 receptors
causes the radial muscle of the iris to dilate. Blockade of these receptors causes pupillary constriction.
Cholinergic stimulation of the iris sphincter muscle via the third cranial nerve also causes pupillary
constriction and miosis. Anticholinergic blockade causes mydriasis.
Miosis.
Parasympathetic stimulation of the iris constricts the pupils. Extremely constricted or “pinpoint” pupils are
associated with opioid effects. Other causes of miosis include central a2 agonists (clonidine, guanfacine,
guanabenz, imidazolines), phenothiazines, organophosphates, carbamates, physostigmine, phencyclidine,
and some sedative-hypnotics. Miosis also occurs with topical ophthalmologic miotics such as pilocarpine.
Central pontine lesions secondary to trauma, tumor, or vascular insult also cause miosis.
Mydriasis.
Mydriasis is a less specific physical finding than miosis. Sympathomimetics, anticholinergics, antihistamines,
and hypoxia cause the pupils to dilate. Amphetamines, cocaine, LSD, and withdrawal from sedative-
hypnotics and opioids can cause mydriasis due to sympathetic stimulation of pupillary dilator muscles. The
topical application of sympathomimetics such as phenylephrine (Neo-Synephrine) to the eye also causes
mydriasis. Antihistamines and anticholinergics block iris sphincter muscle contraction. Unilateral mydriasis
has been reported in association with scopolamine patches placed behind the ear.[68] This blockade of
parasympathetic tone causes nonreactive, fixed, dilated pupils, which may be differentiated from the
reactive, dilated pupils associated with sympathomimetic toxicity. This difference, however, is not consistent.
Certain opioids and sedative-hypnotics such as meperidine and glutethimide can also cause mydriasis.
Botulinum toxin can cause delayed mydriasis. Methanol and quinine cause mydriasis due to the blindness
and loss of pupillary light reflex that result from their toxic effects.
A useful test to distinguish mydriasis induced by a topical mydriatic agent such as scopolamine from that
due to a third nerve palsy involves the administration of pilocarpine eye drops (0.5 or 1 per cent). Topical
pilocarpine eye drops will not constrict a pupil blocked by a mydriatic agent but will constrict a pupil dilated
secondary to injury to the third cranial nerve.[44] At times, the distinction between drug-induced mydriasis
and anoxic brain injury may be difficult.
Nystagmus.
Nystagmus is commonly associated with exposure to anticonvulsants (especially carbamazepine and

phenytoin), lithium,[15][16] ethanol, barbiturates, and sedative-hypnotics. MAOIs and isoniazid may also
cause nystagmus. Phencyclidine characteristically causes both rotatory and vertical nystagmus.[79]
Retinal Manifestations of Poisoning.

Methanol causes retinal hyperemia. Arteriolization of retinal veins has been reported with cyanide
poisoning.[40] Papilledema can occur with methanol, quinine, and vitamin A toxicity and other drug causes of
pseudotumor cerebri. Emboli can be seen in the fundi of intravenous drug abusers. Carbon monoxide[53]
and methaqualone can cause retinal hemorrhages. Retinal hemorrhages should always suggest the
possibility of physical abuse in infants and children. They are also associated with hypertensive
encephalopathy, subarachnoid hemorrhage, and endocarditis.
Movement Disorders.
Movement disorders associated with decreased movement are classified as akinesias; those associated
with increased movement are classified as dyskinesias. The most common akinesia associated with drugs
or toxins is parkinsonism. Dyskinesias include tremors, chorea, dystonia, tardive dyskinesia, myoclonus, and
asterixis.
Toxin-induced parkinsonism manifests as resting tremor and extrapyramidal rigidity and can be seen
following poisoning with carbon disulfide, carbon monoxide, cyanide, manganese, and 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP). It is also a common adverse effect of the therapeutic use of neuroleptic
drugs.
Tremors that increase with movement are called postural tremors. Causes of postural tremors include
amiodarone, amphetamines, caffeine, cocaine, cyclic antidepressants, ergotamine, lithium, mercury,
phenytoin, theophylline, valproic acid, and withdrawal from ethanol and sedative-hypnotics.
Chorea is characterized by rapid, jerky, involuntary movements of the major joints, trunk, and face. Dystonic
reactions are involuntary, slow, twisting spasms typically involving proximal muscles of the extremities, trunk,
and neck. Neuroleptic drugs, antimalarials, cyclic antidepressants, phenytoin, strychnine, lithium, cocaine,
and phencyclidine cause dystonic reactions. Tardive dyskinesia is characterized by choreoathetoid
movements of the trunk, limbs, and face that occur after prolonged use of neuroleptic drugs.
Myoclonus is a series of forced, alternating contractions and partial relaxations of the same muscle. Toxic
causes of myoclonus include lithium and anticholinergic drugs. Myoclonus may occur secondary to fatigue. It
is also seen with disorders associated with hyperactive reflexes such as upper motor neuron disease,
hyperthyroidism, hypocalcemia, and brain stem tumors.
Asterixis is an abnormal flapping tremor characterized by involuntary transient relaxation of muscles that
causes a brief loss of posture. Asterixis was originally described in patients with hepatic failure but is also
associated with many drug-induced encephalopathies, including anticonvulsants, benzodiazepines, bismuth,
cyclic antidepressants, DDT, ethanol, lead, levodopa, mercury, methylbromide, and sedative-hypnotics.


FOCUSED PHYSICAL EXAMINATION: DERMATOLOGIC MANIFESTATIONS OF TOXINS
Cyanosis
Cyanosis is a dark blue or purple discoloration of the skin and mucous membranes. When cyanosis cannot
be explained by cardiac or pulmonary disease, the diagnosis of methemoglobinemia should be considered.
Methemoglobin is an abnormal hemoglobin in which the iron molecule is in the oxidized ferric (Fe3+ ) state
rather than the normal ferrous (Fe2+ ) state. Methemoglobin is darker than unoxygenated hemoglobin and
may cause a marked cyanosis even without other symptoms. Oxygen saturation measured by the bedside
pulse oximeter can be falsely estimated in patients with methemoglobinemia. Methemoglobinemia follows
exposure to an oxidizing drug or chemical, especially organic nitrates, nitrites, benzocaine, dapsone,
phenazopyridine (Pyridium), and aniline dyes.[67] Rare causes of hereditary methemoglobinemia may also
occur[18](see Chapter 24 for a complete discussion).
Erythema
Dry, flushed skin is a hallmark of anticholinergic poisoning. Erythema or flushing is also associated with
ethanol, very high levels of carbon monoxide, and nitrites. Niacin ingestion causes sudden marked flushing.
Chronic boric acid poisoning is associated with intense erythema and desquamation, resulting in a “boiled
lobster appearance.”[70] Rapid intravenous infusion of vancomycin may cause extreme flushing that is
sometimes referred to as the “red man syndrome.” Scombroid fish poisoning is associated with intense
erythema of the upper torso and face due to a release of histamine. Disulfiram-ethanol interaction and
disulfiram-like interactions between ethanol and other agents such as metronidazole, sulfonylureas,
cephalosporins, chloral hydrate, griseofulvin, carbon disulfide, trichloroethylene, and Coprinus mushrooms
may also manifest by erythematous flushing. Ingestion of monosodium glutamate (MSG) causes the flushing
associated with Chinese restaurant syndrome. Examples of medications that induce photosensitivity
reactions include tetracyclines, captopril, cyclic antidepressants, furosemide, nonsteroidal anti-inflammatory
drugs (NSAIDs; especially piroxicam), phenothiazines, warfarin, antihistamines, griseofulvin, and
sulfonamides. Flushing, headache, and hypertension are hallmarks of the tyramine reaction seen in patients
on MAOIs who ingest foods that contain tyramine.
Ecchymosis
Anticoagulant toxicity may inhibit clotting and present with ecchymosis.
Icterus
Exposure to naphthalene mothballs or arsine gas can cause hemolysis that results in jaundice. Various
forms of toxin-induced liver injury result in jaundice, including exposure to acetaminophen, carbon
tetrachloride, chloroform, cyclopeptide- and monomethylhydrazine-containing mushrooms, copper,
phosphorus, and iron.
Bullous Lesions
Barbiturate poisoning is associated with bullous skin lesions. The mechanism of barbiturate-induced skin
lesions is controversial. Some authors propose a direct toxic effect that results in sweat gland necrosis[57];
others argue that the lesions are simply due to prolonged recumbency.[1][4][7][20][63] Methadone,
meprobamate, carbon monoxide,[53] and glutethimide have also been associated with bullous skin lesions.
Track Marks
Intravenous drug use results in scarring along veins, or “track marks.”
Skin Necrosis
The extravasation of certain intravenous medications may result in skin necrosis. These agents include
potassium salts, calcium salts, phenytoin, norepinephrine, and chemotherapeutic agents.
Diaphoresis
Diaphoresis can occur with sympathomimetic agents such as cocaine or amphetamines, as well as with
organophosphates, salicylates, and withdrawal from ethanol, sedative-hypnotics, and barbiturates.
Hypoglycemia, thyroid storm, and shock can also result in diaphoresis.
Alopecia
Alopecia (hair loss) can occur as a result of illness, hormonal disturbances, and numerous drugs. Arrested
hair growth and hair loss are commonly associated with the use of agents that interfere with rapidly dividing
cells, such as chemotherapeutic agents and metals. The combination of rapid, diffuse alopecia and
gastrointestinal and neurologic abnormalities is pathognomonic for thallium toxicity. [25] Lithium and valproate
have been reported to cause diffuse but rarely total hair loss.[74] Total hair loss has been associated with
selenium.[71] Alopecia areata (patchy alopecia) has been described with fluconazole[62] and amiodarone.[2]
Delayed alopecia occurs after exposure to arsenic and colchicine. Localized alopecia can occur late after
carbon monoxide poisoning.[53] Scarring and nonscarring alopecia has been reported with gold therapy.[13]
Fortunately, drug-induced alopecia usually reverses after the drug is withdrawn.
Hair Color
Copper workers have been reported to have green hair as a result of exogenous deposition of copper.[30][49]
Nails
Several weeks after poisoning with arsenic and thallium, patients develop horizontal white lines on the
finger- and toenails known as Mees lines. Cancer chemotherapeutic agents have been associated with the
development of horizontal notches in the nail plate known as Beau lines. Nail staining has been associated
with direct exposure to iodine (brown), nicotine (yellow-brown), cupric sulfate (blue), mercury (red), and
formaldehyde (gray).


FOCUSED PHYSICAL EXAMINATION: GASTROINTESTINAL MANIFESTATIONS OF TOXINS
Oral Cavity
Salivation or the lack of salivation may be a helpful physical finding. Hypersalivation (sialorrhea) has been
associated with cholinesterase inhibitors (organophosphates, carbamates, physostigmine), clozapine,
caustic agents, and iodides. Foaming of the mouth may also be a manifestation of drug- or toxin-induced
pulmonary edema. Dry mouth (xerostomia) may be caused by anticholinergics and opioids. Angioedema of
the lips, mouth, and oropharynx occurs with allergic reactions and may occur secondary to burns from strong
acids or alkalis. Captopril and other angiotensin-converting enzyme (ACE) inhibitors may cause significant
tongue swelling that can compromise the airway. Ulcerative burns to the lips, mouth, and oropharynx occur
after exposure to strong acids and alkalis and other caustic or corrosive agents.
Breath Odors
The odor of mothballs suggests ingestion of naphthalene or paradichlorobenzene. Acetone smells fruity.
Arsine gas, thallium, and organophosphates cause a garlic-like odor. The scent of wintergreen suggests
methyl salicylate exposure. Cyanide has a bitter almond odor detectable by 60 to 80 per cent of the
population.
Vomiting/Hematemesis
Causes of vomiting in poisoned patients include direct irritation of the gastric mucosa (alkalis, acids,
salicylates, colchicine, mushrooms, fluoride, thallium, iron, mercury, and arsenic) or stimulation of the
chemoreceptor trigger zone in the fourth ventricle by substances in the blood or cerebrospinal fluid (opioids,
nicotine, cardiac glycosides, theophylline, and carbon monoxide).[53] Vomiting also occurs with excessive
acetylcholine activity due to poisoning with acetylcholinesterase inhibitors such as organophosphates.
Cocaine, amphetamines, and phenylpropanolamine can cause intracranial hemorrhage that presents with
vomiting. Severe lead poisoning can also cause elevated intracranial pressure and vomiting. Increased
intracranial pressure due to anoxic brain injury, traumatic hematomas, and other mass lesions must also be
considered.
Hematemesis results from direct toxic injury to the intestinal mucosa, toxin-induced coagulopathy, or a
Mallory-Weiss tear associated with persistent vomiting.
Altered Intestinal Activity
Diarrhea.
Causes of diarrhea include intestinal irritation and increased autonomic activity of the bowel. Direct irritation
or injury to the bowel mucosa results from chemical burns, mushrooms, solanine-containing plants,
cathartics, heavy metals, and colchicine. Cholinesterase inhibitors, nicotine, and opioid withdrawal can
cause diarrhea by increasing autonomic activity. Diarrhea also occurs with ingestion of magnesium-
containing compounds and sorbitol and in a variety of marine ingestions (see Chapter 121 ).
Constipation.
Anticholinergic agents, calcium channel antagonists, opioids, and sedative-hypnotics decrease bowel
activity, leading to constipation. Bowel sounds may be absent or diminished after exposure to anticholinergic
agents.
Abdominal Pain
Black widow spider envenomation is characterized by spasms of large muscle groups that may present as a
rigid abdomen.
Urinary Bladder
Palpation of the lower abdomen should include assessment of bladder size. Urinary retention occurs with
overdose of anticholinergic agents.


TOXIDROMES
Anticholinergic, sympathomimetic, opioid, anticholinesterase, and sedative-hypnotic or barbiturate

poisonings may be recognized by their characteristic toxidromes. In the clinical setting when the patient’s
history is limited or nonexistent, characteristic physical findings suggesting a specific drug class may be
critical in refining the diagnosis, focusing the management, and directing the antidotal intervention, such as
naloxone for opioids or physostigmine for anticholinergic overdoses. Limitations of this approach include the
not infrequent occurrence of mixed intoxications and presentations that manifest only a few of the “textbook”
signs and symptoms. Failure of the physical findings to be readily categorized as a toxidrome certainly does
not exclude a toxic etiology.
Anticholinergic Syndrome
Drugs and toxins that block acetylcholine at muscarinic receptors cause the anticholinergic toxidrome.
Physical findings include elevated temperature; delirium; mumbling speech; tachycardia; dry, flushed skin;
dry mucous membranes; urinary retention; decreased to absent bowel sounds; mydriasis; and blurred vision.
Seizures and coma may also occur. A simple mnemonic, “hot as a hare, blind as a bat, dry as a bone, red as
a beet, mad as a hatter, bloated as a bladder,” describes many of the features of the anticholinergic
toxidrome.
Atropine and atropine-like agents cause this syndrome. Atropine-like agents include a number of commonly
used over-the-counter cold medications containing antihistamines, antiparkinson medications such as
benztropine and trihexyphenidyl, topical mydriatics, antispasmodics such as Donnatal and dicyclomine,
muscle relaxants such as cyclobenzaprine and orphenadrine, and belladonna alkaloids such as
scopolamine and hyoscyamine. Cyclic antidepressants also cause anticholinergic symptoms. Plants that
contain belladonna alkaloids include jimson weed (Datura stramonium), deadly nightshade (Atropa
belladonna), and henbane (Hyoscyamus niger).
Sympathomimetic Syndrome
Sympathetic agonists such as cocaine and amphetamine produce hypertension, diaphoresis, tachycardia,
tachypnea, hyperthermia, and mydriasis. Restlessness, agitation, excessive speech, tremors, and insomnia
also occur. Severe cases are associated with dysrhythmias and seizures. Other agents that may cause
sympathomimetic effects include over-the-counter decongestants such as phenylpropanolamine, ephedrine,
and pseudoephedrine. Theophylline and caffeine may cause many of these findings by enhancing
catecholamine release. Overdoses with ß2-adrenergic receptor agonists, methylphenidate, and Ephedra
species such as ma huang cause sympathomimetic symptoms.
This symptom complex may be difficult to distinguish from the anticholinergic syndrome. Whereas sweating
and normal to hyperactive bowel sounds are associated with sympathomimetic overdose, the anticholinergic
toxidrome is manifested by dry skin and diminished bowel sounds.
Opioid Syndrome
The classic triad of opioid intoxication is mental status depression, respiratory depression, and pinpoint
pupils. Bradycardia, hypotension (rare), hypothermia, hyporeflexia, and needle marks may be present.
Opioids commonly associated with this toxidrome include morphine, heroin, designer fentanyls, oxycodone,
hydromorphone, and propoxyphene. Meperidine, pentazocine, and dextromethorphan may cause CNS and
respiratory depression but are often associated with dilated pupils. Central a2-receptor agonists such as
clonidine, guanabenz, guanfacine, and imidazoline derivatives that act on the locus ceruleus of the CNS
cause many of these same symptoms in the overdose setting.
Anticholinesterase Syndrome
Organophosphates are commonly available as insecticides. They are readily absorbed through the skin,
mucous membranes, and respiratory and gastrointestinal tracts. Organophosphates inactivate
cholinesterase enzymes, resulting in accumulation of acetylcholine at receptor sites and overstimulation of
muscarinic, nicotinic, and central acetylcholine receptors. Other causes of cholinesterase inhibition include
carbamates and therapeutic cholinesterase inhibitors such as physostigmine, pyridostigmine, neostigmine,
and edrophonium.
Clinical findings suggestive of acute anticholinesterase intoxication include muscarinic effects as well as
muscle weakness, fasciculations, altered mental status, seizures, and coma. DUMBELS is a mnemonic
used to recall many of the muscarinic effects: defecation, urination, miosis, bronchorrhea, bronchospasm,
bradycardia, emesis, lacrimation, and salivation.
Sedative-Hypnotic Syndrome
Sedative-hypnotic overdoses are associated with hypotension, bradypnea, hypothermia, mental status
depression, slurred speech, ataxia, and hyporeflexia. The sedative-hypnotic group includes barbiturates,
benzodiazepines, buspirone, paraldehyde, chloral hydrate, meprobamate, methaqualone, ethchlorvynol,
glutethimide, and zolpidem. Of course, ethanol intoxication may also present with many of these symptoms.
Ingestion of neuroleptics, cyclic antidepressants, and skeletal muscle relaxants may also cause significant
sedation. Bullous lesions have been reported in some patients with sedative-hypnotic overdoses.
Paradoxical excitement is seen with some of the sedative-hypnotics, especially in very young and elderly
patients.


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Chapter 5 – Gastrointestinal Decontamination
KEN KULIG
“Gastrointestinal decontamination” is a common term in toxicology, but it is not synonymous with “gastric
emptying,” with which it is often confused. Such confusion has caused this aspect of patient care to be
controversial, when in fact decisions involving the initial management of an overdose patient can be logical
and relatively straightforward if the physician has a clear goal in mind—preventing drug absorption in the
most effective manner.
The typical overdose patient presenting to the emergency department is an adult who has acutely ingested
multiple medications in a suicide attempt approximately 3 hours before arrival.[60] Alcohol as a co-ingestant
is often involved. The patient is often minimally symptomatic despite the delay in presentation. The history is
often inaccurate regarding what was ingested and when, as well as the amounts of medications ingested.
This hypothetical typical patient is the focus of the treatment modalities discussed.
This chapter discusses methods of gastrointestinal (GI) decontamination—syrup of ipecac gastric lavage,
activated charcoal, observation alone, cathartics, whole bowel irrigation ( Table 5–1 )—as well as the initial
treatment of the body packer/body stuffer. The objective is to provide a basis for simplified decision making
when the goal is to decontaminate the entire GI tract not just the stomach while reducing the risk of
iatrogenic harm.
Table 5-1 -- Common Methods of Gastrointestinal (GI) Decontamination

Activated charcoal
Adult dose: 50 g orally or down nasogastric (NG) tube. May repeat q 2–4 hr if the ingested substance is
adsorbed to charcoal, the ingestant is likely to result in significant toxicity, and the patient has bowel sounds
and an intact GI tract.
Pediatric dose: 25 g orally or down NG tube. May repeat q 2–4 hr if the ingested substance is adsorbed to
charcoal, the ingestant is likely to result in significant toxicity, and the patient has bowel sounds and an intact GI
tract.
Gastric lavage
Adult tube size: 32–40 Fr
Pediatric tube size: 16–32 Fr
Tube placement should be clinically verified in every case. Stomach contents should be aspirated first, then
aliquots of water or saline, 50–100 mL in children and 250 mL in adults, should be instilled and then aspirated
repeatedly until clear. Airway equipment and suction should be readily available. Instillation of activated
charcoal before lavage should be considered. Gastric lavage should not be done routinely.
Syrup of ipecac
Adult dose: 30 mL orally; may repeat in 20 min.
Pediatric dose: 10 mL orally if between 9 and 12 mo of age; 15 mL orally if older than 1 year of age; may
repeat in 20 min. Should not be given to children younger than 9 mo of age.
Syrup of ipecac is rarely if ever indicated in the emergency department.
Cathartics
Sorbitol adult dose: 1 g/kg
Sorbitol pediatric dose: 1 g/kg
Magnesium sulfate (10%) adult dose: 15 g
Magnesium sulfate pediatric dose: 250 mg/kg up to 15 g
Magnesium citrate (6%) adult dose: 300 mL
Magnesium citrate pediatric dose: 4 mL/kg up to 300 mL
Cathartics are commonly used but are of questionable benefit. If used, only one dose should be given with the
first dose of activated charcoal. Some commercial charcoal preparations come premixed with sorbitol.
Whole bowel irrigation
Adult dose: start at 500 mL/hr, increase as tolerated to 2000 mL/hr, continue until rectal effluent clear.
Pediatric dose: 20 mL/kg/hr, increase as tolerated to 50 mL/kg/hr to 500 mL/hr maximum, continue until rectal
effluent clear.
SYRUP OF IPECAC
Ipecac is rarely if ever indicated in the prehospital or emergency department setting, for a number of
reasons. It is a mixture of alkaloids that includes emetine and cephaeline, both of which are potent emetic
agents that stimulate the mucosa locally as well as the chemoreceptor trigger zone in the brain. It is
available over the counter in syrup form for ease of administration and rapid absorption. Syrup of ipecac
initially gained its popularity as a home treatment for pediatric ingestions, where it is still commonly used,
although firm data on outcome improvement even in this setting are lacking.
One traditional approach to the overdose patient in the emergency department has also been to empty the
stomach by using syrup of ipecac. This became popular in the 1960s, when several animal and clinical
studies documented that syrup of ipecac was a safe and effective emetic in terms of its ability to induce
vomiting in 20 to 30 minutes and to remove a small amount of a marker given shortly before the
ipecac.[1][9][12][25][26] Inducing emesis per se became synonymous with efficacy, as opposed to altering
clinical outcome.
Subsequent studies in human volunteers or patients demonstrated that in many cases, after 30 to 60
minutes, ipecac was not able to decrease absorption of drugs and was inferior to activated charcoal at most
time points studied.[28][59][72][79][80][81][82][83][84][85][86][98][110] It gradually became clear that although ipecac
administration resulted in vomiting in almost all cases within 20 to 30 minutes, the amount of drug actually
removed was small and variable. In addition, serious complications have been reported after ipecac
administration, including aspiration pneumonia, gastric rupture, and stroke in an elderly patient.
Contraindications to ipecac include acid or alkali ingestion (if there are no co-ingestants), hydrocarbon
ingestion (unless the hydrocarbon is also a systemic toxin such as a halogenated hydrocarbon or is a
vehicle for a toxin such as a pesticide), and cases in which the ingested agent is likely to result in rapid onset
of central nervous system (CNS) depression (e.g., a tricyclic antidepressant).
The administration of ipecac also results in a substantial delay in the administration of activated
charcoal.[60][93] Data from the American Association of Poison Control Centers have demonstrated a steady
decline in the use of ipecac and a steady increase in the use of activated charcoal over the past several
years.


GASTRIC LAVAGE
Gastric lavage should not be performed routinely in overdose patients. As the name implies, gastric lavage
is a procedure that is intended to remove material from the stomach. It is not intended to, nor could it,
remove drugs from the small bowel, the primary site of drug absorption. Most lavage tubes or systems in
common use today use a large-bore hose (adults, 36–40 French; pediatrics, 16–28 French). Aliquots of
about 50–250 mL of water or saline are used to repeatedly rinse the stomach, with the patient usually in the
Trendelenburg position on the left side to prevent aspiration.[23] Most clinicians believe that lavage can be
performed safely without prior endotracheal intubation if the patient can adequately protect his or her own
airway and is monitored carefully and if there is airway equipment and suction on hand if the patient vomits
or otherwise rapidly deteriorates.
As previously noted, adult drug overdose patients tend to present to the emergency department at least 3
hours after ingestion, making it unlikely that a significant amount of drug is still in the stomach. The holes in
even the large-bore lavage tubes are too small to allow many pills to pass through them. Experimental
evidence in both animals and humans demonstrates that lavage can remove only a small amount of material
from the stomach even when it is performed shortly after administration of a study marker.[1][9][12][26][110] The
life-threatening complications of gastric lavage include aspiration pneumonitis, esophageal perforation,
endotracheal placement, cardiac arrhythmias, and oxygen desaturation.[3][44][53][60]
Clinical studies of overdose patients have not demonstrated a beneficial effect of lavage when compared
with the administration of activated charcoal alone.[3][60][75][93] The one exception was in a small subset of
patients already obtunded on presentation who seemed to improve if lavage was done within 1 hour of
ingestion (not presentation). [60] However, this study did not show that lavage is beneficial within 1 hour of
presentation in patients who are minimally symptomatic. Three other studies could not demonstrate a benefit
to lavage in any group of patients.[3][75][93]
Gastric lavage should be reserved for those patients who have ingested a significant dose of a medication or
chemical that is likely to result in morbidity, and only if the procedure can be done very soon after ingestion.
If the drugs or chemicals are known to be well adsorbed to charcoal ( Table 5–2 ), the clinician must have an
adequate rationale for performing lavage, with its known complications, instead of just administering
activated charcoal either orally or down a nasogastric tube. In cases in which lavage is to be performed,
administering a dose of charcoal down the lavage tube first, before stomach washes, is theoretically
attractive.[18] In cases in which only a liquid (e.g., ethylene glycol or methanol) has been ingested, aspirating
stomach contents with a smaller-bore nasogastric tube instead of a large orogastric lavage tube is an
alternative treatment. Activated charcoal can then be administered down the tube if the substance is
adsorbed to charcoal (see Table 5–2 ).
Table 5-2 -- Charcoal Adsorption of Drugs and Chemicals Commonly Cited as Not Being Adsorbed
Not Significantly Adsorbed *
Substance Study
Smith et al, 1967[102]
Iron
Decker 1968[31]
Lithium Favin 1988[38]
Decker 1968[31]
Borates
Oderda 1987[86]
Bromide Edwards 1967[34]
Potassium Welch 1986[115]
Cooney 1980[24]
Mineral acids and alkalis
Decker 1968[31]
Andersen 1948[4]
Smith 1967[103]
Neuvonen 1984[84]
Ethanol † Hulton 1985[51]
Jackson 1980[52]
Minocha 1986[76]
Katona 1989[55]
Evidence of Significant Adsorption *
Substance Study
Andersen 1946[5]
Cyanide
Lambert 1988[61]
Picchioni 1966[91]
Malathion Decker 1968[31]
Hayden 1975[46]
Parathion Guven 1994[43]
Diazinon Orisakwe 1993[88]
Dichlorvos Guven 1994[43]
DDT Decker 1968[31]
Carbamates Buck 1986 ‡ [13]
Mercuric chloride Andersen 1946[5]

Methanol Decker 1981[32]
N-Methyl carbamate Decker 1968[31]
Decker 1981[32]
Ethylene glycol
Szabuniewicz 1975[105]
Kerosene Decker 1981[32]
Turpentine Decker 1981[32]
Isopropyl alcohol Burkhart 1992[16]
Tolbutamide Neuvonen 1982[81]
* “Significant adsorption” in this context is arbitrarily assumed to exist when 50 g of activated charcoal could adsorb a toxic dose (significant
symptoms expected) in adults based on an extrapolation of in vitro data, or when in vivo studies have shown that toxicity or morbidity was
decreased by charcoal.
† Ethanol appears to be adsorbed in vitro but not in vivo in human studies.
‡ Typographical error in manuscript; 10/10 (not 0/10) animals given activated charcoal after carbaryl survived, versus 0/10 controls.


ACTIVATED CHARCOAL ALONE
Administering charcoal to the typical overdose patient without gastric emptying has become a common
treatment modality. There is significant literature support for this approach.
Charcoal has been used for medicinal purposes since antiquity; the first recorded use was by the ancient
Egyptians circa 1550 B.C. [24] The first recorded scientific studies of charcoal being used to treat human
poisoning were from France, England, and America in the 1800s. Medical use of charcoal has greatly
increased since those earliest studies alluded to its effectiveness.[20][21][22][23][24][33][42][50][55][90][102][113]
Modern activated charcoal is a far more efficient product than that used in initial studies. It is manufactured
by the pyrolysis of wood or other carbonaceous material, which is then oxidized at high temperatures using
steam, air, carbon dioxide, or oxygen. Metallic chlorides may be used to enhance pore development and
removed later with a dilute acid. The final product has a surface area of 950 to 2000 m2/g. A superactivated
charcoal with a surface area of 3150 m2/g was previously marketed[29] but is not currently available.
There are several advantages to the use of activated charcoal not seen with other methods of GI
decontamination:
1. It can be administered very quickly. If the patient is awake and cooperative, the patient may drink a
dose immediately after presentation. If the patient is comatose or uncooperative, the dose can be
quickly administered down a nasogastric tube. Drugs or chemicals can continue to be absorbed during
more time-consuming procedures such as ipecac-induced emesis or gastric lavage.
2. Charcoal is effective even if the history is inaccurate. Even if the substances in question and the time of
ingestion are unknown, charcoal can still be effective, as it adsorbs most commonly ingested drugs and
chemicals (see Table 5–2 ).
3. Unlike induced vomiting and lavage, which under the best of circumstances might remove some of the
ingested material still in the stomach, a charcoal slurry can easily pass through the pylorus to the
primary site of drug absorption—the small intestine.
There are no contraindications to the use of activated charcoal in overdose patients if the GI tract is intact
(i.e., without perforation) and there is no bowel obstruction or ileus to impede passage through the gut.
Because acids and alkalis are not well adsorbed to charcoal, and because charcoal may obscure the view of
an endoscopist, it should not be given in cases of isolated acid or alkali ingestion. However, if charcoal is
administered for other ingested agents that are systemic toxins, the corrosive is not a contraindication. There
are no published cases of anaphylaxis from charcoal.
There are several disadvantages to and complications from activated charcoal:

1. Charcoal may induce vomiting in some patients.[77] Whether this is due to the gritty texture of the
charcoal, the volume administered, additives such as sorbitol, or a combination of factors is unclear.
Volunteers who drink charcoal have a low incidence of vomiting.[79] Some options for antiemetics in
patients vomiting from either the charcoal or the ingested drugs are shown in Table 5–3 .
Table 5-3 -- Parenteral Antiemetics of Possible Utility in Poisoned Patients with Severe
Vomiting
Generic Name Trade Name Adult IV Dose Pediatric IV Dose *
Prochlorperazine Compazine 2.5–10 mg q 4 hr 0.06 mg/lb IM †
Promethazine Phenergan 12.5–25 mg q 4 hr 0.50 mg/lb IM †
Metoclopramide Reglan 10 mg 0.25 mg/kg
Droperidol Inapsine 1.25–5 mg q 4 hr prn 0.05 mg/kg/dose ‡
Ondansetron Zofran 4–32 mg qd 0.1 mg/kg qd
Granisetron Kytril 10 µg/kg qd 10 µg/kg qd
Dolasetron Anzemet 12.5 mg qd 0.35 mg/kg qd up to 12.5 mg qd
* For children 2 years of age and older. Doses may be based on those used during chemotherapy; the package insert may not
have a recommended pediatric dose.
† Children are very susceptible to the dystonic effects of these agents, and they should be used only if essential for treatment.
Based on the package insert, intramuscular (IM) and not intravenous (IV) use is recommended.
‡ May cause significant sedation or dysphoria.
2. Although charcoal itself is inert, aspiration into the lungs can result in a mechanical obstruction of the
airways, particularly if the slurry is inadequately diluted. This may result in respiratory failure and other
pulmonary complications.[35][44][53][74][92][94] In most cases, aspiration of the acidic stomach contents is
the likely cause of the pneumonitis seen, and the presence of charcoal in the aspirate is incidental.
3. Charcoal may cause constipation and mechanical bowel obstruction when used in a multiple-dose
manner.[10][41][69][114] This is not seen after a single dose.
4. Charcoal may not be readily accepted by children, which might necessitate a nasogastric tube for
administration.
5. Charcoal might theoretically adsorb oral antidotes such as N-acetylcysteine, D-penicillamine, and DMSA
(dimercaptosuccinic acid; Chemet). Usual adult doses of charcoal have not been shown to significantly
alter absorption of N-acetylcysteine.
6. Charcoal is generally unpleasant for health care personnel to use, as it stains clothing, walls, floors,
ceilings, and so forth.
The evidence for the efficacy of activated charcoal in the treatment of poisoning comes primarily from in vitro
binding studies, in vivo mortality studies, volunteer studies, and comparison studies in overdose patients.
The combined knowledge gathered from these studies demonstrates that charcoal effectively binds the vast
majority of drugs and chemicals likely to be acutely ingested (see Table 5–2 ). There have been some
differences of opinion regarding what constitutes “significant adsorption,” resulting in numerous review
articles claiming that, for example, cyanide, DDT, N-methyl carbamate, and others are not adsorbed. If the
goal of charcoal therapy is to bind an amount of toxin that could result in major toxicologic effects (for
example, as defined by the Amercian Association of Poison Control Centers), then by extrapolating these
data to humans or by examining the in vivo data, these chemicals are adsorbed by charcoal. Using the same
criteria, substances more clearly shown not to be adsorbed are also listed in Table 5–2 .
Cyanide is an example of the importance of the principles just outlined. The original research[6]
demonstrated that 1 g of charcoal could bind 35 mg of potassium cyanide in vitro. This was claimed in
multiple review articles to demonstrate lack of adsorption, which seems to overlook that as little as 200 mg
of potassium cyanide is a potentially lethal dose in humans, while 50 g of charcoal is a typical charcoal dose.
If this stoichiometry holds at higher doses, 50 g of charcoal might bind up to 1750 mg of cyanide, which
would be multiple potential lethal doses. Adsorption was clearly demonstrated by in vivo research,[61]
whereby the mortality rate in rats given 35 mg/kg of cyanide was reduced from 93 per cent to 33 per cent
when charcoal was administered immediately afterward, and from 100 per cent to 27 per cent when a dose
of 40 mg/kg of cyanide was used. It is disturbing that clinicians relying on inaccurate information over the
years might have withheld charcoal therapy in patients known to be poisoned by cyanide.
Another approach to the issue of adsorbability is demonstrated for boric acid. In this case, the original
research[31] showed that 5 g of charcoal could bind 30–45 mg of borate. Another in vitro study[86]
demonstrated that 30 g of charcoal bound 38.6 per cent of 1 g of boric acid. Extrapolating the latter data,
100 g of charcoal would likely be unable to bind a significant amount of a toxic adult dose of borate
(approximately 15 g).
The advantage of in vitro work is that many different substances can be tested at the same time, and the
research is relatively less expensive and less time intensive than other types of charcoal research.
Historically, in vitro studies[4][5][6][22][31][32][65] have provided important background that has driven the
enthusiasm for the use of charcoal in patients and for additional charcoal research.
In vivo studies of charcoal are commonly performed in small animals in which the median lethal dose (LD50)
or LD100 of the substance in question is administered, with and without activated charcoal, and the decrease
in mortality is evaluated. Assuming that the doses of drug and charcoal are, by extrapolation, analogous to
what might be seen in overdose patients, this type of study provides some evidence for the efficacy of
charcoal in humans. However, because of the higher metabolic rates of small animals, charcoal is usually
administered very soon after the toxin. This technique has been employed, for example, for cyanide [61] and
carbamates.[13]
A different in vivo approach in dogs was used to evaluate lavage versus charcoal versus a charcoal-lavage-
charcoal approach in which the 6-hour level of salicylate was measured and used to compare efficacy.[18] In
this study, charcoal was superior to lavage, and the combined approach tended toward even more efficacy
but did not achieve statistical significance. This type of charcoal study can be very valuable, as toxic doses
of drugs can be administered, but it has the disadvantage of requiring anesthesia and a large budget.
Volunteer studies in general have attempted to compare activated charcoal with ipecac or lavage when
volunteers are given a therapeutic or slightly supratherapeutic dose of medications. By examining the area
under the serum concentration time curve, or the total amount of drug excreted (by implication, the amount
absorbed), a comparison of the efficacy of charcoal versus lavage versus ipecac can be attempted. This
technique has been used to evaluate many drugs, including acetaminophen, ampicillin, aspirin,
chlorpropamide, theophylline, and numerous others.[63][72][79][80][81][82][83][84][85][98][110] In most cases,
charcoal alone proved superior to ipecac and lavage either alone or with charcoal. The obvious
disadvantage to volunteer studies is the inability to administer an overdose of medications and chemicals,
the kinetics and the binding ability of charcoal not necessarily being similar to what is seen after overdose.
Charcoal studies in actual overdose patients are few in number and may be the hardest to interpret because
of the heterogeneous nature of overdose patients and the difficulty in determining whether it was the
charcoal that altered the outcome. The first of these compared charcoal alone versus ipecac plus charcoal
and found no difference in clinical outcomes.[60] The same study also compared charcoal by nasogastric
tube alone versus lavage plus charcoal and detected a difference only if lavage was performed within 1 hour
of ingestion in patients who were already obtunded from the overdose. It was clear from these data that
charcoal alone was a viable treatment option to gastric emptying.
A similar study[3] examined ipecac plus charcoal versus charcoal alone in overdose patients. Outcomes
were similar, but the group that received ipecac had a higher incidence of iatrogenic complications (5.4 per
cent vs. 0.9 per cent; p < .05), which included four cases of aspiration pneumonitis after ipecac-induced
vomiting.
One must be cautious in ascribing certain complications to “charcoal,” as if they occurred from a single dose
and not from multiple doses. The two main published complications have been pulmonary aspiration with
sequelae[35][44][45][53][74][92][94] and GI obstruction.[10][69][95][114] The pulmonary complications are more
commonly seen after multiple-dose rather than single-dose charcoal, and it is not clear whether they are
from the charcoal or the accompanying acidic gastric contents in the aspirate.
Likewise, inspissated charcoal causing obstruction is not seen from single-dose charcoal and should not be
considered a complication of “charcoal” but of repeated use in patients with decreased GI motility.
There have been reports of corneal abrasions from charcoal getting into the eyes of overdose patients
during vomiting.[71] This complication should be avoidable or easily treatable if it occurs.
Not infrequently, it is desirable to administer charcoal to a patient who is vomiting and therefore unlikely to
retain charcoal or an oral antidote in the GI tract. Antiemetics can be effectively used in this setting (see
Table 5–3 ). Serotonin 5-HT3 antagonists appear particularly effective in this regard but are very expensive.
The less expensive agents may be used first, with the more expensive agents used only if the former are
ineffective.


CATHARTICS
It is recommended that one dose of a cathartic, preferably sorbitol 1 g/kg, be administered with the first dose
of activated charcoal. However, it has never been shown in clinical studies that the use of cathartics makes
a difference in clinical outcome. When given, cathartics are commonly co-administered with activated
charcoal on the theory that they may cause the drug-charcoal complex to be excreted more quickly, thereby
resulting in less risk of desorption (de-binding of the charcoal-drug complex) or charcoal inspissation. Some
experimental evidence suggests that cathartics do not interfere with charcoal adsorption of drugs and may
actually enhance it. Sorbitol may also make the charcoal more palatable. Cathartics in common use include
magnesium sulfate, magnesium citrate, and sorbitol. Some commercial charcoal preparations come
premixed with sorbitol.
Several case reports have demonstrated the dangers of multiple doses of magnesium-containing cathartics
resulting in life-threatening hypermagnesemia. Excessive sorbitol use in children may result in severe
dehydration. The use of multiple doses of cathartics is not recommended, as their theoretic benefit is
outweighed by the potential for harm.


OBSERVATION ALONE
An innovative approach was taken in one study of overdose patients in which one group of asymptomatic or
minimally symptomatic patients received neither gastric emptying nor charcoal, but observation only.[75] This
study demonstrated a higher incidence of aspiration pneumonitis in patients in whom gastric emptying was
performed (8.5 per cent vs. 0 per cent; p = .001) but failed to demonstrate a beneficial effect of activated
charcoal use. The authors concluded that in asymptomatic overdose patients presenting to the emergency
department, observation only is an option.
Although this may be a safe approach in some patients with trivial ingestion, if the patient has not provided
an accurate history and has really ingested something very dangerous, the absence of any initial
decontamination measures may be of clinical and medicolegal significance.


WHOLE BOWEL IRRIGATION
Whole bowel irrigation entails flushing the entire GI tract with a nonabsorbable isotonic electrolyte solution
containing polyethylene glycol (PEG).[30][36][57][100][106][108][109][110] This can be done by having the patient
drink the solution or by infusing it down a nasogastric tube. Typical doses in adults are 500 mL/hr of Colyte
or GoLYTELY initially down a nasogastric tube, which can be increased to 1000–2000 mL/hr in patients who
are not vomiting.
Pediatric doses are generally 100–200 mL/hr by nasogastric tube. This is generally administered until the
rectal effluent is clear or, in cases in which the ingested substance is radiopaque, such as iron, until the
abdominal films are clear. A dose of activated charcoal can be administered first if the ingested material is
adsorbed to it to both prevent absorption and act as a marker for the procedure. Some studies have shown a
slightly decreased efficacy of charcoal in the presence of PEG.[47][58][99]
Much of the evidence for the effectiveness of the procedure is anecdotal. It has been used for a variety of
drugs, including sustained-release preparations.[7][8][14][15][17][37][57][73][78][87] Whole bowel irrigation seems to
be, from both a practical and an effectiveness standpoint, useful primarily when the ingested drugs are not
adsorbed to charcoal or when bags of illicit drugs have been ingested that need to be removed as quickly as
possible before rupture occurs (see discussion later). Drugs or chemicals not well adsorbed to charcoal for
which this procedure might be particularly beneficial include iron,[37][54][66][106][108][109] lead,[96] other
metals,[62] lithium,[103][106][108] and borates (see Table 5–2 ).


THE BODY PACKER/BODY STUFFER PATIENT
Body packers and stuffers may be therapeutic dilemmas in GI decontamination, because the packets
containing the illicit drugs are large and not easily removed, and a life-threatening situation can occur if a
packet ruptures (iatrogenically or spontaneously).[19][39][68][70][116] Drugs can also leak from intact packets.[2]
Body packers are smugglers who swallow tightly sealed packets of cocaine, amphetamines,
tetrahydrocannabinol (THC), or heroin.[70] Body stuffers are usually drug sellers on the street who are
suddenly confronted by the police and swallow the evidence, which is often not tightly or efficiently
packaged.[97] Crack vials may also be ingested.[48] Radiographic evidence of packets in the GI tract may be
seen, with the larger, denser packets in body packers being far more likely to be visible than those in body
stuffers.[11][19] Abdominal computed tomography (CT),[27] plain films with contrast,[40][67] or ultrasonography
may also be useful in visualizing packets. If packets are not clearly seen despite a good history of ingestion,
consultation with the radiologist is recommended to determine which of these procedures is preferable.
Screening ultrasonography can often be performed by the emergency department physician, although its
value in the detection of drug packets is currently unknown.
The drugs involved (cocaine,[111] heroin, amphetamines, or THC) are adsorbed to charcoal, but if rupture
occurs, there must be a large amount of charcoal in the immediate vicinity of the packets to be effective.
Surgery is an option but is unnecessary if the packets can be removed by less invasive maneuvers. If
packets rupture, however, surgery may be lifesaving. Endoscopy may be useful to visualize packets, but
packets may rupture if the endoscopist attempts to snare and remove them. Ipecac has been used
successfully to remove packets from the stomach,[64] but doing so is theoretically dangerous and seldom
recommended.
Whole bowel irrigation is often useful in body packers and stuffers.[48][49] The solution may act as a
lubricating surface in addition to a mechanical force to push packets along and out the GI tract. At least one
dose of activated charcoal should be administered first, although the PEG solution will decrease its efficacy
somewhat.[65] If the drug involved is heroin, naloxone or naltrexone should be kept at the bedside and
administered at the first sign of opioid toxicity. Whenever packet rupture is suspected on the basis of patient
deterioration, emergent surgery to remove packets should remain an option.[104][112]
Whole bowel irrigation after one dose of charcoal, without ipecac, lavage, or endoscopy, is the current
treatment recommendation for both body packers and body stuffers.
Because of the potential for catastrophic deterioration, patients should be kept in a closely monitored setting
with frequent observation and measurement of vital signs. It is prudent to maintain the patient in that setting
for at least 12 hours after it is thought that the last packet has been removed, based on radiographic studies,
clinical appearance, vital signs, and, in some cases, the number of packets ingested by history, if known.
Patients on a police hold should be monitored as closely as patients who are not.


CONCLUSION
Which methods of GI decontamination to use in a specific overdose patient can be determined largely by
common sense. For the typical adult overdose patient who has ingested several different drugs several
hours ago and is minimally symptomatic, the most sensible as well as the easiest approach is to simply
administer a dose of activated charcoal. If the history turns out to be inaccurate, the clinician has still
addressed the other drugs or chemicals ingested, except in the rare case of ingestion of drugs not adsorbed
to charcoal. There is little reason to perform lavage in these patients, and no reason to administer ipecac.
One dose of a cathartic is commonly used but is of unproven benefit. Multiple dose of cathartics should be
avoided. Whole bowel irrigation should be reserved for patients who have ingested iron, other metals and
radiopaque material, and substances not adsorbed to charcoal or for body packers or body stuffers.


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Chapter 6 – Extracorporeal Removal of Drugs and Toxins
JANIS M. ORLOWSKI SUSAN HOU JERROLD B. LEIKIN
Although very few toxic exposures require, or are effectively treated by, extracorporeal techniques, these
techniques are essential modalities that may be lifesaving in the treatment of selected poisoned patients.
The extracorporeal techniques most commonly employed for the removal of toxins are hemodialysis and
charcoal hemoperfusion, although plasmapheresis, exchange transfusion, and continuous ultrafiltration
techniques may also be used. According to the 1998 American Association of Poison Control Centers
(AAPCC) data, extracorporeal procedures were utilized in fewer than 0.05 per cent of cases, with
hemodialysis accounting for 93 per cent. [33] Implementation of these invasive techniques requires the 24-
hour availability of nephrologists and other critical care specialists, dialysis equipment, technicians, and
reference laboratory personnel who monitor the efficacy of treatment.
Employing extracorporeal techniques to remove toxins should be considered if, in so doing, total body
elimination of the toxin can be increased by 30 per cent or more.[45] Specific criteria related to physical
characteristics of the toxin, the efficacy of alternative therapies, the presence of renal failure, and the
severity of poisoning guide decisions regarding the utilization of these techniques ( Table 6–1 ). Certain
agents that predictably cause severe toxicity are routinely dialyzed, based on an assessment of blood levels
or clinical manifestations of toxicity. These include lithium, ethylene glycol, methanol, salicylates, and
theophylline ( Table 6–2 ). Extracorporeal techniques may also be beneficial in the treatment of severe
poisoning with other agents ( Tables 6–3 and 6–4 ). Physical characteristics that predict the successful
removal of an agent by dialysis or charcoal hemoperfusion include low volume of distribution (<1 L/kg), the
presence of the toxin in the central compartment, and low endogenous clearance (< 4 mL/min per kilogram).
Additionally, for hemodialysis, a low molecular weight (<500 daltons), low protein binding, and water
solubility of the toxin are necessary, whereas for hemoperfusion, adsorption of the toxin to activated
charcoal is important ( Table 6–5 ). For some toxins, extracorporeal removal is instituted in an effort to
prevent delayed toxicity. Early removal of toxic alcohols prevents toxicity from their conversion to toxic
metabolites, which are also removed by hemodialysis. [23] For some drugs, hemodialysis results in not only
removal of the drug but also correction of the metabolic consequences of the poisoning; for example, the
metabolic acidosis associated with salicylates, ethylene glycol, methanol, or metformin.[7] Although the great
majority of patients poisoned with barbiturates and sedative-hypnotic agents, such as phenobarbital, chloral
hydrate, ethanol, or isopropyl alcohol, do well with supportive care, extracorporeal removal may be indicated
for unstable patients. Patients with renal or cardiac insufficiency may not tolerate the alkaline load required
for treating salicylism, and may benefit from the earlier institution of dialysis or initiation at lower serum levels
of the toxin.[14] In addition to removal of a toxin, the treatment of renal failure and the correction of the
metabolic abnormalities associated with poisoning, hemodialysis increases the temperature of the blood in
poisonings complicated by hypothermia.[15]
Table 6-1 -- Indications for Extracorporeal Removal of Extractable Drugs and Toxins
Intoxication with a drug or poison whose removal is enhanced 30 per cent or more by extracorporeal
techniques
AND ONE OR MORE OF THE FOLLOWING:
Blood level or ingested quantity that is generally associated with severe or lethal toxicity
Natural removal mechanism impaired
Clinical condition deteriorating with supportive care
Clinical evidence exists of severe toxicity, including hypotension, coma, metabolic acidosis, respiratory
depression, dysrhythmias, or cardiac decomposition
Ingestion of a toxin with serious delayed effects
Table 6-2 -- Toxins for Which Extracorporeal Removal Is Indicated

Molecular
Weight Volume of
Toxin Serum Level (Daltons) Distribution (L/kg) Protein Binding Modality
Ethylene 50 mg/dL 62 0.6–0.7 Negligible HD
glycol
Lithium Clinical 0.8 Negligible HD
Methanol 50 mg/dL 32 0.6–0.7 Negligible HD
Phenobarbital Clinical 232 0.50–0.88 50% HP/HD
Salicylates Acute: =100 mg/dL 138 0.15–>0.3 (increases 50–90% (binding HD
with increasing decreases with
Chronic: Clinical levels) increasing levels)
Theophylline Acute: 90 µg/mL 180 0.5 56% HP/HD
Chronic: 40 µg/mL
and poorly responsive
to therapy
Table 6-3 -- Toxins and Drugs Removed by Hemodialysis/Hemoperfusion

Common Uncommon *
Barbiturates Aminoglycosides
Ethylene glycol Atenolol
Lithium Boric acid
Methanol Bromide
Salicylates Carbamazepine
Theophylline Chloral hydrate (trichloroethanol)
Common Uncommon *
Diethylene glycol
Ethanol
Isopropanol
Magnesium
Metformin
Methotrexate (high flux)
Paraquat (very early)
Procainamide/N-acetylprocainamide
Sotalol
Thallium
Valproic acid
* Extracorporeal removal uncommonly performed or use based on one or more case reports and not well established.
Table 6-4 -- Therapeutic Agents Removed by Hemodialysis or Hemoperfusion

Aminoglycosides
ß-Adrenergic receptor antagonists (atenolol, sotalol)
Carbamazepine
Glutethimide
Isoniazid
Methaqualone
Methyldopa
Metronidazole
Penicillins
Procainamide
Pyrazinamide
Quinidine
Sulfonamides
Thyroid hormone
Valproic acid
Vidarabine
Table 6-5 -- Characteristics of Toxin Removed by Extracorporeal Therapy

Hemodialysis Hemoperfusion
Distribution time Short Short
Low endogenous clearance <4 mL/min/kg <4 mL/min/kg
Volume of distribution =1 L/kg =1 L/kg
Protein binding Low Low or high
Solubility Water Water or lipid
Molecular weight =500 daltons =40,000 daltons
TYPES OF EXTRACORPOREAL THERAPY

Intermittent Hemodialysis
Hemodialysis is accomplished by actively pumping blood past a semipermeable membrane, most commonly
configured as a bundle of hollow fibers that has a nonsterile solution on the opposite side of the membrane.
The diffusion of dialyzable substances across the membrane, from an area of high concentration to an area
of low concentration, allows their removal. Solutes dissolved in fluid are also removed by convection, which
has a more prominent role in some of the continuous forms of dialysis therapy.
Most of the hemodialysis systems currently in use are single-pass systems; that is, the dialysate comes in
contact with the blood only one time. Single-pass systems use 30 to 40 L/hr of nonsterile treated water,
which dilutes a concentrated solution of electrolytes. The maximum gradient between the serum and the
dialysate is maintained throughout the treatment.
In the acute setting, the REDY sorbent system, which regenerates dialysate and requires only 6 L of water
per treatment, is sometimes used in place of a single-pass system.[46] Dialysate is regenerated by passage
through a five-layered sorbent cartridge that uses urease to convert urea to ammonium carbonate and binds
other toxins at other levels of the cartridge. A disadvantage of this system is that the toxin may be
incompletely bound by the cartridge, so that over time the concentration of the toxin in the dialysate
increases, thereby decreasing the gradient of toxin from blood to dialysate and markedly decreasing the
efficiency of toxin removal. This system is less efficient for poison removal and should be used only if
standard hemodialysis is not available.
Effect of the Dialysis Membrane on Toxin Removal
Many characteristics of the dialysis system influence the efficacy of dialysis, including membrane surface
area, pore size, and rate of blood flow through the dialyzer. The ability of a substance to cross the
membrane depends on membrane thickness and on pore size and shape. There is significant variation in
the characteristics of dialysis membranes. They are divided into three basic categories based on
permeability to solutes and ease of ultrafiltration of fluid: standard, high-efficiency, and high-flux. High-flux
membranes can be used only with specialized dialysis machines that continuously adjust ultrafiltration,
based on computerized measurements. Dialysis machines require recalibration to switch from standard to
high-flux membranes. For the treatment of acute poisoning, time constraints and availability of personnel
usually make it necessary to use the more readily available standard hemodialysis systems. There is little
advantage to a more efficient dialyser for small molecules such as lithium (atomic weight = 6.94), which are
almost completely removed by the passage of blood through any dialyzer.[18] Larger molecules, such as
methotrexate (molecular weight = 454.45 daltons) are poorly removed by standard dialyzers but may be
removed by high-flux dialyzers and highly permeable filters used for continuous therapies. [38] The
permeability of the membrane is usually expressed in terms of the clearance of urea. Most manufacturers
also specify the clearance of vitamin B12 as a representative of molecules of middle molecular weight. A
knowledge of the permeability characteristics of the dialyzers that are available in a specific setting allows
the nephrologist to better predict the efficacy of dialysis for the removal of a given substance.
Effects of Characteristics of the Toxin on Efficacy of Removal by Dialysis
There are several characteristics of toxins that determine the efficacy of dialysis in the treatment of
poisoning or overdose.
Size and Charge
The rate at which molecules travel down a concentration gradient and across the dialysis membrane is
inversely proportional to molecular weight. Simply put, large molecules move more slowly than small
molecules. From the example noted earlier, a molecule of vitamin B12 (molecular weight = 1355 daltons)
would be dialyzed more slowly than a molecule of urea (molecular weight = 60 daltons), and a molecule of
lithium would be dialyzed more rapidly than a molecule of methotrexate.
Protein Binding.
The dialysis membrane is designed to prevent the movement of large quantities of plasma proteins into the
dialysate. For this reason, only drugs that are not protein bound are removed by dialysis. Protein binding
may vary with the concentration of a drug. Although both salicylates and valproic acid are highly protein
bound at therapeutic levels, the fraction of protein binding is decreased at toxic levels, allowing for their
removal by hemodialysis.[28][53]
Volume of Distribution
The volume of distribution is the theoretical space over which a substance is distributed. Substances that are
widely distributed in tissues have a higher calculated volume of distribution than substances that are
confined to the intravascular space. For example, the administration of a given amount of a toxin that is
confined to the intravascular space results in a higher serum concentration and a lower volume of
distribution than the same amount of a substance that is distributed into the intravascular space plus fat and
muscle. Hemodialysis removes only the toxins that are in the intravascular space. Substances that can be
effectively removed by dialysis have a volume of distribution that is less than 1 L/kg. Although widely
distributed substances may be efficiently extracted from the blood by hemodialysis or hemoperfusion, they
are still not effectively removed because only a small percentage of the toxin is in the intravascular space.
An example is cyclic antidepressants, which have a volume of distribution of more than 10 L/kg. Although
easily removed from the intravascular space by dialysis, they are so widely distributed in tissue that their
removal has little impact on total body burden and toxicity. For some of these substances, there is a critical
time period between ingestion of the toxin and the concentration of toxin in tissues, when removal is
feasible.
Water Solubility
In order to be removed by hemodialysis, a substance must be soluble in the aqueous phase of plasma.
Lipid-soluble drugs are poorly removed. Lipid-soluble drugs also frequently have a large volume of
distribution.
Rate of Transfer from Tissues
As a substance is removed from the intravascular space, a portion of the drug distributed in tissue (including
red blood cells) and in interstitial water diffuses into the serum. This movement accounts for the postdialysis
rebound in the blood level of some drugs that occurs independent of continued gastrointestinal absorption.
The rate of transfer during the treatment affects the efficiency of removal. This rebound effect is prominent
following the removal of lithium by hemodialysis.[18]
Hemoperfusion
Hemoperfusion is similar to hemodialysis except that blood passes through a cartridge containing either
charcoal or a resin that adsorbs the toxin directly, rather than passing through a hollow fiber. Hemoperfusion
efficiently removes toxins that adsorb to activated charcoal or resin, including substances that are lipid
soluble or have a higher molecular weight than those able to pass a hollow-fiber hemodialyzer.[19] It is also
more effective in removing substances that are protein bound. Hemoperfusion is very efficient in removing
toxin located within the intravascular space, including the lipid portion of plasma as well as red blood cells. It
does not overcome the problem of removing a toxin that has a large volume of distribution.
Although the same machine used for hemodialysis can be used for hemoperfusion, hemoperfusion is not as
readily available as hemodialysis. Cartridges are not available in many hospitals, and familiarity with
hemoperfusion, even by nephrologists, is limited owing to its low frequency of utilization. Certain
complications occur frequently, including hypotension, thrombocytopenia, leukopenia, and electrolyte
disturbances. The causes of hypotension are multifactorial. It may be caused by the toxin itself, the blood
volume used to prime the filter, or a pyrogen reaction to the filter itself. Leukopenia and thrombocytopenia
are frequently seen, although with newer hemoperfusion cartridges, thrombocytopenia is usually limited to
approximately a 30 per cent drop in platelet count.[19] Nonselective binding of important molecules, such as
calcium, phosphate, and glucose, to the charcoal or the resin in the hemofiltration cartridge requires close
monitoring for hypocalcemia, hypophosphatemia, and hypoglycemia. Systemic anticoagulation, which is
necessary to prevent clotting of the filter, may lead to bleeding problems. Charcoal embolization has been
reported but is uncommon with the newer hemofiltration cartridges.
The efficiency of hemoperfusion may be increased by using a standard hemodialyzer and hemoperfusion
cartridges in series. The removal of small molecules, such as urea, by hemodialysis decreases their
concentration in the blood reaching the hemoperfusion cartridge, thus decreasing their binding to the
charcoal or resin. This leaves a greater portion of the cartridge surface area available for binding the
targeted toxin, increasing the time before the cartridge is saturated and must be replaced. As with any
extracorporeal system for toxin removal, repeated treatments may be necessary, as plasma levels of the
toxin rebound. While hemoperfusion has been used in the treatment of numerous poisonings, there are few
studies comparing the long-term outcomes of patients treated with hemoperfusion versus those treated with
conservative therapy.[52]
Continuous Therapies
Continuous renal replacement therapies, introduced for the treatment of acute renal failure in
hemodynamically unstable patients, allow ongoing removal of small volumes of fluid and toxins at low blood
flow rates.[35] Blood is pumped continuously through a very permeable hollow-fiber membrane, either from
an artery to a vein, relying on the patient’s own blood pressure, or by a blood pump from a large vein with a
double-lumen catheter. The permeable membrane allows for an ultrafiltration rate as high as 1 to 1.5 L/hr.
When continuous arteriovenous hemofiltration (CAVH) is done without the use of a blood pump, the
ultrafiltration rate is determined by the positive pressure caused by venous resistance on the blood side of
the filter and the negative pressure generated by gravity as determined by the height of the drain bag on the
ultrafiltrate side. When the rate of ultrafiltration exceeds the desired rate of fluid removal, replacement fluid is
given. A wide range of sophisticated ultrafiltration controls are available for continuous venovenous
hemofiltration (CVVH) or CAVH, with new refinements being introduced regularly. For all continuous
therapies, toxins are removed by convection in concentrations approximately equal to the unbound blood
level, but the serum concentration does not change until replacement solution is given. Continuous therapies
are relatively inefficient for solute (and thus toxin) removal. The efficiency can be increased by circulating
dialysate on the outside of the hollow fibers. Because the membrane is permeable enough to allow the
passage of larger molecules, including inflammatory mediators, the dialysate solution must be sterile. One of
a number of specifically formulated dialysis fluids, including peritoneal dialysate, can be used. Many of the
fluids designed for continuous systems use lactate as the base precursor, which needs to be changed to a
bicarbonate-containing solution in patients with lactic acidosis. The dialysate flow rate with continuous
therapies is usually no more than 4 L/hr (more commonly 1 or 2 L/hr), rather than the 30 L/hr used in
hemodialysis.
Continuous methods have several advantages. The larger pore size allows removal of molecules up to
50,000 daltons. These methods are better tolerated in hemodynamically unstable patients. For conditions in
which there is endogenous production of a toxic substance, such as lactate or ongoing absorption from an
inadequately decontaminated gastrointestinal tract, continuous therapies provide ongoing removal. Finally,
they avoid the problem of rebound toxicity by removing the toxin continuously as it reenters the intravascular
space.
Peritoneal Dialysis
Peritoneal dialysis involves instillation of a dialysate of electrolytes, glucose, calcium, and magnesium into
the peritoneal space through a percutaneously placed catheter. Toxins from the splanchnic circulation
diffuse across the abdominal mesentery into the dialysate, which is then drained from the body. The
efficiency of dialysis depends largely on dialysate flow rate. When acute dialysis is done, the fluid is usually
changed hourly. Peritoneal dialysis is much less efficient than hemodialysis in the removal of toxins, and it is
generally used only when hemodialysis is not available.[51] Peritoneal dialysis is more efficient in children
than in adults because the peritoneal surface area in children is larger than that in adults relative to body
surface area.[10] The base precursor in most peritoneal dialysis solutions is lactate, which precludes its use
in intoxications associated with lactic acidosis. When dialysis is instituted for the treatment of toxin-induced
renal failure, rather than for toxin removal, peritoneal dialysis is an acceptable alternative in all but the most
catabolic patients.
Plasmapheresis
Plasmapheresis is the removal of plasma in exchange for albumin or fresh frozen plasma from another
donor. It removes toxins only from the intravascular space. The plasma concentration of toxins is lowered by
the plasma volume exchanged. Double-lumen central access is required, as well as a centrifugal separator
to remove the plasma. Specifically trained technicians are required for monitoring plasma removal, with
appropriate physician directed replacement. Complications include hypotension, bleeding, hypocalcemia,
alkalosis secondary to the citrate preservative in the blood products, and complications of central venous
access. Bleeding complications are exacerbated when albumin is used for replacement because the
patient’s clotting factors are removed, along with plasma and the toxin. Plasmapheresis is most useful for
removing protein-bound toxins, such as phenytoin, that are not removed by hemodialysis and are
inefficiently removed by hemoperfusion.[30]
Exchange Transfusion
Exchange transfusion is the technique of removing blood from a patient, followed by transfusions of the
similar quantity of blood from a donor. The process is usually repeated several times, in order to remove a
sufficient quantity of the toxin. This technique is theoretically helpful in situations of hemoglobin toxicity, such
as methemoglobinemia, or in cases of severe hemolysis.[42] This technique is rarely used except in
neonates. The complications are those associated with the risk of transfusions.
Chelation Therapy Combined with Extracorporeal Removal
Occasionally, metals such as iron and aluminum accumulate in the body in quantities sufficient to cause
neurologic and hematologic toxicity, severe bone disease, or liver disease. Patients with renal failure are at
particular risk for the accumulation of metals. The neurologic complications of aluminum accumulation
include myoclonus, dementia, and coma. Aluminum can also cause a microcytic anemia and osteomalacia.
Iron accumulates in patients receiving frequent blood transfusions. Patients with renal failure who receive
frequent transfusions or intravenous infusions of iron as part of treatment with erythropoietin are at particular
risk for iron accumulation, with its associated liver and heart disease. Removal from the body is achieved
only after combination of these metals with chelating agents. Chelation therapy may be effective in patients
with normal renal function, but in patients with renal failure chelation of some metals must be combined with
hemodialysis in order to have effective removal.[34][50] Caution must be taken when one uses chelating
agents to avoid precipitating acute toxicity because of an increase in serum levels due to mobilization from
tissues. This therapy is also associated with anaphylactic reactions and severe hypotension. Long-term
therapy with deferoxamine can predispose to fungal infections. [34][49]


DRUGS AND TOXINS COMMONLY REMOVED BY EXTRACORPOREAL THERAPY
Because of the characteristics required for effective removal of a drug or toxin by extracorporeal techniques,
the number of drugs for which hemodialysis is useful is relatively small. For the drugs that are removed well
by both hemoperfusion and hemodialysis, hemodialysis is usually preferred because of the greater
experience with its use and because it simultaneously corrects associated electrolyte abnormalities. For
drugs and toxins for which hemoperfusion is superior, hemodialysis should be used only when
hemoperfusion is not available.
Barbiturates
Most patients with barbiturate overdose do well with supportive care. Chronic users of these drugs may
tolerate very high levels with minimal symptoms, so that a decision to dialyze a patient with barbiturate
overdose should be based on evidence of severe toxicity unresponsive to conservative management, rather
than on blood levels. Phenobarbital can be removed by hemoperfusion or hemodialysis because of its low
volume of distribution, its adsorbency to activated charcoal, and its slow intrinsic elimination rate. It is the
barbiturate most frequently considered for extracorporeal removal. Hemoperfusion (more effective) or
hemodialysis should be considered for toxicity associated with hypotension, respiratory depression, or deep
and prolonged coma. [26][32] When extracorporeal removal is instituted for barbiturate overdose, the treatment
may precipitate a state of acute withdrawal manifested by seizures or delirium tremens in the chronic user.
Ethylene Glycol
Ethylene glycol is converted by multiple enzymatic reactions to metabolites that cause metabolic acidosis,
renal failure, pulmonary edema, and central nervous system damage, including cerebral edema. The
treatment for ethylene glycol poisoning consists of inhibiting alcohol dehydrogenase, the initial enzyme in the
metabolic pathway, and instituting hemodialysis to remove the parent compound and its metabolites, to treat
the metabolic acidosis and to treat the renal failure. The indications for dialysis include an ethylene glycol
level of at least 50 mg/dl or evidence of ongoing metabolic acidosis with end-organ failure; for example,
rising serum creatinine, decreased urine output, pulmonary edema, and cerebral edema, regardless of the
serum level.[11] Hemodialysis clearance rates of 156 mL/min and 210 mL/min have been achieved for
ethylene glycol. These clearances are significantly greater than the normal renal clearance rate reported at
27.5±4.1 mL/min.[43][47] Glycolate, the metabolite responsible for the acidosis, is also cleared by
hemodialysis. In 10 patients studied as part of a multicenter, prospective trial[5] the hemodialysis clearance
of glycolate was 170±23mL/min (flow rates 250 to 400 mL/min) with an elimination half-time of 155±42
minutes. This compared favorably to a nonhemodialysis elimination rate of 1.08±0.67 mmol/L per hour with
an elimination half-time of 626±474 minutes.[39]
Lithium
Lithium is ideally suited to removal by hemodialysis. With a weight of 74 daltons, it passes readily across
virtually all dialysis membranes. It has a volume of distribution of 0.8 L/kg of body weight and is not protein
bound. Extraction by dialysis is 90 per cent. In a series of 14 patients, hemodialysis clearances in three
patients ranged from 63.2 to 114.4 mL/min.[20] Because 70 to 80 per cent of lithium filtered by the kidney is
reabsorbed in the proximal tubule, removal by dialysis is more efficient than removal by the kidney. In the
study of 14 patients discussed earlier, mean renal clearance was 17.2±5.4 mL/min. In patients in whom
renal function is preserved, dialysis and renal excretion are additive. Hemodialysis should be instituted
regardless of serum levels if moderate to severe central nervous system abnormalities such as confusion,
stupor, coma, or seizures are present. The serum lithium level is effectively lowered by hemodialysis.
However, a rebound in serum lithium levels that peaks at 6 to 8 hours after a treatment occurs as lithium
enters the blood from the interstitial and intracellular spaces. This rebound often necessitates repeated
treatments until the serum lithium level remains below 1.0 mEq/L.[20] Lithium is also removed via continuous
hemofiltration. In 7 patients treated with CAVH or CVVH for 18 to 44 hours, mean lithium clearances were
41.4±4.6 mL/min (CAVH, flow rate 4 L/hr) and 48.4±1.4 to 61.9±2.3 mL/min (CVVH, flow rate 1 to 2 L/hr). No
significant rebound in the serum lithium levels occurred.[31] This technique may also be employed after initial
hemodialysis.[4]
Methanol
Methanol toxicity causes blindness, severe metabolic acidosis, central nervous system toxicity, and death.
Formic acid is responsible for the toxic manifestations and acidosis. It is produced when methanol is
metabolized to formaldehyde by alcohol dehydrogenase and then to formic acid by aldehyde
dehydrogenase. Like ethylene glycol, methanol poisoning is treated by infusion of an alcohol dehydrogenase
inhibitor to block metabolism, followed by hemodialysis.
Hemodialysis indications mirror those for ethylene glycol listed earlier and include a plasma level of 50
mg/dL or greater or evidence of ongoing metabolic acidosis with end-organ failure; for example, visual
disturbances, metabolic acidosis, cerebral edema, and seizures. Hemodialysis clearance rates of 142 to 286
mL/min have been reported for methanol, while formic acid clearances range 148 to 203
mL/min.[9][22][24][25][48] However, the hemodialysis elimination half-time of formic acid does not vary
appreciably from the nonhemodialysis half-time. In a prospective multicenter trial involving 11 patients
poisoned with methanol, seven of whom underwent hemodialysis, the nonhemodialysis half-time of formic
acid was 205±25 minutes, while the hemodialysis half-time was 185±62.7 minutes. Overall, the hemodialysis
clearance for formic acid was 223±24.5 mL/min.[29]
When hemodialysis is used to treat methanol or ethylene glycol intoxication, the dose of fomepizole or
ethanol should be increased during dialysis to offset the removal of these alcohol dehydrogenase inhibitors
(see Chapter 93 ).
Salicylates
Salicylates are poorly removed by dialysis at therapeutic levels because protein binding exceeds 90 per
cent. However, at toxic levels, protein binding saturates and decreases to 50 to 75 per cent, leaving a large
free fraction that can be readily removed.[1] Hemodialysis should be instituted when the serum level is 100
mg/dL or greater or when altered mental status (cerebral edema), noncardiogenic pulmonary edema,
noncorrectable severe acid-base disturbances, renal failure, or a deteriorating clinical condition occur at
lower levels.[53] Hemoperfusion removes salicylates more effectively; however, hemodialysis facilitates
correction of the associated acid-base disturbances while also removing the toxin.
Theophylline
Hemoperfusion is the preferred method for removal of theophylline, which is more than 50 per cent protein
bound, but hemodialysis is also effective.[52] Theophylline avidly binds to the activated charcoal cartridges.
The level at which extracorporeal removal should be instituted depends on whether the poisoning results
from acute ingestion or chronic toxicity. With acute ingestion, extracorporeal removal is usually instituted if
the serum level is 90 µg/mL or more. In the setting of chronic ingestion, hemoperfusion or hemodialysis is
instituted if serum levels are more than 40 µg/mL and the patient manifests serious toxicity.[13]
Extracorporeal removal should be used in the presence of ventricular dysrhythmias, metabolic acidosis,
refractory hypotension, or seizures. See Chapter 48 for a more extensive discussion of the indications for
extracorporeal therapy and extracorporeal elimination rates in theophylline toxicity.


COMPLICATIONS AND LIMITATIONS OF EXTRACORPOREAL REMOVAL OF TOXINS
Although in the United States only 900 to 1000 poisoned patients are treated with hemodialysis yearly, the
total number of hemodialysis treatments performed annually has reached the tens of millions. Extensive
experience has made it a relatively safe procedure, particularly when only a few treatments are needed.
Although it is rational to use extracorporeal techniques in cases of severe poisoning when these techniques
can remove significant amounts of toxin, there are few data that clearly demonstrate decreases in mortality
and long-term disability produced by these interventions.
Vascular Access
With the exception of peritoneal dialysis, all the aforementioned therapies require access to the intravascular
space with a large-bore catheter. For hemodialysis or CVVH, a large-bore catheter is placed in either the
femoral, subclavian, or jugular vein. For poisoned patients who do not have renal failure, treatment is limited
to one or two treatments and the problems of long- or intermediate-term vascular access are usually not of
concern. If short-term treatment is anticipated, placement of the catheter in the femoral vein carries the
lowest risk of complications. Perforation of an artery or of the opposite side of the vein is a risk associated
with placement of a line in any of these vessels, but control of bleeding is easiest with the femoral
placement. Placement in the subclavian vein also carries the risk of pneumothorax, hemothorax,
hemopericardium, and laceration of the thoracic duct. A later complication of subclavian lines is stenosis of
the subclavian vein. CAVH requires the placement of a catheter in a large artery, and the patient must be
monitored for signs of arterial occlusion distal to the catheter. As with any intravenous access, catheters
placed for hemodialysis or hemoperfusion can introduce infection. The risk increases with the length of time
the catheter is in place.
Hypotension
Hypotension, the most common complication of dialysis, is most often precipitated by fluid removal. The
extracorporeal circuit itself contains 70 to 175 mL in the dialyzer and 100 to 150 mL in the blood lines. The
blood flow is usually 200 to 400 mL/min. In an otherwise stable patient, dialysis without the removal of fluid
causes hemodynamic demands that are easily met. In the patient with a drug overdose, dialysis may
exacerbate hypotension in a patient with hemodynamic instability from the effects of the drug. If the
intoxication involves a drug that causes renal failure, the patient may have received large quantities of fluid
during an attempt at conservative treatment that must now be removed by dialysis. When hemodynamic
instability is a limiting factor, a continuous therapy such as CVVH may be used, although the efficacy of
these modalities is unknown. Hypotension may also be caused by sepsis, bleeding, or pericardial
tamponade or by toxin-induced sympathetic blockade, acidosis, myocardial depression, or dysrhythmia.
Bleeding
The performance of hemodialysis, CAVH and CVVH are facilitated by the use of heparin or other
anticoagulants, although hemodialysis can be performed without anticoagulation in patients at high risk for
bleeding. When heparin is not used, there is an increased risk of clotting of the extracorporeal circuit, but the
risk of late bleeding is minimal. Hemoperfusion cannot be done without full anticoagulation. The bleeding
tendency increases during hemoperfusion if thrombocytopenia develops owing to platelet adherence to the
cartridge. Bleeding may occur at any site, and severe bleeding into the retroperitoneum may occur without
clinical manifestations until hypotension develops.
Citrate has been used as an anticoagulant in continuous therapies that combine diffusive and convective
clearance.[37] It is associated with fewer bleeding complications, but with a higher risk of disturbances of
calcium metabolism and metabolic alkalosis.
Accidental disconnection of blood lines in any of these therapies can result in death from exsanguination.
The risk is higher with continuous therapies in which the caretaker generally has other responsibilities in
addition to tending the renal replacement therapy. Hemodialysis machines are equipped with alarms that will
detect a change in pressure associated with disconnection and stop the blood pump and clamp the blood
lines. The most sophisticated machines will not run if the alarms are disarmed. Most pumps for CVVH are
similarly equipped with pressure monitors and air detectors. CAVH, which does not employ a blood pump,
requires that the connections always be exposed so that accidental disconnection is immediately detected.
The use of Luer lock connections minimizes this risk.
Other Complications
The use of intermittent hemodialysis on a widespread basis for acute and chronic renal failure has led to
technology that minimizes many of the risks. Several of the most feared complications of dialysis have
become uncommon. Virtually all dialysis machines are equipped with air detectors that shut off the blood
pump and prevent air emboli. Many machines will not function unless the air detector is armed. On the
outflow path of the dialysate, there is a colorimetric blood leak detector that will detect small quantities of
blood in the dialysate exiting the dialyzer. If small quantities of blood are detected, the blood pump is shut
off, preventing the return of blood contaminated by nonsterile dialysate to the patient. The amount of blood
loss with rupture of the membrane in a hollow fiber kidney is trivial.
There are monitoring systems that detect changes in the osmolality of dialysate and shunt blood away from
the dialysate to prevent exposure to very hypotonic or hypertonic solution. A temperature monitor prevents
exposure to overheated dialysate that may result in hemolysis.
Some dialyzers, particularly with membranes made of cuprophane, have occasionally been associated with
anaphylactic reactions. These membranes have been replaced largely by more biocompatible synthetic
membranes, particularly in the hospital setting, which have been associated with a more rapid recovery from
acute renal failure.
Removal of Therapeutic Agents
During dialysis it should be remembered that some drugs will be removed and must be supplemented.
Categories of drugs removed by extracorporeal therapy are listed in Table 6–4 .[3] Not every drug in a
category is removed equally well. As new drugs in each category are introduced, the need for replacement
during or after extracorporeal therapy should be checked. For some drugs, removal with extracorporeal
therapy may be sufficient to interfere with therapeutic levels, but such therapy may not be good enough to
reliably treat overdose. When dialysis is used in the absence of renal failure, the loss of some solutes that
are generally present in excess in renal failure may become a problem. These include phosphorus and
magnesium.
Toxic Injuries Caused by Exposure to Dialysis During Treatment of Chronic Renal Failure
Chronic dialysis patients have received significant toxic exposures via contaminated dialysis equipment. The
primary vehicle of toxic exposure is contaminated water used in the dialysis process. Elevated water levels
of calcium,[12] copper,[36] fluoride,[2] chloramines,[8] hydrogen peroxide,[16] sodium,[40] formaldehyde,[41]
sodium azide,[17] sodium hypochlorite,[21] aluminum,[6] and zinc[44] all have been reported to cause toxicity in
dialysis patients. Recently, 50 deaths occurred in Brazil when microcystins produced by Cyanobacteria in
the public water system caused acute hepatic failure in dialysis patients at one dialysis center.[27]
SUMMARY
Extracorporeal removal of drugs and toxins is an essential though infrequently utilized tool in the
management of the poisoned patient. Specific criteria related to the physical characteristics of the toxin, the
efficacy of alternative therapies, and the severity of poisoning guide decisions regarding the utilization of
these techniques. These are not “last ditch” heroic maneuvers, but essential modalities for toxin removal that
have an important role in the treatment of selected poisoned patients.


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15. Gentilello LM, Cobean RA, Offner PJ, et al: Continuous arteriovenous rewarming: Rapid reversal of
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17. Gordon SM, Drachman J, Bland LA, et al: Epidemic hypotension in a dialysis center caused by sodium
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18. Groleau G: Lithium toxicity. Emerg Med Clin North Am 1994; 12:511.
19. Gurland H, Samtleben W, Lysaght MJ, Winchester JF: Extracorporeal blood purification techniques:
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21. Hoy RH: Accidental systemic exposure to sodium hypochlorite (Chlorox) during hemodialysis. Am J
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22. Jacobsen D, Jansen H, Wilk-Larsen E, et al: Studies on methanol poisoning. Acta Med
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23. Jacobsen D, McMartin KE: Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin
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24. Jacobsen D, Ovrebo S, Sejersted OM: Toxicokinetics of formate during hemodialysis. Acta Med
Scand 1983; 214:409.
25. Jacobsen D, Webb R, Collins TD, et al: Methanol and formate kinetics in late diagnosed methanol
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phenobarbital poisoning. Eur J Clin Pharm 1984; 26:109.
27. Jochimsen EM, Carmichael WW, An JS, et al: Liver Failure and Death after Exposure to Microcystins at
a Hemodialysis Center in Brazil. N Engl J Med 1998; 338:873.
28. Johnson LZ, Martinez I, Fernández MC, et al: Successful treatment of valproic acid overdose with
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29. Kerns W, Tomaszewski C, McMartin K, et al: Formate kinetics in methanol poisoning [abstract]. J
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33. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 Annual Report of the American Association of
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36. Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia: A new complication of
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37. Mehta RL, Dobos GJ, Ward DM: Anticoagulation in continuous renal replacement therapy. Semin
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38. Molina R, Fabian C, Cowley B: Use of charcoal hemoperfusion with sequential hemodialysis to reduce
serum methotrexate levels in a patient with acute renal insufficiency. Am J Med 1987; 82:350.
39. Moreau CL, Kerns W, Tomaszewski CA, et al: Glycolate kinetics and hemodialysis clearance in
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40. Nickey WA, Chinitz VL, Kim DE, et al: Hypernatremia from water softener malfunction during home
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41. Orringer EP, Mattern WD: Formaldehyde-induced hemolysis during chronic hemodialysis. N Engl J
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42. Osborn HH, Henry G, Wax P, et al: Theophylline toxicity in a premature neonate: Elimination kinetics of
exchange transfusion. J Toxicol Clin Toxicol 1993; 31:639.
43. Peterson CD, Collins AJ, Himes JM, et al: Ethylene glycol poisoning: Pharmacokinetics during therapy
with ethanol and hemodialysis. N Engl J Med 1981; 304:21.
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45. Pond SM: Extracorporeal techniques in the treatment of poisoned patients. Med J Aust 1991; 154:617.
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47. Sabeel AI, Kurkus J, Lindholm T: Intensified dialysis treatment of ethylene glycol intoxication. Scand J
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48. Swartz RD, Millman RP, Billi JE, et al: Epidemic methanol poisoning: Clinical and biochemical analysis
of a recent episode. Medicine 1981; 60:373.
49. US Department of Health and Human Services: Hemoperfusion in Conjunction with Desferoxamine for
the Treatment of Aluminum Toxicity and Iron Overload in Patients with End-Stage Renal Disease,
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Chapter 7 – Laboratory Testing in Emergency Toxicology
JOHN D. OSTERLOH
INTRODUCTION
The majority of toxicologic diagnoses and therapeutic decisions are made on a clinical basis, even though
technology has provided the ability to measure many toxins. The applications of these laboratory
measurements are limited by practical considerations. Analytic turnaround time is often longer than the
critical time course of an overdose, and laboratories cannot support the cost of maintaining the procedures,
instruments, training, and specialized labor that would be needed to analyze every toxin.[34] In addition, most
hospital laboratories do not have discrete toxicology sections; many of the laboratory tests used by
toxicologists are distributed throughout the laboratory. This trend will continue with the use of more
automated analyzers that incorporate a diverse selection of tests and with ongoing workforce reductions.
This can mean more rapid turnaround time for some tests but will tend to dilute expertise in a specialty area
such as toxicology and preclude time-consuming searches for unusual or less prevalent toxins.
The initial workup of a poisoned patient always starts with a history and physical examination, during which a
preliminary toxicologic diagnosis can usually be made based on the constellation of signs and
symptoms.[12][26][33] General laboratory tests help identify and confirm the presence of a pathologic process
or a nonhomeostatic state on which a suspected diagnosis can be postulated. The use of arterial blood
gases, electrolytes, anion gaps, osmol gaps, metabolic substrates and products (e.g., glucose, ketones),
and markers of organ damage (e.g., creatine kinase, creatinine, alanine aminotransferase, amylase) are
discussed in other chapters.
Some tests for drugs can aid in the diagnosis and treatment of an intoxicated patient. The interpretation of
such measurements requires that the relationship between the presence or concentration of a toxin and its
pharmacologic or toxicologic effects be known. Sometimes the drug concentration and its concentration-
related toxic effects can provide a better indicator of clinical condition or prognosis than the clinical signs
(e.g., with acetaminophen toxicity). Unfortunately, our knowledge of such relationships is limited for most
toxins. Even when toxins have been well studied, there may be no clear relationship. For example, a toxin at
an effector site may not be in rapid equilibrium with the sampled fluid (e.g., lithium in the serum is not
representative of lithium in the brain during acute overdose), or the measured toxin may be metabolized to
an unknown, unmeasured, and active metabolite (e.g., organophosphate toxicity). In addition, predictions
based on pharmacokinetics or pharmacodynamics in the therapeutic range do not always extrapolate to
overdose (e.g., theophylline elimination is first order at therapeutic doses and zero order in overdose).
The prior probability (prevalence) strongly influences the reliability of any test (predictive value of a positive
or negative test) at any given sensitivity and specificity. For example, in employee drug screening (low prior
probability of drugs being present), toxicologic methods are adapted to improve sensitivity and specificity for
finding low concentrations of a few drugs in unselected populations.[18][41] Without such adaptations, the
false positives would be too high in this low-prevalence setting. In emergency toxicology, procedures are
geared toward rapidly finding a large number of drugs at a high concentration in populations clinically
suspected of overdose (i.e., high prior probability, diagnostic situations).
In brief, for any test to serve its function, it must be (1) analytically valid (defined and tested for detection
limits, calibration-response relationship, precision, referenced accuracy, dynamic range, interferents); (2)
clinically reliable (investigated for clinical sensitivity, specificity, and predictive value in the actual clinical
setting); (3) applied correctly to monitor (measure change), diagnose (categorize or sort), or screen (find
without preselection); and (4) useful (i.e., the test result will assist in making a diagnosis or change the
course of therapy or disposition of the patient).
The following discussion is limited to currently available drug tests used in the emergency evaluation of
acutely overdosed patients. Methadone testing programs, employee (surveillance) drug testing, forensic
(cause-of-death) testing, therapeutic drug monitoring, and mechanisms or methodologies of tests are not
discussed here.


TOXICOLOGY SCREENS
Toxicology (tox) screens have limited utility and should be applied when the diagnosis (drug vs. disease) is
not known. Use of history and clinical signs and symptoms precludes the need for screens on most
occasions. When a tox screen in necessary:
•
Write the suspected diagnoses and suspected drugs on the requisition form.
•
Know which drugs are included and not included on the screen to avoid interpretive false positives and
negatives.
•
Do not order emergency screens for surveillance purposes.
The techniques for detecting the presence of drugs include a variety of chromatographic methods,
immunoassays, and chemical and spectrometric techniques. Each of these general techniques can be
adapted to detect a wide number of drugs and chemicals, or focused to detect and quantitate certain drugs.
The analysis of drugs, chemicals, or toxins requires matching the properties (e.g., chemical,
chromatographic, light absorption) of a substance with those of a reference compound. For each drug, a
laboratory must possess that particular reference compound. Because the blood or urine sample may
contain components that can interfere in the detection of a drug, isolation of the drug from the sample is
often necessary before applying characterization procedures.
Immunoassays are most widely used for discrete analysis, and gas chromatographic techniques are used
for broad screens. A comparison of the common toxicologic methods is given in Table 7–1 . Most broad
screening methods are limited by the range of drugs detectable or by sensitivity. Methods that can detect
many drugs simultaneously can vary considerably in their sensitivity to individual drugs.[14 ] For example,
ease of detection for morphine would be ranked in order of sensitivity as follows: immunoassay (IA), thin-
layer chromatography (TLC), gas chromatography (GC); for fluoxetine, the order is reversed. Tables 7–2 and
7–3 show the types of discrete tests applied to urine and serum and some common interferents.
Table 7-1 -- Comparison of Generic Toxicologic Methods for Drugs

Chemical spot
+
+
No
No
<0.5
+
0
500
Spectrometric †
+
+
No
Some
<2–4
++
++
10,000
Immunoassay †
++
++
Some
Some ‡
<1
+
+
15,000
Thin-layer chromatography
++
+
Yes
No
2–4
+++
+++
1500
Gas chromatography
++
++
Yes
Yes ‡
<4
++
++
15,000
High-performance liquid chromatography
++
++
Yes
Yes ‡
<4
++
++
20,000
Gas chromatography–mass spectrometry
+++
+++
Yes
Yes ‡
<8
+++
++++
60,000
Multidrug Initial
Specificity Sensitivity Detection Quantitative Turnaround Labor Technical Capital
Method * * Possible Ability Time (hr) Intensive Expertise Costs ($)
*
Relative comparison for a specific analyte.
†
Can be performed on analyzers widely used in clinical laboratory.
‡
Adaptable.
Table 7-2 -- Qualitative Toxicologic Methods Used in Urine

Salicylate
Trinder’s
Spot, SC
TD (<1 d), OD
Salicylamide, diflunisal, ketonuria, phenylketonuria, proteinuria, sulfonamides, hippuric acids (from toluene,
xylene ‡ )
Acetaminophen (p -aminophenol detected)
Orthocresol
Spot, SC
TD (<1 d), OD
N -acetylcysteine, phenols from throat lozenges and mouthwashes ‡ , proteinuria
Phenothiazines (metabolites)
Forrest or ferric-perchlorate-nitric (FPN)
Spot
TD for some (<3 d), OD
Salicylates, ketonuria ‡ , proteinuria
Ethchlorvynol
Diphenylamine
Spot, SC
OD (<3 d)
Phencyclidine-methadone-tricyclics
Tetrabromophenophthalein ethyl ester
Spot
OD
Other opiates, antihistamines, antipsychotics ‡
Chloral hydrate (trichloroethanol)
Fujiwara
Spot
OD (<2 d)
Chlorinated hydrocarbons ‡
Opiates (morphine, codeine)
EMIT, FPIA, KIMS, CEDIA, RIA, CMI
IA
RD (<3 d), OD
Other opiates (hydrocodone, hydromorphone, oxycodone, dihydrocodeine), morphine from poppy seeds,
adulterants § , rifampin, ofloxacin
Barbiturates
IA
RD (<4 d), OD
Other less used barbiturates, NSAIDs # ¤ , adulterants §
Benzodiazepine (metabolites)
EMIT, FPIA, KIMS, CEDIA, CMI
IA
TD for some, OD (days to weeks)
Other less used benzodiazepines, NSAIDs # ¤ , less sensitive to triazolam, lorazepam, and alprazolam
(diazepam, nordiazepam, chlordiazepoxide, temazepam, midazolam, oxazepam are typically detected)
Amphetamines (amphetamine/methamphetamine)
IA
RD (<2 d), OD
Newer-generation assays react with MDA, MDMA, STP, and L -methamphetamine (in Vicks inhaler); older
assays cross-reacted with many adrenergic amines ¥ , chlorpromazine ‡
Marijuana (11-nor-9-carboxy-tetrahydrocannabinol)
IA
RD (<2 wk, <2 mo (if chronic), OD
Adulterants §
Cocaine (benzoylecgonine)
IA
RD (<2 d), OD
Few; teas made from coca leaf, adulterants §
Phencyclidine
IA
RD (<1 wk), OD
PCP analogs, chlorpromazine, diphenhydramine, dextromethorphan
Ethanol
Enzymatic
SC
RD (<1 d), OD
Microbiologic production of ethanol in poorly stored urine
CEDIA, cloned enzyme donor immunoassay; CMI, colloidal cold microparticle immunoassay; EMIT, enzyme
multiplied immunoassay technique; FPIA, fluorescent polarization immunoassay; IA, immunoassay; KIMS,
kinetic interaction of microparticle spheres; MDA, methylenedioxyamphetamine; MDMA,
methylenedioxymethamphetamine; RIA, radioimmunoassay; SC, spectrochemical; STP, 2,5-dimethoxy-4-
methylamphetamine.
*
Method sensitive to overdose dosage (OD), therapeutic dosage (TD), or recreational dosage (RD) for window of time detectable in parentheses.
†
Reagent/Method Type of Sensitivity * (Detection Interferences,
Drug/Group Name Method Interval) Nonspecificity †
*
Method sensitive to overdose dosage (OD), therapeutic dosage (TD), or recreational dosage (RD) for window of time detectable in parentheses.
†
Immunoassays vary in cross-reactivity.
‡
Requires extremely large amounts.
Amitriptyline and similar tertiary amine tricyclic antidepressants.

§
Adulterants intended to cause false negatives.
#
Not all reagents/methods cross-react to the same extent.
¤
Negative interference.
¥
Adrenergic amines such as phenylpropanolamine, ephedrine, pseudoephedrine, fenfluramine, phentermine, isometheptene, propylhexedrine.
Also ranitidine, ritodrine, labetalol, and others in the past.
Table 7-3 -- Potential Interferences in Quantitative Serum Drug and Chemistry Tests Used in
Emergency Toxicology
Acetaminophen
SC *
Salicylate, salicylamide, methyl salicylate (each will increase acetaminophen level by 10% of salicylate level
using mg/L for salicylate); bilirubin; phenols; renal failure (each 1 mg/dL increase in creatinine = 30 mg/L
acetaminophen)
HPLC *
Cephalosporins; sulfonamides
Amitriptyline
HPLC, GC
Cyclobenzaprine
Carboxyhemoglobin
SC
Fetal hemoglobin
Chloride
SC, EL
Bromide (0.8 mEq Cl = 1 mEq Br)
Creatinine
SC *
Ketoacidosis (may increase creatinine up to 2–3 mg/dL); cephalosporins; creatine (e.g., with rhabdomyolysis),
isopropanol
ENZ
Lidocaine metabolite, 5-fluorouracil
Digoxin
IA
Endogenous digoxin-like immunoreactive substances (up to 1 ng/mL) in newborns, renal failure, pregnancy, liver
failure; oleander and toad toxin ingestion (cardiac glycosides identified as digoxin); after digoxin antibody (Fab)
administration
Ethylene glycol
SC *
Other glycols; elevated triglycerides
GC
Propylene glycol
Iron
SC
Deferoxamine causes 15% lowering of total iron-binding capacity (TIBC); Lavender-top Vacutainer tube contains
EDTA, which lowers total iron
Isopropanol
GC
Skin disinfectant containing isopropyl alcohol used before venipuncture (highly variable, usually trivial, but up to
40 mg/dL)
Lithium
F, EL
Green-top Vacutainer specimen tube (contains lithium heparin) may cause marked elevation (up to 6–8 mEq/L)
SC
Quinidine, procainamide
Methemoglobin
SC
Sulfhemoglobin (cross-positive 10% by oximeter); methylene blue (2 mg/kg dose gives transient false positive as
high as 15% methemoglobin); hyperlipidemia (triglyceride, 6000 mg/dL, may give false methemoglobin up to
28.6%)
Falsely decreased level with in vitro spontaneous reduction to hemoglobin in Vacutainer tube (~10%/hr); analyze
within 1 hr
Osmolality
Osm
Lavender-top (EDTA) Vacutainer Specimen tube (15 mOsm/L); gray-top (fluoride-oxalate) tube (150 mOsm/L);
blue-top (citrate) tube (10 mOsm/L); green-top (lithium heparin) tube (theoretically, up to 6–8 mOsm/L). Falsely
normal if vapor pressure method used (alcohols are volatilized)
Salicylate
SC
Diflunisal > ketosis, salicylamide; accumulated salicylate metabolites in patients with renal failure (~10%
increase)
IA
Diflunisal
SC
Decreased or altered salicylate level with bilirubin; phenylketones
Theophylline
SC *
Diazepam; caffeine; accumulated theophylline metabolite
HPLC *
Acetazolamide; cephalosporins; endogenous xanthines; theophylline metabolites in renal failure (minor effect)
IA
Caffeine; accumulated theophylline metabolites in renal failure
EL, electrochemical; F, flame emission; GC, gas chromatography (interferences primarily with older methods);
HPLC, high-pressure liquid chromatography; IA, immunoassay; SC, spectrochemical; TLC, thin-layer
chromatography; ENZ, enzymatic; Osm, osmometer.
*
Method rarely used today.
Drug or Toxin Method Causes of Falsely Increased Blood Level
*
Method rarely used today.
Components
A toxicology screen is a combination of procedures aimed at identifying common drugs in emergency

toxicology and is often adapted to reflect regional differences in drug prevalence.[27 ] Also, screens can be
tailored to suit particular diagnostic categories (e.g., panels for coma drugs, seizure drugs, illicit drugs, or
comprehensive screens). Most laboratories do not report a drug unless it has been confirmed by two
procedures or by a single method that is known to be highly specific for a highly prevalent intoxicant (e.g.,
ethanol by GC). Initial identification of a drug by one method (e.g., codeine-morphine by IA) is only
presumptive. Subsequent confirmation (e.g., by TLC or GC-MS [gas chromatography–mass spectrometry])
would make the result reportable, and lack of confirmation would be reported as not detected. Confirmation
is not always a requirement in clinical testing; it depends on the prevalence of the drug, the specificity of the
initial test, and the implications of a positive result. For illicit drugs, confirmation should always be used,
because the consequences of recording this event in the medical chart may extend beyond the patient’s
care. Some highly prevalent drugs, such as benzodiazepines, may not require confirmation or individual
identification, as these drugs often are present in hospital populations (high prior probability) and may
contribute little to the clinical picture. Communication between the treating physician and the laboratory
reduces the likelihood of false positives or false negatives, speeds up analysis time, and helps the laboratory
better use its resources.
A comprehensive urine toxicology screen is a labor-intensive approach intended to detect as many drugs as
reasonably possible using common techniques. A comprehensive screen may include the following
methods: two spot tests (salicylate and phenothiazines); eight IAs (for codeine-morphine, benzodiazepine
metabolite, amphetamine-methamphetamine, methadone, phencyclidine, ethanol, cocaine metabolite, and
barbiturates); TLC for 30 to 60 drugs; and GC (or GC-MS) by two columns using nitrogen-phosphorus and
flame ionization detectors, which detect about 60 to 80 drugs. The drugs screened by this combination of
methods are listed in Table 7–4 . Toxins not usually detectable in such a comprehensive toxicology screen
are listed in Table 7–5 . Many of these unscreened drugs have low prevalence or low toxicity, but many
important intoxicants are not detected in comprehensive screening procedures (e.g., ethylene glycol,
isoniazid, cyanide). Drugs not detectable on the tox screen can often be requested separately for screening
or sent out for quantitation. Because the composition of tox screens varies from laboratory to laboratory, the
clinician should know which drugs or toxins are not included on the tox screens at their hospitals (see Tables
7–4 and 7–5 , for example).
Table 7-4 -- Common Drugs Included on a Comprehensive Toxicology Screen *

Alcohols: ethanol, methanol, isopropanol, acetone
Barbiturates/sedatives: amobarbital, secobarbital, pentobarbital, butalbital, butabarbital, phenobarbital,
glutethimide, ethychlorvynol, methaqualone
Antiepileptics: phenytoin, carbamazepine, primidone, phenobarbital
Benzodiazepines: chlordiazepoxide, diazepam, alprazolam, temazepam
Antihistamines: diphenhydramine, chlorpheniramine, brompheniramine, tripelennamine, trihexyphenidyl,
doxylamine, pyrilamine, methapyrilene
Antidepressants: amitriptyline, nortriptyline, doxepin, imipramine, desipramine, trazodone, amoxapine,
maprotiline, fluoxetine, paroxetine
Antipsychotics: trifluoperazine, perphenazine, prochlorperazine, chlorpromazine
Stimulants: amphetamine, methamphetamine, phenylpropanolamine, ephedrine, MDA, MDMA (other
phenylethylamines) cocaine, phencyclidine
Opioid analgesics: heroin, morphine, codeine, oxycodone, hydrocodone, hydromorphone, meperidine,
pentazocine, propoxyphene
Other analgesics: salicylates, acetaminophen
Cardiovascular drugs: lidocaine, propranolol, metoprolol, quinidine, procainamide, verapamil
Others: theophylline, caffeine, nicotine, oral hypoglycemics, strychnine
MDA, 3,4-methylenedioxyamphetamine; MDMA, 3,4-methylenedioxymethamphetamine.
*
Comprehensive screens vary considerably in content, and the physician should be familiar with the drugs tested at a particular hospital. Tailored
screens, such as “drugs of abuse screens,” usually focus on illicit drugs using 4–8 immunoassays in the initial screening process.
Table 7-5 -- Toxins Not Detectable by Emergency Toxicology Screens Classified by Area of Difficulty
Too polar: antibiotics, diuretics, isoniazid, ethylene glycol, lithium, lead, iron
Too nonpolar: steroids, tetrahydrocannabinol (THC), digoxin, polychlorinated biphenyls, organochlorine
pesticides
Too nonvolatile: plant and fungal alkaloids, some phenothiazines
Too volatile: aromatic and halogenated hydrocarbon solvents, anesthetic gases, noxious gases (hydrogen
sulfide, nitrogen dioxide, carbon monoxide)
Concentration too low (potent drugs or drugs with large volume of distribution): clonidine, fentanyl, colchicine,
ergot alkaloids, lysergic acid diethylamide (LSD), dioxin, digoxin, THC, polychlorinated biphenyls
Toxic anions (too polar): thiocyanate, cyanide, fluoride, bromide, borate, nitrite
New drugs: buspirone
Because the turnaround time for comprehensive screens is often several hours to several days, their utility
and impact are limited. A focused screen , most commonly for illicit drugs or drugs of abuse, is composed of
the four to eight IAs with confirmation procedures as needed, and results can be available in minutes. This
screen is used mostly by emergency and psychiatric services, where cases of drug overdose and abuse
constitute the largest proportion of screening requests. Such limited screens detect many of the prevalent
drugs in emergency departments, but the limitations of sensitivity and specificity must be realized (see Table
7–2 ). For example, an illicit drug panel may include an IA for benzodiazepines but not detect a potent
benzodiazepine such as triazolam. Also, many laboratories do not screen for marijuana metabolite in
emergency situations because it is present in many overdoses among the drug-using population, is rarely
considered responsible for serious toxicologic effects, is excreted in urine for a long time after use, and may
not be related to the acute clinical picture.
Rationale and Use of Toxicology Screens
In the emergency setting, specimens should be obtained as soon as a toxicologic diagnosis is considered in
a seriously ill patient. Although comprehensive screening is unlikely to affect emergency management (see
under Clinical Utility later), the results may assist the admitting physicians in evaluating the patient if the
diagnosis remains unclear.
Urine is the best specimen for finding the greatest number of drugs and produces the highest rate of positive
findings when compared with serum or gastric aspirates.[20 ] [23 ] [34 ] The earlier the urine collection, the
greater the chance of finding a drug, because many have short intervals of detection (see Table 7–2 for
detection intervals of common illicit drugs). Rarely has a drug gone undetected because the urine collection
was too soon after a single acute ingestion. Adding a blood sample to a urine specimen produces a slightly
greater overall yield of positives when extraordinary screening techniques are available. However, because
of lower concentrations in serum or blood, smaller sample size, and incompatibility with some
methodologies, serum or blood testing cannot identify as many drugs as urine screening. Gastric specimens
often contain high concentrations of the parent drugs, which can help in identification when the drug is
extensively metabolized and is not identifiable on the basis of urinary metabolites, although this is rarely
necessary. In one study, patients who had received gastric lavage for initial management showed the
following percentage of the positive results in their specimens: urine 93 per cent, serum 54 per cent (only
sedative-hypnotics screened), and gastric aspirate or lavage 38 per cent.[1 ]
Tox screens should be applied as diagnostic tests and not screening tests. These “screens” are intended to
aid the physician in considering whether a set of signs and symptoms is drug induced or has some other
cause. When ordering a tox screen, suspected drugs or drug classes, key symptoms, or the working
diagnosis should be written on the requisition. This will facilitate testing as well as communication back to
the ordering physician. For instance, if a tox screen is ordered with “clonidine” as the suspected drug
causing “pinpoint pupils,” the laboratory can call the physician and indicate that the screening methods
would be unlikely to detect clonidine but could rule out opiates. In another case, a physician may order only
a test for “amphetamine” in urine because of a “bizarrely acting” patient. Because antihistamines are
common and produce anticholinergic delirium with similarities to both functional and amphetamine
psychoses, a tox screen or limited screen may be better. Fligner and Robertson indicated that the best
method of communication is with adequate prompting and space on requisition forms, but only 48 per cent
of forms surveyed had space to list suspected drugs.[15 ]
Drug Overdose and Drugs Found
The drug categories responsible for the most deaths reported by poison control centers are analgesics
(opioid and nonopioid), antidepressants, stimulants (including amphetamines, cocaine, phencyclidine),
sedative-hypnotics, cardiovascular drugs, and alcohol.[28 ] All these classes of drugs are detectable by
comprehensive toxicology screening. Comprehensive toxicology screening is positive for 50 to 80 per cent of
the cases in which testing is requested (varies by center and composition of the screen), and the top five
drug classes account for 70 to 90 per cent of all drugs found.[20 ] [34 ] The most common second drug group
detected is benzodiazepines, regardless of the primary drug abused.[39 ] From the 1970s through the 1980s,
there was a decrease in the incidence of barbiturates and ethanol and an increase in benzodiazepines,
tricyclic antidepressants, sympathomimetic amines, and cocaine. Bailey[2 ] reported that the incidence of
cocaine-positive tox screens rose from 1 per cent in 1978 to 10 per cent in 1986. In larger centers dealing
with emergency drug testing, cocaine may be positive in a quarter or more of all submitted specimens.
In contrast to tox screens and poison control center reports, medical examiners report a slightly different
spectrum of drug involvement, including carbon monoxide (includes fire deaths), ethanol, sedative-
hypnotics, opioids, cyclic antidepresssants, and propoxyphene as the more common causes of drug-related
deaths.[9 ] [32 ] In pediatric overdose, suicide and drug abuse are less likely. Drugs are responsible for only a
minority of all exposures in children (40 per cent) but account for a large portion of intoxications, hospital
admissions, and deaths, particularly in the teenage group.[13 ] [21 ] [28 ] [44 ] Drug exposures in patients
younger than 6 years old are usually due to single agents, whereas 27 to 66 per cent of adults ingested
multiple drugs.[34 ]
Analytic Accuracy of Toxicology Screens
Clinicians should realize that not all drugs are detectable with the technologies used in toxicologic testing.
For the average laboratory today, false negatives occur at a rate of 10 to 30 per cent (when considering all
drugs) and false positives at a rate of 0 to 10 per cent. The most common reason for an analytic false
negative is that the laboratory has not validated or quality controlled its detection limits. The most common
reason for a clinical false negative is ordering a screen in which the suspected drug is not included. Many
false positives and some false negatives are due to misidentification within a class (e.g., pentobarbital for
amobarbital), so the impact on the clinical diagnosis would be small.
Hospital laboratories can be assessed by participation in proficiency testing programs from the American
Association of Clinical Chemists and College of American Pathologists. A random sample of proficiency test
results for a single quarter demonstrated that, in a set of four specimens, false negatives for a rare drug
such as carisoprodol were as high as 60 per cent, versus about 10 per cent for a common drug such as
codeine.[10 ] False positives are low partly because of high concentrations and confirmatory techniques. A
more difficult challenge was presented to 26 specialty toxicology laboratories in the West.[7 ] A case history
was presented along with a urine sample containing four drugs. Only two laboratories were able to identify
all four drugs present. Sixty-five per cent identified dihydrocodeine, 54 per cent identified MDEA (3,4-
methylenedioxymethamphetamine), 23 per cent identified naloxone, and 23 per cent identified
aminoflunitrazepam (metabolite of Rohypnol).
False negative identification may also be due to interferences from adulterants. These are more likely in
surveillance programs (probational, employee, methadone) and are unusual in emergency toxicologic
screening. Common adulterations include dilution (by ingestion or direct addition of water), substitution (with
purchased urine or the urine of a second person or animal), ingestion of weak acids and bases (vinegar,
bicarbonate) to influence the excretion of acidic or basic drugs, the use of interfering substances to alter test
results (e.g., benzalkonium chloride), and the addition of strong chemicals to impair biologically based IAs
(soap, bleach, glutaraldehyde).[17 ] [30 ] [40 ] [46 ] The aim of adulterant use is to interfere with the initial test by
IA. Because there is a wide variety of IA methodologies, not every adulterant will have the same effect in
each assay.
Accuracy of the Clinical Diagnosis
Rygnestad and Berg[37 ] showed that in 265 self-poisoned overdoses, the correct drug or class of drug could
be identified in 85 per cent of the cases using patient history, physical examination, and basic laboratory
tests, including acetaminophen, salicylate, barbiturates, and lithium. Diagnosis was incorrect or unknown in
14 per cent when compared with extensive follow-up and other toxicologic testing. Toxicologic screening
was needed to identify drugs in only 5 per cent of cases and was most useful in identifying ethanol and
benzodiazepines. Nice and colleagues[31 ] assessed the use of “toxidromes” for the identification of drug-
intoxicated patients and showed that nurses, physicians, and clinical pharmacists could identify the drug or
class causing intoxication in over 80 per cent of cases. In contrast, Bury and Mashford[6 ] indicated that
information on drug intake was unreliable or unavailable in 75 per cent of 167 drug overdose cases,
confirming earlier suspicions of Teitelbaum and associates.[43 ] Complete concordance of clinical predictions
with toxicology results (all drugs named vs. all drugs found) is estimated at only 20 to 32 per cent, because
additional drugs are often found by screening (20 to 48 per cent of the time). The clinically predicted drug is
not found in 9 to 25 per cent of cases.[34 ]
Clinical Reliability of Toxicology Screens
Overall clinical reliability depends on analytic sensitivity and specificity, whether the laboratory will test for
the drugs that are expected in the screen, and the prevalence of drug-positive cases and intoxications in the
clinical setting. The prevalence of drug-positive screens in past surveys of overdoses is about 50 to 80 per
cent,[34 ] but it varies by situation and by region.
If the prior probability of drugs being present in a patient is 50 per cent and the tox screen has an average
sensitivity of 70 to 90 per cent (based on proficiency testing data given earlier), the predictive value of a
negative test is 63 to 83 per cent. With a specificity of 90 to 100 per cent, the predictive value of a positive
test is 83 to 100 per cent. Thus the “rule-in” value of the tox screen is better than the “rule-out” ( Fig. 7–1 ).
Kellermann and colleagues[24 ] indicated that most physicians tend to use tox screens to rule out drug
toxicity as a diagnosis and are less likely to use tox screens for rule-in purposes. This is disconcerting if tox
screens have a higher positive than negative predictive value in high-prevalence settings. In contrast, when
diagnostic choices are few and the working diagnosis is less likely to be drug intoxication, rule-out testing
makes some sense (see Fig. 7–1 ). For example, if a patient was strongly believed to have a non–drug-
induced coma, the prior probability of detectable drugs might be considered very low (e.g., 5 per cent). With
this prior probability and the same specificity and sensitivity of the tox screen, the predictive value of a
negative test is 76 to 90 per cent, and the predictive value of a positive test is 33 per cent; hence there is a
better rule-out value.
Figure 7-1 Posterior probability of finding any common drug in the toxicology screen at various prevalences (prior probabilities) given a
screen that is 70 per cent sensitive (on average to any of the drugs detectable) and a specificity of 95 per cent. PV+ is posterior probability
of a positive test and PV- is posterior probability of a negative test.
Clinical Utility of Toxicology Screens
Tox screens are reliable for limited clinical use, but do the results make a diagnosis or change a plan of
management? Tox screens may be suspected of having little usefulness because (1) diagnostic and
management decisions are made before results are returned; (2) benign and diagnostic intervention may
preclude the need for these tests (e.g., response to naloxone for opioids); (3) there are only a few specific
interventions or antidotes in toxicologic management that could possibly hinge on toxicologic test outcomes[5
] ; (4) the incidence of morbidity is less than 1 per cent[21 ] [28 ] ; and (5) toxicity is often apparent on
presentation. Clinical features not only identify a toxic syndrome but also are prognostic for outcome. In 209
overdose patients, Brett demonstrated that they could be categorized as low or high risk with respect to
developing complications or requiring intensive care interventions based on initial clinical, blood gas, or
electrocardiogram findings.[4 ]
Although comprehensive screens can detect most of the drugs causing toxicologic deaths as well as many
drugs unsuspected by the physician, their impact is limited. Most studies in Table 7–6 indicate that the
impact of screening on clinical diagnosis and management is low (<15 per cent). In prospective evaluations
of diagnostic certainty before and after the return of toxicologic screen results, Kellermann and colleagues[24
] showed that the use of toxicologic screening increased diagnostic certainty by 16.5 per cent (the prior
probability of drug toxicity was 75.5 per cent and increased to an after-test probability of 92.0 per cent), and
that these changes in diagnostic certainty occurred in 66 per cent of the 183 cases evaluated. Such
estimates of utility validate the impression of most toxicologists. However, many of the studies in Table 7–6
focused only on positive tox screen results. The impact of a negative test is difficult to assess. No
intervention as a result of a negative test can also be considered contributory to the diagnostic and treatment
process. For example, when considering the differential diagnosis of drug-induced or functional psychosis,
the negative toxicology screen is considered by some as a predictor of the need for greater psychiatric
care.[38 ] However, thorough study of this hypothesis is needed.
Table 7-6 -- Impact of Toxicology Screening on Clinical Diagnosis and Management

Wiltbank (1974)[45 ]
148
<7
R, chart review
ED
Helliwell (1979)[19 ]
108
15
P, verbal, chart
ED coma
Bury (1981)[6 ]
167
66
R, chart review
OD *
Mahoney (1987)[29 ]
176
8
R,?
OD
Kellermann (1987)[24 ]
183
4.4 (66.3) †
P, questionnaire before/after
ED-OD
Brett (1988)[4 ]
198
1.5
R, records review
Intentional OD
ED, emergency department patients suspected of drug toxicity; OD, overdosed patients; P, prospective; R,
retrospective.
Reference No. of Patients % of Cases in Which Diagnosis or Study Type of
(Year) Studied Management Altered Due to Tox Screen Methods Patient
*
Self-poisoning excluded.
†
4.4% altered management; 66.3% had slightly improved diagnostic certainty.
Copyright © 2007 Elsevier Inc . All rights reserved. - www.mdconsult.com


SERUM QUANTITATION OF OVERDOSED DRUGS
For serum concentrations of a drug to be useful, there must be a relationship between the drug
concentration and the toxic effects or therapeutic decision points. The underlying clinical condition of the
patient may alter the concentration-effect relationship or its interpretation. Serum concentrations have
proved useful in only a limited number of emergency situations.
Rationale and Uses
Quantitative drug levels in overdose can monitor the course of the patient, predict whether toxicity is
occurring but not yet clinically apparent, or predict that toxicity will occur in the future. In the emergency
setting, there are relatively few quantitative measurements that meet these goals. These measurements
include quantitation for acetaminophen, salicylates, theophylline, methanol, ethanol, ethylene glycol, iron,
carboxyhemoglobin, and lithium. Quantitation is also useful when hazardous therapy is being considered or
in evaluating the efficacy of such therapy.
Two criteria need to be satisfied for blood levels to be useful. First, there should be an absence of reliable
clinical indicators that reveal the status or condition of the patient. If a toxin is suspected and toxicity is
apparent (clinical effects), a drug level will yield little additional information, except for the drugs listed
earlier. For most drug intoxications, the clinical indicators of toxicity are better indicators than are drug
concentrations. For example, the clinical manifestations of a cyclic antidepresssant overdose indicate the
course and severity of the ingestion better than drug concentrations.[3][8]
The second criterion for the use of drug concentrations is the existence of a concentration-effect
relationship. In therapeutic drug monitoring, these relationships are well described for the endpoints of
efficacy or toxicity, but these cannot be extrapolated to the overdose setting. For instance, carbamazepine is
an anticonvulsant at therapeutic concentrations of 5–10 mg/L but may cause seizures in overdose (see
under Altered Pharmacokinetic and Pharmacodynamic Relationships in Overdosage).
Prescott[35] considered the most important role for the toxicology laboratory to be the quantitation of drug
concentrations to determine the need for dangerous or expensive treatment. These drugs may require
hemoperfusion (e.g., theophylline, phenobarbital) or hemodialysis (e.g., salicylate, methanol, lithium) to
avoid life-threatening concentrations, to shorten coma, and to evaluate the efficacy of extracorporeal
elimination. Drug concentrations are required for similar reasons when deciding to treat a digoxin overdose
with Fab fragments (Digibind) and for the appropriate use of chelators in metal poisoning. Table 7–7
presents commonly used criteria for evaluating when to use these hazardous interventions.
Table 7-7 -- Examples of the Utility of Drug Concentrations in the Use and Evaluation of Hazardous
Therapies
Concentration Rationale for
Drug/Toxin Clinical Presentation * Criteria Therapy † Intervention
Acetaminophen History or none >150 µg/mL @ 4 NAC Prevent hepatotoxicity
hr
Hypotension, seizures, >90–100 µg/mL Avoid seizures,
Theophylline HP/HD
dysrhythmias (acute OD only) dysrhythmias, fatality
Altered mental status, >1.5 mEq/L ‡ Reduce CNS effects,
Lithium HD §
rigidity, renal insufficiency (chronic OD) avoid seizures
AG metabolic acidosis ±
Methanol >50 mg/dL HD Avoid blindness, fatality
osmol gap, visual changes
AG metabolic acidosis ± Avoid renal failure,
Ethylene glycol >50 mg/dL HD
osmol gap fatality
AG metabolic acidosis,
>100 mg/dL (acute
Salicylates confusion, pulmonary or HD Avoid fatality
OD only)
cerebral edema, seizures
AV block, hyperkalemia,
>4 ng/mL § (acute Avoid cardiovascular
Digoxin symptomatic bradycardia or Fab
OD) failure, fatality
ventricular ectopy
Avoid cardiovascular
Iron History, nausea, vomiting >350–500 µg/dL Deferoxamine collapse, acidosis,
hepatic failure
Stupor, coma, acidosis,
Carboxyhemoglobin >15% Oxygen, HBO Avoid CNS injury
ischemic chest pain
AG, anion gap; AV, atrioventricular; CNS, central nervous system; HBO, hyperbaric oxygen; HD, hemodialysis;
HP, hemoperfusion; NAC, N-acetylcysteine, OD, overdose.
* Important signs or symptoms that suggest the need for the listed therapy. All diagnostic symptoms are not listed.
† Only concentration-related therapies listed; other therapies may be instituted at earlier stages. In some cases, the clinical condition may
indicate the need for the listed therapy at lower than listed concentrations.
‡ Upper limit of therapeutic range, varies by locale.
§ Therapeutic decision weighted more heavily on clinical signs and symptoms than on drug levels.
Consider contribution of digoxin metabolites with renal insufficiency and digoxin-like immunoreactive substances to the measured digoxin
concentration.
Availability and Reliability
Measurements should be available on an immediate, 24-hour basis and should be precise (not
semiquantitative) in order to discern real change in the concentration within a given patient. With the
increasing use of quantitative IAs on rapid chemistry analyzers, most large hospital laboratories have assays
available for therapeutic drug monitoring (TDM). However, of all hospitals capable of routine chemistry tests,
only 63 per cent performed iron tests, 38 per cent lithium, 79 per cent theophylline, 51 per cent salicylate,
and 51 per cent acetaminophen.[10]
Although serum quantitations require adequate precision to recognize change from time point to time point,
they should also be accurate so that management decisions can be made correctly. The accuracy and
interlaboratory variability of quantitative concentrations may be assessed from proficiency testing
programs.[10] In general, accuracy (defined as nearness to target concentrations) and agreement between
laboratories are most apparent for drugs measured commonly and by uniform techniques, such as
antiepileptic drugs. For drugs that are measured infrequently and by more diverse methods, the results are
more diverse. Today, most TDM-type drugs demonstrate interlaboratory variation of less than 8 per cent and
biases of less than 15 per cent.[10]
Altered Pharmacokinetic and Pharmacodynamic Relationships in Overdosage
Serum drug quantitations must be evaluated with respect to each patient’s clinical condition. The variation in
pharmacology from person to person, the interactions of diseases and medications, the altered
pharmacodynamics and pharmacokinetics with overdose, and potential interferences in assays (see Table
7–3 ) may change how a drug concentration is interpreted.[36] For example, salicylate overdose is more toxic
than linear extrapolation of therapeutic concentrations would predict. This is due to increased free (unbound)
concentrations at increasing serum concentrations, increased central nervous system (CNS) penetration at
acidic blood pH, and slower (saturated) metabolism at higher concentrations. Also important in interpreting
concentration–toxic effect relationships are the conditions under which these relationships were established.
Therapeutic concentrations and concentrations associated with lithium toxicity are based on chronic dose
regimens in which there is equilibrium between serum and CNS concentrations. Early in an acute lithium
overdose (without chronic use), serum levels appear high but do not yet reflect CNS concentrations, and the
patient can be asymptomatic. Many other drugs have different clinical presentations in acute versus chronic
overdose (e.g., salicylate, theophylline, digoxin).
Interpretation of drug levels may be altered by multiple factors simultaneously. For instance, a patient with
renal failure on digoxin may have no digoxin-related symptoms with a level of 4 ng/mL while taking normal
doses. Falsely measured digoxin-like immunoreactive substances in renal failure may raise the patient’s
measured “digoxin” level by 1 ng/mL, and cross-reaction of accumulated metabolites due to poor renal
clearance may falsely raise the measured level an additional 2 ng/mL. In contrast, another patient with a
level of 2 ng/mL may exhibit digoxin-related toxicity due to exacerbation from hypokalemia. Therefore, each
drug concentration must be interpreted relative to the condition of the patient and less by the use of rigid
therapeutic windows.


TESTING FOR OTHER TOXINS
Toxins from plants, animals, microorganisms, and chemical sources are numerous, but exposure to them is
relatively infrequent compared to drug ingestions. Although there are many potent and deadly toxins in those
categories, most exposures tend to be insufficient in quantity, short-lived, or benign in toxicity. Therefore,
few tests have been developed or studied or have any commercial potential. Certain plant toxins such as
nicotine, strychnine, and atropine can be recognized on comprehensive toxicology screens. Specific tests for
digoxin (and oleander), cyanide (from cyanogenic glycoside-containing plants, fires, or chemical ingestion),
and carbon monoxide (as carboxyhemoglobin) can be ordered from larger hospitals laboratories. Many
specific plant and fungal toxins cannot be measured, and the clinician must use the history and physical
examination as a guide. However, most regional poison centers have contacts with a wide variety of
agencies that may help in identifying specimens from plants, mushrooms, or chemicals used in agriculture.
In hazardous chemical exposure (e.g., metals, hydrocarbons), guidelines for interpreting concentrations are
usually based on timed or chronic exposures. These guidelines and cutoffs are often used to discern
excessive but not necessarily toxic exposure rather than amounts associated with ill effects. Guidelines and
laboratory methods are available for a narrow variety of commonly encountered chemicals (e.g., lead,
mercury, cadmium, arsenic, trichloroethylene, benzene, toluene, hexane, polychlorinated biphenyls).[25][42]
SUMMARY
Emergency physicians using toxicologic testing should learn the capabilities of their laboratories: What is
detectable? What is not? What is the expected turnaround time? Do pharmacologic relationships exist? The
laboratory should allow the physician to order limited test combinations, and the physician can assist the
laboratory in the search for unknowns by indicating the possible diagnosis and suspected drugs. Only a few
drugs require quantitation in serum in order to assist in therapeutic decisions ( Table 7–8 ). Comprehensive
urine drug screening is useful in documenting intoxications due to drugs and in demonstrating other drugs
not clinically expected. The impact of comprehensive drug screening on diagnosis and therapy in
emergency patients appears to be low. However, focused screens based on IAs that can be turned around
quickly are widely used. Generally, drug screening in the emergency setting has a better positive predictive
value (rule in) than negative predictive value. Drug testing on patients in hospital settings may prove to have
other benefits affecting patient disposition.
Table 7-8 -- Situations in Which Toxicology Testing Is Useful

Overdoses and toxic conditions requiring serum drug concentration to diagnose severity, monitor course,
assess need or effectiveness of therapy
Acetaminophen
Salicylates
Theophylline
Lithium
Digoxin
Ethanol
Carboxyhemoglobin
Methemoglobin
Iron
Methanol
Ethylene glycol
Lead, mercury, arsenic
Organophosphates (cholinesterases)
Anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine, valproate)
Situations in which qualitative toxicology tests or screens have utility
When the differential diagnosis is sufficiently narrowed to a drug cause vs. a disease cause (e.g.,
psychosis—functional vs. amphetamines)
Documentation that the working diagnosis was correct (post facto)
After admission if the diagnosis is still unclear
Future directions include new IAs that can be used directly within the emergency department. Also, with
improvements in technology, screening of serum drugs will become more common, including the discovery
of more quantitative relationships between serum concentration and toxic effects.


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12. Ellenhorn MJ, Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, New
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15. Fligner CL, Robertson WO: Request and report forms in toxicology screening [abstract]. Vet Hum
Toxicol 1985; 28:306.
17. Goldberger BA, Kaplan YH: Effect of glutaraldehyde (UrinAid) on detection of abused drugs in urine by
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18. Griner PF, Glaser RJ: Misuse of laboratory tests and diagnostic procedures. N Engl J
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19. Helliwell M, Hampel G, Sinclair E: Value of emergency toxicological investigations in differential

diagnosis of coma. BMJ 1979; 2:819.
20. Hepler BR, Sutheimer CA, Sunshine I: The role of the toxicology laboratory in emergency medicine. II.
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21. Jacobsen D, Fredericksen PS, Knutsen KM, et al: A prospective study of 1212 cases of acute poisoning:
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23. Kellerman AL, Fihn SD, Logerfro JP, et al: Utilization and yield of drug screening in the emergency
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24. Kellermann AL, Fihn SD, Logerfro JP, et al: Impact of drug screening in suspected overdose. Ann
Emerg Med 1987; 16:1206.
25. Kneip TJ, Crable JV: Methods for Biologic Monitoring: A Manual for Assessing Human Exposure to
Hazardous Substances, Washington, DC, American Public Health Association, 1988.
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27. Lasky FD, Wesley JF, Marx AJ: Changes in the pattern of drugs detected in a toxicology screen in an
upstate New York hospital. Pathol Annu 1985; 20:161.
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31. Nice A, Leikin JB, Maturen A, et al: Toxidrome recognition to improve efficiency of emergency urine
drug screens. Ann Emerg Med 1988; 17:676.
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34. Osterloh JD: Utility and reliability of emergency toxicologic testing. Emerg Med Clin North
Am 1990; 8:693.
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37. Rygnestad T, Berg KJ: Evaluation of benefits of drug analysis in the routine clinical management of
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in clinical toxicology. Clin Tox 1977; 10:417.
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Dupont aca methods. Clin Chem 1986; 32:230.
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AACC study. Clin Chem 1989; 35:891.
Jacobsen D, Halvorsen K, Marstrander J, et al: Acute poisonings of children in Oslo. Acta Paediatr
Scand 1983; 72:553.


Chapter 8 – Radiology
SANDRA A. CRAIG
Poisoned patients present to the clinician in a number of ways. Some are known to be victims of a toxin at
the outset, and for these patients diagnostic radiology can be a valuable tool in documenting the presence of
the toxin or assessing its impact on the patient. Other patients present with symptoms not recognized as
being related to a poison, and the physician must always consider the possibility that a clinical or radiologic
finding might be related to an unrecognized toxin.
THE ABDOMEN
Direct Visualization of Toxins
Solid Medications
Much has been written about the use of plain abdominal radiography in the assessment of patients
suspected of ingesting solid medications ( Table 8–1 ). Early studies by Handy [25] and O’Brien and
associates[44] evaluated the radiopacity of common solid medications using a 20-cm water bath to simulate
the radiodensity of the human abdomen. A variety of medications were found to be visible using this
technique, leading to the often-quoted mnemonic “CHIPES” for solid medications likely to be visible on
abdominal films. This mnemonic, first coined by Handy and later revised by others, stands for Chloral
hydrate, calcium carbonate, Heavy metals, Iron, iodides, Psychotropics, potassium preparations, and
Enteric-coated and Slow-release formulations.[53]
Table 8-1 -- Toxins Known to Cause Abnormalities on Abdominal Imaging Studies

Kidney-Ureter-Bladder Views
Direct Visualization of Toxin
Solids
Iron tablets (except chewable vitamins with iron)
Contraband drug packets
Lead-containing products
Zinc sulfate tablets
Thallium-tainted foods
Elemental mercury
Arsenic
Button batteries
Paradichlorobenzene deodorizers/moth repellents
Liquids
Carbon tetrachloride
Methylchloroform
Methylene iodide
Kerosene
Indirect Clues
Colonic Ileus
Amphetamine
Heroin
Methadone
Morphine
Antiparkinsonian drugs
Anticholinesterase insecticides
Diltiazem
Clonidine
Multiple-dose activated charcoal
Phenothiazines
Verapamil
Small Bowel Obstruction
Activated charcoal
Aluminum hydroxide antacids
Pneumoperitoneum
Cocaine
Pneumatosis Intestinalis
Intravenous drug use
Nifedipine overdose
Phenobarbital overdose
Abdominal Computed Tomography
Aluminum hydroxide antacid bezoar
Brodifacoum rodenticide-induced hemoperitoneum
Upper Gastrointestinal Series
Enteric-coated aspirin concretions
Use of the CHIPES mnemonic in clinical practice is limited by several factors. One is the failure of the water
bath model to accurately simulate the heterogeneous radiodensity of the human abdomen. Savitt and
coworkers[52] demonstrated that, of 312 medications tested, the only ones consistently radiopaque when
placed inside a human cadaver were chloral hydrate, calcium carbonate, iron preparations, iodinated
compounds, acetazolamide, busulfan, and potassium preparations. Second, neither a water bath nor a
human cadaver model accounts for the time-dependent process of dissolution of these solid medications in
gastric secretions.
Dissolution data collected by Handy in 1971 suggest that medications that are radiopaque in the human
cadaver and likely to remain undissolved at least 90 minutes after ingestion include iron preparations,
potassium iodide, and potassium chloride. In actual clinical practice abdominal films have been reported
helpful only in the case of iron ingestion, both for documenting the presence of medication in the
gastrointestinal tract and tracking its elimination during decontamination procedures.[43]
In summary, the literature supports the following conclusions with respect to the use of plain abdominal
radiography in patients with known or suspected ingestion of solid medications:
1. The majority of solid medications are not radiopaque on abdominal films, and nonvisualization of a
medication should never be the sole criterion used to eliminate the possibility of a toxic ingestion.
2. Specific medications will not be identifiable based on their radiographic appearance; hence, routine
abdominal radiography is of little benefit in the patient who has ingested an unknown medication.
3. Of the medications included in the mnemonic CHIPES, those that have been visualized on radiographs
of the human cadaver and have a measured dissolution time of at least 90 minutes in gastric secretions
are limited to iron preparations, potassium chloride, and potassium iodide.
4. The abdominal radiograph has been reported clinically useful only in ingestions of iron tablet
preparations and not in the subgroup of chewable multivitamins with iron.[21] Serial radiographic
examinations can be useful to document successful gastrointestinal decontamination in a patient with
significant iron tablet ingestion whose initial abdominal radiograph demonstrates presence of iron pills
in the gastrointestinal tract ( Fig. 8–1 ).
Figure 8-1 Iron tablets (arrow) visualized on abdominal radiograph.
Liquid Toxins
Visualization of ingested liquid poisons on plain abdominal radiographs is rarer still but has been
documented in several cases of chlorinated hydrocarbon ingestion. Chlorinated hydrocarbons are
immiscible in water and have a radiopacity that is proportional to the number of chlorine atoms in the
molecule, so that their presence in the upright stomach can create a triple layer sign in which the ingested
hydrocarbon is seen as a layer of increased radiopacity below gastric gas and above gastric secretions.
Halogenated hydrocarbons that have been visualized on upright abdominal films include carbon
tetrachloride (CCl4), methylchloroform (CH 3CHCl3), and methylene iodide (CH2I2). [4][18][59]
A similar gastric layering phenomenon has also been noted in cases of kerosene ingestion.[17] Kerosene is
less dense and less radiopaque than are gastric secretions and, therefore, will form a layer of intermediate
radiodensity overlying the gastric contents on upright films. Some authorities suggest that the patient be
given a glass of water to drink before obtaining the film to ensure the presence of water density within the
stomach.[2] An unusually sharp demarcation between gastric fluid and gaseous layers has also been noted
in these cases.
Body Packers and Body Stuffers
Plain abdominal radiography can help in the evaluation of patients who ingest illegal drugs. These patients
can be divided into two groups with distinctive characteristics in terms of radiographic evaluation and clinical
outcome: body packers and body stuffers. Drug smugglers, known as “body packers,” ingest drug-filled
packets to avoid detection of drug contraband by customs officials. Typically, they administer a laxative on
arrival at their destination so that these packets can be expelled from the gastrointestinal tract and retrieved
for trafficking. These drug packets are carefully assembled and typically composed of two to seven layers of
latex, each tied at one end.[13] These packets are swallowed in groups of 50 to 200 at a time, and a co-
ingested constipating agent facilitates packet retention in the gastrointestinal tract during smuggling.[30] Body
packers typically present to the emergency department after being apprehended at an airport. Although they
may initially deny ingestion of drug contraband, they know precisely the number of packets ingested.[13]
Plain abdominal radiography is positive in 75 to 90 per cent of these patients, typically showing numerous
smooth, oval foreign bodies, often with a rosette-type pattern at one end representing the tied free end of the
outermost layer of latex ( Fig. 8–2 ).[6][15][38] These densities are most easily seen in the stomach and
ascending colon, where gas provides a radiovisible interface with the homogeneous drug packet.[54]
Figure 8-2 Abdominal radiograph, body packer.
“Body stuffers,” on the other hand, ingest drug contraband in an urgent attempt to eliminate evidence when
they are confronted with the possibility of capture. These patients typically present in custody of police who
witnessed these ingestions during drug arrests, or they are brought from jail having been found
unresponsive shortly after incarceration. The hastily ingested drugs are typically unwrapped or contained
within a sandwich bag or single layer of aluminum foil or latex. Polypharmacy ingestion is common, and the
quantity of ingested contraband is smaller than that of the body packer.[50] Anecdotal experience suggests
these hastily assembled drug packets are less likely to be seen on plain abdominal radiograph than are the
professionally wrapped packages of the body packer.[50] Case reports imply that use of oral contrast or
abdominal computed tomography (CT) may be helpful in documenting the presence of gastrointestinal tract
contraband in this group, but formal studies are lacking.[46]
Other Ingestants
Plain abdominal radiography has been useful in documenting acute ingestions of lead-containing products (
Fig. 8–3 ), zinc sulfate tablets, thallium-tainted candies and foods, elemental mercury, arsenic, and button
batteries.[10][35][49] In addition, abdominal films can be useful in patients who ingest household deodorizers
and moth repellents of uncertain composition. These products typically contain either paradichlorobenzene
or naphthalene mixed with essential oils and fragrances and compressed into a solid ball. Differentiating the
two can be important because naphthalene causes significantly more toxicity than does
paradichlorobenzene. Paradichlorobenzene is radiopaque in anecdotal human reports and in one in vitro
study.[60] In contrast, naphthalene was radiolucent in this same study[60] ( Fig. 8–4 ).
Figure 8-3 Abdominal radiograph, lead in intestines.

Figure 8-4 Abdominal radiograph, radiopaque mothball.
Clinical Clues
Aside from direct visualization of ingested toxins, abnormalities on abdominal films can provide clues to the
presence of a specific class of toxin. Intestinal pseudo-obstruction, also known as colonic ileus, has been
documented after morphine overdose, chronic methadone use, heroin addiction; the ingestion of
amphetamines, phenothiazines, cyclic antidepressants, antiparkinsonian drugs, diltiazem, verapamil,
clonidine, and multiple dose-activated charcoal; and exposure to anticholinesterase insecticides.[5][45] Plain
films show gaseous distention of the small bowel and colon, with or without large amounts of retained fecal
material. Mechanical obstruction of the small bowel, with typical findings of dilated loops of small intestine
with air fluid levels on flat and upright abdominal films, has been associated with concretions of activated
charcoal and aluminum hydroxide antacids.[23] Intestinal perforation with free intra-abdominal air is a well-
documented consequence of cocaine use ( Fig. 8–5 ).[34] Pneumatosis intestinalis and gas in the portal
system have developed in association with necrotizing enteritis due to intravenous drug use with nonsterile
needles and after overdoses of phenobarbital and nifedipine.[5] Finally, metallic densities found in the gluteal
soft tissues of an elderly patient may indicate a course of antisyphilis therapy in the distant past, typically
with bismuth or arsenicals.[24]
Figure 8-5 Pneumoperitoneum secondary to cocaine use.
Special Studies
Ultrasound can detect solid medications within the stomach,[1] but clinical usefulness will likely be limited by
the dissolution phenomenon. Only enteric-coated and sustained-release preparations are formulated to
remain intact in the human stomach for as long as 2 hours. Further studies are needed to determine whether
ultrasound can alter the clinical management of patients who ingest solid medications. Upper
gastrointestinal series using barium contrast have been used to visualize concretions of enteric-coated
aspirin in the stomach,[55] and in one case an antacid concretion was diagnosed by CT of the abdomen.[57]
Medication concretions have also been reported after ingestion of verapamil and of theophylline and after
heavy use of aluminum hydroxide gel antacids. Abdominal CT documented the presence of
hemoperitoneum in a case of brodifacoum rodenticide poisoning. [42]


THE CHEST
Chest radiography, first used widely in the 1920s to detect pulmonary tuberculosis, now plays a major role in
the diagnosis and treatment of a wide variety of cardiovascular and pulmonary conditions. Toxins can be
responsible for radiographic findings of pulmonary edema or infiltrates, cardiomegaly, obstructive airway
disease, pleural effusion or thickening, pneumothorax, pneumomediastinum, and aortic dissection.
Noncardiogenic Pulmonary Edema
Noncardiogenic pulmonary edema (NCPE) is defined in radiologic terms as pulmonary edema in the
absence of cardiomegaly or signs of pulmonary venous distention. Mild cases may demonstrate only
interstitial edema, with interstitial markings persisting into the peripheral lung fields, Kerley A and B lines,
and fluid in the interlobar fissures. More severe cases will manifest diffuse ill-defined alveolar infiltrates in
which edema fluid leaves the interstitium and collects in the alveoli. These infiltrates are typically most
visible centrally and fade out peripherally, producing a “butterfly” or “bat wing” pattern on the chest film.
Alveolar edema may be impossible to distinguish from diffuse inflammatory alveolar infiltrates based on
radiography alone. Rapid onset over several hours is more typical of noncardiogenic pulmonary edema,
whereas gradual progression over one to several days suggests inflammatory alveolar infiltrates.
A considerable number of toxins have been reported to cause noncardiogenic pulmonary edema. The most
common offenders are salicylates and opioids. In one series, NCPE was noted in up to 35 per cent of
patients older than the age of 30 who overdosed on salicylate ( Fig. 8–6 ).[58] Opioids associated with NCPE
include heroin, propoxyphene, and methadone. Edema may occur up to 24 hours after overdose, and after
reversal of opioid toxicity with naloxone. Cholinergic excess due to organophosphate insecticides may give
rise to patchy areas of pulmonary edema, typically associated with clinical signs of excessive salivation,
lacrimation, urination, defecation, and emesis. Other drugs reported to cause NCPE include ethchlorvynol,
ritodrine, isoxsuprine, salbutamol, terbutaline, hydrochlorothiazide, protamine, recombinant interleukin 2,
cyclosporine, cyclic antidepressants, amiodarone, Vinca alkaloids, mitomycin, bleomycin, iodinated contrast
agents, and cytarabine. [47]
Figure 8-6 Chest radiograph, noncardiogenic pulmonary edema secondary to salicylate use.
Alveolar Infiltrates
Alveolar infiltrates are most commonly caused by infectious agents but can also result from exposure to a
variety of toxins. This exposure can occur through inhalation of toxins, by aspiration during ingestion of liquid
toxins, or indirectly as part of a systemic reaction to the offending agent. In contrast to the homogenous
“butterfly” distribution of opacities seen with noncardiogenic pulmonary edema, the radiographic distribution
of infiltrates is patchy and often asymmetric.
Several inhaled gases, vapors, or aerosols are capable of producing pulmonary infiltrates, and the ability to
do so is to a great degree dependent on their water insolubility. Inhalants that are highly water soluble tend
to dissolve in the upper airway mucosa, causing irritant symptoms and alerting the victim to escape the
environment. Thus, these agents tend to cause fewer pulmonary effects. Representative water-soluble
inhalants include ammonia, chlorine, bromine, fluorine, sulfur dioxide, and sulfuric, hydrochloric, and
hydrofluoric acids. In contrast, water-insoluble inhalants produce few to no irritant symptoms in the upper
respiratory tract. Longer exposure times engender more severe effects on the lower respiratory tract and the
development of patchy infiltrates. Examples include isocyanates, methyl bromide, nitrogen dioxide (silo
filler’s disease), and phosgene (COCl2).
Alveolar infiltrates have also developed with acute exposure to metal fumes and after subcutaneous
injection of polydimethylsiloxane (Dimethicone) fluid used in cosmetic procedures. [15] Hydrocarbons
aspirated into the tracheobronchial tree during ingestion or subsequent emesis are another well-known
cause ( Fig. 8–7 ).
Figure 8-7 Chest radiograph, patchy infiltrates due to hydrocarbon aspiration.
Hypersensitivity pneumonitis may manifest days to months after initiation of drug therapy and gives rise to ill-
defined patchy opacities or an interstitial pattern in the lung fields that may or may not be accompanied by
fever and blood eosinophilia. Radiographic findings typically resolve on discontinuation of the offending
medication. The bipyridyl herbicide paraquat found in commercial weed killers such as Gramoxone, Weedol,
and Pathclear can cause extensive pulmonary opacities after ingestion of less than one mouthful of a 20 per
cent commercial solution. These opacities are often followed by progressive pulmonary fibrosis and death. A
more complete list of the numerous agents known to cause pulmonary infiltrates is found in Table 8–2 .
Table 8-2 -- Toxins Reported to Cause Pulmonary Infiltrates on a Chest Radiograph

Inhaled Gases, Vapors, or Aerosols
Water Soluble
Ammonia
Bromine
Chlorine
Fluorine
Hydrochloric acid
Hydrofluoric acid
Sulfur dioxide
Sulfuric acid
Water Insoluble
Isocyanates
Methyl bromide
Nitrogen dioxide
Phosgene
Hydrocarbons
Chloroform
Freon 11 (fluorocarbon 11)
Gasoline
Mineral seal oil
Toluene
Trichloroethane
Trichloroethylene
Turpentine
Hypersensitivity
Nitrofurantoin
Penicillin
Sulfonamides
Tetracycline
Isoniazid
Phenytoin
Propranolol
Gold salts
Penicillamine
Tolbutamide
Chlorpropamide
Tolazamide
Carbamazepine
Methotrexate
Procarbazine
Azathioprine
Bleomycin
Cromolyn sodium
Metal Fumes
Aluminum
Antimony
Arsenic
Beryllium
Brass
Cadmium
Chromium
Cobalt
Copper
Iron
Lead
Magnesium
Manganese
Mercury
Nickel carbonyl
Selenium
Silver
Tin
Zinc
Miscellaneous
Paraquat
Polydimethylsiloxane (silicone)
Radiation therapy
Organophosphates
Amiodarone
Nonsteroidal anti-inflammatory drugs
Scorpion envenomation
Interstitial Lung Disease
Interstitial lung diseases featuring reticular, nodular, or mixed reticulonodular patterns are most often seen in
patients with sarcoidosis, collagen vascular disorders, or idiopathic pulmonary fibrosis, but approximately
one third of cases are toxin induced.[16] Over 135 agents have been associated with interstitial lung disease.
The most common offenders include inhaled inorganic dusts of silica, asbestos, and coal, which produce the
pneumoconioses. Also commonly implicated are the organic dusts of various living species, which give rise
to extrinsic allergic alveolitis. The third major group is the drug-induced form of interstitial lung disease
caused by an ever-expanding list of medications. The patient with evidence of interstitial infiltrates on chest
radiography should be questioned closely regarding occupational exposures and medication use and the
medication list examined for agents known to be associated with interstitial lung disease ( Fig. 8–8 ). A
history of intravenous drug use raises the possibility of granulomatous interstitial lung disease due to talc
particles that commonly contaminate injected heroin.
Figure 8-8 Chest radiograph, interstitial lung disease.
Obstructive Airway Disease
Radiographic signs of obstructive airway disease have been associated with toxins and can easily be
mistaken for asthma or chronic obstructive pulmonary disease due to cigarette smoking. Toxin-mediated
small airway disease, also known as bronchiolitis obliterans, may appear on chest radiograph as
hyperinflation, focal atelectasis, interstitial prominence, or even restrictive lung disease. It has developed
after exposure to nitrogen dioxide, sulfur dioxide, ammonia, chlorine, phosgene, chloropicrin,
trichloroethylene, ozone, cadmium, methyl sulfate, hydrogen sulfide, hydrogen fluoride, zinc chloride, talcum
powder, high-dose oxygen therapy, and free base cocaine ( Fig. 8–9 ).[33]
Figure 8-9 Chest radiograph, bronchiolitis obliterans.
Pleural Disease
Pleural fibrosis and plaques have primarily been associated with long-term exposure to asbestos ( Fig. 8–10
), but other substances are causative. Long-term use of methysergide, ergotamine, and bromocriptine have
also been reported to cause pleural fibrosis. [11] Pleural plaques have been noted in workers exposed to
mineral wool fibers. Pleural effusions may be seen after single or multiple dose methotrexate therapy, as a
hypersensitivity reaction to nitrofurantoin, or as part of a drug-induced lupus syndrome secondary to
hydralazine, procainamide, quinidine, isoniazid, phenytoin, or chlorpromazine.[11]
Figure 8-10 Chest radiograph, pleural plaques secondary to asbestosis.
Pneumothorax has been reported repeatedly in intravenous drug users who attempt to use neck veins for
injection. In one series from Detroit Receiving Hospital this injection technique accounted for approximately
20 per cent of pneumothoraces diagnosed during a 2-year interval.[20] This complication is especially likely
in those engaged in “pocket shooting” into the supraclavicular fossa. The chest radiograph may also
demonstrate retained needle fragments broken off during injection attempts. Pneumothorax and
pneumomediastinum have also occurred in those who perform a forceful Valsalva maneuver while smoking
marijuana or crack cocaine and after recreational sniffing of trichloroethane or nitrous oxide cartridges used
in commercial whipped cream dispensers.
Cardiovascular Abnormalities
On a chest radiograph, cardiovascular abnormalities will occasionally be related to toxic exposure.

Cardiomegaly with dilated cardiomyopathy occurs with chronic exposure to ethanol, cocaine, and emetine,
the active ingredient in ipecac. The chemotherapeutic agents daunorubicin and doxorubicin cause
cardiomegaly, congestive heart failure, and pericardial effusion up to 6 months after exposure and in a dose-
related fashion. In rare cases, carbon monoxide has caused an ischemic cardiomyopathy with cardiomegaly.
Chest radiograph has occasionally assisted in the diagnosis of acute aortic dissection in patients who
present with chest pain after a cocaine binge.[22] Findings include clear lung fields with a widened
mediastinum. The diagnosis is confirmed by transesophageal echocardiogram, helical CT scan of the chest,
or aortography ( Fig. 8–11 ).
Figure 8-11 A, Chest radiograph, aortic dissection after cocaine use. B, Chest CT scan, aortic dissection after cocaine use.


BONES AND SOFT TISSUES
Toxins that alter the radiographic characteristics of the musculoskeletal system generally do so by either
increasing or decreasing the density of bone or by causing ectopic calcific densities in the soft tissues.
Effects may be localized or diffuse and in most cases resolve on withdrawal of the offending agent, when
and if it is identified.
Lead
Perhaps the best known finding in this category is the “lead line” associated with subacute or chronic lead
toxicity. Lead and calcium are used interchangeably by bone. In adults, lead deposition is relatively
homogeneous throughout the skeleton and discrete hyperdense lead lines are not seen. In children,
however, lead deposited at centers of rapid bone growth, especially at the metaphyses of the femur and
tibia, interferes with bone remodeling during the growth process. It is this growth disturbance, and not
visualization of skeletal lead itself, that gives rise to transverse bands of increased density best seen at the
distal femur, distal radius ( Fig. 8–12 ), and the proximal tibia and fibula. Similar markings have been noted
along the margin of the iliac crest and within vertebral bodies, reflecting the regions of active growth of the
pediatric skeleton. Lead lines have been seen in a group of children whose average serum lead level was as
low as 50 µg/dL.[7] They have been noted in infants as young as 23 days after in utero contact with lead and
may be multiple in cases of repeated exposure.[48] Similar bands of increased metaphyseal bone density
may be seen in children with bismuth or metallic (yellow) phosphorus poisoning and in association with
healed rickets.[48] Normal infants younger than age 3 will sometimes have increased metaphyseal density,
which is prominent enough to be mistaken for lead lines. One study by Blickman and associates,[7] in 1986,
suggested that presence of the radiodense band in the proximal fibula is more specific for plumbism and can
be used as an adjunct to distinguish true lead lines from physiologic metaphyseal sclerosis. In all cases,
suspicion of lead toxicity should be confirmed by determination of serum lead levels.
Figure 8-12 Lead lines in the distal radius.
Retained Lead Ammunition
Unfortunately, humans frequently choose to bestow on each other another potential source of lead toxicity in
the form of a bullet. Despite the occurrence of thousands of incidents of retained missiles in the human body
over the centuries, fewer than 40 cases of lead toxicity related to retained ammunition have been clearly
documented in the literature.[19] In general, lead projectiles that come to rest in human soft tissues become
encased in fibrous tissue, which isolates the missile from the systemic vascular supply. This foreign body
reaction and the relatively small surface area of lead exposed to potential dissolution seem to protect the
victim from lead toxicity in the vast majority of cases. Dillman and colleagues[19] reviewed symptomatic lead
poisoning resulting from retained lead missiles and noted common features. Nine of 18 cases involved
retention of numerous particles of buckshot or shrapnel, with a greater surface area of exposed dissolvable
lead. In 15 of 18 cases the lead missile was retained within a joint or bone. Eight of these 15 cases involved
contact of the missile with synovial fluid, and in 6 of the 15 an associated arthritis was documented. This
information suggests that the incidence of symptomatic lead toxicity is related to surface area of the retained
fragments, presence of fragments within bone, and contact with a synovium-lined cavity ( Fig. 8–13 ). Time
from gunshot wound to onset of symptoms varied from 2 days to 40 years. Scattered case reports suggest
that plumbism may appear in a previously asymptomatic patient during periods of increased bone
metabolism such as fever, hyperthyroidism, or limb immobilization. [12] More recently, lead toxicity has been
attributed to bullets lying in contact with a pancreatic pseudocyst, the pleural space, and the cranium.[39][32]
Treatment may require surgical removal of missile fragments and synovial stripping in addition to chelation
therapy.[56]
Figure 8-13 Lead bullet arthrogram.
Skeletal Sclerosis
Increased bone density throughout the skeleton is more closely associated with Paget’s disease or
osteoblastic metastases of prostate or breast carcinoma, but a number of toxins should be included in the
differential diagnosis as well.[31] Skeletal fluorosis is characterized by roughening of the bones of the pelvis
and spine, with thickening and merging of bony trabeculae. Ultimately, diffuse sclerosis of the axial skeleton
occurs with periosteal thickening and ligamentous calcification.[9] Chronic vitamin A poisoning in children is
also associated with hyperostosis, primarily involving the ulna and metatarsals. Hypervitaminosis D causes
osteoporosis in adults but in children produces diffuse skeletal sclerosis, with periarticular soft tissue
calcifications. Periostitis involving the ribs, scapulae, humeri, femora, tibiae, and fibulae has also been noted
after long-term therapy with prostaglandins E 1 and E2. Milk alkali syndrome, resulting from prolonged intake
of large volumes of alkali and milk, is mainly associated with soft tissue calcification, but sclerosis of the
skull and long bones has been noted as well.[2]
Osteopenia
Decreased bone density is a more common radiographic finding than osteosclerosis, in large part due to the
frequent occurrence of osteoporosis in postmenopausal women. Here again, the possibility of bone
rarefaction due to toxic agents should not be overlooked. Chronic cadmium exposure, endemic in parts of
Japan and occasionally seen after prolonged occupational contact, presents as bone pain and severe
osteomalacia with pseudofractures and biconcave deformation of the vertebrae. In addition, several
medications have been associated with osteopenia ( Table 8–3 ).
Table 8-3 -- Medications Associated with Radiographic Signs of Osteopenia
Aluminum (antacids) Methotrexate
Barbiturates Phenytoin
Corticosteroids Primidone
Cyclosporine Etidronate disodium
Heparin (long term) Vitamin D (adults)
From Hart RG, Boop BS, Anderson DC: Oral anticoagulants and intracranial hemorrhage: Facts and hypotheses.
Stroke 1995; 8:1471–1477.
Finally, local rarefaction of bone may develop after long-term exposure to a variety of medications and
toxins. Avascular necrosis, typically of the femoral head, is a prime example ( Fig. 8–14 ). Agents linked to
avascular necrosis include cyclophosphamide, ethanol, glucocorticosteroids, radiation, and the combination
of bleomycin and vinblastine. Slipped capital femoral epiphyses have been reported after use of growth
hormone supplements and after pelvic radiation therapy. Polyvinyl chloride exposure produces a distinctive
pattern of transverse bandlike bone rarefaction in the phalanges known as acro-osteolysis. Silastic implants
in the joints of patients with rheumatoid arthritis can lead to cystic degeneration in adjacent carpal bones.
Local bony degeneration has also been noted after hydrofluoric acid injury.
Figure 8-14 Avascular necrosis due to long-term corticosteroid use.


CENTRAL NERVOUS SYSTEM
The development of cranial CT and magnetic resonance imaging (MRI) and their inclusion in routine clinical
practice facilitated recognition of toxin-associated central nervous system radiographic abnormalities ( Table
8–4 ). Cerebral atrophy, intracranial hemorrhage, cerebral edema, ischemia, and infarction have all been
precipitated by toxins, and recognition of a toxic cause is critical in preventing further morbidity in these
cases.
Table 8-4 -- Toxins Causing Radiographic CNS Abnormalities

Atrophy
Ethanol
Phenytoin intoxication
Phenytoin therapy
Lithium therapy
Toluene
Methyl mercury
Podophyllin
Radiation therapy
Glucocorticosteroids
Adrenocorticotropic hormone (ACTH)
Amphetamine
Cerebral Ischemia
Amphetamine
Cocaine
Ergot derivatives
High-dose oral contraceptives
Sympathomimetic nasal decongestants
Carbon monoxide
Cyanide
Methanol
Subarachnoid Hemorrhage
Amphetamine
Cocaine
Phencyclidine
Cerebral Edema
Carbon monoxide
Ethylene glycol
Pentachlorophenol insecticides
Sodium valproate
Pseudotumor Cerebri
Vitamin A
Glucocorticosteroids
Tetracycline
Oral contraceptive agents
Nalidixic acid
Levothyroxine
Lithium
Mestranol/norethisterone
Intracranial Hemorrhage
Phenylpropanolamine
Amphetamine
Cocaine
Anticoagulant drugs
Rodenticides
Scorpion envenomation
Subdural Hematoma
Anticoagulants
Cerebral Atrophy
To some degree this condition is an expected consequence of the aging process, but it can be accelerated
by some toxins. Chronic exposure to ethanol is a familiar example, initially documented with
pneumoencephalography in the 1960s and better delineated in recent years with CT and MRI. The
characteristic pattern is one of cerebellar degeneration, which may be confined to the vermis or may involve
both the vermis and the cerebellar hemispheres. Milder degrees of cerebral atrophy are typically noted as
well. These radiographic abnormalities are found in up to 40 per cent of chronic alcoholics studied and were
noted in 29 per cent of alcoholics younger than the age of 35 in one series.[28] Clinical signs of cerebellar
dysfunction are not evident in over half of those with CT findings of alcoholic cerebellar degeneration; hence,
radiographic recognition of this syndrome may allow for intervention before clinical signs manifest.[29]
Cerebellar atrophy has also been associated with acute phenytoin intoxication,[36] chronic therapy with
phenytoin or lithium, and chronic toluene exposure.[51] MRI in chronic toluene abuse typically shows mild to
marked cerebral and cerebellar atrophy and ventriculomegaly.
There is increased periventricular white matter signal intensity and loss of gray-white differentiation on T2-
weighted sequences where gray-white contrast is normally best demonstrated.[51]
Focal cerebral atrophy has also been noted on CT after chronic exposure to methyl mercury. A cluster of
cases occurred near Minamata Bay, Japan, after ingestion of fish and shellfish contaminated with methyl
mercury from a nearby chemical factory.[37] Cranial CT in these patients revealed atrophic changes of the
calcarine gyrus of the occipital lobe and the cerebellar vermis and hemispheres. These findings
corresponded to clinical symptoms of constricted visual fields, dysarthria, and ataxia. Diffuse cerebral
atrophy has also been noted on CT and MRI 1 year after podophyllin exposure in a patient with disabling
long-term neurologic sequelae, as a consequence of radiation therapy, and after exposure to
glucocorticosteroids, adrenocorticotrophic hormone (ACTH), amphetamines, and toluene.[14][51]
Cerebral Edema
Cranial CT manifestations of cerebral edema include narrowing of the sulci and diminution of the lateral and
midline ventricles. Nontoxicologic causes include anoxic insult to the brain, closed-head injury, altitude or
heat exposure, and idiopathic pseudotumor cerebri, but a number of toxins should also be considered.
Cerebral edema has been noted after acute exposure to carbon monoxide, ethylene glycol, and
pentachlorophenol insecticides, and with both acute exposure to and therapy with sodium valproate.
Patients with pseudotumor cerebri have abnormally small ventricles in 5 per cent of cases. This syndrome of
benign intracranial hypertension has been induced by a variety of agents including vitamin A,
glucocorticosteroids (use and withdrawal), tetracycline, oral contraceptives, nalidixic acid, thyroid
supplements, lithium, and mestranol/norethisterone supplements in postmenopausal women.[2]
Focal Cerebral Ischemia
This is a manifestation of atherosclerotic cardiovascular disease in a majority of cases, and for that reason
the possibility of toxic etiology is rarely entertained. In younger patients presenting with cerebral infarction, a
history of exposure to cocaine, amphetamine, ergot derivatives, high-dose oral contraceptives, or excessive
sympathomimetic nasal decongestants should be sought. Venous infarction due to thrombosis of an
intracranial venous sinus is another well-described complication of oral contraceptive agents.[8]
Distinctive patterns of focal cerebral ischemia have been observed on cranial CT and MRI in patients with
carbon monoxide and cyanide poisoning and after toxic ingestion of methanol. In one series of 60 patients
who presented comatose after carbon monoxide exposure, 23 had abnormalities on cranial CT scan.[41] In
21 of the 23 patients, symmetric and diffuse low density abnormalities were seen in the cerebral white matter
and the severity of these white matter changes correlated with prognosis. In 18 of the 23 patients, bilateral
low density changes were seen in the globus pallidus as well, although these findings did not correlate with
clinical outcome ( Fig. 8–15 ). Focal ischemia of the putamen and globus pallidi have been visualized on CT
and MRI in several cases of cyanide toxicity.[40] These lesions were sometimes absent on cranial CT scans
obtained in the initial weeks after exposure. Methanol ingestion has produced symmetric areas of low
attenuation in the putamen that correlated to areas of necrosis noted on subsequent autopsy ( Fig. 8–16 ).[3]
In anecdotal reports extension of pathologic changes into the white matter and hemorrhagic transformation
portended a bad prognosis, whereas regression of putaminal lesions on follow-up MRI correlated with
neurologic recovery and absence of extrapyramidal disturbance.[3][26]
Figure 8-15 CT scan of head, ischemia of bilateral globus pallidus due to carbon monoxide exposure.
Figure 8-16 CT scan of head, focal ischemia after methanol ingestion.
Intracerebral Hemorrhage
These are associated with nontoxic causes such as hypertension and cerebral aneurysm. However, toxic
causes should be considered, especially in younger patients. Phenylpropanolamine, scorpion evenomation,
amphetamines, cocaine, anticoagulant drugs, and rodenticides have been implicated ( Fig. 8–17 ).
Anticoagulants have also been associated with an increased incidence of subdural hematoma.[27] Bleeding
in the abdomen and other sites may also occur ( Fig. 8–18 ). Subarachnoid hemorrhage has followed use of
amphetamines, phencyclidine, and cocaine. An underlying cerebral aneurysm may or may not be found.
Figure 8-17 CT scan of head, intracerebral hemorrhage after cocaine.

Figure 8-18 CT scan of abdomen, spontaneous hemoperitoneum due to long-acting anticoagulant rodenticide toxicity.


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Chapter 9 – Pharmacokinetics and Toxicokinetics
WILLIAM A. WATSON S. RUTHERFOORD ROSE
Pharmacokinetics is the science of drug movement through the body. The movement of a drug or substance
in the body can be described in terms of its absorption, distribution, and elimination.[6] Pharmacokinetics
describes the concepts that govern these processes, the impact of patient and disease variables, and the
mathematical description of the processes. This chapter provides an overview of “just what you need to
know” to understand pharmacokinetic concepts. These concepts are the basis for applying pharmacokinetic
information to toxicokinetics. Toxicokinetics is used to describe the absorption, distribution, and elimination
of drugs and other substances at doses that produce clinical toxicity.
Pharmacokinetics improves our understanding of the relationship between the dose of a drug and its effect
over time ( Fig. 9–1 ). The relationship between dose and effect would be best defined by measuring the
amount of drug at the site of action. Because we cannot collect samples from patients to measure the
amount of drug at the site of action, kinetics is useful in predicting the relationship based on drug
concentration in samples such as plasma that can be collected. Samples should be obtained from a site that
can be related to drug at the site of action. In this chapter plasma is used as the fluid for teaching purposes.
Other samples such as whole blood, breath, urine, arterial blood, cerebrospinal fluid, and tissue are less
useful and infrequently used.
Figure 9-1 The role of pharmacokinetics.
The application of pharmacokinetics to patient care is directed toward individualizing the use of therapeutic
agents such as aminoglycosides, digoxin, lidocaine, and theophylline. In this setting the patient receives a
known drug dose and clinical effects can be observed. A plasma drug concentration, usually a trough
concentration at steady state, is measured during a known dosing regimen. Application of the drug’s
pharmacokinetic parameters allows the drug dosing regimen to be adjusted to either increase or decrease
the plasma drug concentration and increase drug efficacy or decrease toxicity. The information and clinical
conditions when pharmacokinetics and toxicokinetics are used are generally much different ( Table 9–1 ).
The trough plasma drug concentration is the lowest value during the repeated dosing of a drug. The trough
occurs immediately before the next dose of drug is administered. There is no trough drug concentration after
an acute, single dose poisoning episode. Additionally, there is no intent to adjust the dose of an ingested
drug that is producing clinical toxicity.
Table 9-1 -- Comparison of Kinetics in Therapeutic and Toxic Situations

Therapeutic Toxic
Well identified, low Often unknown, may be altered by therapy,
Dose
dose high dose
Time of administration Well identified Often unknown
Controlled research describing:
Kinetics Yes No
Concentration effect Yes No
Plasma concentrations measured at
Yes No
steady state
Drug effects alter kinetics No Yes
In overdose and poisoned patients toxicokinetic concepts are most often used in the interpretation of drug
concentrations in plasma or urine drug testing results. Toxicokinetics may also be used to predict the onset
of symptoms and duration of toxicity. Kinetic parameters such as area under the plasma concentration–time
curve (AUC), half-life, and clearance are used to evaluate the efficacy of gastrointestinal decontamination
and methods of increasing drug removal from the body. These parameters are used as outcomes in
volunteer or animal studies where the dose administered and time intervals are defined.[1][8][15]
BASIC PRINCIPLES
Kinetics is based on the mathematical description of changes in drug concentrations over time. For the
equations and mathematical background necessary to do pharmacokinetic calculations, the reader should
use kinetic consultants and reference texts.[4][7]


ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
Absorption, distribution, and elimination are the processes that substances undergo after administration by
all routes except direct injection into blood, which foregoes the absorption process. Elimination is the
combination of metabolism and renal excretion ( Fig. 9–2 ). The peak plasma concentration is achieved at
the point in time when the combination of distribution and elimination are occurring at the same rate as drug
absorption. The shape of the concentration-time curve depends on the relative rates of these processes.
Figure 9-2 Drug absorption, distribution, and elimination for a drug with first-order absorption and elimination.
Absorption
Absorption is usually a first-order process. This indicates that it is the passive, concentration gradient
dependent movement of drug into the body. A half-life can be calculated to describe the absorption rate.
Half-life is the amount of time required for absorption of 50 per cent of drug in the gastrointestinal tract. Half-
life is more commonly used to describe the elimination rate when it is a first-order process. The elimination
half-life is the length of time it takes for the plasma concentration to decrease by 50 per cent, after
distribution is complete. With a first-order process the half-life will be the same when the plasma
concentration decreases from 100 to 50 units, 50 to 25 units, and 25 to 12.5 units.
In addition to the concentration gradients, the physical state of the molecule is important in determining the
absorption rate. The drug must be in solution, and nonionized molecules cross membranes more easily than
ionized molecules. The pKa of the substance, pH of the environment around the drug (gastrointestinal fluid),
and molecular size are important in determining the rate of absorption. Because most ingested substances
are solids, disintegration and dissolution of the solid tablet are required before absorption can occur.[21] The
primary site of absorption is the small intestine, which has greater surface area than the stomach. This
suggests that the physiologic process of emptying stomach contents through the pylorus into the small
intestine should be an important variable controlling the rate of absorption.
Ingestion of a drug dose does not mean that all the dose will be absorbed and end up in the systemic
circulation. Bioavailability is the term used to define the fraction of a dose that is absorbed and available for
systemic activity. Drug may be degraded or metabolized in the gastrointestinal tract before absorption. Most
commonly, a drug will be metabolized or degraded in the gastrointestinal tract or as it passes through the
liver on the way to the systemic circulation. For some drugs, this “first-pass effect” will significantly decrease
the amount of parent drug that is available for distribution to the site of action, and the bioavailability will be
less than 1.0. Cocaine and ethanol are examples of drugs that can have their bioavailability decreased both
in the gastrointestinal tract and in the liver. Cocaine is hydrolyzed by water and ethanol is metabolized by
alcohol dehydrogenase in the gastrointestinal tract. Both drugs are extensively metabolized by hepatic
enzymes. The bioavailability of ethanol (from beer) is approximately 0.80. The bioavailability of an oral dose
is determined by comparison with an intravenous dose, which does not require absorption. The area under
the AUC is used to compare the bioavailability of an oral dose of drug to an equal intravenous dose. Using
AUC as a measure of bioavailability without an intravenous control can be misleading. The best example of
this problem occurred when acetylcysteine and activated charcoal were studied (see Fig. 9–2 ).[20]
Data about drug absorption rates are usually more difficult to obtain than other kinetic parameters. The
number and timing of sample collection is very important. An adequate number of samples is usually not
collected. As an example, Figure 9–3 demonstrates plasma acetaminophen concentrations after the
administration of 5.0 g of acetaminophen solution to a healthy volunteer. As can be seen, if the 2-hour
sample were not collected, the peak plasma concentration achieved with the dose would be significantly
underestimated.[15]
Figure 9-3 The usefulness of getting as many serum concentrations as possible. (Redrawn from Rose SR, Gorman RL, Oderda GM,
et al: Simulated acetaminophen overdose: Pharmacokinetics and effectiveness of activated charcoal. Ann Emerg Med 1991; 20:1064.)
Distribution
Distribution is the process of drug movement throughout the body. Drugs distribute into various tissues to
different extents. The distribution phase can often be seen on a concentration-time curve after intravenous
drug administration because it results in a rapid decline in plasma concentrations immediately after
administration, until equilibrium is reached ( Fig. 9–4 ). Plasma and other organs into which drugs rapidly
distribute are called the central compartment, and areas into which the drug distributes more slowly are
called peripheral compartments. Distribution is important because it is during this process that the drug
reaches its site of action. During distribution there is binding of drug to plasma proteins such as albumin.
This decreases the amount of free drug that will be available to produce an effect at the site of action.
Figure 9-4 Log plasma drug concentration versus time curve after intravenous bolus of a drug with first-order elimination kinetics.
During the distribution phase plasma drug concentrations decrease more rapidly, because distribution into body tissue and elimination
are both occurring.
Distribution is also a concentration-gradient dependent process, and the distribution half-life into central and
peripheral compartments can be calculated. If the site of action is in the peripheral compartment and
distribution is relatively slow, there may be a time delay before the onset of toxicity. This could explain the
delay in onset of seizures with high initial plasma theophylline concentrations, compared with the lower
concentrations associated with seizures with chronic theophylline therapy. [12] In a very elegant series of
experiments with rats, Ramzan and Levy demonstrated that the dose of theophylline that resulted in seizures
was dependent on the rate of intravenous infusion.[14] The dose that caused seizures increased as
theophylline was more rapidly infused. They also demonstrated that cerebrospinal fluid theophylline
concentrations were not predictive of the concentration of theophylline at the site of central nervous system
action.
The calculated term volume of distribution is a measure of the apparent space that a dose of drug would
distribute into if the concentration of drug was equal throughout that volume. Distribution varies depending
on how water or fat soluble the drug is and on how much it binds to proteins and other tissues. The volume
of distribution is usually “apparent,” because it may not be a physiologically real number. The volume of
distribution does not identify the specific anatomic areas where the drug will be found but can provide
general information about where the drug is. The volume of distribution for some drugs is approximately
equal to the intravascular volume (gentamicin) or to total body water (ethanol). For very lipid soluble drugs
and those highly bound to tissue it will exceed 1000 mL/kg (1.0 L/kg), a value that is physiologically
impossible. A very large volume of distribution indicates that most of the drug is not in plasma but rather is in
other tissue.
The volume of distribution can be calculated under different conditions, such as after a single intravenous
dose or at steady state.
Metabolism and Elimination
The elimination of a drug is primarily the combination of metabolism via different pathways and the renal
excretion of unchanged drug in urine. Some drug is also eliminated by other routes, including the
gastrointestinal tract (fecal), and volatile gases may be exhaled via the lungs. Additional routes that usually
contribute a small amount to drug elimination include sweat, hair, and tears. Metabolism is that portion of
elimination that involves enzyme activity, usually hepatic. When hepatic metabolism is the predominate
means of drug elimination, the amount of drug metabolized per unit time will usually have a maximum rate
that is equivalent to that achieved when enzyme saturation occurs. Renal elimination of drugs can be
concentration dependent or enzyme mediated, depending on the drug. Other pathways for both metabolism
and elimination are usually less important than the liver and the kidneys. When the liver and kidneys do not
function normally (e.g., renal failure), these secondary pathways become more important.
Clearance is the removal of drug from plasma per time. Clearance may be described as total body clearance
or clearance by the kidneys or liver. The use of extracorporeal methods to clear drug, such as
hemoperfusion or hemodialysis, can also be described with a calculated clearance term. The extraction ratio
of an organ or of an extracorporeal method of drug removal describes how efficiently the drug is removed.
For example, if the kidneys are presented with 100 mL of blood per minute and the drug in that blood is
completely removed, then the extraction ratio would be 100 per cent.
This points out the importance of blood flow in determining the clearance rate. The combination of clearance
rate and volume of distribution determine the half-life of the drug.


MATHEMATICAL DESCRIPTIONS
When a known amount of drug is administered and serial plasma concentrations are measured, various
equations can be used to determine kinetic parameters, including the drug’s absorption half-life (with oral
administration), distribution half-life, elimination rate (half-life, or Km and Vmax), clearance, volume of
distribution, and area under the AUC. The units for these terms are presented in Table 9–2 . The calculation
of these parameters allows for a standardized method of mathematically describing the drug’s movement
through the body. The kinetics of a drug are usually presented visually as a graph of plasma concentration (y
axis) plotted over time (x axis). Before the equations are selected to describe a drug’s kinetic parameters,
the plasma concentrations should be graphed and visually inspected. This will provide information about
what processes are most likely occurring, using the shape of the line and whether concentrations are
graphed as raw or log data ( Fig. 9–5 ; see Figs. 9–2 and 9–4 ).
Table 9-2 -- Units and Abbreviations for Kinetic Parameters

Half-life (t½): time (often hours-1).
Volume of distribution (Vd): volume per weight (usually mL/kg, can be L/kg).
Area under the plasma concentration/time curve (AUC): concentration per time, usually in the form (amount)
(volume-1) (time).
Clearance (CL): volume per time (e.g., mL/min).
Km: the Michaelis constant, which is the drug concentration at which the elimination rate is equal to 50% of its
maximum.
Vmax: the maximum rate of metabolism for a drug that undergoes Michaelis-Menton metabolism kinetics.
Figure 9-5 Comparison of linear and log concentrations.
The concentration-time curve is a mathematically best-fit line that describes measured plasma drug
concentrations at known times. To accurately define a given portion of the curve it is generally stated that a
minimum of 3 to 5 points is necessary. In addition, in order to accurately describe the elimination phase of
the concentration-time curve, the measured points should be spread out over a time period that is expected
to be at least two or three half-lives long.
Although the large number of points necessary to describe a line is often impractical, obtaining fewer
samples may not accurately reflect the drug’s true movement through the body (see Fig. 9–3 ).
Linear kinetics are also called first-order kinetics. The parameter calculated is half-life, which indicates the
length of time required for half of the dose to be eliminated. For example, if there was 100 mg of drug in the
body at time zero after absorption and distribution and the half-life of elimination was 2 hours, then the
amount of drug in the body would be 50 mg at 2 hours, 25 mg at 4 hours, 12.5 mg at 6 hours, 6.25 mg at 8
hours, and 3.125 mg at 10 hours (one, two, three, four, and five half-lives, respectively). This demonstrates
that the rate of drug elimination from the body is not a constant amount per hour but a constant fraction of
drug remaining. The general rule is that all first-order processes will be nearly complete after five half-lives.
A graph of this process using the plasma concentration–time curve is curved when the concentration is
plotted on the y axis and time on the x axis and linear when the natural log of concentration is used (see Fig.
9–5 ). The presence of a first-order process suggests that the process does not rely on an enzyme system
that is saturated. Half-lives can also be calculated for absorption and distribution when they are linear.
Nonlinear processes are described by the Michaelis-Menten function. The Michaelis-Menten function is used
when there is limited enzyme activity relative to the amount of drug present. In this case, the rate of drug
elimination changes as the amount of drug changes, and the rate is described by an equation using the
terms Vmax and Km. Km is the concentration of drug that is 50 per cent of the maximum elimination rate, and
Vmax is the maximum rate of elimination. Drugs with Michaelis-Menten elimination do not have a constant
elimination half-life. The elimination rate of some drugs with Michaelis-Menten kinetics may appear linear
when the log concentration is plotted over time. In this case a half-life can be calculated.[10] It is acceptable
to think of elimination in this manner as long as results are not extrapolated to concentrations outside the
studied range.
Zero-order processes occur at a constant rate independent of the amount of drug present. There is usually a
range of drug concentrations in which zero-order processes occur. An example would be ethanol. Over the
blood ethanol concentration range of 50 to 200 mg/dL, the decline in blood ethanol concentrations is an
average of approximately 20 mg/dL/hr.[5]


PHARMACOKINETICS IN CLINICAL TOXICOLOGY
Pharmacokinetics Versus Toxicokinetics: Does Dose Change Kinetics?
Whether a drug’s absorption, distribution, and elimination differs between therapeutic and toxic doses is an
important consideration. In general, it is believed that differences in kinetics will be seen as the dose is
significantly increased. If this concept is correct, then the pharmacokinetic parameters that describe
absorption, distribution, and elimination at therapeutic doses may not be applicable with the toxic doses
involved in poisonings and overdoses. In general, if the ingestion of a large dose of drug alters kinetics, the
following changes may occur: (1) the absorption rate may slow down; (2) the volume of distribution may
increase; (3) the rate of hepatic metabolism may be saturated, and secondary elimination pathways become
important; and (4) the elimination rate of the drug may be slowed.[13][18][19]
Evidence supporting the changes in absorption, distribution, and elimination is not available for most drugs
at toxic doses, because controlled trials are extremely difficult to perform. Examples that are available
include phenytoin and aspirin. The absorption rate of phenytoin is slowed significantly as the oral dose is
increased, and aspirin’s elimination rate is lengthened as the amount of drug in the body increases.[19]
Kinetics and Interpreting Toxicology Laboratory Results
The kinetics of a drug should be considered before interpreting toxicology laboratory results or
recommending collection of a biologic sample (blood, serum, plasma, urine, breath) to determine the
concentration of a drug or its presence. Interpretation of plasma concentrations requires at least an estimate
of the time between dosing and the collection of the biologic sample. To imply a concentration-effect
relationship, at a minimum the drug’s absorption and distribution must be complete. This requires knowledge
of the rate of absorption and distribution of the drug and characteristics that may alter these parameters.
As previously discussed, most concentration-effect relationships are developed with steady-state trough
plasma concentrations, which occur immediately before the next dose of drug in therapeutic dosing. The
trough concentration is the most constant relationship between the drug concentration in plasma and the site
of action. Because there is no trough concentration with poisoned and overdosed patients, this concept
cannot be used. Because steady-state trough concentrations are not available, ensuring that drug
absorption and distribution are complete before making a correlation between plasma concentration and
clinical toxicity is very important. An example of the application of absorption kinetics to plasma
concentration interpretation is the Matthews-Rumack nomogram for prediction of acetaminophen-induced
hepatotoxicity.[17] Plasma concentrations collected within the 4-hour period after ingestion cannot be
interpreted, because absorption may still be occurring. There is generally more disagreement about
interpreting plasma iron concentrations. The relationship between plasma iron concentrations at various
times after ingestion and the risk of severe toxicity has not been well defined, possibly because the time
from ingestion to sample collection has not been well documented.[9][11]
Toxicokinetics and Drug Metabolites

Kinetics and evaluation of plasma drug concentrations are generally considered more important for drugs
that have toxic metabolites because the development of toxicity is delayed until metabolite formation. For
these agents, knowledge about the relationship between the parent drug and the toxic metabolite must be
well defined before the kinetics of the parent drug can be useful for predicting toxicity. If factors impacting
the toxicity of the metabolite are not reflected by the kinetics of the parent drug, then useful interpretation of
plasma concentrations is difficult. An example would be the amount of glutathione in the liver and
interpretation of a plasma acetaminophen concentration. Patients with dramatic depletion of hepatic
glutathione would be expected to develop liver toxicity at lower plasma acetaminophen concentrations than
might be expected based on the Matthews-Rumack nomogram.
Kinetics and Prediction of Drug Effects
Onset of Effect
Because most drug poisonings and overdoses involve the oral ingestion of substances, an understanding of
absorption and distribution could be useful in predicting the onset of toxicity. These kinetic predictions
should be considered as general rather than precise. Unfortunately, there are generally less data available
regarding the absorption rate for oral overdoses than is available for elimination rates. Case reports suggest
that the ingestion of large numbers of tablets may slow tablet dissolution and result in delayed, erratic
absorption. This is supported by animal models; however, there is little information that is useful for
predicting how rapidly absorption will occur after the ingestion of a toxic oral dose. [2][3][16]
Duration of Effect
The duration of toxicity for drugs that produce their toxicity by reversibly binding to a receptor may be
predictable by the elimination rate. The duration of effect will be less predictable when acute tolerance (often
of the central nervous system) develops, when toxicity is secondary to a metabolite, or when receptor
binding is irreversible and the offset of toxicity is based on another process, such as the generation of new
enzymes. An example is the duration of untreated organophosphate toxicity that depends on the formation
of new acetylcholinesterase.


KINETICS IN TOXICOLOGY RESEARCH
In studies designed to measure the effects of treatment on drug toxicity, kinetic parameters are often used
as a surrogate for clinical outcome. To be useful, the change in kinetics should be related to a reasonably
expected change in toxicity. Establishing this relationship is difficult because volunteer studies must use
nontoxic doses. In these models kinetics may not reflect what will happen with toxic doses.
Kinetic outcomes are commonly used to evaluate the impact of gastrointestinal decontamination on drug
absorption. The most important consideration is whether the kinetic parameter accurately reflects the
percentage of the dose that is absorbed. Most commonly the area under the plasma concentration versus
time curve is used to define the amount of drug absorbed. Using this endpoint requires prior knowledge
about the relationship between intravenous and oral AUCs. This ensures that using the AUC after an oral
dose will adequately reflect the total dose absorbed. With some drugs, such as acetylcysteine, the AUC may
not adequately reflect the absorbed dose.[20] The calculated AUC should use plasma concentration points
sufficient to accurately reflect the true AUC, and it works best under conditions of first-order elimination.
Comparison of the AUC of the control group compared with that achieved with treatment will give a
reasonable indication of the efficacy of decontamination.
A more valid method of evaluating the efficacy of gastrointestinal decontamination would be to quantitate the
amount of drug actually recovered in emesis, gastric lavage effluent, or feces. These methods are
infrequently used. An indirect method useful for drugs with zero-order or Michaelis-Menten elimination
kinetics may be measurement of drug and metabolite recovered in urine. With drugs in which the total
amount administered can be recovered in urine over a reasonable period of time, subtraction of the amount
recovered from the dose administered provides a measure of the amount that was not absorbed secondary
to gastrointestinal decontamination. This method has been used for salicylate and provides a much more
accurate estimate of the efficacy of gastrointestinal decontamination than AUC.[1]
Calculation of half-life and drug clearance can be used to determine the efficacy of treatments such as
multiple-dose activated charcoal, hemoperfusion, or modification of urinary pH used to enhance drug
elimination. Because determination of clearance requires knowledge of the dose ingested, these
calculations may not be appropriate for many overdose patient observations, unless the dose ingested can
be verified and was not altered by some method of gastrointestinal decontamination. In addition, it is
important to determine the increase in clearance rate necessary to produce a clinically useful treatment
effect. Calculation of clearance evaluates the efficacy of extracorporeal methods of drug removal, such as
hemoperfusion and hemodialysis.


REFERENCES
1. Dillon ED, Wilton JH, Barlow JC, et al: Large surface area activated charcoal and the inhibition of aspirin
absorption. Ann Emerg Med 1989; 18:547-552.
2. Dupuis RE, Cooper AA, Rosamond LJ, et al: Multiple delayed peak lithium concentrations following acute
intoxication with an extended-release product. Ann Pharmacother 1996; 30:356-360.
3. Eppler J, Johnson D, Verjee Z, et al: Measurement of serum acetylsalicylic acid in a porcine model of
aspirin overdose. Vet Hum Toxicol 1996; 6:409-412.
4. In: Evans WE, Schentag JJ, Jusko WJ, ed. Applied Pharmacokinetics: Principles of Therapeutic Drug
Monitoring, 2nd ed. Vancouver, WA: Applied Therapeutics; 1986.
5. Garriott JC: Forensic aspects of ethyl alcohol. Clin Lab Med 1983; 3:385-395.
6. Gibaldi M, Levy G: Pharmacokinetics in Clinical Practice: I. Concepts. JAMA 1976; 235:1864-1876.
7. Gibaldi M, Perrier D: Pharmacokinetics, New York, Marcel Dekker, 1975.
8. Johnson D, Eppler J, Giesbrecht E, et al: Effect of multiple-dose activated charcoal on the clearance of
high-dose intravenous aspirin in a porcine model. Ann Emerg Med 1995; 26:569-574.
9. Ling LJ, Hornfeldt CS, Winter JP: Absorption of iron after experimental overdose of chewable vitamins.
Am J Emerg Med 1991; 9:24-26.
10. Mauro LS, Mauro VF, Brown DL, et al: Enhancement of phenytoin elimination by multiple-dose activated
charcoal. Ann Emerg Med 1987; 16:1132-1135.
11. Mills KC, Curry SC: Acute iron poisoning. Emerg Med Clin North Am 1994; 12:397-413.
12. Olson KR, Benowitz NL, Woo OF, et al: Theophylline overdose: Acute single ingestion vs. chronic
repeated overmedication. Am J Emerg Med 1985; 3:386.
13. Platt D: Pharmacokinetics of drug overdose. Clin Lab Med 1990; 10:261-269.
14. Ramzan IM, Levy G: Kinetics of drug action in disease states: XVI. pharmacodynamics of theophylline-
induced seizures in rats. J Pharmacol Exp Ther 1986; 236:708-713.
effectiveness of activated charcoal. Ann Emerg Med 1991; 20:1064-1068.
16. Schwartz HS: Acute meprobamate poisoning with gastrotomy and removal of a drug-containing mass.
N Engl J Med 1976; 295:1177-1178.
17. Smilkstein MJ, Knapp GL, Kulig KW, et al: Efficacy of oral N-acetylcysteine in the treatment of
acetaminophen overdose: Analysis of the national multicenter study (1976 to 1985). N Engl J
Med 1988; 391:1557-1562.
18. Sue YJ, Shannon M: Pharmacokinetics of drugs in overdose. Clin Pharmacokinet 1979; 23:93-105.
19. Watson WA: Toxicokinetics and management of the poisoned patient. US Pharm 1990; 15:H1-H15.
20. Watson WA, McKinney PE: Activated charcoal and acetylcysteine absorption: Issues in interpreting
pharmacokinetic data. DICP Ann Pharmacother 1991; 25:1081-1084.
21. Watson WA, Vraa EP, Neau SH: Acetaminophen tablet dissolution [letter]. Ann
Pharmacother 1997; 31:1262-1263.


Chapter 10 – Fluids and Electrolytes
KURT C. KLEINSCHMIDT KATHLEEN A. DELANEY
Optimal metabolic and physiologic function requires a consistent fluid volume with a stable composition.
Pathologic alterations in fluid or electrolyte concentrations result from changes in absorption, elimination,
regulatory mechanisms, or transcellular shifts between fluid compartments. These alterations occur with
diseases affecting gastrointestinal, renal, and skeletal functions and exposure to environmental elements,
medications, or toxins. In this chapter the pathophysiology, clinical presentations, differential diagnoses, and
management of body fluid volume and electrolyte disorders are discussed with a focus on disorders
associated with drugs and toxins.
WATER AND SODIUM

Regulation of Fluid and Electrolyte Pools
Water accounts for 60 per cent of body weight, with two thirds of total body water (TBW) in the intracellular
fluid (ICF) space and one third in the extracellular fluid (ECF) space. The ECF is divided into intravascular
(25 per cent) and interstitial (75 per cent) compartments. Most solutes, including electrolytes, do not cross
cellular membranes, but free movement of water allows different compartments to remain in osmotic *
equilibrium. Sodium salts are the primary extracellular osmoles within the ECF, whereas potassium salts
comprise most of the ICF osmoles. Water volume and sodium concentration are interdependent, and
changes in the TBW reflect changes in serum sodium concentration. Changes in the intravascular sodium
concentration alter the osmolarity of other compartments by affecting the movement of water between them.
Both the adrenal and the pituitary glands contribute to the regulation of blood volume and serum osmolarity.
Hypothalamic receptors stimulate thirst after very small increases in osmolarity.[51] The pituitary
neurohypophysis releases antidiuretic hormone (ADH) in response to increased plasma osmolarity or
decreased blood volume or blood pressure. ADH stimulates absorption of free water at the distal renal
tubule. Decreases in renal perfusion lead to release of renin by the renal juxtaglomerular apparatus, which
converts angiotensinogen to angiotensin I. Pulmonary angiotensin-converting enzymes change angiotensin I
to angiotensin II, which stimulates release of aldosterone from the adrenal cortex. Aldosterone is also
released in response to hyperkalemia. It causes sodium reabsorption and potassium secretion in the renal
cortical collecting tubules and acts on epithelial cells in the colon and the sweat and salivary glands to
increase sodium conservation in those tissues.
Disorders of ADH regulation result in impairment of sodium and water balance. The syndrome of
inappropriate secretion of ADH (SIADH) occurs when ADH is released despite normal or hypo-osmolarity.
This condition is characterized by hyponatremia and an inability to dilute urine to an osmolality less than 100
mOsm/kg water. Patients characteristically gain 4 to 5 L of water before stabilizing. Diabetes insipidus
occurs when ADH deficiency impairs renal water conservation, resulting in hypernatremia if water intake is
restricted. Diabetes insipidus is termed neurogenic if it results from inappropriate osmolality sensing or ADH
release. Nephrogenic diabetes insipidus is a result of insensitivity of the renal collecting tubule to ADH.
* An osmole is a unit measure for the total number of particles in a solution. Concentrations of osmoles are called osmolarity when expressed as
osmoles per liter of solution and osmolality when expressed as osmoles per kilogram of water. The differences between the two concentration
terms are small when referring to solutions of the human body; thus, osmolarity is used more commonly because body fluids are more easily
expressed in liters. Osmosis is the diffusion of water from a compartment of lower osmolarity to one of higher osmolarity.
Differential Diagnosis of Toxin-Induced Fluid Deficits
Fluid deficits can result from agents that (1) cause vomiting or diarrhea; (2) injure tissue with resultant third
spacing (caustic agents); or (3) increase urination, sweating, or respiratory rate. Toxins that precipitate
vomiting include acetaminophen, anticholinesterases, aspirin, caffeine, carbon monoxide, cardiac
glycosides, colchicine, disulfiram/ethanol interactions, ipecac abuse, iron, metals, mushrooms, nicotine, and
theophylline. Diarrhea is associated with ingestion of anticholinesterases, cathartics, colchicine, iron, lithium,
metals, mushrooms, nicotine, phosphorus, and podophyllin. Anticholinesterases, diuretics, and lithium
increase urination. Diaphoresis can result from cocaine or other sympathomimetic agents, disulfiram/ethanol
interactions, anticholinesterases, phencyclidine, theophylline, and salicylates. Insensible pulmonary losses
are increased by agents that enhance respiratory drive by causing metabolic acidosis (e.g., cyanide, glycols,
iron, toluene, salicylates, toxic alcohols, metformin) or respiratory alkalosis (e.g., sympathomimetics,
salicylates).
Clinical Assessment of Hydration
The heart rate, blood pressure, orthostatic vital signs, mental status, urine output, mucosal moistness, and
the temperature, color, moistness, and turgor of the skin provide clinical information about the state of
hydration. Drugs and toxins that alter these findings make a clinical determination of volume status more
difficult. Numerous medications affect the pulse, respiratory rate, and blood pressure. Vasodilators, a- and ß-
adrenergic receptor antagonists, central a-adrenergic receptor agonists, cyclic antidepressants, and
phenothiazines cause postural hypotension. Anticholinesterase medications increase urinary frequency, and
diuretics increase urinary output. Anticholinergic agents result in urinary retention that may not be
appreciated unless a Foley catheter is placed. Anticholinergic agents cause the skin to be warm, flushed,
and dry whereas sympathomimetics, such as cocaine and theophylline, make the skin cool and damp
regardless of the state of hydration. When present, laboratory indicators of volume depletion such as
elevation of the hematocrit, serum bicarbonate, and blood urea nitrogen are helpful in assessing the volume
status of poisoned patients.
Hyponatremia
Pathophysiology
Acute hyponatremia causes cerebral edema because water moves across the blood-brain barrier into
relatively hyperosmolar neurons. Compensatory mechanisms reduce the osmotic gradient by moving
sodium, potassium, and chloride from the neurons and cerebral interstitium into the cerebrospinal fluid.
Persistent hyponatremia results in the loss of other neuronal osmoles, particularly amino acids, further
decreasing the osmotic gradient.[73]
Clinical Presentation
The symptoms of hyponatremia are primarily neurologic and include headache, dizziness, anorexia, nausea,
mental status alteration, irritability, myoclonus, tremors, seizures, and coma. Musculoskeletal symptoms
such as weakness, abdominal pain, and muscle cramping also occur. [99] The severity of symptoms
correlates with the magnitude of hyponatremia and, most importantly, with its rate of development.
Significant hyponatremia that develops slowly may cause minimal symptoms.
Differential Diagnosis
True hyponatremia, defined as a plasma osmolality less than 280 mOsm/kg, is often classified according to
the ECF volume status. Hypovolemic hyponatremia results from gastrointestinal, skin, and renal losses of
water and sodium. Euvolemic hyponatremia is usually due to SIADH with various pulmonary conditions,
central nervous system (CNS) infections, and tumors.[86] Certain drugs and toxins (discussed later) have
also been associated with the development of SIADH. Dilutional hyponatremia with increased ECF results
from renal failure, cirrhosis, nephrotic syndrome, and congestive heart failure.
Hyponatremia Associated with Drugs and Toxins
The synthesis and activity of aldosterone are affected by angiotensin-converting enzyme inhibitors and
potassium-sparing diuretics. Thiazide and loop diuretics commonly cause a mild, insignificant hyponatremia.
Profound hyponatremia due to diuretics is a rare, idiosyncratic reaction.[70] Ethanol-induced hyperlipidemia
may result in a pseudohyponatremia. [27]
Many medications may cause SIADH, including cyclic antidepressants, selective serotonin reuptake
inhibitors, monoamine oxidase inhibitors, phenothiazines, butyrophenones, and sulfonylureas ( Table 10–1
). [44][86] Chlorpropamide has been shown to increase ADH activity, whereas the mechanism by which
tolbutamide, another sulfonylurea, produces SIADH is less clear. Acetaminophen and the biguanide
antihyperglycemics, phenformin and metformin, also accentuate ADH activity but have not been associated
with hyponatremia.[60]
Table 10-1 -- Agents That Decrease Serum Sodium Levels: Hyponatremia

SIADH-Associated Agents Non–SIADH-Associated Agents
Increased Antidiuretic Hormone Secretion Inhibits Angiotensin I–Converting Enzyme
Barbiturates Captopril
Carbamazepine Inhibits Aldosterone (Renal Tubular Cells)
Clofibrate Potassium-sparing diuretics
Morphine Increased Gastrointestinal Loss
Nicotine Colchicine
Oxcarbazepine Other or Unknown Mechanism
Vincristine Silver nitrate *
Increased Antidiuretic Hormone Activity Lithium †
Biguanides Thiazide or loop diuretics
SIADH-Associated Agents Non–SIADH-Associated Agents
Metformin Glycine (transurethral prostatectomy syndrome)
Phenformin Licorice (glycyrrhiznic acid)
Cyclophosphamide Nonsteroidal anti-inflammatory drugs
Paracetamol Arginine
Sulfonylureas
ADH-like
Desmopressin
Oxytocin
Other or Unknown Mechanism
Psychotropics
Tricyclic antidepressants (amitriptyline)
Nontricyclic antidepressants
Fluoxetine
Tranylcypromine
MAO inhibitors
Butyrophenones
Phenothiazines
Thioridazine
Thiothixene
Clonidine
Diazoxide
Data from references 11 , 14 , 20 , 34 , 41 , 44 , 60 , 86 and 94 .
* Rare now that silver nitrate is not used in burn wound dressings; occurred owing to osmotic redistribution of sodium from the wound into the
hypotonic silver nitrate in the dressing.
† Rare. Lithium is usually associated with diabetes insipidus.
Management
Hyponatremia is most life-threatening when the sodium drops abruptly to levels below 120 mEq/L over a 24-
hour period. When the time course cannot be deduced from the clinical setting, the presence of severe
neurologic symptoms implies an acute development of hyponatremia. These patients require aggressive
treatment to avoid the neurologic sequelae of acute hyponatremia.[79] In patients who have significant
neurologic symptoms the serum sodium should be rapidly corrected to 120 to 125 mEq/L at a rate of 1
mEq/L/hr or less using hypertonic (3 per cent) sodium chloride or isotonic saline with a concomitant
diuretic.[19][89] Hypertonic saline should be stopped once the serum sodium concentration reaches this level.
Most patients who present in an outpatient setting will have chronic hyponatremia. The extent of cerebral
adaptation to hyponatremia, which correlates with the duration of hyponatremia, must be considered before
treatment is instituted because replacement of neuronal osmoles, depleted by the compensatory response
to hyponatremia, occurs slowly. The absence of severe neurologic symptoms implies a slow onset of
hyponatremia. Rapid administration of saline will make the extracellular fluids relatively hyperosmotic,
causing neuronal dehydration as water exits the neurons. Excessively rapid correction of chronic
hyponatremia has been associated with the neurologically devastating syndrome referred to as central
pontine myelinolysis. More recently this has been termed osmotic demyelination syndrome because it has
been demonstrated to also occur outside the pons.[89]
Asymptomatic or mildly hyponatremic patients who are euvolemic or hypervolemic are best managed with
water restriction. Infusion of isotonic saline solutions is appropriate for mildly symptomatic patients with
hypovolemic hyponatremia. These patients should be corrected no faster than 12 mEq/L/d.[88]
Hypernatremia
Pathophysiology
Hypernatremia causes water to move from cells out to the relatively hyperosmotic ECF, resulting in cellular
dehydration. The brain slowly adapts to this extracellular fluid shift by increasing its intracellular content of
amino acids (so-called idiogenic osmoles), which draw water back into the cells and restore their volume.
Symptom severity is related to the degree of hypernatremia and its rate of onset. CNS symptoms are most
prominent and include irritability, delirium, lethargy, and coma. Neuromotor symptoms include weakness,
tremor, rigidity, and increased deep tendon reflexes. A normal mental status can be maintained up to serum
sodium levels of 170 mEq/L if the onset is slow enough to allow compensation to occur. Small blood vessels
may tear during cerebral contraction causing subdural and subarachnoid hemorrhages. Seizures also result
from focal intracerebral bleeding.[99] Profound hypotension is unusual even when significant dehydration is
present because the intravascular volume is restored by the movement of intracellular fluid into the ECF.
Despite preservation of the circulatory volume, most patients are clinically dehydrated and the skin turgor is
decreased. Whereas diabetes insipidus may be associated with significant hypernatremia if the patient does
not have access to water, polyuria and polydipsia are the only symptoms when the patient can drink freely.
The most common cause of hypernatremia is a decrease in TBW due to reduced intake or increased loss of
fluids. Common causes include diarrhea, vomiting, hyperpyrexia, and excessive sweating. Various agents
can cause hypernatremia by (1) increasing the sodium load, (2) increasing free water losses by impairing
ADH release or response, or (3) increasing obligatory loss of free water in the kidneys or gastrointestinal
tract through osmotic effects ( Table 10–2 ).[5][14] Excessive use of hypertonic povidone-iodine solutions on
wounds can cause extracorporeal diffusion of water.[14] Oral salt exposures can cause significant elevations
of serum sodium despite ingestion of seemingly small amounts of salt. The ingestion of one level tablespoon
of salt (250 mEq sodium) by a 3-year-old child with 10 L of TBW could potentially increase the serum
sodium by 25 mEq/L. [8][58] Most salt poisonings are unintentional, occurring when infant formula is
inadvertently prepared with salt instead of sugar, or following the use of salt as an emetic.[58]
Table 10-2 -- Agents That Increase Serum Sodium Levels: Hypernatremia

Diabetes Insipidus–Associated Agents Non–Diabetes-Insipidus–Associated Agents
Nephrogenic Increased Sodium Load
Amphotericin B Antacids (backing soda)
Colchicine Sodium exchange resins
Demeclocycline Tablet salt
Foscarnet Fleet Phospho-soda
Gentamicin Increased Urinary Excretion
Lithium Glycerin
Lobenzarit Isosorbide
Mesalazine Mannitol
Methoxyflurane Urea
Propoxyphene Increased Gastrointestinal Loss
Rifampin Lactulose
Streptozotocin Sorbitol
Decreased Central ADH Secretion Other or Unknown Mechanism
Phenytoin Cholestyramine
Ethanol Povidone-iodine topical
Data from references 5 , 11 , 14 , 23 , 30 , 40 , 41 , 56 , 58 , 63 , 68 , 76 , 84 and 87 .
Diabetes insipidus is diagnosed by the demonstration of hypotonic urine in the setting of a concentrated
serum osmo-lality. Neurogenic diabetes insipidus may result from tumors, infections, and granulomatous
diseases, or various toxins (see Table 10–2 ) that affect the CNS. Ethanol is a well-recognized inhibitor of
ADH release; however, it has not been associated with clinically significant diabetes insipidus.[14]
Nephrogenic diabetes insipidus results when the kidney does not appropriately respond to ADH. It may
result from both toxicologic (see Table 10–2 ) and nontoxicologic causes. [11] Therapeutic levels of lithium
commonly cause polyuria with small elevations of the serum sodium concentration; however, the incidence
of nephrogenic diabetes insipidus during therapy with lithium is unclear.[11]
Management
The management of hypernatremia depends on the underlying etiology and the patient’s state of hydration.
If hypernatremia is due to a sodium gain, volume expansion will be present and the administration of a
diuretic is appropriate. Most cases occur in patients with extracellular fluid loss who are hypovolemic.[54]
These patients should receive volume replacement with normal saline, which is relatively hypotonic, until
vital sign abnormalities are corrected.[54] Patients whose hypernatremia has developed over more than 2 to
3 days will have formed intracellular idiogenic osmoles so that rapid correction of hypernatremia may cause
cerebral edema, seizures, or other neurologic sequelae. Acute cases of hypernatremia can be corrected
over 48 hours, whereas chronic cases require at least 72 hours of cautious correction.
Therapy for diabetes insipidus depends on its cause. Neurogenic diabetes insipidus requires replacement of
ADH with aqueous vasopressin or desmopressin (DDAVP), a modified vasopressin that has a longer
therapeutic half-life. Other agents that increase the release of endogenous ADH include chlorpropamide,
clofibrate, and carbamazepine.[11] Nephrogenic diabetes insipidus does not respond to exogenous ADH.
Thiazide diuretics, which paradoxically decrease the urine output in patients with diabetes insipidus, are the
mainstay of treatment of nephrogenic diabetes insipidus. They work by causing mild volume depletion,
which results in enhanced proximal tubular resorption of filtrate and decreased delivery of water to the distal
tubule. Nonsteroidal anti-inflammatory agents also reduce polyuria by inhibiting the renal synthesis of
prostaglandins, enhancing the response to ADH.[11]


POTASSIUM
Regulation
Potassium homeostasis is maintained primarily by renal regulation with some contribution from
gastrointestinal absorption and losses and intracellular and extracellular shifts. Renal potassium regulation
is affected by plasma potassium concentration, aldosterone levels, and the rate of delivery of free water to
the distal collecting tubules. Both increased plasma potassium and increased aldosterone stimulate sodium-
potassium (Na+,K+) pumps in the tubular cells of the distal tubule and collecting tubules. This increases the
intracellular potassium concentration and results in increased passive diffusion of potassium into the
tubules. Elevated plasma potassium also stimulates aldosterone secretion by the adrenal cortex. Increased
flow of water in the collecting tubules dilutes the luminal potassium. This increases passive potassium
diffusion from the tubular cells into the lumen.[38] The electrical gradient created by sodium reabsorption in
the distal tubule is offset by co-transport of accompanying anions of sodium, usually chloride. However, if
sodium presents to the distal tubule with anions that are not able to enter tubular cells, then the potential
difference between the distal tubule and the tubular cells becomes more negative. Impermeable anions
include bicarbonate, sulfate, and penicillins.[5] The increased negative gradient causes the potassium to
move from the cell into the tubular lumen, also resulting in increased potassium losses.
Hypokalemia
Pathophysiology
Although the ECF contains less than 2 per cent of total body potassium, small changes in serum potassium
have significant effects on cellular function.[5] Potassium affects many enzymatic processes including
glycogenesis and mitochondrial oxidative metabolism. It also affects osmotic pressure and acid-base
balance.[15] Hypokalemia decreases the resting membrane potential of electrically active cells, inhibiting the
generation of action potentials and decreasing neuromotor, cardiac, and gastrointestinal activity.
Hypokalemia commonly causes muscular weakness that primarily affects the lower extremities and proximal
muscle groups. Severe potassium deficiency results in death due to respiratory paralysis. Impaired
gastrointestinal motility results in abdominal distention, cramping, nausea, and vomiting.
Electrocardiographic (EKG) changes include the development of U waves, lengthening of the PR and QRS
intervals, T wave flattening, ST segment depression, bradydysrhythmias, heart blocks, atrioventricular
dissociation, and ventricular tachycardia. Cardiac contractility and vasomotor tone are depressed. Mental
status impairment is rare. Hypokalemia promotes the intracellular movement of hydrogen ions that results in
serum alkalosis with intracellular acidosis. Profound hypokalemia results in the kidney excreting hydrogen
ions despite the presence of alkalosis in an attempt to maintain serum potassium levels. This paradoxical
aciduria reflects the severity of the hypokalemia. The kidney cannot correct the alkalosis until the potassium
is replenished.[99]
Hypokalemia results from intracellular movement of potassium and from renal and enteric fluid losses.
Diarrhea leads to significant losses of potassium due to its high concentration in diarrheal fluids. Although
gastric secretions contain minimal amounts of potassium, hypokalemia occurs in vomiting patients because
of intracellular shift of potassium associated with the vomiting-induced metabolic alkalosis.[5] Renal losses in
the setting of primary or secondary hyperaldosteronism can be significant. Profound hypokalemia resulting
in paralysis is seen in the familial disorder “periodic hypokalemic paralysis.” This is associated with rapid
intracellular shifts of potassium.
Many pharmacologic agents are associated with hypokalemia ( Table 10–3 ). Diuretic therapy is the most
common cause of hypokalemia.[49] Potassium losses are not usually large, and total body stores are not
affected.[40][70] Thiazide diuretics are more often implicated in the development of hypokalemia than are loop
diuretics.[70] Hypokalemia is common in alcoholics and is attributed to decreased potassium intake,
increased intracellular shifts from ß-adrenergic receptor stimulation, respiratory alkalosis, hyperinsulinemia
due to hypophosphatemia, diarrhea, and inappropriate kaliuresis due to hypomagnesemia.[27]
Sympathomimetic agents cause an intracellular shift of potassium that is not usually significant unless it
results from overdose.[5][40] Intracellular shift of potassium is also associated with the inhalation of
toluene.[91] In some cases the chronic abuse of toluene has been associated with profound hypokalemia,
resulting in paralysis. This has been attributed to renal potassium losses in the setting of a toluene-induced
renal tubular acidosis.[91] Salicylates cause hypokalemia through respiratory alkalosis and other unclear
mechanisms.[32] Patients with geophagia develop hypokalemia when potassium is bound to certain types of
clay.[36] The glycyrrhizic acid in licorice has been proposed to cause hypokalemia by binding and stimulating
aldosterone receptors.[40] Carbenoxolone, used for the treatment of peptic ulcers in Europe, has significant
mineralocorticoid activity and has been associated with hypokalemia.[74] Very high doses of hydrocortisone
have caused hypokalemia.[69]
Table 10-3 -- Agents That Affect Serum Potassium

Hyperkalemia Hypokalemia
Increased Potassium Load Increased Urinary Excretion (Nonreabsorbable Anions)
Salt substitutes Bicarbonate
Saltpeter (K+NO 3) Carbenicillin
Potassium supplements Penicillin G
Penicillins (potassium salts) Sulfates
Decreased Urinary Excretion (Inhibits Aldosterone) Increased Urinary Excretion (Tubular Damage)
Heparin Gentamicin
Potassium-sparing diuretics * Tetracycline (outdated)
Angiotensin-converting enzyme inhibitors Amphotericin B
Decreased Urinary Excretion (Other/Unclear) Increased Urinary Excretion (Aldosterone-like)
Heparin Licorice (glycyrrhizic acid)
Nonsteroidal anti-inflammatory drugs Glucocorticoids
Cyclosporins Carbenoxolone
Hyperkalemia Hypokalemia
Transcellular Shift Out of Cells Terlipressin
Alpha-adrenergic agonists Increased Urinary Excretion (Other)
Arginine Diuretics (except potassium sparers)
Beta2-adrenergic blockers Methylxanthines
Cardiac glycosides Caffeine
Glucagon Increased Gastrointestinal Loss
Fluoride Cathartics
Succinylcholine Colchicine
Cyclophosphamide Laxatives (phosphate enemas)
Fluoride Sodium polystyrene sulfate
Rhabdomyolysis-Inducing Agents Trancellular Shift into Cells
Chloroquine
Dextrose
Sympathomimetics
Theophylline
Beta-adrenergic agonists
Insulin
Toluene
Other, Unknown, or Mixed Mechanisms
Barium (soluble salts)
Clay (geophasia)
Ethanol
Methyl mercury
Salicylates
Data from references 5 , 14 , 18 , 30 , 36 , 40 , 41 , 45 , 61 , 68 , 92 , 93 and 96 .
* Amiloride and triamterene also decrease potassium excretion by a mechanism independent of aldosterone.
Management
Treatment of symptomatic hypokalemia consists of an intravenous infusion of 10 to 20 mEq of potassium

chloride in 50 to 100 mL of dextrose 5 per cent in water or normal saline per hour. The rate should not
exceed 40 mEq/hr, unless the hypokalemia is life-threatening. Patients with renal impairment must be
observed carefully during potassium administration. Cardiac monitoring is advisable when potassium is
administered faster than 40 mEq/hr or the patient has renal impairment. Oral therapy is safer in
asymptomatic patients. Hypokalemia may be resistant to potassium repletion if hypomagnesemia is
concurrently present.[53]
Hyperkalemia
Pathophysiology
Hyperkalemia results from increased intake, decreased urinary excretion in the setting of acute renal failure
or hypoaldosteronism, or shift from the intracellular to the extracellular space. Extensive tissue injury is
associated with significant release of intracellular potassium. Toxins may result in hyperkalemia from all of
these mechanisms (see Table 10–3 ). Severe hyperkalemia as a direct consequence of acute poisoning is
infrequent and occurs primarily with inhibition of sodium-potassium adenosine triphosphatase (Na+,K+-
ATPase) activity.[13] The rate of rise of the serum potassium level is an important determinant of its clinical
effects. Patients who are chronically hyperkalemic may tolerate very high potassium levels without serious
sequelae.
The primary clinical effects of potassium toxicity are reflected in characteristic EKG abnormalities. Acute
elevations of potassium to levels around 6 mEq/L result in a more positive resting membrane potential, and
cell activation occurs more readily. The rate of repolarization also increases, resulting in narrow, peaked T
waves and shortened QT intervals. As the potassium level approaches 7 mEq/L, conduction delays result in
PR interval and QRS complex widening. ST segments become depressed and P waves lose amplitude,
widen, and are eventually lost. Above 8 mEq/L a confluence of the widening QRS complex with the T wave
occurs, resulting in a sine-wave appearance of the EKG tracing. This progresses to ventricular fibrillation or
cardiac standstill as levels rise above 10 to 12 mEq/L. The presence of concomitant hypocalcemia,
hyponatremia, acidemia, and the rate of change of the potassium levels cause variations in the relationship
between these EKG changes and the specific serum potassium levels. [73][99]
The primary neuromuscular effect of hyperkalemia, seen at potassium levels greater than 8 mEq/L, is
weakness that typically affects the lower extremities first. Ascending paralysis has also been reported,
although this is more classically associated with hypokalemia.[73] Patients who became toxic after ingestions
of potassium salts commonly complain of abdominal pain, nausea and vomiting, and occasional
gastrointestinal bleeding.[13]
Hyperkalemia can result from increased potassium intake, transcellular shifts in the setting of diabetic
ketoacidosis, tissue destruction (rhabdomyolysis, crush injury, burns), and decreased mineralocorticoid
effects. Dangerous hyperkalemia most commonly results from acute renal failure and oliguria. Medication-
induced hyperkalemia (see Table 10–3 ) is generally mild and clinically significant only in association with
renal failure. Beta-adrenergic receptor antagonists commonly cause small elevations of serum potassium.
Aldosterone resistance or decreased renin-angiotensin system activity are associated with potassium-
sparing diuretics, heparin, and angiotensin-converting enzyme inhibitors.[40][68] Nonsteroidal anti-
inflammatory agents inhibit renal prostaglandin synthesis, which in turn inhibits prostaglandin-mediated
secretion of renin. This can result in hyperkalemia associated with hyporeninemic hypoaldosteronism or a
type 4 renal tubular acidosis.[40][68] Large potassium loads from potassium-containing salt substitutes and
saltpeter (KNO3) have been associated with significant hyperkalemia.[14][87] Potassium-sparing diuretics
increase potassium and magnesium levels by decreasing their renal clearances.[70] Inhibition of cell
membrane Na+,K+-ATPase pumps by cardiac glycosides, primarily digoxin and digitalis, is of particular
importance. Therapeutic doses of digitalis cause insignificant elevations in serum potassium; however, acute
intoxication results in hyperkalemia, which correlates with mortality.[7][81] Drugs that are associated with
significant rhabdomyolysis are also associated with hyperkalemia.
Management
The urgency of treatment is determined by the severity of EKG changes. Calcium directly antagonizes the
cardiac effects of hyperkalemia and is indicated if significant EKG changes (QRS widening, heart block, or
ventricular dysrhythmia) are present.[28][83] Ten milliliters of 10 per cent calcium gluconate (0.5–1.0 mL/kg)
should be given over 2 to 3 minutes and may be repeated every 5 minutes as long as the EKG
manifestations persist. The antagonistic effects of calcium start within minutes and last 30 minutes. Calcium
is contraindicated in the treatment of hyperkalemia related to digoxin toxicity.[53]
Various agents lower potassium acutely by promoting its redistribution into the intracellular space. Nebulized
albuterol decreases serum potassium 0.5 to 1.5 mEq/L within 30 minutes, with effects lasting 4 to 6 hours.[4]
One ampule (44 mEq) of sodium bicarbonate in adults (1.0–2.0 mEq/kg in children) works within 30 minutes
with a duration of 2 hours. Dextrose (25 g in an adult or 1.0 g/kg in a child) plus insulin (10 units of regular
insulin in an adult or 0.1 U/kg in a child) also work within 30 minutes with a 2-hour duration of effect.[28][53][83]
Orally or rectally administered cation exchange resins, such as sodium polystyrene sulfate (Kayexalate),
decrease potassium levels by binding it before elimination from the body. The oral dose is 15 to 20 g mixed
in 30 to 100 mL of a 20 to 70 per cent sorbitol solution to prevent constipation. Rectal administration as an
enema is also effective. Fifty to 60 g is given in 200 mL of tap water and retained at least 30 minutes, but
preferably for 2 to 3 hours. The recommended pediatric oral or rectal dose is 1.0 g/kg.[83] Sodium
polystyrene sulfate releases sodium in exchange for potassium and may precipitate sodium-induced fluid
retention and heart failure.[53][73] It is important to emphasize the appropriate treatment for hyperkalemia in
the setting of cardiac glycoside overdose is the use of antidotal treatment for digoxin poisoning (see Chapter
44 ). The primary cardiotoxic effects in this situation are related to digoxin toxicity, not to hyperkalemia,
which is just a marker of digoxin effects on the Na+,K+-ATPase pump.


CALCIUM
Regulation
Ninety-nine per cent of the body’s calcium is in bone, with 1 per cent in equilibrium between inactive protein
bound and active ionized states. The ionized form mediates the physiologic effects of calcium. Levels of
physiologically active ionized calcium are regulated by vitamin D and parathyroid hormone (PTH). Vitamin D
comes from dietary sources or ultraviolet-mediated skin conversion of 7-dehydrocholesterol to
cholecalciferol, which is converted by liver microsomal enzymes to 25-hydroxycholecalciferol, which is then
converted in the kidneys to the active form, 1,25-dihydrocholecalciferol (Calcitriol). Prolactin, parathyroid
hormone, estrogens, and hypophosphatemia stimulate the final step in the production of 1,25-
dihydrocholecalciferol. Epinephrine, dopamine, and decreases in levels of ionized calcium increase PTH
release. PTH raises serum calcium by increasing calcitriol production and, in combination with calcitriol,
increasing osteoclastic activity and intestinal and renal reabsorption of calcium. Calcitonin, which lowers
serum calcium by decreasing bone osteoclastic activity, is increased primarily by hypercalcemia.[2]
Standard laboratory measurements of calcium reflect the total of bound and ionized calcium, which varies
directly with the serum albumin concentration. Despite wide variations in total calcium levels that reflect
varying serum albumin concentrations, levels of ionized calcium remain constant in the patient whose
calcium regulatory mechanisms are functioning normally. [10][100] An estimate of the normalized serum
calcium is given by the following formula:
Corrected calcium = Serum calcium (mg/dL) + 8[4 – Serum albumin (g/dL)]
Whenever physiologically significant abnormalities in the serum calcium are suspected the ionized calcium
should be measured directly.
Hypocalcemia
Pathophysiology
Calcium is critical to neurotransmitter function within the central and autonomic nervous systems,
neuromuscular junctions, and adrenal medulla. It is required for depolarization of nerves and muscle cells
and for secretion of many hormones, including adrenocorticotropic hormone, adrenal corticosteroids, ADH,
and insulin.[99] Hypocalcemia makes membranes more permeable to sodium, resulting in hyperexcitability.
The symptoms of hypocalcemia are primarily neurologic and correlate with its level and rate of development.
Paresthesias and numbness of the hands, extremities, and face typically occur first and progress to
fasciculations, muscle cramps, carpopedal spasm, tetany, and seizures.[99] Chvostek’s or Trousseau’s signs
may be elicited in patients with minimal hypocalcemic symptoms. Although rare, laryngeal spasm with
dyspnea is the most common cause of death due to hypocalcemia.[99] Cardiac contractility is decreased, and
heart failure can occur. EKG changes include prolonged ST segments and Q-Tc intervals and inverted
terminal T waves.[99] Hypocalcemia manifests in infancy with hyperirritability, twitching, tremors, seizures,
vomiting, and spells of apnea.[57]
Hypocalcemia may result from hypoparathyroidism, pseudohypoparathyroidism, renal failure, short bowel
syndrome, pancreatitis, vitamin D deficiency, and hypomagnesemic or hyperphosphatemic states.
Hyperventilation results in symptoms of tetany due to stimulation of increased protein binding of calcium by
respiratory alkalosis. Many agents can cause hypocalcemia ( Table 10–4 ). Phosphate complexes with
calcium to produce hypocalcemia. Hypocalcemia has been associated with phosphate-containing enema
solutions, ingestions, parenteral infusions, and white phosphorus burns. [14][55] Patients who ingest and
metabolize ethylene glycol may develop hypocalcemia secondary to complexation of the oxalate metabolite
with calcium. Fluoride ions rapidly complex with calcium, and lethal hypocalcemia has occurred in patients
burned with hydrofluoric acid.[45] Induction of the microsomal electron transport system by ethanol,
phenytoin, phenobarbital, or other agents increases the metabolism of vitamin D to an inactive form,
resulting in hypocalcemia.[14] Colchicine and mithramycin inhibit bone resorption[61] whereas cadmium
causes renal tubular defects and calcium wasting.[77] A decrease in ionized serum calcium attributed to the
binding of calcium by foscarnet has been reported in patients treated for cytomegalovirus retinitis with this
agent.[37]
Table 10-4 -- Agents That Affect Serum Calcium

Hypercalcemia Hypocalcemia
Aluminum Increased Phosphate Load
Androgens Enemas
Antacids (calcium-containing) Oral agents
Beta-adrenergic receptor agonists White phosphorous burns
Foscarnet * Increased Urinary Excretion
Lithium Aminoglycosides
Potassium Bicarbonate
Tamoxifen Cadmium
Thiazide diuretics Loop diuretics
Vitamin A Calcium Complexes Formed
Vitamin D Citrate
Oxalate (ethylene glycol)
Fluoride
Microsomal Oxidizing System Induction
Phenobarbital
Hypercalcemia Hypocalcemia
Phenytoin
Inhibition of Bone Resorption
Calcitonin
Cisplatin
Colchicine
Mithramycin
Ethanol
Foscarnet *
Ibuprofen
†
Toluene
Data from references 1 , 14 , 26 , 41 , 52 , 61 , 62 , 85 , 96 and 100 .
* Foscarnet is associated with both hypercalcemia[33] and hypocalcemia.[37]
† Both increased and very decreased magnesium levels associated with suppression of parathormone.
Management
Clinically suspected hypocalcemia should be confirmed by measurement of the ionized calcium. If patients
have significant symptoms (seizures, hypotension, dysrhythmias, or tetany), empirical management should
be initiated before the return of the ionized calcium. Calcium is available either as a 10-mL ampule of 10 per
cent calcium gluconate (93 mg of elemental calcium) or as a 10-mL ampule of 10 per cent calcium chloride
(360 mg of elemental calcium). An initial dose of 100 to 300 mg of elemental calcium will increase the serum
ionized calcium for 1 to 2 hours. If symptoms continue, doses should be repeated or an infusion at a rate of
0.5 to 2.0 mg/kg/hr can be initiated.[71] Children should receive 0.5 to 1.0 mL/kg of 10 per cent calcium
gluconate.[57] Patients with hypomagnesemia may fail to respond to calcium supplementation until
magnesium is also replaced. Calcium chloride has significant tissue toxicity and should only be infused
through a well-secured, large-bore intravenous line. Calcium should not be added to bicarbonate-containing
parenteral solutions because they can precipitate as calcium salts.[53] Asymptomatic patients should receive
oral calcium supplements. Management should also focus on correcting the underlying cause of the
hypocalcemia.
Hypercalcemia
Pathophysiology
Hypercalcemia inhibits neuronal activation and excitability by decreasing membrane permeability to sodium.
Neurotransmitter release is also decreased. Heart contractility is increased and ventricular systole is
shortened, reflecting calcium’s role in cardiac excitation-contraction. Dysrhythmias may result from the
shortened refractory period and slowed conduction. The most consistent EKG changes are Q-Tc interval
shortening with increased PR intervals, widening of the QRS complex, and T wave flattening. The most
common renal effect is loss of concentrating ability. Electrolyte absorption in the proximal tubule and water
permeability in the distal tubule are also decreased.[25][99]
CNS depression is a prominent symptom with fatigue and weakness that may progress to delirium, lethargy,
or coma. Cardiac dysrhythmias may occur, particularly atrioventricular blocks. An osmotic diuresis results in
polyuria with loss of electrolytes and dehydration. Other symptoms include constipation, nausea and
vomiting, and abdominal pain.[99]
Primary hyperparathyroidism is the most common cause of hypercalcemia. The most severe cases of
hypercalcemia result from malignancies metastatic to bone or from tumors with ectopic parathormone
activity. Other causes include immobilization, hyperthyroidism, Addison’s disease, milk-alkali syndrome, and
multiple endocrine adenomas. Toxin-related causes are infrequent and typically due to inappropriate use of
calcium or vitamin D supplements (see Table 10–4 ).[14] Oral calcium, often taken in the form of antacids,
can cause mild elevations.[14] Hypervitaminosis A or D[24] or aluminum-containing antacids[85] increase
osteoclastic bone absorption. Dietary potassium supplementation increases calcium retention by
suppressing calcitriol synthesis.[52] Beta-adrenergic receptor agonists increase PTH secretion.[26] Unlike
loop diuretics, thiazides increase renal tubular calcium reabsorption.[70] Lithium causes hypercalcemia in
patients with primary hyperparathyroidism but not in normal individuals.[14]
Management
Hypercalcemia should be confirmed with evaluation of the ionized calcium. Volume replacement and saline
diuresis are the mainstays of initial therapy. Intravenous normal saline at 2.5 to 4.0 L/d, depending on the
patient’s volume status, can lower total calcium levels by 1.5 to 4.0 mg/dL/d.[10] Loop diuretics enhance the
calciuric effect of diuresis.
Various agents specifically inhibit bone resorption. The biphosphonates, etidronate (7.5 mg/kg intravenously
over 4 hours daily for 3 to 7 days) and pamidronate (15–45 mg daily for up to 6 days) are safe and effective.
They begin to decrease calcium within 2 days of the onset of dosing. The antitumor agent mithramycin (25
µg/kg IV over 3 to 6 hours), a potent inhibitor of RNA synthesis in osteoclasts begins to work within 12 hours
and has maximal reduction in 48 to 72 hours. Unfortunately, it is associated with hepatotoxicity,
nephrotoxicity, and thrombocytopenia and is contraindicated in patients with these disorders.[10][17]
Calcitonin (4–8 units/kg intramuscularly every 6 to 12 hours) begins to inhibit bone resorption within hours of
its administration but is the least effective.[10] Glucocorticoids are helpful when hypercalcemia is due to
hematologic cancers but not other causes.[10]
Mild hypercalcemia (less than 12 mg/dL) usually responds to saline diuresis alone. Severe or persistent
symptoms despite diuresis indicate a need for additional therapy of moderate elevations of 12 to 14 mg/dL.
Regardless of symptoms, all patients with levels greater than 14 mg/dL require the prevention of bone
resorption. Patients with life-threatening symptoms should be treated with calcitonin plus mithramycin, if not
contraindicated, or a biphosphonate. The ultimate management of hypercalcemia requires correction of the
underlying etiology.


MAGNESIUM
Regulation
Magnesium is the second most abundant intracellular cation and is the only cation not under direct hormonal
control. Most magnesium is not readily exchangeable. Bone and skeletal muscle are the major reservoirs,
containing 60 per cent and 20 per cent of the total magnesium, respectively. Only 1 to 2 per cent of the total
body magnesium is in the ECF, and one third of that is protein bound.[62][64] Gastrointestinal absorption is
unregulated, whereas magnesium’s homeostasis is well maintained by its renal elimination.[62] Patients with
normal renal function may vary their daily magnesium excretion from more than 400 mEq/d in those with
hypermagnesemia to less than 1 mEq/d in those with deficiencies.[29] Proximal tubular magnesium
reabsorption is increased by PTH and decreased by volume expansion, osmotic diuresis, hypercalcemia,
and various medications.[62]
Hypomagnesemia
Pathophysiology
Magnesium is a cofactor in most cellular metabolic and energy-related reactions that involve phosphorus,
including membrane-bound ATPase. It is required for glycolysis and oxidative phosphorylation.[97]
Hypomagnesemia results in widespread membrane instability and has diverse neuromuscular and
cardiovascular effects.
Central nervous system and neuromuscular manifestations of hypomagnesemia include hyperexcitability,

seizures, irritability, disorientation, psychotic behavior, ataxia, and athetoid movements. It is unclear whether
these symptoms attributable to hypomagnesemia are due to the magnesium or to the commonly associated
hypocalcemia or hypokalemia.[65] Cardiovascular effects include congestive heart failure and both
supraventricular and ventricular dysrhythmias. EKG changes include ST segment depression, PR interval
prolongation, and QRS complex widening.
Alcoholism is the most common cause of hypomagnesemia in the United States.[65] Diarrheal diseases,
hyperaldosteronism, and renal disorders may also cause hypomagnesemia. Many medications are
associated with hypomagnesemia ( Table 10–5 ). Diuretics are classically associated with
hypomagnesemia[62][65][70]; however, one review suggests that the data supporting this are poor.[21]
Potassium-sparing diuretics protect against diuretic-induced magnesium deficiency.[65]
Table 10-5 -- Agents That Affect Serum Magnesium

Hypermagnesemia Hypomagnesemia
Antacids (magnesium-containing) Increased Urinary Excretion
Cathartics (magnesium-containing) Aminoglycosides
Epsom salt Amphotericin
Lithium Calcium
Cisplatin
Diuretics (loop, thiazide, osmotic)
Ethanol
Growth hormone
Thyroid hormone
Increased Gastrointestinal Loss
Colchicine
Laxatives
Transcellular Shift into Cells
Cardiac glycosides
Insulin
DDT
Fluoride poisoning
Ibuprofen
Data from references 1 , 2 , 41 , 45 , 61 and 64 .
Management
Because serum magnesium levels correlate poorly with total body magnesium, some recommend the
administration of magnesium salts to high-risk patients (alcoholics, patients on loop diuretics) even in the
absence of serum hypomagnesemia. [65] Oral supplementation is adequate for mild (serum level > 1 mEq/L),
asymptomatic hypomagnesemia. Gastrointestinal absorption is slow and inappropriate for significant
depletions. Oral therapy may be complicated by diarrhea. Symptomatic patients or those with serum levels
below 1 mEq/L likely have significant total body depletions of 1 to 2 mEq/kg of body weight.[29] These
patients are best replenished with parenteral magnesium. However, even patients with significant deficits
lose most parenterally administered magnesium in the urine. One gram of salt is equivalent to 4 mmol (8
mEq) of magnesium. Serum magnesium equilibrates slowly with intracellular magnesium, and replacement
of the total body deficit requires at least 3 to 4 days of therapy. Routine parenteral replacement
recommendations vary from 0.5 to 1 mmol/kg (approximately 10 g of magnesium sulfate for a 70-kg adult)
over the first 24 hours[65] to 4 to 6 g of a 10 to 20 per cent solution over 3 hours repeated every 6 to 12
hours.[29][31] Magnesium-deficient patients with malignant dysrhythmias, digoxin toxicity, seizures, or tetany
should be treated more emergently with 2 to 3 g (10–15 ml of a 20 percent solution) of magnesium sulfate
intravenously over 1 minute. This is followed by a continuous infusion of 2 per cent magnesium sulfate (1 g
in 500 mL of dextrose 5 per cent in water) at 100 mL per hour for 5 hours.[65] Parenteral therapy in children
is done with 25 to 50 mg/kg of magnesium sulfate diluted in 25 to 100 mL of normal saline over 20 to 30
minutes. In more emergent situations, the same amount may be provided by direct intravenous bolus.[75]
Serum magnesium should be checked daily. Close monitoring is required in patients with renal impairment,
and the amount of magnesium administered should be decreased in these patients.[29][31] Parenteral
infusions of magnesium may be complicated by hypocalcemia, hypotension, or respiratory depression due
to hypermagnesemia.[53]
Hypermagnesemia
Pathophysiology and Clinical Presentation
Hypermagnesemia causes neuromuscular suppression manifested as decreased deep tendon reflexes and
weakness that can progress to paralysis and respiratory failure. Lethargy is common. Hypotension may
result from decreased vascular tone. Cardioinhibitory actions include bradydysrhythmias, atrial fibrillation,
and heart blocks. EKG changes include increased PR intervals, QRS complex widening, and conduction
delays.[16][65] Death may result from respiratory depression, severe hypotension, or cardiac arrest secondary
to loss of impulse formation and conduction.[65]
Because the kidneys have a profound capacity to excrete magnesium, the most common cause of
hypermagnesemia is renal insufficiency.[62][65] However, patients with normal renal function have developed
profound hypermagnesemia after the acute ingestion of massive magnesium loads.[64][65] Other causes of
hypermagnesemia include hypothyroidism, milk-alkali syndrome, adrenal insufficiency, tumor lysis,
rhabdomyolysis, and hyperparathyroidism.
Various medications can cause hypermagnesemia (see Table 10–5 ). Magnesium is available in many over-
the-counter products, including antacids and laxatives. Most severe cases involving massive gastrointestinal
exposures result from the administration of magnesium sulfate or magnesium citrate as cathartics.[65]
Significant oral exposures have also resulted from ingestion of Epsom salts (magnesium sulfate).[64]
Inadvertent administration has also occurred when ampules of magnesium were mistaken for other
therapeutic agents, such as glucose.[39] Vitamin D supplementation in a patient with renal insufficiency has
resulted in hypermagnesemia. [82]
Management
The first step is to ensure that patients receive no further magnesium. This may be all that is required if there
are no life-threatening signs and the patient has normal renal function. Saline infusions and loop diuretics
promote diuresis. Because calcium will also be diuresed and hypocalcemia may exacerbate the signs and
symptoms of hypermagnesemia, calcium levels should be monitored during therapy. Severely symptomatic
patients, particularly those with cardiac dysrhythmias or neuromuscular manifestations, should receive
calcium intravenously to antagonize the effects of hypermagnesemia. Calcium chloride or gluconate should
be administered at a rate of 100 to 200 mg of elemental calcium every 3 to 5 minutes until the cardiovascular
or neuromuscular instability has been improved.[65] Dialysis should be considered in patients with renal
insufficiency or who do not respond to the just mentioned therapy.[53][65] Dialysis has been used in severely
hypermagnesemic patients who have normal renal function.[43]


PHOSPHATE
Regulation
Phosphate is the major intracellular anion, and serum levels may not reflect the total body stores.
Homeostasis is primarily under the direct hormonal influence of PTH, which increases phosphate excretion
within the proximal renal tubules. Gastrointestinal absorption is relatively unregulated. Transcellular shifts
can be significant, with insulin, glucose, and alkalosis all driving phosphate intracellularly to promote
glycolysis.[62] Phosphate homeostasis is closely related to that of various cations. Bone resorption, induced
by hypophosphatemia, also releases calcium. Magnesium or calcium inhibition of PTH release results in
phosphate retention. Renal tubular reabsorption is inhibited by hypokalemia. [95]
Hypophosphatemia
Pathophysiology
Phosphorus is found in all nucleic acids, phospholipids, and nucleotides. The chemical energy required for
cellular metabolism is stored in phosphorylated adenine (adenosine triphosphate [ATP]) and guanine
(guanosine triphosphate [GTP]) nucleosides. Phosphorus also serves as a cofactor in numerous enzymatic
processes, regulates glycolysis, and is required for the mitochondrial electron transport system.[48] Red
blood cell ATP and 2,3-diphosphoglycerate (2,3-DPG) combine with hemoglobin to decrease its binding of
oxygen. Because phosphate is required for ATP and 2,3-DPG production, hypophosphatemia results in
impaired oxygen delivery. Depletion of ATP in white blood cells results in decreased leukocyte motility,
chemotaxis, and bacterial killing. Most effects of hypophosphatemia reflect the inability of cells to regenerate
ATP when inorganic phosphate falls too low.[66]
The most common effects of hypophosphatemia are neuromuscular and hematologic. Symptoms include
weakness, tremors, paresthesias, decreased deep tendon reflexes, altered mental status, and
hyperventilation. Depletion of red and white blood cells and platelets results in impaired oxygen delivery,
tissue hypoxia, an increased incidence of infections, and bleeding. Rhabdomyolysis due to
hypophosphatemia is seen in starvation and in alcoholics after a few days of carbohydrate loading, which
may occur with hospitalization.[12][50][66]
Hypophosphatemia is associated with decreased oral intake of phosphate, increased urinary excretion
(vitamin D deficiency, renal tubular disorders), and alkalosis. Alcoholism is the most common cause
because of poor oral intake and malnutrition. Medications can cause hypophosphatemia through multiple
mechanisms ( Table 10–6 ). Antacids bind phosphate and prevent its absorption, and symptoms can
develop in as little as 2 weeks.[78] Paracetamol, even without liver failure, is associated with
hypophosphatemia.[42]
Table 10-6 -- Agents That Affect Serum Phosphate
Hyperphosphatemia Hypophosphatemia
Increased Phosphate Load Increased Gastrointestinal Loss
Enemas Antacids (aluminum, magnesium, calcium)
Oral agents Colchicine
White phosphorous burns Iron
Increased Urinary Excretion
Androgens
Bicarbonate salts
Diuretics
Estrogens
Glucagon
Hypomagnesemia
Steroids (chronic)
Transcellular Shift into Cells
Alkalosis
Glucose
Insulin
Salicylates
Toluene
Theophylline
Arginine
Ethanol (chronic, withdrawal)
Paracetamol
Data from references 12 , 22 , 34 , 41 , 55 , 61 , 62 , 66 , 72 , 78 and 96 .
Management
As with any predominantly intracellular ion, determining the magnitude of deficiency is difficult and treatment
is empirical. Asymptomatic patients or those with mild hypophosphatemia (>1 mg/dL) may be managed with
oral supplements such as skim milk (1 g/L) or a phosphate salt (up to 1.3 g/dL).[12][66][90] Those with serum
levels less than 1 mg/dL should receive 2.5 mg/kg of intravenous potassium phosphate or sodium
phosphate, diluted in 1 L, over 6 to 12 hours. Symptomatic patients should receive 5.0 mg/kg.[35][90]
Parenteral administration should be discontinued when the serum phosphate concentration exceeds 2
mg/dL.[12][90] Phosphate administration, particularly parenterally, can worsen hypocalcemia or
hypomagnesemia, and these cations also need to be monitored closely.[12][35][66]
Hyperphosphatemia
Pathophysiology and Clinical Presentation
Symptoms of hyperphosphatemia are primarily due to resultant hypocalcemia. Symptoms reflect

hyperexcitability and are mostly neurologic, including muscle cramps, paresthesias, tetany, and
seizures.[12][66] EKG changes include Q-T c prolongation.[46][66] Metabolic acidosis occurs frequently.[46]
Calcium-phosphate extraskeletal precipitation may occur if the solubility product for phosphate and calcium
is greater than 58 mg/dL.[66]
Hyperphosphatemia is associated with renal failure, hypoparathyroidism, pseudohypoparathyroidism, and

tumor lysis after chemotherapy. Dangerous hyperphosphatemia is rare but can result from the administration
of oral, parenteral, or rectal phosphate preparations. Phosphate enemas have been associated with both
serious morbidity and death, primarily in children.[22][55][72]
Management
Mild hyperphosphatemia does not require treatment except for the treatment of the underlying cause.
Antacids containing divalent cations including aluminum, calcium, or magnesium are effective intestinal
phosphate binders and are the mainstay for preventing hyperphosphatemia of renal failure. Each of these
binders can result in their own complications, and their use requires appropriate attention.[12][66] Assuming
normal renal function, severe acute hyperphosphatemia may be managed with intravenous saline
administration coupled with diuretic therapy.[12] Glucose and insulin administration induce a transcellular
shift with a decrease in plasma phosphate concentration. [12] Hemodialysis may rarely be required if the
hyperphosphatemia has been refractory to standard therapy in the setting of renal failure.[12][66] Intravenous
calcium administration may be cautiously considered in patients with severe symptoms such as tetany or
seizures.[12] However, calcium administration may be complicated by extraskeletal precipitation of calcium
phosphate.


EFFECTS OF DECONTAMINATION TECHNIQUES AND ANTIDOTES ON FLUID AND
ELECTROLYTE BALANCE
Gastric decontamination with syrup of ipecac or lavage generally does not alter fluid or electrolyte levels,
even when using water to facilitate the procedure.[67] However, overzealous lavage with water has resulted
in water intoxication with associated hyponatremia, particularly in children.[6] Hypernatremia due to lavage
with large quantities of normal saline has been described. Isotonic polyethylene glycol solutions have been
used for gastrointestinal surgery preparation and for whole-bowel irrigation decontamination. Doses of up to
1 L/hr do not alter volume status or electrolyte levels.[9][39]
Cathartics
A single dose of a magnesium cathartic is safe, but multiple doses can cause hypermagnesemia.[80]
Magnesium absorption is increased when intestinal motility is decreased.[80] Caution must be exercised
when using magnesium in adults with renal insufficiency or in small children whose immature renal function
may make them more prone to hypermagnesemia. [59]
The hypertonic intestinal load with the cathartic sorbitol causes movement of free water from the body into
the intestinal tract, resulting in diarrheal volumes as large as 4 to 5 L within 12 to 24 hours. Sorbitol caused
severe hypernatremic dehydration in a child after a single excessive dose and in an adult after multiple
doses.[3] When multiple doses of charcoal are used, a cathartic should only be given with the first dose. It is
of concern that in a recent study it was found that charcoal was available only in combination with sorbitol in
16 per cent of the hospitals surveyed.[98]
Antidotes
Some antidotes can cause electrolyte alterations. Dextrose, particularly when accompanied by insulin,
causes potassium to shift intracellularly and hypokalemia may ensue.[53] Euglycemic hyperinsulin therapy
(constant infusion of 4 U/min) plus a 20 per cent dextrose solution to maintain euglycemia has been used to
reverse verapamil toxicity in an animal model. Hypokalemia may result from this therapy.[47] Digoxin-specific
antibody fragments can cause hypokalemia by reactivating the Na +,K+ pump.[7] Alkalinization with sodium
bicarbonate or induced hyperglycemia can cause hypokalemia by shifting potassium intracellularly.
Calcium is used to manage severe hyperkalemia or hypermagnesemia, calcium channel blocker overdose,
fluoride poisoning, and hypocalcemia resulting from ethylene glycol or fluoride poisoning. Overzealous
calcium administration may cause hypercalcemia.
SUMMARY
Fluid and electrolyte abnormalities may result from exposure to various medications and toxins. Fortunately,
the clinical significance of these abnormalities is usually minimal. Some toxins may make hydration
assessment difficult by altering clinical findings and vital signs. Many medications induce the syndrome of
inappropriate ADH, resulting in hyponatremia. Hyponatremia or hypernatremia induced by pharmacologic
agents are often chronic, necessitating slow correction to avoid problems due to rapid fluid shifts.
Hypermagnesemia occurs infrequently unless renal insufficiency is present. Alcoholism is the most common
cause of both hypomagnesemia and hypophosphatemia because of poor nutrition and increased diuresis.
The management of poisoned patients, particularly children, can cause problems. Inappropriate use of either
magnesium products or sorbitol for gastrointestinal decontamination has resulted in electrolyte-related,
deleterious outcomes, particularly in children. Antidotes can affect electrolytes, including hypokalemia
resulting from either dextrose or digoxin specific antibody fragments.


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Pediatrics 1977; 60:305-307.
85. Spencer H, Lender M: Adverse effects of aluminum-containing antacids on mineral metabolism.

86. Spigset O, Hedenmalm K: Hyponatraemia and the syndrome of inappropriate antidiuretic hormone
secretion (SIADH) induced by psychotropic drugs. Drug Safety 1995; 12:209-225.
87. Sporer KA, Mayer AP: Saltpeter ingestion. Am J Emerg Med 1991; 9:164-165.
88. Sterns RH: Severe symptomatic hyponatremia: Treatment and outcome. Ann Intern
Med 1987; 107:656-664.
89. Sterns RH, Riggs JE, Schochet SS: Osmotic demyelination syndrome following correction of
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Chapter 11 – Acid-Base Disturbances in the Poisoned Patient
KATHLEEN A. DELANEY
Acid-base disturbances occur frequently in poisoned patients, both as a primary manifestation of the
poisoning and as a secondary consequence of hypoxia, shock, or seizures. In the patient who is poisoned
with an unknown substance, acid-base disturbances offer a clue to the nature of the toxin ( Table 11–1 ).
Simple and familiar examples of acid-base disturbances in poisoned patients include the respiratory
alkalosis associated with salicylate or theophylline toxicity or the respiratory acidosis commonly noted in
serious opioid and sedative hypnotic overdoses. Mixed acid-base disturbances are also common, for
example, the respiratory alkalosis and metabolic acidosis of salicylate poisoning or the metabolic and
respiratory acidosis that might occur in a patient poisoned with propoxyphene who has had a seizure and
has respiratory depression. Several serious poisonings discussed later are associated with a primary anion
gap metabolic acidosis. In this chapter, a rational clinical approach is offered to the diagnosis of common
pure and mixed acid-base disturbances and both the toxicologic and nontoxicologic differential diagnoses
are reviewed.
Table 11-1 -- General Approach to Acid-Base Disturbances in the Poisoned Patient

1. Determine the pH and PCO2 from the arterial blood gas.
2. Calculate the anion gap from the serum electrolytes.
3. Classify the disturbance:
a. Respiratory alkalosis (see Table 11–8 )
1) Toxic: salicylates, sympathomimetic agents
2) Nontoxic: increased intercerebral pressure, liver failure, hypoxia, heart failure, sepsis
b. Respiratory acidosis (see Table 11–7 )
1) Toxic:
a) Severe: barbiturates, ethanol, opioids, botulism, tetanus
b) Mild to moderate: -hydroxybutyrate, cyclic antidepressants, benzodiazepines
2) Nontoxic: severe hypokalemia, Guillain-Barré syndrome, cervical cord injury, myasthenia gravis
c. Metabolic alkalosis (see Table 11–6 )
1) Toxic: chronic use of antacids, diuretics, licorice
2) Nontoxic: volume depletion (any cause), gastric outlet obstruction, Bartter’s syndrome, hyperaldosteronism,
magnesium deficiency
d. Anion-gap metabolic acidosis (see Table 11–4 )
1) Toxic: chronic use of antacids, diuretics, licorice
a) Common: salicylates, carbon monoxide, paraldehyde, cyanide, isoniazid (+ seizures), iron, methanol,
ethylene glycol, hydrogen sulfide
b) Less common: phenformin, metformin, toluene, ibuprofen
2) Nontoxic: lactic acidosis (nontoxic causes), ketoacidosis, uremia
e. Non–anion gap metabolic acidosis (see Table 11–5 )
1) Toxic: chronic toluene exposure, acetazolamide
2) Nontoxic: bicarbonate wasting conditions such as renal tubular acidosis or diarrhea, ketonuria
f. Mixed disorder
4. For an anion-gap metabolic acidosis, see Table 11–4 .
a. Consider the clinical situation and likely causes of anion-gap acidosis.
b. Measure lactate.
b. Measure lactate.
c. Measure ketones.
d. Calculate the osmol gap.
e. Assess the response to resuscitation.
CHARACTERIZATION OF THE ACID-BASE DISTURBANCE
The primary acid-base disturbances are metabolic acidosis, metabolic alkalosis, respiratory acidosis, and
respiratory alkalosis. These are defined in Table 11–2 . Many combinations of these disturbances are
possible, resulting in mixed disorders. The data provided by the serum electrolytes and an arterial blood gas
analysis are used to identify and characterize the acid-base disturbance.
Table 11-2 -- Specific Acid-Base Disorders

Condition pH Primary Change
Metabolic acidosis <7.35 Decreased bicarbonate
Anion gap
Nonanion gap
Metabolic alkalosis >7.45 Increased bicarbonate
Respiratory acidosis <7.35 Increased PCO2
Respiratory alkalosis >7.45 Decreased PCO2
Mixed disorders Any combination
The first step in the characterization of an acid-base disturbance is to be certain that the laboratory data are
accurate. The clinical formula H+ = 24 × PCO2/HCO3– can be used to confirm the accuracy of acid-base data,
which may be distorted by laboratory error and errors of timing.[27](See Table 11–3 for determination of the
H+ concentration represented by a given pH.) This formula is derived from the Henderson-Hasselbalch
equation pH = pK + log (HCO3–)/(H2CO3), which is a mathematical description of the equilibrium equation
for the bicarbonate buffer system:
Table 11-3 -- Chart to Determine [H+]

pH [H+]
7.00 100
7.05 90
7.10 80
7.15 70
7.22 60
7.30 50
7.40 40
7.52 30
7.60 28
7.70 20
8.00 10
The Henderson-Hasselbalch (H-H) equation * describes the relationship between the three critical variables
that determine the physiologic acid-base state: the pH (the negative log of the hydrogen ion concentration),
the PCO2, and the serum HCO3-. It allows calculation of any of the three acid-base variables, given two of
the three, and helps confirm that the measured components of the acid-base system are consistent with the
laws of systems in equilibrium.[11][27]
* The true H-H equation is pH = pK + log (HCO 3–/H2CO3). The pK (the pH at which 50 per cent of the H2CO3 is dissociated) of carbonic acid is
6.1. The concentration of H2CO3 is given by multiplication of the P CO2 by a constant 0.03 mEq/L/mmHg, which relates the solubility of gaseous
CO2 in liquid. Using these numbers and taking the antilog of both sides, the equation becomes H+ (nmol/L) 24 × P CO 2/HCO 3–.[27]


USE OF THE HENDERSON-HASSELBALCH EQUATION IN THE CLINICAL SETTING
An 18-year-old woman presents with status epilepticus associated with cocaine injection. Her seizures are
controlled after the administration of intravenous diazepam. The arterial blood gas analysis shows a pH of
7.30 and PCO2 of 30 mmHg. The serum HCO3- measured in the chemistry laboratory is 5 mEq/dL.
These numbers do not seem “right,” so their accuracy is checked by the H-H equation, which gives a
calculated HCO3- of 14 mEq/dL:
Because the laws of equilibrium demand that the H-H equation apply in all cases, the inconsistency between
the measured HCO3- and the calculated HCO 3- suggests a laboratory error. Another explanation of this
difference between the calculated and measured serum HCO3- is that the electrolytes were drawn early
during placement of the intravenous line to control the seizures and the arterial blood gas sample was drawn
later when some recovery from the lactic acidosis produced by the seizures had occurred. This “time
discrepancy” between the serum electrolyte measurement and the arterial blood gas measurement is a
common cause of error in acid-base data gathered in the clinical setting.


METABOLIC ACIDOSIS
Metabolic acidosis is a marker of potentially serious underlying illness or poisoning. It is generally well
tolerated and is rarely as important clinically as the process that caused the acidosis. The determination of
the cause of the acidosis is of great concern to the physician because it dictates appropriate therapy. The
following is a step-by-step approach to the diagnosis of the patient with metabolic acidosis.
Step 1: Calculate the Anion Gap
Metabolic acidosis is classified as “anion gap” and “non–anion gap” acidosis. The discussion of processes
that change the anion gap without affecting the acid-base state is beyond the scope of this chapter (see
references 12 , 17 , 27 for more detailed reading). A non–anion gap acidosis is most commonly caused by
the loss of HCO3-, with compensatory retention of chloride to maintain electroneutrality. An anion gap
acidosis is caused by the addition of an acid (AH) to the blood. An acid is a combination of a base or anion
with a hydrogen ion, defined by the equation: AH = A- + H+. When endogenously generated organic acids
(ketoacids, lactic acid) or exogenous acids (salicylates, formic acid from methanol, glycolic acid from
ethylene glycol) are added to serum, they combine with HCO3-, releasing CO2 and H2O and adding an
“unmeasured anion”:
The addition of an acid to blood leads to an increase in the number of “unmeasured anions,” creating an
anion gap. The anion gap is given by the following formula (in mEq/L): Na+ - (Cl- + HCO3–). Because serum
potassium is small and relatively constant, it is usually left out of the equation. The “normal” anion gap
depends on values determined in the specific chemistry laboratory. Historically, the normal anion gap has
been reported to be 12 mEq/L ± 4.[29][34] Because newer instruments measure higher chloride values, the
“normal” anion gap in many laboratories is lower, in the range of 7 mEq/L ± 4.[42]
The term anion gap is somewhat misleading, because the laws of electroneutrality dictate that the number of
anions (negatively charged) and cations (positively charged) in a solution be equal. Anion gap refers to an
increase in the normal amount of unmeasured anions. In normal plasma, the total of “unmeasured” anions
(albumin + phosphate + sulfate + organic acids) is 23 mEq/L, whereas the total amount of “unmeasured”
cations (potassium + magnesium + calcium) is 11 mEq/L. Total serum cations must equal total serum
anions; therefore, unmeasured cations (UC) plus sodium equal unmeasured anions (UA) plus chloride and
HCO3-, which can be transformed to Na+ - (Cl- + HCO3-) = UA - UC = the anion gap. In addition to the
presence of metabolic acidosis, the anion gap is also increased by a decrease in unmeasured cations such
as calcium and magnesium. [1][17][29] A significant decrease in serum albumin will decrease the anion gap by
lowering the unmeasured anions. This may result in underestimation of the significance of a metabolic
acidosis.[13]


ASSESSMENT OF THE PATIENT WITH ANION GAP ACIDOSIS
Step 2: Consider the Common Causes of Anion Gap Metabolic Acidosis ( Table 11–4 )
The presence of an anion gap metabolic acidosis often suggests a serious underlying disorder, especially
when the acidosis persists after resuscitation. Clearly, many poisoned patients will have a history of a toxic
exposure, simplifying the physician’s diagnostic task. In other cases, there will be no history available and
the broader differential diagnosis of the anion gap acidosis must be considered.
Table 11-4 -- Causes of Anion Gap Metabolic Acidosis

Lactic acidosis:
Non-toxic: sepsis, hypoxia, shock, tumors, thiamine deficiency, ischemia (especially bowel infarction)
Toxic: iron, metformin, phenformin, paraldehyde, isoniazid (+ seizures), cyanide, carbon monoxide, sodium
azide, hydrogen sulfide
Mixed acidosis (partial lactate): methanol, ethylene glycol, salicylates, severe ketoacidosis, ibuprofen (rare)
Ketoacidosis: alcoholic, starvation, diabetic
Salicylism: includes lactate and ketoacidosis, as well as salicylic acid
Toxic alcohols: methanol, ethylene glycol (predominantly toxic metabolites plus component of lactic acidosis)
Uremia: accumulation of phosphoric and sulfuric acid metabolites
Benzoic and hippuric acidemia: acute toluene poisoning (rarely detected due to rapid metabolism and renal
clearance of metabolites)
Ibuprofen: propionic acid and metabolites (presumed)
A commonly used mnemonic:
M methanol, metformin
U uremia (creatinine >4 mg/dL, anion gap <25 mEq)
D diabetic ketoacidosis (also alcoholic, starvation)
P paraldehyde, phenformin
I iron, isoniazid, ibuprofen
L lactate (shock, seizures, sepsis, ischemia, carbon monoxide, HsS, cyanide)
E ethylene glycol
S salicylates, solvents
Common nontoxic causes of anion gap acidosis include lactic acidosis from sepsis, shock, hypoxia, and
seizures. Uremia is associated with an anion gap acidosis due to uncleared sulfuric acid and phosphoric
acid moieties. The anion gap generally does not exceed 25 mEq/L in the uremic patient, and an anion gap
acidosis is not seen until the creatinine rises above 4 to 6 mg/dL.[12][29] Ketoacidosis is a common cause of
anion gap acidosis that may be severe. It develops as a consequence of the absence of insulin in the
insulin-dependent diabetic patient or in the carbohydrate-depleted alcoholic patient. Mild ketoacidosis has
also been observed in patients with salicylism and cyanide toxicity. The presence of a significant anion gap
metabolic acidosis in a vomiting alcoholic patient frequently raises concerns about the possibility of a toxic
alcohol ingestion. The demonstration of significant ketoacidosis suggests the alternate diagnosis of alcoholic
ketoacidosis. Initially, ketones may not be measurable in these patient, making the diagnosis more
difficult.[14][21][24] In addition, some lactic acid may be present in patients with severe ketoacidosis.
Several common toxins cause metabolic acidosis as a primary manifestation of their toxicity. Methanol and
ethylene glycol are broken down to acid metabolites, formic acid and glycolic acid, respectively. Lactic
acidosis contributes part of the acidosis caused by these toxic alcohols.[8][15][20] Salicylates cause lactic
acidosis due to uncoupling of oxidative phosphorylation and interfere with fatty acid metabolism, resulting in
mild ketoacidosis.[12][16] In the setting of a severe overdose, iron is associated with a metabolic acidosis
predominantly due to lactate.[30] Phenformin has been associated with lactic acidosis as an unpredictable
response to therapeutic doses.[32][41] Metformin has also been associated with lactic acidosis in the setting
of overdose and in chronic toxicity secondary to decreased renal clearance.[17a][39] Older articles cite
paraldehyde as a cause of lactic acidosis. This agent is no longer used for the treatment of alcohol
withdrawal and is currently of historical interest.[12] Toxins that lead to tissue anoxia such as carbon
monoxide and methemoglobin producers, or toxins that shut down the electron transport system such as
hydrogen sulfide, cyanide, sodium azide, and methanol, are associated with lactic acidosis, which may be
profound.[4][6][9][40] Any toxin that causes shock, hypoxia, or seizures can also produce a lactic acidosis as a
manifestation of these processes. Isoniazid causes a profound lactic acidosis, always in the setting of
seizures.[7] Severe agitation precipitated by poisoning with stimulants such as phencyclidine or cocaine is
also associated with lactic acidosis. Lactate produced by reversible conditions (agitation, seizures,
hypotension, hypoxia) clears rapidly when the precipitating condition is treated. Metabolic acidosis caused
by cellular toxins or by toxins that produce acid metabolites does not clear with treatment of shock or
seizures.[28]
Step 3: Measure the Serum Lactate
In cases of acidosis when the serum lactate level is elevated, the contribution of lactate to the anion gap can
be estimated by subtracting the measured lactic acid level (in millimoles per liter) from the anion gap. If the
measured lactate does not account for the anion gap, the presence of another acid must be suspected.
Step 4: Measure Urine and Serum Ketones
Because the renal threshold for the clearance of ketones is very low, the presence of urine ketones is a
sensitive indicator of the presence of serum ketones.[29] The nitroprusside reaction used in the ketone
dipsticks or Acetest tabs detects only the presence of the serum ketones acetoacetate and acetone. Under
conditions of poor tissue perfusion or when the NADH/NAD+ ratio is elevated, as in alcoholic ketoacidosis, a
significant fraction of the serum ketones may be present as ß-hydroxybutyrate, the reduced form of
acetoacetate. This accounts for the apparent paradoxical increase in serum ketones noted as patients with
severe ketoacidosis improve with therapy, and occasionally for undetectable ketones despite the presence
of severe ketoacidosis.[14][24][26]
Demonstrable ketonuria coupled with metabolic acidosis may also indicate salicylate toxicity. Small amounts
of ketones may be demonstrated in as many as 41 per cent of salicylate poisoned patients, owing to the
disruption of fatty acid metabolism. [16] Ketonuria may also theoretically be seen in cyanide poisoning owing
to the disruption of fatty acid metabolism, but the severe lactic acidosis predominates (see Chapter 86 ).
Step 5: Calculate the Osmol Gap
The serum osmolarity is elevated in the presence of small, uncharged osmotically active molecules such as
alcohols, glycols, sugars such as mannitol, and drug vehicles such as propylene glycol.[10][18] In the
diagnosis of an unexplained anion gap acidosis, the demonstration of an osmol gap is occasionally useful
(although not foolproof) in detecting the presence of a toxic alcohol. The osmol gap is the difference
between the serum osmolality, measured by the technique of freezing point depression, and the serum
osmolarity that is calculated from the major contributors to osmolarity: serum sodium, glucose, and blood
urea nitrogen. (In blood, the osmolality, which is the number of particles or moles per kilogram of solution, is
essentially equivalent to the osmolarity, which is the number of particles or moles per liter of solution). When
detected, the blood ethanol level must also be included in the calculation. A large increase in the osmol gap
suggests the presence of small osmotically active molecules such as propylene glycol, methanol, isopropyl
alcohol, or ethylene glycol.[18] Of these, only methanol and ethylene glycol cause a significant and persistent
acidosis, owing to their conversion to toxic acid metabolites. Propylene glycol is metabolized to lactate and
may cause a transient increase in the anion gap. The following formula, used when the blood urea nitrogen,
glucose, and ethanol levels are given in milligrams per deciliter, is a widely accepted means of calculating
an approximate serum osmolarity.[18][25]
The normal osmol gap has been reported to be less than 10 mOsm.[10][12] However, a wide variation has
been reported in normal populations. A recent determination of the “normal” osmolar gap in a pediatric
emergency department population showed a range of -13.5 to +8.9 mOsm (95 per cent confidence intervals)
when this formula was used.[25] A similar study in an adult emergency department demonstrated osmol gaps
between -10 and + 14 mOsm (95 per cent confidence intervals).[19] A small increase in the osmol gap is
seen in chronic renal failure (< 20 mOsm)[33] and significant lactic and ketoacidosis (< 15 mOsm).[10][31]
Because of the wide range of the normal osmol gap in the healthy population, a “normal” osmol gap does
not exclude a significant toxic alcohol or glycol poisoning. For example, a patient with a baseline osmol gap
of -14 who has a calculated osmol gap of 10 mOsm could have an ethylene glycol level as high as 144
mg/dL.[19] In addition, it is important to note that the toxic metabolites of methanol and ethylene glycol do not
raise the osmol gap, and the gap may not be significantly elevated even in clinically severe poisonings if a
substantial amount of the alcohol has been metabolized.[15][35]
Step 6: Assess the Response to Resuscitation
Lactic acidosis due to shock, hypoxia, and seizures resolves quickly when these conditions are corrected.
Spontaneous correction of a lactic acidosis generally occurs within 1 hour of the cessation of lactic acid
production.[28] A persistent metabolic acidosis suggests the presence of acidosis due to a toxin,
ketoacidosis, or an ongoing lactic acidosis. Toxic causes of ongoing lactic acidosis include methanol,
salicylate, phenformin, metformin, iron, and inhibitors of oxygen transport such as cyanide. Nontoxic causes
of persistent lactic acidosis include bowel infarction and sepsis.[2] In cases of severe ketoacidosis in which
ketones are initially negative owing to a predominance of ß-hydroxybutyrate, the urine dip test should
become positive for ketones as resuscitation progresses.[12]


NON–ANION GAP OR HYPERCHLOREMIC METABOLIC ACIDOSIS ( Table 11–5 )
The toxic differential of this disorder is limited. A common toxic cause of a hyperchloremic metabolic
acidosis is the chronic abuse of toluene-containing substances (glue sniffing).[5][36][38] Although toluene
exposure acutely causes an anion gap acidosis owing to its rapid metabolism to benzoic and hippuric acids,
rapid renal excretion of the hippurate anion associated with retention of chloride leads to a hyperchloremic
acidosis that simulates a renal tubular acidosis. [5] Acetazolamide, by inhibiting carbonic anhydrase,
decreases renal acid clearance and results in a non–anion gap metabolic acidosis.[27] The chloride-
containing acids, such as ammonium chloride, hydrochloric acid, arginine, and lysine hydrochloride also
cause a hyperchloremic acidosis when given in excessive amounts.[27] A hyperchloremic metabolic acidosis
has been reported after inhalation of chlorine gas.[37] Cholestyramine, the chloride anion-exchange resin
used to treat pruritus associated with excess production of bile acids, is also associated with a
hyperchloremic metabolic acidosis when large amounts are used.
Table 11-5 -- Causes of Non–Anion Gap Hyperchloremic Metabolic Acidosis

Renal tubular acidosis (renal losses of bicarbonate)
Rapid infusion of saline (dilutional)
Ketoacidosis (renal losses of ketoacids with retention of chloride)
Gastrointestinal loss of bicarbonate
Diarrhea
Small bowel fluid losses
Ureterosigmoidostomy
Ileal-loop bladder
Acetazolamide (inhibition of carbonic anhydrase)
Chronic toluene use (renal losses of hippurate with retention of chloride)
Cholestyramine
Ammonium chloride
The most common nontoxic causes of hyperchloremic non–anion gap metabolic acidosis include two HCO3-
-wasting conditions: renal tubular acidosis and severe diarrhea. It also occurs in patients with ketoacidosis
who lose large amounts of negatively charged ketones in the urine with subsequent chloride retention. This
may result in a simple hyperchloremic metabolic acidosis, when HCO3- is generated as fast as it is titrated
by production of ketoacids, or there may be a mixed acidosis, with both anion gap and hyperchloremic
patterns.[1][2][12][29] Rapid increase in extracellular volume, such as occurs during volume resuscitation with
normal saline, results in dilution of the serum HCO3- and a hyperchloremic metabolic acidosis.[29]


SIMPLE METABOLIC ALKALOSIS ( Table 11–6 )
Metabolic alkalosis is usually not related to poisoning, although it may occur as an indirect consequence of
poisoning with agents that cause fluid losses through mechanisms such as severe diaphoresis, persistent
vomiting, or increased urine output. Excessive use of HCO3- in the treatment of dyspepsia, or abuse of
diuretics for weight control, may result in significant alkalemia. A normovolemic patient without endocrine
abnormality will rapidly excrete a HCO3- load and will not become alkalemic. The maintenance of a
metabolic alkalosis requires two factors:
1. A source of HCO3-, either endogenous (loss of hydrogen ion and retention of HCO3- through vomiting
or aldosterone-stimulation of renal tubules) or exogenous (NaHCO3, Ringer’s lactate, sodium citrate)
and
Table 11-6 -- Causes of Metabolic Alkalosis

Toxic
Licorice (chronic ingestion)
Sodium bicarbonate (chronic use)
Diuretics
Antacids
Penicillins
Nontoxic
Volume depletion
Mineralocorticoid excess
Gastric outlet obstruction
Bartter’s syndrome
Liddle’s syndrome
Magnesium deficiency
Severe potassium depletion
2. A stimulus to the renal tubules to reabsorb HCO3- and secrete hydrogen ion. The latter stimulus is
supplied most commonly by contraction of extracellular volume and secondary stimulation of
aldosterone secretion. The most common causes of metabolic alkalosis are persistent vomiting and
diuretic use.[11]
A rare cause of alkalemia is the presence of excess mineralocorticoid, as may be seen in an aldosterone-
secreting tumor or Cushing’s syndrome. When the cause is in doubt, a random urinary chloride will help to
distinguish the patient with metabolic alkalosis due to volume depletion from the patient with
mineralocorticoid excess. Metabolic alkalosis in the normovolemic patient with mineralocorticoid excess is
associated with a urinary chloride concentration of more than 10 mEq/L. The volume-depleted patient will
show a urinary chloride excretion of less than 10 mEq/L, unless a diuretic is still acting on the renal
tubules.[11]
Another rare cause of alkalemia is severe potassium depletion, in which hydrogen ion is secreted by the
renal tubules in exchange for potassium (paradoxical aciduria).
Excessive use of licorice has been associated with metabolic alkalosis, owing to the effects of glycyrrhizic
acid, which are like a mineralocorticoid.


RESPIRATORY ACIDOSIS ( Table 11–7 )
Respiratory acidosis is caused by depression of ventilation, leading to retention of CO2. In acute respiratory
acidosis, the blood pH is decreased in proportion to the degree of CO2 retention. A familiar example of acute
respiratory acidosis is the patient with a heroin overdose whose arterial blood gas is pH 7.20, PCO2 is 63
mmHg, and serum HCO3- level is 24 mEq/L.
Table 11-7 -- Causes of Respiratory Acidosis

Agents causing central nervous system sedation (opioids, sedative-hypnotics, barbiturates)
Botulism
Tetanus toxin
Cervical cord injury
Severe neuropathy or myopathy (Guillain-Barré syndrome, myasthenia gravis)
Primary pulmonary disorders (restrictive, obstructive)
Upper airway obstruction
Severe hypokalemia
A useful rule of thumb in the patient with acute respiratory acidosis is given by the following: For each 10
mmHg increase in PCO2, the pH decreases by 0.08 mEq.
Many toxins cause respiratory depression, resulting in respiratory acidosis. The most severe depression of
respiration is seen in overdoses of opioids and barbiturates. The hypoxia associated with overdoses of these
agents, and the hypotension associated with barbiturate toxicity, also result in concomitant lactic acidosis.
Other sedative-hypnotic agents such as ethchlorvynol, methaqualone, chloral hydrate, and ethanol as well
as isopropanol also cause significant respiratory acidosis after large ingestions. Milder respiratory
depression is typically seen after large ingestions of benzodiazepines, gamma-hydroxybutyrate, and other
sedative agents such as carbamazepine and neuroleptics. Respiratory impairment by botulinum or tetanus
toxin may also result in acute respiratory acidosis.
Respiratory acidosis may complicate and increase the severity of acidosis during salicylate toxicity or
increase the cardiotoxicity of cyclic antidepressants.
Chronic respiratory acidosis is associated with compensatory renal excretion of HCO3- so that the pH of the
blood is normal (compensatory metabolic alkalosis). A familiar example of this is the patient with chronic
obstructive pulmonary disease (COPD) whose arterial blood gas is pH 7.40, PCO2 is 60 mmHg, and serum
HCO3- level is 36 mEq/dL. Chronic respiratory acidosis is a result of chronic impairment of ventilation in
patients with COPD or neuromotor impairment of respiration and is not a consequence of acute poisoning.


RESPIRATORY ALKALOSIS ( Table 11–8 )
In acute respiratory alkalosis, the pH of the blood is elevated in proportion to the degree of depression of
PCO2. An example of acid-base values in a patient with acute respiratory alkalosis is pH, 7.70; PCO2, 20
mmHg; and serum HCO3- level, 24 mEq/L. Again, a useful rule of thumb for acute respiratory alkalosis is
given by the following: For each 10 mmHg decrease in PCO2 the pH increases by 0.08.
Several toxins and conditions secondary to poisoning are associated with respiratory alkalosis. Salicylates,
strychnine, theophylline, and sympathomimetic agents cause central respiratory stimulation resulting in
respiratory alkalosis. Hypoxia from aspiration or adult respiratory distress syndrome or increased intracranial
pressure from hemorrhage or head injury may also lead to respiratory alkalosis in the intoxicated patient.
Acute hepatic failure, meningitis, sepsis, shock, and acute cardiopulmonary conditions such as pulmonary
embolism, asthma, tamponade, and pneumothorax may all cause respiratory alkalosis. A differential
diagnosis of acute respiratory alkalosis is given in Table 11–8 .
Table 11-8 -- Causes of Respiratory Alkalosis

Early sepsis
Salicylism
Sympathomimetics (e.g., theophylline, amphetamine, cocaine)
Hepatic insufficiency
Psychogenic
Hypoxia
Pericardial effusion/tamponade
Heart failure
Shock
Increased intracranial pressure
Meningoencephalitis
In chronic respiratory alkalosis, significant renal compensation leads to increased excretion of HCO3- so that
the pH of the blood is normal (compensatory hyperchloremic metabolic acidosis). A familiar example is a
long stretch of mild bronchospasm or hypoxia, resulting in a patient with pH, 7.42; PCO2, 20; and serum
HCO3-, 12 mEq/dL.


MIXED ACID-BASE DISORDERS
Several acid-base disturbances may occur simultaneously in the same patient. Although sometimes
challenging, the diagnoses of these processes can be accomplished with some thought and clinical
understanding. The following examples review the most common and clinically relevant mixed acid-base
disturbances.
Patient with Metabolic Acidosis and Respiratory Alkalosis
The rule in metabolic acidosis ( Table 11–9 ) is that the compensatory increase in the respiratory drive does
not overcompensate for the decreased pH; that is, the pH only approaches and is never greater than normal
unless there is a coexistent second acid-base disturbance such as a primary respiratory alkalosis. [3] Clinical
settings in which one might see a respiratory alkalosis and anion gap metabolic acidosis include salicylate
toxicity, theophylline toxicity associated with seizures, and sepsis or head injury with shock or seizures.
Normal renal compensation for a primary respiratory alkalosis would have a respiratory alkalosis with
non–anion gap metabolic acidosis. An example of this type of mixed disturbance would be a patient with a
serum HCO3- level of 12 mEq/L with pH of 7.53 and PCO2 of 15 mmHg.
Table 11-9 -- Clinical Rules of Thumb Regarding the “Pure Metabolic Acidosis”
1. Respiratory compensation never raises the pH to normal (>7.35)[3]
2. Experimental observation: PCO2 does not go lower than 10 mmHg[3][21]
3. Experimental observation: The PCO2 is approximately [1.5 × bicarbonate + 8 ± 2][3][11][21]
4. For a pure anion gap acidosis, the increase in the anion gap should equal the decrease in the bicarbonate.
Patient with Metabolic Acidosis and Respiratory Acidosis
The degree of respiratory compensation that is normally shown by patients with metabolic acidosis is given
by Winter’s equation, which was derived from observation of patients with uncomplicated acute metabolic
acidosis. The expected PCO2 is approximated by the expression: PCO2 = [1.5 × serum HCO3- + 8] ± 2. This
equation is used primarily to detect relative hypoventilation. Patients whose P CO2 is higher than that
predicted by this equation have a superimposed respiratory acidosis. Sometimes this finding simply provides
a clue to a subtle second underlying disorder, and at other times the mixed disturbance is clinically serious
and usually obvious. Consider the patient with a mixed overdose of salicylate and secobarbital with an
arterial blood gas of pH 6.9 and P CO2 of 40 mmHg. Although the PCO2 is normal, the inappropriate degree of
respiratory compensation for this metabolic acidosis is intuitively apparent, and most clinicians would
intubate this patient without resorting to any calculation. In another case, Winter’s equation suggests an
overlooked therapy. A patient took an overdose of propoxyphene and arrived having seizures with an arterial
blood gas of pH 7.10, PCO2 of 30 mmHg, and serum HCO3- level of 9 mEq/L. Winter’s equation (1.5 × 9 + 8)
predicts a PCO2 of 21 mmHg. Clearly, the respiratory compensation for the metabolic acidosis caused by the
seizures is inadequate and is a reminder of the need to manage the respiratory depression caused by the
opioid.
In addition to mixed overdoses, other common clinical settings in which a mixed respiratory acidosis and
metabolic acidosis might occur include (1) barbiturate overdoses with hypotension or (2) seizures or primary
ventilatory impairment and metabolic acidosis.
Patient with a Mixed Metabolic Disturbance
Mixed metabolic disturbances, especially the presence of an anion gap metabolic acidosis and a metabolic
alkalosis, are quite common. The most familiar example is the patient with diabetic ketoacidosis and
persistent vomiting. The vomiting causes loss of hydrogen ion, and a potentially significant metabolic
alkalosis may develop; however, the ongoing production of ketoacids neutralizes the HCO3-. The result may
be a normal or near-normal serum HCO3- with a large anion gap representing the metabolic acidosis. The
best way to analyze this condition is to recognize that for a simple anion gap metabolic acidosis the
magnitude of the increase in the anion gap should approximate the decrease in the serum HCO3- (of course,
we can only approximate the baseline “normal” anion gap). With a superimposed metabolic alkalosis, the
magnitude of increase in the anion gap is greater than the magnitude of the decrease in serum HCO3-; that
is, the change in the anion gap (delta AG) is greater than the change in the serum HCO3- (delta BC).
Situations in which HCO3- is relatively increased, indicating a superimposed metabolic alkalosis, include the
vomiting patient with anion gap metabolic acidosis and the patient with anion gap metabolic acidosis who
has been treated with NaHCO3.[12][17][27]
A very significant metabolic alkalosis, such as that seen in patients with gastric outlet obstruction, may result
in an anion gap in the range of 18 to 20 mEq/L. This is due to the effect of alkalemia in increasing negative
charges on serum proteins and may cause some confusion in the assessment of these patients.[17][23]
When the delta BC is greater than the delta AG, an anion gap metabolic acidosis and a hyperchloremic
non–anion gap metabolic acidosis are present. This “brain teaser” is either clinically obvious or not
particularly significant. It might occur in a patient with a renal tubular acidosis who develops a superimposed
anion gap metabolic acidosis or in a patient with massive diarrhea who develops hypovolemic shock. It also
commonly occurs in the patient with diabetic ketoacidosis when large amounts of ketones are excreted in
the urine.[17][27]
Diagnosis of Mixed Acid-Base Disorders
Definitions and Normal Values
Serum HCO3- = 24 mEq/L

Arterial blood gases: pH =7.40, PCO2 = 40
mmHg
Anion gap = 7 ± 4 mEq/L
Delta BC = change in serum HCO3-
Delta AG = approximated change in anion gap
Case 1
An 80-year-old man has been confused and complaining of shortness of breath for 1 week. He also has a
hearing problem and has seen three otolaryngologists in the past month. Chest radiograph suggests
noncardiogenic pulmonary edema. The following were determined: Na+, 140 mEq/L; K+, 3.0 mEq/L; Cl-, 108
mEq/L; HCO3–, 12 mEq/L; glucose, 120 mg/dl; pH, 7.53; PCO2, 15 mmHg; and PO 2, 70 mmHg. Serum
salicylate level is 70 mg/dL.
1. Calculate the anion gap: 140 - (108 + 12) = 20 mEq/L
2. Calculate the delta BC: 24(normal) – 12 = 12 mEq/L
3. Approximate the delta AG: 20 - 7 = 13 mEq/L (close enough!)
Diagnoses
Respiratory alkalosis (salicylate toxicity with central nervous system stimulatory effect and hypoxia
secondary to pulmonary edema)
Anion gap acidosis (salicylism)
Case 2
A 23-year-old man complained of weakness. He had a history of chronic solvent abuse. The following were
determined: pH, 7.17; PCO2, 35 mmHg; PO 2, 110 mmHg; Na+, 149 mEq/L; K+, 1.0 mEq/L; Cl-, 129 mEq/L;
and HCO3-, 10 mEq/L.
1. Calculate the anion gap: 149 - (129 + 10) = 10 mEq/L (normal)
2. Calculate the expected PCO2 (Winter’s equation): [1.5 × HCO 3-] + 8 = 23 ± 2 mmHg
Diagnoses
Non–anion gap metabolic acidosis (chronic toluene abuse)

Respiratory acidosis (hypokalemic myopathy, also due to
toluene)
Case 3
A 45-year-old alcoholic man has been vomiting for 3 days. His blood pressure is 100/70 mmHg, and his
pulse is 110 beats per minute. The physician just gave him 30 mg of diazepam for tremulousness. The
following were determined: pH, 7.29; PCO2, 43 mmHg; Na+, 145 mEq/L; K+, 3.0 mEq/L; Cl-, 96 mEq/L; and
HCO3-, 19 mEq/L. Serum ketones are positive at 1:2.
2. Calculate the delta BC: 24 (normal) – 19 = 5 mEq/L
3. Calculate the expected PCO2 (Winter’s equation): 1.5 × 19 + 8 = 36.5 ± 2 mmHg
4. Approximate the delta AG: 30 - 7 = 23 mEq/L
Diagnoses
Metabolic alkalosis (vomiting, delta AG > delta BC)

Anion gap metabolic acidosis (likely alcoholic ketoacidosis, given the clinical
picture)
Respiratory acidosis (mild and relative, possibly due to diazepam)
Case 4
A 22-year-old woman took an overdose of propoxyphene. She arrived actively seizing in the emergency
department. The following laboratory studies were obtained on arrival: pH, 7.10; PCO2, 30 mmHg; Na+, 140
mEq/L; K+, 3.4 mEq/L; Cl-, 106 mEq/L; HCO3-, 9 mEq/L.
2. Calculate the expected PCO2: = [1.5 × 9] + 8 = 21.5 ± 2 mmHg
3. Calculate the delta BC: 24 - 9 = 15 mEq/L
4. Calculate the delta AG: 25 - 7 = 18 mEq/L
Diagnoses
Anion gap metabolic acidosis (probably lactic acidosis from

seizures)
Acute respiratory acidosis (opioid toxicity)
Case 5
A 27-year-old woman with a past history of significant iron overdose and subsequent pyloric stricture has
been vomiting for 2 weeks. On admission her pulse is 140 beats per minute and her blood pressure is 60
mmHg by palpation. Also she had pH, 7.40; PCO2, 40 mmHg; PO 2, 300 mmHg on a 50 per cent mask; Na+,
150 mEq/L; K+, 2.6 mEq/L; Cl-, 86 mEq/L; HCO3-, 24 mEq/L; blood urea nitrogen, 80 mg/dL; creatinine, 3.0
mg/dL.
2. Calculate the delta BC: 0
3. Calculate the delta AG: 40 - 7 = 33 mEq/L
Diagnoses
Anion gap metabolic acidosis (hypotension with shock, delta AG > delta
BC)
Metabolic alkalosis (gastric outlet obstruction, vomiting)
Case 6
Mr. Jones is a 22-year-old man with polyuria and polydipsia for 1 week and intractable vomiting for 4 days.
Today he is critically ill, with a temperature of 104°F. The following were also determined: Na +, 150 mEq/L;
Cl-, 100 mEq/L; HCO3-, 20 mEq/L; K+, 3.8 mEq/L; blood urea nitrogen, 50 mg/dL; creatinine, 1.8 mg/dL;
glucose, 650 mg/dL; serum ketones, +1:8; pH, 7.50; PCO2, 26 mmHg; and PO 2, 100 mmHg.
2. Calculate the delta BC: 24 - 20 = 4 mEq
3. Approximate the delta AG: 30 - 7 = 23 mEq
Diagnoses
Anion gap metabolic acidosis (diabetic

ketoacidosis)
Concurrent metabolic alkalosis (vomiting)
Respiratory alkalosis (sepsis?)


REFERENCES
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2. Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. N Engl J

Med 1998; 338:26-34.
3. Albert MD, Dell RB, Winters RW: Quantitative displacement of acid-base equilibrium in metabolic
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4. Albertson TE, Reed S, Siefkin A: A case of fatal sodium azide ingestion. Clin Toxicol 1986; 24:339-351.
5. Batlle DC, Sabatina S, Kurtzman NA: On the mechanism of toluene-induced renal tubular acidosis.
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6. Baud FJ, Barriot P, Toffis V, et al: Elevated blood cyanide concentrations in victims of smoke inhalation.
N Engl J Med 1991; 325:1761-1766.
7. Blanchard PD, Yao JDC, McAlpine DE, Hurt RD: Isoniazid overdose in the Cambodian population of
Olmsted County, Minnesota. JAMA 1986; 256:3131-3133.
8. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of ethylene glycol poisoning:
Methylpyrazole Toxic Alcohols Study Group. N Engl J Med 1999; 340:832-838.
9. Buehler JH, Berns AS, Webster JR, et al: Lactic acidosis from carboxyhemoglobinemia after smoke
inhalation. Ann Intern Med 1975; 82:803.
10. Dorwart WV, Chalmers L: Comparison of methods for calculating serum osmolality from chemical
concentrations and the prognostic value of such calculation. Clin Chem 1975; 21:190-194.
11. Dubose Jr TD: Acidosis and alkalosis. In: Fauci A, Braunwald E, Isselbacher KJ, et al ed. Harrison’s
Principles of Internal Medicine, New York: McGraw-Hill; 1998:277-286.
12. Emmett M, Narins RG: Clinical use of the anion gap. Medicine 1977; 56:38-54.
13. Figge J, Jabor A, Kazda A, Fenci V: Anion gap and hypoalbuminemia. Crit Care Med 1998; 26:1807-
1810.
14. Fulop M, Hoberman HD: Alcoholic ketosis. Diabetes 1975; 25:785.
15. Gabow PA, Clay K, Sullivan JB, Lepoff R: Organic acids in ethylene glycol intoxication. Ann Intern
Med 1986; 105:16-20.
16. Gabow PA, Anderson RJ, Potts DE, Schrier RW: Acid-base disturbances in the salicylate-intoxicated
adult. Arch Intern Med 1978; 138:1481-1484.
17. Gabow PA: Disorders associated with an altered anion gap. Kidney Int 1985; 27:472-483.
17a. Gan SC, Barr J, Arieff AI, Pearl RG: Biguanide-associated lactic acidosis: Case report and review of
the literature. Arch Intern Med 1992; 152:2333-2336.
18. Gennari FJ: Serum osmolity: Uses and limitations. N Engl J Med 1984; 310:102-105.
19. Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR: Osmol gaps revisited: Normal values and
limitations. Clin Toxicol 1993; 31:81-93.
20. Jacobsen D, Webb R, Collins TD, McMartin KE: Methanol and formate kinetics in late diagnosed
methanol intoxication. Med Toxicol 1988; 3:418-423.
21. Levy LJ, Duya J, Girgis M, et al: Ketoacidosis associated with alcoholism in nondiabetic subjects. Ann
Intern Med 1973; 78:213.
23. Madias NE, Ayus JC, Adrogue HJ: Increased anion gap in metabolic alkalosis: The role of plasma
protein equivalency. N Engl J Med 1979; 300:1421-1423.
24. Marliss EB, Ohman JL, Aoki TT, et al: Altered redox state obscuring ketoacidosis in diabetic patients
with lactic acidosis. N Engl J Med 1970; 283:978.
25. McQuillen KK, Anderson AC: Osmol gaps in the pediatric population. Acad Emerg Med 1999; 6:27-30.
26. Miller PD, Heinig RE, Waterhouse C: Treatment of alcoholic acidosis. Arch Intern Med 1978; 138:67.
27. Narins RG, Emmett M: Simple and mixed acid-base disorders: A practical approach.
Medicine 1980; 59:161-187.
28. Oh MS, Uribarri J, Carroll HJ: Electrolyte case vignette: A case of unusual organic acidosis. Am J
Kidney Dis 1988; 11:80-82.
29. Oh MS, Carroll HJ: The anion gap. N Engl J Med 1977; 287:814-817.
30. Robotham JL, Lietman MD: Acute iron poisoning: A review. Am J Dis Child 1980; 134:875-879.
31. Schelling JR, Howard RL, Winter SD, Linas SL: Increased osmol gap in alcoholic ketoacidosis and
lactic acidosis. Ann Intern Med 1990; 113:580-582.
32. Searle GL, Siperstein MD: Lactic acidosis associated with phenformin therapy: Evidence that inhibited
lactate oxidation is the causative factor. Diabetes 1975; 24:741-745.
33. Sklar AH, Linas SL: The osmolal gap in renal failure. Ann Intern Med 1983; 98:481-482.
34. Smithline N, Gardner Jr KD: Gaps—anionic and osmol. JAMA 1976; 236:1594-1597.
35. Steinhart B: Severe ethylene glycol intoxication with normal osmol gap—“a chilling thought.”. J Emerg
Med 1990; 8:583-585.
36. Streicher JZ, Gabow PA, Moss AH, et al: Syndromes of toluene sniffing in adults. Ann Intern
Med 1981; 94:758-762.
37. Szerlip HM, Singer I: Hyperchloremic metabolic acidosis after chlorine inhalation. Am J
Med 1984; 77:581-582.
38. Taher SM, Anderson RJ, McCarthy R, et al: Renal tubular acidosis associated with toluene sniffing. N
Engl J Med 1974; 290:765-768.
39. Teale KF, Devine A, Stewart H, Harper NJ: The management of metformin overdose.
Anaesthesia 1998; 53:698-701.
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Toxicology of Cyanide, Bristol, England: Wright; 1987.
41. Williams RH, Palmer JP: Farewell to phenformin for treating diabetes mellitus. Ann Intern
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Med 1990; 150:311-313.


Uncited reference
Levinsky NG: Acidosis and alkalosis. In: Wilson JD, Braunwald E, Isselbacher KJ, ed. Harrison’s Principles
of Internal Medicine, New York: McGraw-Hill; 1991:289-295.


Chapter 12 – Special Considerations in the Pregnant Patient
KATHLEEN SHILALUKEY GIDEON KOREN
Acute or chronic exposure to potential hazards, whether drug, chemical, or irradiation, can have major
adverse effects on the outcome of pregnancy.[41 ] Although it is standard practice that the mother’s welfare
determines her need for drug therapy, many factors, including cultural norms, may affect this decision as
well.[2 ] [3 ] [4 ] [5 ] [6 ] [7 ] [8 ] [9 ] [10 ] [11 ] [12 ] [13 ] [14 ] [15 ] [16 ] [17 ] [18 ] [19 ] [20 ] [21 ] [22 ] [23 ] [24 ] [25 ] [26 ] [27 ] [28 ] [29
] [30 ] [31 ] [32 ] [33 ] [34 ] [35 ] [36 ] [37 ] [38 ] [39 ] [40 ] [41 ] [42 ] [43 ] [44 ] [45 ] [46 ] [47 ] [48 ] [49 ] [50 ] [51 ] [52 ] [53 ] [54 ] [55 ] [56
Quite often, a pregnant woman may willfully consume massive
] [57 ] [58 ] [59 ] [60 ] [61 ] [62 ] [63 ] [64 ] [65 ] [66 ] [67 ]
doses of harmful drugs or chemicals with the intention of committing suicide or inducing an abortion,
therefore precipitating an acute toxicologic emergency.
In prescribing medication to pregnant women, the benefits of therapy must outweigh the risks. Apart from
direct cost, adverse effects and their economic costs must be considered. In order to provide optimal care
and avoid potential problems, it is vital to have a thorough knowledge of the drug in question. Drug
information varies in quality, usefulness, validity, and credibility. Drug information as it relates to pregnancy
often suffers from a paucity of data and conflicting reports owing to the ethical limitations on the conduct of
such research. To acquire accurate drug information, a combination of literature reviews and consultation
with health professionals and drug information centers is necessary. Communication with the manufacturers
of the drugs concerned is also helpful.
Conventional methods of acquiring authoritative knowledge on drug use in pregnancy have ranged from
case reports (extremely useful when a small number of cases of adverse effects producing consistent
malformations arise from a rare drug) to epidemiologic studies conducted prospectively or retrospectively.
The impact of meta-analysis (the statistical combination of research from independent studies as a method
of summarizing the literature either for observational studies or for controlled clinical trials) has been
important in minimizing bias and using reliable studies.
The creation of teratogen information services in North America and Europe during the past decade has
increased information on issues concerning drug administration in pregnancy and decreased unjustified
fears after exposure to nonteratogens. This has also been shown to reduce unjustified elective abortions that
may occur owing to misinformation on drugs used in pregnancy.
The past decade has experienced the introduction of new techniques to evaluate fetal exposure to drugs,
including the detection of chemicals in neonatal hair and meconium. Furthermore, new in vitro methods such
as the placental perfusion model help elicit new information on drug and chemical transport into the fetal
compartment that cannot be studied in pregnancy owing to obvious ethical limitations.
This chapter addresses characteristics of acute and chronic toxicologic exposures in pregnancy. The figures
and tables review the management of a poisoned pregnant woman and the adverse effects to the neonate
for commonly used drugs and those most harmful during pregnancy. General management principles for the
poisoned mother and the management of selected toxins are alluded to, highlighting special considerations
for selected drugs ( Figs. 12–1 and 12–2 ; Tables 12–1 and 12–2 ).
Figure 12-1 The management of poisoning in a pregnant patient.
Figure 12-2 Pharmacokinetic variables affected by physiologic changes in pregnancy.
Table 12-1 -- Clinical Implications of Drug Consumption and Exposure in Pregnancy

Anticonvulsants[7 ] [11 ] [18 ] [26 ] [38 ]
Drug concentration levels fall because of extracellular fluid with increased Vd; decreased plasma protein binding,
with more free drug for biotransformation; folate supplementation, which increases liver metabolism of phenytoin;
increased GFR, which results in faster clearance rates of drugs eliminated by the kidney
Seizure frequency is increased in 45%, unchanged in 50%, and decreased in 5%
Phenytoin: fetal hydantoin syndrome (see Fig. 12–1: characteristic facial alterations, hypoplastic distal phalanges
and nails), microcephaly, mental retardation, neuroblastoma, cardiac defects, sevenfold increased risk for global
IQ =84
Declining total antiepileptic serum concentrations with increasing free levels may result in toxicity; hence blood
levels should be checked regularly. As polytherapy increases teratogenic risk, monotherapy should be used
wherever possible (e.g., carbamazepine as a first-line drug for grand mal seizures). 4 mg/day of folate decreases
the risk of NTD. Level II ultrasound † and maternal a-feto-proteins or amniocentesis useful to rule out NTDs.
* Carbamazepine
Primidone: phenytoin-like abnormalities
* Phenytoin
Carbamazepine: increased risk for NTD—estimated risk of 1%
* Ethosuximide
Valproic acid: estimated risk of 1–2% for NTD
* Phenobarbital
Ethosuximide: fetal hemorrhage
* Valproic acid
* Primidone
Relative risk of teratogenicity: Risk unknown; however, 5–10% conform to a typical syndrome
Antipsychotics/antidepressants[29 ]
* Lithium carbonate
Drug concentration levels fall due to pregnancy-induced increase in GFR
Patients experience more depression spells
Probable higher risk for Ebstein’s anomaly, spina bifida, VSD, mitral atresia, neonatal withdrawal symptoms,
neonatal jaundice, rapid breathing, cyanosis, bradycardia, urinary retention, GI bleeding, diabetes insipidus,
shock, hyperthyroidism
0.1% of pregnant women use lithium. Lithium crosses the placenta, with concentrations being similar on maternal
and fetal sides. Women needing lithium therapy should continue the drug and undergo ultrasound and
echocardiogram follow-up at 18 weeks as higher doses are used owing to increased clearance rates. However,
after birth, GFR returns to prepregnancy levels, warranting reduction in dose administered. Careful follow-up of
renal and thyroid function tests indicated in neonate. Lithium is not a major teratogen, as reported in earlier
studies.
Lithium has a narrow toxic-therapeutic range; hence the drop in concentration may result in suboptimal therapy
Cyclics (amitriptyline, desipramine)
Desipramine, the major metabolite of imipramine, is also associated with withdrawal signs (e.g., cyanosis,
tachycardia, diaphoresis, weight loss)
Caregivers should be advised of patients on cyclics.
Relative risk of teratogenicity: Initial cases of bilateral amelia not shown to be associated with teratogenicity in
cyclics in subsequent studies
Desipramine inhibits sperm motility in vitro.

Fluoxetine[54 ]
A prospective collaborative study did not show increased risk of major malformation despite earlier studies
implicating fluoxetine in increased prematurity and increased stillbirths and miscarriages
Women treated simultaneously with CAs and fluoxetine have higher rates of miscarriages; hence it is not wise to
prescribe these drugs concurrently.
Anticoagulants[25 ]
Hydroxycoumarins cause fetal warfarin syndrome: characteristic facial alterations, CNS and skeletal
malformations, mental retardation, optic nerve atrophy
The use of heparin in the first trimester should be encouraged, as it does not cross the placenta.
* Hydroxycoumarins (see Fig. 12–2 )
Critical time of exposure is 6–12 weeks gestation, associated with defective ossification of bone, resulting in
nasal hypoplasia and chondrodysplasia punctata; second and third trimester exposure produces optic nerve
atrophy, microcephaly, mental retardation
Women on anticoagulants should be followed up in a high-risk perinatal unit.
Relative risk of teratogenicity: 16% of exposed fetuses have malformations, 3% hemorrhages, 8% stillbirths
Increase in stillbirths, preterm delivery, and death

Risks of coumadin increase toward term and delivery; discontinue its use at 36 weeks to minimize effects.
Heparin[69 ]
Although subcutaneous heparin does not cross the placenta, dose-related bone demineralization causing
osteoporosis in the mother may arise.
* Alkylating agents[7 ] (busulfan, chlorambucil, cyclophosphamide, methlorethamine)
Depends on condition: Acute leukemias have increased spontaneous abortions, premature births, and stillbirths;
also have increased maternal bleeding and infections if mother’s peripheral blood counts are suppressed by
chemotherapy.
Cytotoxic drugs exert effects predominantly on rapidly dividing cells, affecting fetal development and causing
abortion or teratogenicity if given in first trimester
Chemotherapy required for acute leukemia has to be commenced once the diagnosis has been made. However,
therapeutic abortions may be recommended if the diagnosis was made in the first half of pregnancy and poor
maternal prognosis and the effects of multidrug chemotherapy on the fetus have been considered. To initiate
breast cancer treatment in the presence of metastases, termination of pregnancy would be necessary.
Chemotherapy exposure of the female fetus causes concern, as mutations/chromosomal aberrations produced
in female ovules could cause embryo pathology to manifest in subsequent generations.
Relative risk of teratogenicity:
Breast cancer, cervical cancer, Hodgkin’s disease, and ovarian cancer are disease states that do not affect
pregnancy outcomes. However, metastasis to the fetus has been reported with melanoma.
Effects on development include microphthalmia, hypoplastic ovaries, cloudy corneas, agenesis of kidneys,
cardiac effects, digit malformations
Level II ultrasound * will detect visible malformations. Primary lesions warrant prompt surgical intervention once
diagnosed.
Case report data suggest 10–15% of cases were malformed by different drugs; this may be an overinflated
number
* Antimetabolite agents (aminopterin azauridine, cytarabine, 5-fluorouracil, 6-mercaptopurine, methotrexate)[7 ]
Cytotoxic drugs with folic acid antagonism (e.g., methotrexate) have greatest risk, especially when administered
in first trimester. Malformations include hydrocephalus, meningoencephalocele, anencephaly, malformed skull,
cerebral hypoplasia, growth retardation, extremity and finger malformation. Aminopterin syndrome: cranial
dystosis, hydrocephalus, hypertelorism, anomalies of external ear, micrognathia, posterior cleft palate.
Relative risk of teratogenicity: Case report data suggest 7–75% of cases were malformed; this may be an
overinflated number
Antimicrobials
Causes yellow, gray-brown, or brown staining of deciduous teeth and enamel destruction. Critical time of
exposure from 16 weeks of gestation.
Exposure before 14 weeks of gestation associated with no risk.
* Tetracycline[9 ]
Relative risk of teratogenicity: Problems arise in 50% of fetuses exposed to tetracycline; oxytetracycline causes
problems in 12.5% of cases
* Thalidomide[46 ]
Causes limb phocomelia/amelia, hypoplasia, congenital heart and renal defects, abducens paralysis, deafness
Thalidomide is effective against leprosy and is in current use. Two reliable birth control methods advocated when
it is prescribed to fertile females.
Relative risk of teratogenicity: A 20% risk when exposure occurs between 34 and 50 days of gestation
Anesthetic gases[17 ] (thiopental, nitrous oxide, enflurane, halothane)
Not shown to cause untoward embryonic/fetal effects; case reports of increased miscarriages, but methodologic
problems, especially response bias, preclude definite conclusions
Most epidemiologic studies do not suggest congenital anomalies are increased by occupational exposure to
volatile anesthetics. Workplace standards for nitrous oxide: TLV-TWA, 50 ppm. Decreased fertility among female
dental assistants exposed to unscavenged nitrous oxide.
Benzodiazepines[10 ] (diazepam, oxazepam, chlordiazepoxide)
Contrasting kinetics of BDZ attributed to different routes of elimination; increased Vd lowers major demethylation
metabolite of diazepam (i.e., nordiazepam); also increased half-life
BDZ implicated in earlier studies to risk of both cleft lip and cleft palate, but these findings refuted by other
researchers. Also reported are abnormal growth and neurodevelopment and slow gross motor development
normalizing at 18 months. Fine motor functions impaired when BDZ is given at higher doses in Sweden; hence
these effects not seen in studies in North America, where lower BDZ doses are prescribed.
Used near term, BDZ may decrease respiratory rate and cause neonatal withdrawal and hypotonia. Detectable
pharmacologic activity in neonate up to 10 days.
Relative risk of teratogenicity: Initial studies reporting an increased risk of cleft palate refuted; initial studies
associated chlordiazepoxide with increased congenital heart disease, but even with positive association, no
homogeneous pattern of malformation detected
Cannabinoids[6 ]
Marijuana not associated with congenital abnormalities in humans, but neonates have dose-related increased
tremors, increased startle reflexes, and altered visual responsiveness
There is a nearly fivefold increase of maternal blood CO Hb and threefold increase in inhaled tar with smoking
marijuana compared with tobacco cigarettes.
Cigarette smoking[1 ] [28 ] [45 ] [63 ]
Fetal concentrations of carboxyhemoglobin higher than maternal levels due to higher affinity of fetal hemoglobin
for CO. CO decreases oxygen carried to cells, impairs cytochrome enzymes.
Increased high risk for LBW, prematurity, spontaneous abortions, perinatal mortality, sudden infant death;
increased abnormal neurobehavioral development
Nicotine and cotinine determination in fetal hair can now be done. There is good correlation between maternal
and neonatal concentrations of nicotine/cotinine.
Contains nicotine, hydrogen cyanide, benzopyrene, among many substances; CO is an unhealthy by-product of
smoking
Cocaine[23 ]
Causes fetal intracranial hemorrhage, PROM, abruptio placentae, LBW, meconium staining, SIDS, fetal distress.
Recreational use of cocaine is increasing in reproductive-age women. In American inner cities, use is as high as
40%.
Genitourinary malformation increased with cocaine use.

Adverse reproductive effects associated with pregnancy exposure to cocaine are increased in polydrug abusers.
Fetal ultrasound of abdomen and head indicated to rule out malformations and intracranial hemorrhage.
Maternal urine, primarily, and maternal and neonate hair samples are useful in determining cocaine abuse by
detecting cocaine and metabolite benzoylecgonine on a minimum of 8 hair strands. (Neonatal hair grows in last
3–4 months of pregnancy.)
Babies exposed to cocaine, alcohol, and marijuana have poor language skills.
Children with first trimester cocaine exposure revealed lower Bayley scores and lower scores on verbal
comprehension and expressive language.
* Ethanol[8 ] [30 ] [31 ]
FAS (prenatal and postnatal growth retardation), CNS dysfunction, facial dysmorphology ± short palpebral
fissures, flat maxillary area
FAS (see Fig. 12–4) arises in pregnant women drinking at least six standard drinks/day in the first trimester (1
standard drink = 12 oz beer = 5 oz glass of wine = 1.5 oz liquor = 15 g [0.5 oz] absolute ethanol).
Relative risk for teratogenicity: Ethanol >2 g/kg/d over the first trimester results in two-to threefold increased risk
for congenital malformations (~10%)
Long-term problems: attention deficits, MR, spontaneous abortions, abruptio placentae, premature placental
separation, stillbirths, LBW, congenital malformation
Calculate intake of ethanol. If mother is ethanol dependent, refer to addiction center. Level II ultrasound * detects
visible malformations.
Use of diazepam helpful.
Disulfiram contraindicated in pregnant/planning women, because it is associated with spontaneous abortions,

clubfoot, and other limb reductions.
* Ionizing radiation[5 ] (X-rays, gamma rays, radionuclides) Long wavelength electromagnetic waves (radar, FM
radio waves, diathermy, microwaves), sound waves, ultrasound
Ionized radiation has two effects:

Despite increased concern about effects of ionizing radiation on health and reproduction, medical use of X-rays
is growing. No medical justification for terminating pregnancy if radiation exposure = 10 rads.
(1) Deterministic effects: soft tissue function loss at a few hundred millisieverts
The roentgen (R) international unit amount of X-radiation that produces 1 electrostatic unit of charge in 1 cm3 air
under standard conditions: 1 rad = ionizing radiation equal to 100 ergs/g tissue; 100 rad = 1 Gy (Gray) = 1
joule/kg.
(2) Stochastic effects: Random modification of genetic structure resulting from ionizing radiation still permits
proliferation; 2–4 weeks of gestation appear to be the time period for radiation-induced multiple malformations to
arise
The rem (roentgen-equivalent man) causes the same biologic effect as 1 R of X/gamma ray: 100 rem = 1 sv
(sievert).
Microcephaly is the most common adverse outcome of high-dose radiation in pregnancy ± MR

The RBE is a relationship between the absorbed energy (in rad/Gy) and the effectiveness of that energy in
causing damage (a correction factor for predicting the biologic effectiveness of absorbed radiation).
Perinatal deaths and LBW as high as 30% in irradiated Wilm’s
Childhood cancer survivors given abdominal or gonadal irradiation have increased miscarriages as adults
Leukemic children receiving CNS radiation have decreased fertility as adults, indicating that doses of 18–24 Gy
to brain may cause hypothalamic/pituitary injury
Organic solvents[40 ] [70 ]
Aliphatic hydrocarbons associated with spontaneous abortions

Adequate epidemiologic studies difficult to conduct and interpret. Also opposite results on aliphatic
hydrocarbons. Methylene chloride is converted in vivo to CO.
Radionuclides[68 ]
Fetal thyroid has higher affinity for iodides compared with the mother; the lowest dose reported to destroy the
fetal thyroid in a fractionated manner was 12.2 mCi.
Iodine as I125 used to label minute hormonal doses in vitro and in vivo. I123 used for uptake studies, while I131
binds protein.
Sodium pertechnetate for thyroid imaging delivers lower radiation than iodide, as it has a shorter half-life.
Inorganic radioactive potassium, cesium, thallium, selenium, chromium, iron, and strontium cross the placenta
readily.
Sterilents/disinfectants
Probably higher rate of spontaneous abortions

Conflicting studies; exposure in pregnancy best avoided.
Ethylene oxide
* Systemic retinoids[37 ] (isotretinoin, etretinate) (see Fig. 12–3
Causes spontaneous abortions; microcephalus; hydrocephalus; defects of cranium, face, ears, heart, limbs, liver.
Cognitive defects without dysmorphology occur.
Women treated with this medication should be on two reliable birth control methods. Ultrasound can pick up
malformations if late diagnosis is made.
Relative risk of teratogenicity: for isotretinoin ~38%; 80% of malformations observed are CNS
See Table 12–2 for list of abbreviations.
†
Effect of Pregnancy on Effect of Pregnancy on Disease Effect of Drug on Practical
Drug Drug Condition Fetus Points
†
A detailed ultrasound performed between 16 and 18 weeks gestation to detect any visible malformations.
*
Proven human teratogen
Table 12-2 -- Impact of Pregnancy on the Management of Common Drugs and Chemicals
Acetaminophen[20 ]
Transplacental NAC transfer insignificant in humans.
Most common drug ingested in pregnancy after nutritional supplementation.
Use NAC in pregnant woman if clinically indicated.
Acetaminophen toxicity initially can be silent, or mimic morning sickness in pregnancy.
In acetaminophen toxicity, the fetus may not survive or may be spared hepatotoxicity even when the mother
develops it.
Fetus most vulnerable to acetaminophen hepatotoxicity in the third trimester.
Fetal livers have cytochrome P450 and glutathione. Can metabolize via sulfation but lack glucuronidation
metabolism.
* Carbon monoxide[22 ] [41 ] (CO)
More aggressive oxygen and hyperbaric therapy than nonpregnant patients
Mild or moderate CO exposure has caused stillbirth, as fetal CO levels rise and fall more slowly than maternal
levels.
CO levels as low as 15% have caused stillbirths.

Digitalis[39 ] [48 ] [64 ] [66 ] (digitoxin)
Fetal cardiac monitoring helpful.
Digitalis poisoning in pregnancy at 7 months gestation reported nearly four decades ago. Poisoning was fatal for
fetus following spontaneous labor. Autopsy consistent with prolonged intrauterine anoxia.
Purified digoxin-specific antibodies (Digibind) used in life-threatening conditions. Safety and efficacy in a fetus
unknown.
Both digoxin and digitoxin cross the placenta in first trimester, making fetus vulnerable to cardiovascular
dysfunction (e.g., bradycardia).
Data on transplacental passage of Fab antibody lacking.

Iron[4 ] [14 ] [21 ] [34 ] [49 ] [59 ] [61 ] [71 ] [72 ] [73 ]
Standard life support measures, good supportive therapy.
Following deferoxamine administration, skeletal anomalies and ossification delays observed in animal offspring
at more than three times the maximal dose administered to humans. These abnormalities have not been shown
conclusively to occur in humans. However, the metaplasia and dysplasia observed in children receiving
deferoxamine may show possible bony changes not observed in the small cohort published to date.
Exchange transfusion in newborn.
Iron has been used by pregnant women to commit either suicide or abortion.
Use of iron chelators (e.g., deferoxamine) as clinically indicated. Despite proven animal teratogenicity, the 10
case reports, including a large study, suggest that the benefit outweighs the risk of deferoxamine use in
pregnancy.
Deferoxamine does not cross the placenta well.
Lead[2 ] [3 ] [15 ] [16 ] [24 ] [27 ] [33 ] [35 ] [51 ] [58 ] [75 ]
Maternal cord blood screening studies, as well as several case reports, demonstrate that lead freely crosses the
placenta. Lead crosses the placenta as early as 12–14 weeks, probably by both passive diffusion and active
transport.
Only five case reports of lead toxicity with pregnancy in the literature. Lead toxicity ranged from clinical toxicity to
no evidence of clinical toxicity in pregnancy.
Dimercaprol given intramuscularly causes adverse effects; poor drug of choice in pregnancy.
Spontaneous abortion, infertility, microcephaly, prematurity, stillbirth, and fetal death can occur. Nearly 20% of
exposures experience PROM and increased HT at delivery, increased learning disabilities, increased minor
anomalies, hemangiomas, hydrocele, undescended testes, chromosomal aberrations (gaps, breaks, fragments).
Dimercaptosuccinic acid, structurally similar to dimercaprol, given orally seems the best choice; no reported data
during pregnancy.
Pregnancy-induced changes in calcium regulation induce lead mobilization from bones, increased lead
bioavailability to maternal and fetal compartments. Iron deficiencies enhance susceptibility to lead toxicity.
Unlikely that EDTA enters the fetus, as reported in a single case.
Valid use of chelators based on maternal symptoms and toxicity. Chelators should not be used in asymptomatic
pregnant women. Prolonged use of chelators affects essential trace element transport to the fetus. Also,
chelators can mobilize maternal bone lead, potentially increasing fetal exposure.
Organophosphorous pesticides[52 ] [74 ]

Appropriate life support, GI decontamination, meticulous respiratory care, administration of atropine and
pralidoxime.
Pesticide-related agricultural occupational exposure can cause thousands of cases through contaminated food
(e.g., aldicarb-contaminated watermelon).
Monitor fetus; consider delivery if distress documented.
Carbamates do not effectively cross to the CNS.
Removal from exposure until cholinesterase returns to 75% of baseline in mild toxicity.
Trans-GI epithelial passage has occurred with organophosphates, making transplacental transfer plausible.
Mecarbam found in higher concentration in the fetus.
Neonatal plasma and RBC cholinesterase ranged from 50%–70% of adult values; hence increased fetal
sensitivity to pesticides is expected.
TLV-TWA, 0.1 mg/m3 for parathion.

Salicylates[43 ]
Unlike acetaminophen, the parent drug rather than metabolite produces toxicity and places fetus at risk.
Fewer than 10 cases of salicylate toxicity in pregnancy reported.
Salicylates cross the placenta and attain higher levels in the fetus than in the mother.
Salicylate toxicity in the newborn includes hyperpnea, hypertonia, irritability, poor appetite, malnourishment.
Postmortem findings reveal tentorial and cerebral hemorrhage.

BDZ, benzodiazepines; CA, cyclic antidepressant; CNS, central nervous system; CO, carbon monoxide; COHb,
carboxyhemoglobin; EDTA, ethylenediaminetetraacetic acid; FAS, fetal alcohol syndrome; GFR, glomular
filtration rate; GI, gastrointestinal; HT, hypertension; LBW, low birth weight; MR, mental retardation; NAC, N -
acetylcysteine; NTD, neural tube defect; PROM, premature rupture of membranes; RBC, red blood cell; RBE,
relative biologic effectiveness; SIDS, sudden infant death syndrome; TLV-TWA, the time-weighted average
concentration for a normal 8-hour workday; a 40-hour workweek to which nearly all workers may be repeatedly
exposed, day after day without adverse effect; Vd, volume of distribution; VSD, ventricular septal defect.
Drug Management Comments
*
Proven human teratogen.
GENERAL CONSIDERATIONS
Gastrointestinal decontamination with activated charcoal is a mainstay of treatment but is ineffective in

overdoses of iron, lithium, acetone, borates, caustics, alcohols, hydrocarbons, and metals. Management for
specific toxins is discussed in appropriate chapters in this book.
Successful outcome of the maternal-fetal unit is dependent on appropriate and adequate management of the
mother.
Proven effective medications or antidotes should not be withheld, especially in overdose conditions, owing to fear
of adverse effects on the fetus.
The fetus is most vulnerable to teratogenicity during the first trimester. However, knowledge about medications
used in pregnancy and whether they have any teratogenic or other adverse effects on the fetus at any time is
necessary.
Multidisciplinary teamwork among the clinician, obstetrician, perinatologist, and toxicologist can optimize patient
management.


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Chapter 13 – Poison Centers
JERROLD B. LEIKIN EDWARD P. KRENZELOK
In the first half of this century, poison information was nearly nonexistent, and at best viewed as an esoteric
field of medicine. It was placed haphazardly in health science curricula, essentially not taught in medical
schools, and generally not regarded as a specific or separate discipline. Because formal poison control
services did not exist, serious morbidity and mortality from childhood poisoning developed into a significant
problem for both parents and physicians, accounting for up to half of all accidents in the home and a tragic
number of fatalities. However, since 1953, when the first poison information hot line opened in Chicago,
poison control centers have emerged as important health care providers firmly established in our nation’s
health care system.[3][5][23] As poison control centers began to flourish, the American Association of Poison
Centers (AAPCC) was subsequently created in 1958 for the purpose of developing educational programs for
health care providers along with the general public, addressing the needs of its members and, most
importantly, standardizing the operation of poison control centers.[3] Criteria for AAPCC designation as a
regional poison control center include a geographically defined region (with a population base of 1 million to
10 million), continuous 24-hour free availability to the general public and to health care providers, written
protocols, qualified certified specialists in poison information, medical direction, regional data collections,
and educational programs ( Table 13–1 ).[12]
Table 13-1 -- American Association of Poison Control Centers Criteria for Regional Poison Center
Certification
• The center must maintain comprehensive reference sources on poisonings.
• The center must serve a geographic area with a population base of optimally less than 10 million people.
• The center must operate 24 hours a day/365 days per year and be readily accessible by telephone.
• The center must participate in AAPCC’s national data collection system, the Toxic Exposure Surveillance
System (TESS).
• The center must be staffed at all times by licensed pharmacists, nurses, and/or physicians who attained
additional training in clinical toxicology.
• The center must utilize and maintain protocols, follow-up guidelines, and quality assurance strategies that
provide consistent approaches in the evaluation and treatment of the poisoned patient.
• The center must have a medical director and a managing director, and these directors must have specific
qualifications.
• The center must have an ongoing quality-improvement program.
• The center must provide education for the public and for health care professionals.
Rapid growth in the poison control system followed during the 1960s and 1970s. By 1978, there were 661
poison centers operating in the United States and its territories.[23] This tremendous evolution of poison
centers and the poison prevention movement, in conjunction with such legislation as the Poison Prevention
Packaging Act of 1970, led to a marked decline in pediatric deaths from poisoning during this time period.[25]
For example, pediatric deaths from salicylate overdose declined by more than 80% from the 1960s to the
1980s.
In the 1980s and 1990s there was a precipitous decline in the number of poison control centers, from 104 in
1991 to 75 in 1997 in the United States (in 2000 51 were certified by the AAPCC). An updated list can be
obtained from the AAPCC; telephone: 202-362-7217 or the AAPCC website, www.AAPCC.org ). [19] A
poison center certified by the AAPCC has an average human exposure call volume of 38,191 and employs
an average of 10.9 specialists in poison information.[10][19] These specialists in poison information are most
often nurses or pharmacists who have received extensive training in clinical toxicology. The AAPCC offers
an annual certification examination for specialists as a means to standardize poison treatment and attain
quality assurance. Poison centers respond to an average 8.8 human exposures per 1000 population
served.[19] In 1997, American poison centers reporting to the AAPCC Toxic Exposure Surveillance System
(TESS) responded to 2,192,088 human exposures.[19] In addition to human exposure calls, poison centers
manage some cases involving animal exposures and supply information on poisons, poison prevention,
drugs and drug identification, teratogenicity, and occupational, medical, and environmental concerns.
The administrative structure of a regional poison control center varies. Each center must have a managing
director and a medical director; in some centers a single individual fulfills both requirements. About half of
the AAPCC-certified poison centers have a managing director certified by the American Board of Applied
Toxicology (ABAT). Similarly, the medical director in an AAPCC-certified regional poison control center is
usually certified in medical toxicology, either by the now-defunct American Board of Medical Toxicology or
the special American Board of Medical Specialties (ABMS) certification in medical toxicology. The ABMS
examination is sponsored by the American Boards of Emergency Medicine, Preventive Medicine, and
Pediatrics and is administered as a sub-board by the American Board of Emergency Medicine. Additionally,
most poison centers maintain a list of nonphysician consultants, which may include botanists, mycologists,
zoologists, entomologists, and herpetologists.
In the United States, poison centers are information units and do not provide direct treatment. Therefore,
they do not stock antidotes. However, the centers should be aware of the location of important antidotes that
are stocked inadequately by most hospitals. [6][7][8][11][14][16][22][24][27] Although the Joint Commission on
Accreditation of Health Care Organizations (JCAHO) does not address the specific criteria regarding
antidote storage and availability, guidelines have been developed by the American Academy of Clinical
Toxicology (AACT) regarding antidote availability. [1][9][15] Suggested minimum stock quantities of antidotes
are listed in Table 13–2 .[4]
Table 13-2 -- Uses and Suggested Minimum Stock Quantities for 25 Selected Antidotes
Antidote Suggested Minimum Stock Quantity
N-Acetylcysteine (Mucomyst) 600 mL in 10- or 30-mL vials of 20% solution
Amyl nitrite, sodium nitrite, sodium
Three antidote kits
thiosulfate (cyanide antidote kit)
Antivenin polyvalent
10 vials (Note: 30 vials or more may be needed in serious cases)
(Crotalidae)—equine origin
Antidote Suggested Minimum Stock Quantity
Five vials, 20 mL/vial (0.4 mg/mL) and twenty 10 mL (0.1 mg/mL)
Atropine sulfate
ampules. Total: 60 mg
Black widow spider antivenin
1 vial
(Latrodectus mactans antivenin)
Calcium disodium EDTA (Versenate) Two 5-mL ampules, 200 mg/mL
10% calcium gluconate: Five 10-mL vials
Calcium gluconate, calcium chloride
10% calcium chloride: Five 10-mL vials
Deferoxamine mesylate (Desferal) Twelve 500 mg vials
Digoxin immune Fab (Digibind) 20 vials
Dimercaprol (BAL in Oil) Ten 3-mL (100 mg/mL) ampules
Ethanol 8 L of 10% EtOH in D5W and 1 pint 95% ethanol
Twenty 5-mL vials or ten 10-mL vials. Each has 0.1 mg/mL. Total: 10
Flumazenil (Romazicon)
mg
Folinic acid: six 50-mg vials
Folinic acid (Leucovorin), folic acid
Folic acid: six 50-mg vials
Fomepizole (Antizol) 1.5 g/vial, four vials
Fifty 1-mg vials (may offer only 5–10 hours of treatment in serious
Glucagon cases). A 10-mg/10-mL vial is no longer available from the
manufacturer.
Hyperbaric oxygen (HBO) Post the location and phone number of nearest HBO chamber.
Methylene blue Ten 10-mL (10 mg/mL) ampules
Naloxone (Narcan) Naloxone: fifty 1-mL ampules (0.4 mg/mL)
D-Penicillamine (Cuprimine) Bottle of 100 capsules: 125 mg or 250 mg/capsule
Physostigmine salicylate (Antilirium) Ten 2-mL (1 mg/mL) ampules
Phytonadione, vitamin K1
Two 0.5-mL ampules (2 mg/mL) and two 5-mL ampules (10 mg/mL)
(AquaMEPHYTON, Mephyton)
Pralidoxime chloride, 2 PAM (Protopam) 1 g/kit, five kits
Pyridoxine hydrochloride, vitaminB6 Twenty-five 10-mL (1 g) vials or eight 30-mL (3 g) vials
Sodium bicarbonate Twenty-five 20-mEq vials
Succimer (Chemet) Bottle of 100 capsules; 100 mg/capsule
Modified from Burda AM: Poison antidotes: Issues of inadequate stocking with review of uses of 24 common
antidotal agents. J Pharm Pract 1997; 10:235–248.
The cost-effectiveness of poison centers has been evaluated in several studies. With about 72.5% of
reported toxic exposures being treated at home, poison control centers truly represent the nation’s first
successful attempt at home health care services.[19] An economic analysis performed for the Department of
Health and Human Services found that every $1 spent on poison control services resulted in $7 of medical
savings. Compared with various cost-saving preventive health measures for children receiving Medicaid,
only childhood immunizations afforded more cost savings ( Fig. 13–1 ).[20] A second analysis compared
1992 data on incidence, medical spending, and payment sources for poisoning in jurisdictions both with and
without poison center service.[21] Poison centers reduced the number of patients who received outpatient
medical treatment for poisoning by 24 per cent and the number of people hospitalized by 12 per cent. Each
call from the public into a poison center saves an estimated $175 in other medical
spending.[2][13][17][18][20][21][26] Because the average call costs about $28 to a poison center (including indirect
costs), the dollar savings results in almost $6.50 saved in medical care payments for every dollar spent on
poison center services ( Table 13–3 ). This amounts to a reduction of an estimated $355 million nationally in
medical spending (all dollar figures are calculated in 1992 dollars and do not account for the dollar value of
life and functional capacity saved).[21] Furthermore, individuals, private insurance companies, and the
federal government benefit the most, based on cost-savings analysis. [18][21] Increasing regional poison
center coverage to the entire U.S. population would result in significant cost savings ( Table 13–4 ). In spite
of these obvious financial benefits, poison centers continue to struggle for survival. However, government
agencies are aware of these benefits and the potential dilemma facing the nation if more poison centers
close.
Figure 13-1 Selected Cost-Saving Preventive Health Measures. (From Miller TR: Government Financial Options to Preserve and
Expand Poison Control Centers: A Report to Congress.)
Table 13-3 -- Annual Poisonings and Resultant Medical Spending During the Year of Injury (United
States, 1991–1992), by Medical Treatment
Cases Mean$/Case $/Year
Fatal 13,000 * 11,700 155 M
Hospitalized 285,000 8,700 2,475 M
Other medically treated 1,090,000 245 265 M
Poison control consultations —† 28 15 M
Poison control center only 1,820,000 28 50 M
Total 3,208,000 925 2,960 M
M, million.
Data from 1991 US Vital Statistics, 1992 National Hospital Discharge Survey, 1987 National Medical
Expenditure Survey, and 1992 Annual Report of the American Association of Poison Control Centers, adjusted
for nonreporting centers.
From Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers: A
benefit-cost analysis. Ann Emerg Med 1997; 20:239–245.
* Exact count is 13,232.
† There were 600,000 consultations, which are included as cases under “Other medically treated,” but for which costs are shown separately.
Table 13-4 -- Predicted Annual Incidence and First-Year Medical Care Spending for Poisonings with No
Coverage and with Complete Coverage (United States, 1992), by Medical Treatment
No Poison Centers Center for All
Cases $/Year * Cases $/Year
Fatal 13,000 † 155 M 13,000 † 155 M
Hospitalized 325,000 2,810 M 280,000 † 2420 M
Other medically treated 1,440,000 350 M 1,030,000 250 M
Poison control consultations 0 0M —* 20 M
Poison control center only 0 0M 2,115,000 60 M
Total 1,790,000 3,315 M 3,440,000 2905 M
M, million.
Data from 1991 US Vital Statistics and original computations. All estimates were computed before rounding.
From Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers: A
benefit-cost analysis. Ann Emerg Med 1997; 20:239–245.
* The estimated 700,000 consultations are included as cases under “Other medically treated,” although the related costs are shown
separately.
† Rounded number.
Poison centers are essential to the future of the field of clinical toxicology ( Table 13–5 ). In addition to
providing outpatient assessment of exposures or sophisticated toxicology expertise to health care personnel,
poison centers serve as a training site for students, residents, pharmacists, physicians, and medical
toxicology fellows. Fellowship-trained physicians are certified in medical toxicology through the medical
toxicology sub-board administered by the American Board of Emergency Medicine. Pharmacists and other
qualified individuals in related specialties can be certified in toxicology by the ABAT. Medical Review Officer
(MRO) training and certification for Department of Transportation drug analysis can be obtained through the
American College of Occupational and Environmental Medicine. As the focal point for these activities, the
poison center is critical to the training of all aspiring clinical toxicologists and provides a venue to practice
the specialty.
Table 13-5 -- Summary of Health and Economic Benefits of a Regional Poison Control Center
• Reduction of unnecessary emergency department visits and inappropriate use of medical resources
• Decreased burden on a region’s emergency medical transportation system
• Reduction in adverse effects resulting from the use of outdated, hazardous first aid procedures in the home
• A reduction in the time required to diagnose and establish definitive care for the poisoned victim
• Minimizing public health effects of community exposure to toxic materials
• Early detection and elimination of unusually hazardous commercial products through regulatory notification,
recall, repackaging, reformulation, or product discontinuation
• Improved care of poisoning victims, decreasing disabilities, and costly long-term medical care
• Reduced incidence of unintentional poisoning in the home and workplace
• Enhanced management of drug-addicted patients by providing recommendations, referrals, and assistance
• Reduced exposure to potential toxins during pregnancy
• Improved patient care by educating physicians, nurses, paramedics, and other health care professionals in
poison management and medical toxicology
Modified from Litovitz T, Kearney TE, Holm K, et al: Poison Control Centers: Is there an antidote for budget cuts?
Am J Emerg Med 1994; 12:585–599.
REFERENCES
1. American Academy of Clinical Toxicology: Facility assessment guidelines for regional toxicology
treatment centers. J Toxicol Clin Toxicol 1993; 31:211-217.
2. Bindl L, Ruchardt J, Pfeiffer A, et al: Effect of a German poison control center on health care cost
reductions in harmless exposure cases. Vet Hum Toxicol 1997; 39:48-50.
3. Botticelli JT, Pierpaoli PG: Louis Gdalman, pioneer in hospital pharmacy poison information services.
Am J Hosp Pharm 1992; 49:1445-1450.
4. Burda AM: Poison antidotes: Issues of inadequate stocking with review of uses of 24 common antidotal
agents. J Pharm Pract 1997; 10:235-248.
5. Burda AM, Burda NM: The nation’s first poison control center: Taking a stand against accidental
childhood poisoning in Chicago. Vet Hum Toxicol 1997; 39:115-119.
6. Chyka PA, Conner HG: Availability of antidotes in rural and urban hospitals in Tennessee. Am J Hosp
Pharm 1994; 51:1346-1348.
7. Dart RC, Stark Y: Insufficient stocking of poisoning antidotes in hospital pharmacies.

JAMA 1996; 276:1508-1510.
8. Davis NM: Insufficient stocking of poisoning antidotes. Hosp Pharm 1997; 32:1078-1103.
9. de Garbino JP, Haines JA, Jacobsen D, et al: Evaluation of antidotes: Activities of the International
Programme on Chemical Safety. J Toxicol Clin Toxicol 1997; 35:333-343.
10. Felberg L, Litovitz TL, Morgan J: State of the nation’s poison centers: 1995 American Association of
Poison Control Centers survey of U. S. poison centers. Vet Hum Toxicol 1996; 38:445-453.
11. Freeman G: Is your pharmacy sufficiently stocked? Lack of key supplies is a liability risk. Healthcare
Risk Manage 1997; 19:1-12.
12. Geller RJ, Fisher III JG, Leeper JD, et al: American poison control centers: Still the same?. Ann Emerg
Med 1988; 17:599-603.
13. Harrison DL, Draugalis J, Slack MK, et al: Cost effectiveness of regional poison control centers. Arch
Intern Med 1996; 156:2601-2608.
14. Howland MA, Weisman R, Sauter D, et al: Non-availability of poison antidotes. N Engl J
Med 1986; 314:927-928.
15. Joint Commission on Accreditation of Healthcare Organizations : 1994 Accreditation Manual for
Hospitals, Oakbrook Terrance, IL: JCAHO; 1994:162.
16. Kanatani MS, Kearney TE, Levin RH, et al: Treatment of toxicologic emergencies—antidote
preparedness: An evaluation of Bay Area hospital pharmacies and its impact on emergency planning. Vet
17. Kelly NR, Ellis MD, Kirkland RT, et al: Effectiveness of a poison center: Impact on medical facility visits.
Vet Hum Toxicol 1997; 39:44-48.
18. Litovitz T, Kearney TE, Holm K, et al: Poison control centers: Is there an antidote for budget cuts?. Am
J Emerg Med 1994; 12:585-599.
19. Litovitz TL, Klein-Schwartz W, Dyer KS, et al: 1967 Annual report of the American Association of Poison
Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1998; 16:443-497.
20. Miller TR: Government Financial Options to Preserve and Expand Poison Control Centers: A Report to
Congress.
21. Miller TR, Lestina DC: Costs of poisoning in the United States and savings from poison control centers:
A benefit-cost analysis. Ann Emerg Med 1997; 29:239-245.
22. Parker DP, Dart RC, McNally JJ: Critical deficiencies in the treatment of toxicologic emergencies:
Antidote stocking in Arizona hospitals. Vet Hum Toxicol 1990; 32:376.
23. Scherz RG, Robertson WO: The history of poison control centers in the United States. J Toxicol Clin
Toxicol 1978; 12:291-296.
24. Spoeke DG: Guide to the acquisition, storage, and use of antidotes. Am J Hosp Pharm 1981; 38:498-
506.
25. US Consumer Product Safety Commission. Poison prevention packaging: A text for pharmacists and
physicians. Washington, DC, 1993; pp 5–7.
26. Williams RM: Are poison control centers cost-effective?. Ann Emerg Med 1997; 29:246-247.
27. Woolf AD, Chrisanthus K: On site availability of selected antidotes: Results of a survey of
Massachusetts hospitals. Am J Emerg Med 1997; 15:62-66.


Chapter 14 – Managing Patients with Hazardous Chemical Contamination
MARK KIRK
The odds are high that man and chemicals will come together. Hundreds of thousands of chemicals are
manufactured, then transported by rail, waterway, highway or pipeline and ultimately stored for use in the
community, workplace, or home. Chemicals are helpful when used and properly contained but can be
hazardous if misused or accidentally released. Hazardous materials are not dangerous if appropriately
contained but can injure life and damage the environment following uncontrolled release from their
containers.[18] For example, chlorine is not harmful until its transport container ruptures and it escapes into
the environment.
Patients harmed by hazardous chemicals require special handling and treatment. Emergency care
providers, prehospital or hospital-based, must assess the situation before treating victims of hazardous
chemical accidents; otherwise, the would-be rescuer may become a victim.[1][31][51][59][60][77] In an
unprepared emergency department (ED), one contaminated patient may disrupt departmental operations,
overwhelm staff, deplete supplies, and create a disaster. A hazardous chemical release producing hundreds
to thousands of victims is the most extreme hazardous material (Haz-Mat) situation a community can face.
Prehospital resources and hospitals were overwhelmed in Bhopal, India, when methyl isocyanate was
accidentally released, and in Japan when sarin, a nerve agent, was deliberately released into the Tokyo
subway system.[49][52][60]
RECOGNIZING PATIENTS WITH CHEMICAL CONTAMINATION
Rapidly recognizing hazardous chemical contamination is most important for effective management.
Contamination may go unrecognized because multiple traumatic injuries, sudden unconsciousness, or
unexplained cardiac arrest of victims may distract health care workers. In patients ingesting toxic
substances, off-gassing of vapors from the GI tract or vomitus may harm health care workers.[1] The true risk
to these workers is difficult to estimate because no procedure or instrument is available to rapidly detect
chemical contamination on patients. Therefore, prehospital and ED personnel must be alert for high-risk
situations. Table 14–1 lists situations in which hazardous chemical contamination is likely.
Table 14-1 -- Indications of Possible Chemical Contamination

Site of incident
Industrial
Chemical manufacturing plant
Hazardous waste site
Pipeline
Transportation accidents
Train derailment
Tanker truck
Plane (crop duster)
Barges and cargo ships
Agricultural
Farm accidents
Type of incident
Fire
Explosion
Ruptured tank
Spill
Structural collapse
Terrorism
Clandestine laboratories
Findings at the incident
Vapor clouds
Dead animals, insects, or fish
Several people with similar complaints
Rescue from enclosed spaces
Chemical odors
Patient findings
Unexplained unconsciousness in otherwise healthy person
Unexplained cardiac arrest in otherwise healthy person
Strong odors on clothes, skin, or breath
Unidentified liquids or particulates on skin or clothing
Chemical burns
Irritation of the eyes, mucous membranes, or skin
Methemoglobinemia
Overdoses of cleaning or agricultural chemicals


MANAGEMENT STEPS FOR CHEMICALLY CONTAMINATED PATIENTS
Confusion, panic, a major rescue response, and many seriously ill victims were pictured by the media after
the release of sarin in the Tokyo subway system in 1995.[59][60] Effectively dealing with chemically
contaminated patients requires an organized approach in order to minimize chaos. This approach includes
management of (1) information, (2) resources, and (3) medical therapies for specific patient problems.
Information Management
Toxin identification must be a priority in the emergency response and must be communicated to hospitals
prior to transporting patients. Notification is essential even if a toxin is only suspected and not confirmed.[7]
When chemical identification or the hazards of exposure are uncertain, the treatment team must assume the
patient is contaminated by a highly toxic chemical.
Information must also be as accurate and reliable as possible in order to minimize confusion and fear and
optimally guide critical decisions for patient care, ED operations, and mass casualty response. In general,
information gathered by on-scene professionals is more reliable than hearsay from an injured victim or a
news broadcast. Reliable facts help physicians make decisions that are best for the patient and ED
operations. Reacting to a worst-case scenario removes staff from their work areas, disrupts emergency
department operations, and delays specialized or life-saving medical care. In many cases, a less extensive
response may be safe and effective. For example, a patient with carbon monoxide poisoning is not a
contamination risk. To treat such patients, the staff does not need protective equipment and the patient does
not require decontamination procedures. Accurate, specific information can guide actions and keep safety a
priority.
Decisions made in the early stages of an incident are very important because mistakes tend to be magnified
manyfold as the response progresses.[76] Thoughtful decisions and advanced preparation, based on reliable
and accurate information, can mean the difference between effectively handling a situation and turning the
hospital into a disaster zone.
The following specific questions will help guide information management.
What is the risk involved?
Is the hospital at direct risk from the Haz-Mat incident?[7] For example, a plume of toxic gas can enter the
ventilation system from a nearby incident. In these situations, actions such as sheltering in place or
evacuation may be necessary to protect the staff and patients from harm.
If the hospital is not at risk, advanced preparation for victims should include an estimation of the magnitude
of an incident and the resources available to handle it. Mass casualty plans and specialized resources
should be activated as soon as the need is recognized.
Specific information to obtain includes (1) the expected numbers and categories of victims, both
critical/ambulatory and contaminated/uncontaminated, and (2) the circumstances surrounding the incident,
such as explosion, fire, or building collapse, to guide mobilization of specialty resources (e.g., hyperbaric
oxygen, trauma surgery, radiation expertise).
What is the suspected chemical?
Accurate identification of chemical(s) involved can be difficult. Aids to identification are listed in Tables 14–2
and 14–3 . By law, identification placards must be used for the transportation and storage of hazardous
chemicals. Shipping papers, Material Safety Data Sheets (MSDS), and inventory lists may be helpful. In
some cases, recognizing a specific toxic syndrome can assist with chemical identification. A regional poison
center can be extremely helpful in identifying chemical names from placards, chemical code numbers, or
symptoms.
Table 14-2 -- Information Resources for Chemical Identification

Container labels
Placards/markings
Department of Transportation (DOT) placard categories
Explosive
Flammable
Oxidizer
Poisonous
Radioactive
Corrosive
National Fire Protection Association (NFPA) Classification System
United Nations (UN) Hazard Class Numbers
Bills of lading, shipping papers
Material Safety Data Sheets
Plant supervisors/company representatives/company chemists
Fire department incident commander
On-scene chemical detection
Regional poison center/medical toxicologist
Specific toxic syndromes
Odors (see Table 14–3 )
Table 14-3 -- Odors Related to Chemical Identification

Odor Toxin
Sharp, pungent Ammonia
Fishy Aniline
Garlic or fishy Arsine, phosphine
Benzene
Toluene
Xylene
Sweet, ether-like
Ethylene oxide
Methylene chloride
Trichloroethylene
Chlorine
Pungent
Formaldehyde
Hydrochloric acid
Sharp, choking
Chlorine
Bitter almond Hydrogen cyanide
Rotten egg Hydrogen sulfide
Musty or fruity Methyl bromide
Irritating, sharp Nitrogen oxides
Garlic or solvent odor Organophosphate pesticides
Sweet, acrid Phenol
Musty or new-mown hay Phosgene
Fruity and pungent Toluene diisocyanate
At the scene of an incident, a wide range of instruments and detection devices can be used to detect the
presence and approximate concentrations of chemicals. However, a specific chemical detected on the
scene may not be the cause of a patient’s problems. The observed symptoms and physical findings in
exposed victims must be consistent with those expected from the identified toxin.
Once the chemical is identified, specific chemical characteristics, toxic effects, and specific therapies can be
found by using any of several resources ( Table 14–4 ). Additional information that will help with decision
making can be found by answering the following questions.
Table 14-4 -- Information Resources for Health Risk Information *

Material Safety Data Sheets
Computer data bases
Poisindex/Tomes (Micromedex)
Hazardous Substance Data Bank (HSDB)
Chemical Hazard Response Information System (CHRIS)
Toxicology Data Network (TOXNET)
National Library of Medicine (Medline)
Internet Connections (Examples)
ATSDR Web Site: http://www.atsdr.cdc.gov/atsdrhome.html
CDC Home Page: http://www.cdc.gov.ezproxy.med.nyu.edu/

EPA Home Page: http://www.epa.gov/
TOXIKON: Medical Toxicology Online: http://toxikon.er.uic.edu/
Vermont SIRI MSDS Collection: http://hazard.com/msds
Reference Texts
Agency for Toxic Substance and Disease Registry (U.S. Department of Health and Human Services).
Managing Hazardous Materials Incidents, Volume 3. Medical Management Guidelines for Acute Chemical
Exposures. 1994.
Agency for Toxic Substance and Disease Registry. (U.S. Department of Health and Human Services.)
Managing Hazardous Materials Incidents, Volume 2. Hospital Emergency Departments, 1991.
Sullivan JB, Krieger GR: Hazardous Materials Toxicology: Clinical Principles of Environmental Health.
Baltimore, Williams & Wilkins, 1992.
Borack J, Callan M, Abbott W: Hazardous Materials Exposure: Emergency Response and Patient Care.
Englewood Cliffs, NJ, Prentice-Hall, 1991
1996 North American Emergency Response Guidebook: A Guidebook for First Responders during the Initial
Phase of a Hazardous Materials/Dangerous Goods Incident. Washington, DC, U.S. Department of
Transportation, 1996.
Klaassen CD: Casarett and Doull’s Toxicology: The Basic Science of Poisons. 5th ed. New York, McGraw-Hill,
1995.
Rom WN: Environmental and Occupational Medicine. 3rd ed. Philadelphia, Lippincott Williams & Wilkins,
1998.
Agencies with Telephone Hotlines
Regional poison centers
County and state health departments
Agency for Toxic Substances and Disease Registry (ATSDR) 1-404-639-0615
Chemical Transportation Emergency Center (CHEMTREC) 1-800-424-9300 (toll free in the United States and
Canada)
Environmental Protection Agency (EPA)—contact regional office
Centers for Disease Control and Prevention (CDC) 1-404-639-2888
National Response Center and Terrorist Hotline 1-800-424-8802
Radiation Emergency Assistance Center/Training site (REAC/TS) 1-865-576-1005 (ask for REAC/TS)
Other
Industrial plant representative (chemist or toxicologist)
* Do not rely on a single reference source for information. Attempt to verify information from two additional reference sources. This is not an
all-inclusive list of references but has been selected as a representative list for use in an emergency department. Most regional poison
centers will have many of these references available.
Does this chemical pose a risk of secondary contamination?
Primary contamination is the direct contact of a chemical on a patient. Secondary contamination occurs
when chemical contamination is passed onto rescue personnel, health care workers, or equipment.
Hazardous materials pose a risk of secondary contamination only if they are both toxic and likely to be
carried on the skin, clothing, or hair of a patient in quantities large enough to harm staff[1] ( Table 14–5 ). In
most cases, emergency treatment does not need to be delayed for special decontamination procedures if
victims have been decontaminated at the scene or have been exposed to chemicals posing a low likelihood
of secondary contamination.[1]
Table 14-5 -- Secondary Contamination Risks

Materials that pose serious risk of secondary contamination
Highly toxic liquids
Highly toxic solids
Highly toxic finely divided solids
Vapors that condense to a liquid state on clothing and skin
Ingested substances that can form toxic gases (off-gassing)
Vomitus from ingested toxic substances
Radioactive liquids and dusts
Certain biologic agents
Materials that pose little risk of secondary contamination
Gases
Vapors (unless condensed to liquid on clothing or skin)
Substances with no serious toxicity
Source: Adapted from Agency for Toxic Substances and Disease Registry (ATSDR, U.S. Department of Health
and Human Services). Managing Hazardous Materials Incidents, Volume 3. Medical Management Guidelines for
Acute Chemical Exposures. 1994.
What is the dose?

The dose is the total amount of chemical absorbed by the patient during an exposure. A patient’s dose may
be estimated from various information available from the patient, incident commander, emergency medical
services (EMS) personnel, or chemical information. The dose of any substance depends mostly on the
concentration of the chemical and the duration of the exposure. Other factors include the route of exposure,
absorption characteristics of the chemical (e.g., lipid-soluble chemicals tend to be more readily absorbed by
the skin) and the site of the exposure (e.g., enclosed space versus outdoors). Additionally, warning
properties of some chemicals can be clues to the extent of exposure. A warning property is the
concentration at which a chemical’s odor can be detected or irritant symptoms occur. However, some toxins
have a detectable odor or cause irritant symptoms only after exposure to extremely high concentrations that
may cause other serious toxic effects. For example, phosgene produces serious toxic effects at
concentrations near the odor threshold. Hydrogen sulfide will cause olfactory nerve paralysis as air
concentrations rise to lethal levels. It is important not to rely on detection of odors alone in order to estimate
the potential exposure.
What is the clinical significance of the estimated dose?
Data from on-scene air measurements may be available to estimate the magnitude of the exposure. The
Occupational Safety and Health Administration (OSHA) has developed guidelines for workplace exposures.
Acute toxicity levels, such as immediately dangerous to life and health (IDLH) and short-term exposure limit
(STEL), apply to occupational exposures and are less useful for acute environmental exposures.[5][80]
Nevertheless, they can be used as estimates of a clinically significant dose ( Table 14–6 ).
Table 14-6 -- Terms Used to Estimate Exposure to Hazardous Materials

PEL: Permissible exposure level (OSHA). An 8-hour time-weighted average (TWA) of chemical concentration
in air that cannot be exceeded. Also known as the threshold limit value (TLV-TWA) by the American Congress
of Governmental Industrial Hygienists (ACGIH).
Ceiling limit: A chemical’s airborne concentration that can never be exceeded.
IDLH: Immediately dangerous to life and health. A chemical’s concentration that poses immediate threat to life,
or causes irreversible or delayed effects, or compromises ability to escape the environment.
STEL: Short-term exposure level. A 15-minute TWA that should not be exceeded at any time during the work
day.
What are the anticipated toxic effects of the chemical?
Table 14–4 illustrates the variety of available resources containing information on human toxic effects of
chemicals and treatment. The reliability of hazard information varies among the many resources. For
example, Material Safety Data Sheets (MSDS) are a good source for chemical identification, but information
regarding human health effects is often incomplete or inaccurate.[10][32][37][40][48] Inert ingredients listed on
the MSDS may actually be toxic to humans at certain levels, but they are inert when the products are used
as intended. Regional poison centers and medical toxicologists are often the most reliable resources for up-
to-date human health risk information and specific treatment recommendations.[13][58]
Despite published research, the human health risks of many chemicals remain uncertain. Potential toxic
effects should be anticipated from those chemicals with little or no documented toxicity.
Is there a specific treatment or antidote?
Early recognition of the need for specific therapies and antidotes allows time to accumulate amounts
sufficient for the anticipated needs. In addition, it allows time to become familiar with special administration
procedures and potential adverse effects.
Are there delayed or long-term effects?
Identifying those toxins with slow onset of toxic effects allows appropriate medical observation of exposed
patients. Injury to the liver, kidney, or bone marrow may not be evident for several days. Serious effects such
as dermal sensitization, asthma, cancer, or risks to unborn children are not a major concern in the acute
phases of an emergency response, but appropriate follow-up must be assured. Far more uncertainty exists
regarding long-term effects than risks from acute exposures. Additionally, community resources such as the
local health department and primary health care providers should be utilized for follow-up and monitoring of
long-term effects.
Resource Management
Resources are defined as the facilities, medical and specialized equipment, supplies, pharmaceuticals, and
personnel required for management of a hazardous material incident.
Facility
Any facility, including a hospital receiving casualties, must have management plans and procedures in place
prior to an incident. These plans must provide for the decontamination and care of contaminated patients
while minimizing the risk of secondary contamination of staff and other patients. A confinement area for
potentially contaminated patients (“hot zone”) should be established. This area should be clearly marked
and contain decontamination and resuscitation equipment. Entry to and exit from this area should be
carefully controlled, and it should be the only access into the hospital. Contaminated patients are taken to
the “hot zone,” where decontamination and resuscitation procedures are performed. Also, anyone with
suspected chemical exposure should be denied hospital entry and instead moved into this area for
decontamination or verification of a nontoxic exposure. For many EDs, outside decontamination is the most
practical option.[19] Inside the hospital, decontamination can occur in specially designed facilities equipped
with separate ventilation systems that provide adequate air flow.[26] Ideally, “clean” patients from the hot
zone are delivered to a patient treatment area. Staff in the hot zone should be limited in order to avoid
unnecessary personnel exposure.
Equipment, Supplies, and Antidotes
Necessary specialized equipment and supplies are listed in Table 14–7 . In addition, standard resuscitation
equipment and medical supplies should be available in the hot zone. Lifesaving procedures must be
performed in this area until decontamination is complete. Use older or disposable equipment and supplies in
the hot zone, because they are likely to be contaminated. Antidotes and other needed pharmaceuticals may
not be available in sufficient quantities in the ED.[21][82] For example, a large number of organophosphate-
poisoned patients will quickly deplete the atropine and pralidoxime stores of most hospitals.[21][82] Once the
toxic chemical has been identified or a specific toxic syndrome recognized, appropriate amounts of the
antidotes can be acquired. The hospital pharmacy or a regional poison center can assist in locating
antidotes at other hospitals or local pharmaceutical warehouses.
Table 14-7 -- Recommended Equipment and Supplies

Stretcher with plastic tub or foldable rubber tubs for top of stretcher (several manufacturers)
Warm water source
Hose with shower head
Mild soap
Soft-bristled brushes
Plastic garbage bags
Wading pool for containing water run-off
Clean dry clothing for decontaminated patients
Privacy barrier
Disposable medical equipment and supplies
Portable suction with disposable collection bags
Oxygen source
Optional decontamination equipment
Portable outdoor showers
Dedicated decontamination rooms with separate ventilation and method of containing water run-off
Personnel protective equipment (PPE)
Chemical-resistant clothing
Chemical-resistant suits (e.g., Tyvek or Saranex) with built-in hood and boots
Rubber aprons
Chemical-resistant gloves (e.g., butyl rubber) taped at the sleeve
Splash-protective eyewear
Respiratory protection (requires specific training, fit testing, and record keeping)
Self-contained breathing apparatus
Supplied air respirators
Air-purifying respirators
Personnel
All personnel involved in the care of Haz-Mat victims must avoid self-contamination.[68] Personnel directly
working with victims must put on adequate protective equipment prior to caring for patients; the level of
protection must be adequate for the toxicity of the chemical(s). Training in the use of specialized personal
protective equipment is essential, because improper use may result in injury.[3]
Contaminating vapors or fumes may harm hospital staff, especially if respiratory protective equipment is not
worn and the work area is not ventilated to the outside. Surgical masks do not protect from toxic gases,
vapors, or fumes. Patients with noticeable chemical odors or exposure to chemicals with the potential to
release toxic vapors or fumes should remain outside the ED until properly decontaminated. The absence of
an odor does not reliably exclude a toxic chemical, because some highly toxic chemicals are odorless.
Recommended protective equipment for decontamination and resuscitation team members is listed in Table
14–7 .[3][15] No consensus exists for the minimal level of protection required for hospital decontamination,
especially with regard to respiratory protection. Selecting the appropriate protective equipment depends on
the specific toxin identified. For example, a patient contaminated with a strong corrosive such as hydrofluoric
acid should be handled with splash-protective equipment, including chemical-resistant clothing, gloves, and
eye protection. In addition, ED personnel require full respiratory protection when caring for a patient
contaminated with a highly toxic chemical that continues to produce fumes or vapors, such as sodium azide.
Resource Management for Mass Casualty Incidents
A disaster is defined as a situation that overwhelms available resources. Management of equipment,

supplies, personnel, and specific antidotes is necessary to maximize good outcomes for the greatest
number of potential survivors. The hospital’s mass casualty incident coordinator must assess available
resources and forecast future needs. Maintaining specialized supplies may be a problem. For example, the
decontamination procedure requires special supplies that are not stockpiled in most emergency
departments.
Security officers are essential to secure a perimeter and control access to the hot zone and other hospital
entrances. A single hospital entrance for patients must be established to prevent contamination of areas
outside the hot zone. Traffic control around the hospital may be problematic because of the use of outside
areas to hold patients prior to decontamination. Others, such as reporters, volunteers, and family, must be
kept out of the hot zone.
Patient Management
Chemically contaminated patients require special handling and treatment. Emergency care providers must
first protect their personal safety and create a safe environment prior to patient assessment or even
lifesaving interventions. Visualizing the contaminated patient as someone engulfed in flames may help.
Extinguishing the “flames” terminates further injury to the patient but, just as important, protects emergency
care providers from getting burned.
Triage
Triage is the sorting of patients, based on the likelihood of survival given the resources available.[38][76] The
duty to one person is abandoned in favor of saving many.[23][53][76] The initial triage decision focuses on
treating life-threatening problems in potentially salvageable patients while assessing the urgency for
decontamination. Assessment of vital signs may be unreliable because of impaired vision and dexterity of
staff in full protective gear.[39] Doing the best for the most may require using resources to decontaminate
less seriously ill patients (even asymptomatic patients) over those more critically ill.
Decontamination at the scene decreases the likelihood of “load and go” transport. In turn, this may result in
delayed transport of critically ill patients. Conversely, improperly trained prehospital care providers or an
overwhelmed EMS system may transport patients prematurely to the hospital prior to adequate
decontamination, thus risking secondary contamination of personnel.[47] Patients may also arrive by private
vehicle, with no prior decontamination performed.[60] A mechanism for triaging those patients must be in
place.
Decontamination
The objectives of decontamination are to prevent spread of contamination and to terminate the patient’s
toxin exposure. Data regarding decontamination are limited, but fundamental principles can be found in
military chemical battlefield studies and radiation accident protocols.[46][62][68] Decontamination should occur
as close to the site of exposure as possible to limit the spread of toxic agents and to decrease the time to
initial treatment.[16] In a Haz-Mat incident, decontamination is best performed in the prehospital setting. The
need and urgency for decontamination procedures are determined by chemical toxicity and the potential for
secondary contamination, with urgency further influenced by patient condition ( Fig. 14–1 ). An
asymptomatic patient exposed to a highly toxic chemical needs decontamination before any medical
treatment, while decontamination procedures must occur simultaneously with lifesaving treatment for a
critically ill patient. Contaminated patients may bypass the EMS system and walk into the ED. Therefore,
hospitals should be prepared to decontaminate patients arriving by transport independent of the EMS
system.
Figure 14-1 Determining the need for decontamination.
Toxic chemicals cause injury when inhaled or absorbed through the skin, open wounds, or mucous
membranes. Airborne toxins account for most exposures in Haz-Mat incidents, and removal from the source
may be sufficient to prevent further exposure.[77] However, toxic fumes may contain aerosolized chemicals
or vapors that can condense on skin or clothing.[28] Continued chemical contact with the skin may worsen
toxicity through direct skin injury or systemic absorption. Some toxins, such as caustics and solvents, directly
damage the structural integrity of the skin, yet other toxins (e.g., pesticides, hydrogen fluoride, and
methemoglobin inducers) penetrate tissues, enter the circulation, and cause systemic toxic
effects.[36][57][70][74] Skin irritation, burns, or deposits of liquid and solid materials on skin and clothing are
clues to the presence of hazardous materials requiring decontamination. Copious water irrigation within
minutes of exposure, and definitely within the first hour, following a chemical burn is crucial in reducing direct
corrosive effects (incidence of full thickness burns) and systemic toxic effects.[20][29][33][44][54]
Using a universal substances decontamination protocol that is not specific for any chemical will reduce
confusion and avoid delays.[19][43] Basic principles for decontamination of radiation exposures can be
adapted for chemical decontamination [43][46]( Table 14–8 ). Contaminated clothing is a source of primary and
secondary contamination, can enhance toxin absorption by acting as an occlusive dressing, and should be
removed expeditiously.[79] Copious water irrigation will dilute a chemical and decrease its duration of contact
with a patient’s skin. Occasionally detergents, dilute bleach, corn meal, or specific neutralizing agents may
be recommended, but water irrigation should never be delayed to search for these additional agents. Avoid
hot water, strong detergents, vigorous scrubbing, or stiff brushes; skin abrasion or vasodilation may enhance
toxin absorption. Associated ocular injuries are common with chemical burns, and eye irrigation may be
needed.[11][56][65]
Table 14-8 -- Decontamination Procedures

Establish hot zone
Set up decontamination equipment
Put on personal protective equipment
Remove all of patient’s clothing
Handle clothing as hazardous waste (Place in plastic bag)
Immediately remove any obvious contamination
Wash or wipe away liquid material
Brush away solid or particulate material
Prioritize decontamination
1. Obvious contamination sites
2. Contaminated wounds
3. Eyes (remove contact lenses)
4. Mucous membranes
5. Skin
6. Hair
Use copious low-pressure water irrigation
Do not delay water irrigation searching for specialized decontamination solutions or neutralizing agents
Use mild soap
Gentle washing
Contain water run-off *
Decontaminate all equipment and personnel prior to leaving hot zone
* Containment may be unnecessary because concentrations of chemicals in water run-off from a contaminated patient arriving at the hospital
are relatively low compared to primary spills. Most cases do not require special containment (exceptions include elemental mercury and
radioisotopes) but should be contained when in doubt. Local regulations should be understood before deciding not to contain water run-off.
Unfortunately, the effectiveness of decontamination must be judged without the benefit of objective criteria.
Studies suggest that copious water irrigation and soap cleansing are highly effective in removing many
chemical contaminants.[11][12][33][43][45][79] The skin’s stratum corneum is the protective barrier against
penetration of many chemicals. Soap and water cleansing may mechanically remove the upper layers of the
stratum corneum where many chemicals are deposited.[78] Unfortunately, toxins with high lipid solubility,
such as pesticides, can penetrate the skin rapidly and may be incompletely removed by washing.[27][29][79] In
these cases, delayed systemic effects can occur despite decontamination.
Immediate Stabilization
After decontamination, treatment of victims exposed to hazardous materials primarily involves symptomatic
and supportive care. In many cases, decontamination can occur simultaneously with lifesaving interventions.
A rapid primary and secondary survey of the patient will guide therapeutic decisions. Early endotracheal
intubation is recommended in the presence of upper airway edema, central nervous system depression,
hypoxia, hypoventilation, or excessive bronchial secretions. Administering supplemental oxygen is important
because many hazardous materials can produce hypoxia. Hypotension should be treated initially and
cautiously with crystalloid fluids, because many toxins have the potential to cause the adult respiratory
distress syndrome. Vasopressors and inotropes may be required after the intravascular volume status has
been optimized.
A secondary survey should identify systemic toxic effects, coexisting trauma, or other medical illnesses.
Obtaining past medical history may be helpful because toxic effects may be exaggerated by underlying
medical conditions or exacerbation of pre-existing illnesses, such as asthma or cardiac disease. Identifying a
toxic syndrome can guide subsequent medical therapy or antidote administration, even if the specific toxin is
unknown. Specific antidotes exist for a limited number of chemical exposures. Table 14–9 lists those
antidotes most often needed.
Table 14-9 -- Examples of Antidotes for Hazardous Material Exposures

Antidote Toxin
Cyanide antidote kit Cyanide
Oxygen/hyperbaric oxygen Carbon monoxide
Methylene blue Methemoglobin inducers
Atropine/pralidoxime Organophosphates/carbamates
Calcium Hydrofluoric acid
Chelators (BAL, DMSA, EDTA) Metals (lead, mercury, arsenic)


MEDICAL PROBLEMS ENCOUNTERED WITH CHEMICAL CONTAMINATION
Patients from Haz-Mat incidents can present with (1) contamination without apparent injury, (2) associated
trauma, (3) chemical burns, (4) irritant gas symptoms, (5) a variety of systemic toxic syndromes, or (6)
psychological harm ( Table 14–10 ).
Table 14-10 -- Hazardous Material Toxic Syndromes

Toxic Syndrome Common Signs and Symptoms Examples
Chemical burns Painful, burning skin Acid or alkaline corrosives,
hydrofluoric acid, phenol, hydrocarbon
solvents such as degreasers or
defatters
Mucous membrane irritation
Systemic toxic effects
Ammonia, chlorine, isocyanates,
Mucous membrane irritation acrolein, sulfur dioxide, hydrogen
chloride
Irritant gas syndrome Coughing, dyspnea
Acute bronchospasm
Pulmonary edema, noncardiogenic
Xylene, toluene, benzene,
Mucous membrane irritation isocyanates, methyl bromide,
methylene chloride
Acute solvent
Headache, lightheadedness, dizziness,
syndrome Aliphatic hydrocarbons
nausea
Chest tightness, dyspnea, lethargy, confusion,
coma, dysrhythmias
Aniline, nitrogen oxides, amyl nitrite,
Cyanosis unresponsive to oxygen therapy
chlorates, dinitrophenol
Methemoglobinemia Headache, lightheadedness, dizziness,
nausea, chest tightness, dyspnea,
dysrhythmias
Nerve agents: sarin, soman, tabun,
Pinpoint pupils and eye pain VX, organophosphate, carbamate
insecticides
Dyspnea, chest tightness, acute
Acetylcholinesterase bronchospasm, pulmonary edema
Toxic Syndrome
Acetylcholinesterase Common Signs and Symptoms Examples
poisoning Headache, lightheadedness, muscle
weakness, coma, seizures
Tachycardia or bradycardia, diaphoresis,
salivation, lacrimation, vomiting, diarrhea,
abdominal cramps
Early or low-level exposure: nausea, vomiting, Cyanide, hydrogen sulfide, azides,
headache, dizziness phosphine, carbon monoxide
Coma, seizures, syncope
Metabolic poisoning
Cardiac dysrhythmias, hypotension
Metabolic acidosis
“Knocked down”—cardiac arrest
Arsine, chlorine, ethylene oxide,
Pulmonary edema, noncardiogenic methyl bromide, nitrogen oxides,
phosgene, phosphine
Delayed toxic effects Hepatic injury Carbon tetrachloride, 2-nitropropane
Renal injury Cadmium
Hemolysis (arsine)
Headache, faintness, dizziness, nausea, chest
tightness, weakness, extremity numbness, Often indistinguishable from many
Psychogenic illness
dyspnea or hyperventilation, mucous serious toxic exposures
membrane irritation
Contamination Without Apparent Injury
Frequently, patients exposed to toxic chemicals will have no medical problems, and decontamination is the
only treatment necessary. Most often, no further risk of harm is present. However, some toxins, such as
pesticides, have the potential to reach the systemic circulation or cause delayed onset of toxicity despite
adequate decontamination. With such exposures, a prolonged period of observation is necessary even if the
patient appears relatively asymptomatic at the time of evaluation.
Associated Trauma
Haz-Mat accidents are frequently associated with fire, explosion, structural collapse, or transportation
accidents, and the likelihood of associated trauma is high. Traumatic injuries may be so apparent and seem
so urgent that appropriate precautions are not taken for the concomitant chemical contamination. In addition,
toxic effects may be overlooked. Conversely, the treatment team may focus on chemical contamination
problems at the expense of recognizing traumatic injuries. Bandages, trauma dressings, splints, and cervical
immobilization devices applied in the field may be sources of secondary contamination. Open wounds are
especially problematic. They can absorb a chemical directly into the systemic circulation and thus deserve
priority in the decontamination process.
Chemical Burns
Chemicals harm skin by producing an inflammatory reaction, necrosis, or desiccation. Corrosives such as
hydrochloric acid or sodium hydroxide cause coagulation or liquefaction necrosis. Hydrocarbons act as
defatting agents to the skin, and vesicants such as mustard agents damage cellular DNA.
After removing chemicals from the skin by copious water irrigation, most burns are treated similarly to
thermal burns. Few antidotes or specific therapies are required for toxins causing chemical burns.
Complications of chemical burns result from the loss of the skin’s protective barrier. This lost barrier allows
chemical absorption into the systemic circulation, intravascular fluid losses, and microorganism invasion.
Systemic toxic effects after dermal absorption include metabolic, electrolyte, hepatic, renal, or hematologic
abnormalities. For example, hydrofluoric acid burns can be associated with profound hypocalcemia and
rapid hemodynamic compromise.[74]
Inhalation Injury
Acute pulmonary injury can occur along any part of the respiratory tract. Toxins induce inflammatory and
irritant reactions that cause mucosal edema. The loose tissue of the upper airway is vulnerable to massive
edema. For example, edema from corrosive injury due to ammonia can occlude the upper airway. In addition
to edema, cellular debris, secretions, and bronchospasm cause bronchiolar obstruction. Ventilation may be
difficult owing to intense toxin-induced bronchoconstriction and should be treated with ß-adrenergic agonist
bronchodilators and frequent suctioning. Inhalants with low water solubility have poor warning properties that
allow significant concentrations to reach the alveoli. Phosgene and nitrogen oxides are examples of
inhalants that produce delayed onset of pulmonary edema.
Lifesaving treatment must focus on a patent airway and adequate ventilation. Early endotracheal intubation
is crucial in the critically ill patient. Succinylcholine for rapid sequence intubation should be used cautiously
in patients poisoned with acetylcholinesterase inhibitors because neuromuscular blockade can be
prolonged. In these cases a short-acting, nondepolarizing neuroparalytic such as vecuronium may be
preferable. Parenchymal injury is best managed with oxygen, positive end-expiratory pressure, and
avoidance of overhydration. Insufficient data exist to support a beneficial effect of glucocorticosteroids on
either upper airway or alveolar injury. Their use may increase the risk of bacterial pneumonia, and they
should not be used in this setting.[55]
Systemic Effects
Many organ systems are vulnerable to the systemic effects of toxins. Serious central nervous system effects
such as seizures, delirium, or coma can occur. The comatose patient often requires only supportive care, but
for the actively seizing patient, benzodiazepines should be titrated to seizure termination. Less serious
complaints of headache, dizziness, nausea, and vomiting are common manifestations of many poisons.
Several toxins such as cyanide, acrylonitriles and hydrogen sulfide interfere with cellular use of oxygen and
produce metabolic acidosis. Hemolysis from arsine gas and methemoglobinemia from aniline and nitrites
are examples of toxins affecting the hematologic system. Delayed effects such as hepatic injury, acute renal
failure, aplastic anemia, or cancer may ultimately develop. Systemic manifestations of acetylcholinesterase
inhibitors such as pesticides and nerve agents are probably most important to recognize. Identifying the
signs and symptoms of excess acetylcholine will make the diagnosis, alert the need for rescuer protection
and guide antidote therapy.
Psychologic Harm
When there has been a large chemical accident, television coverage may show dramatic images of black
billowing clouds of smoke, firefighters dressed in “moonsuits,” and neighborhood evacuations. Along with
the drama, facts about the incident are often conflicting or unknown. These images and information
problems may provoke anxiety and fear among emergency responders, victims, nearby residents, and even
the entire community.
The public is aware of the dangers of toxic chemicals and may perceive exposures to even small amounts of
chemicals as harmful. The public’s opinion of risk is often based on trust and fear rather than the critical
analysis of scientific evidence. [72] Acute anxiety reactions and the syndrome of mass psychogenic illness are
common in chemical accidents. [9][34][67] In the attempt to “do the best for the most,” health care workers must
learn to respond to these reactions.
Psychogenic-induced symptoms seem very real to the victims and may mimic those produced by a toxic
exposure. Headaches, faintness, dizziness, nausea, chest tightness, difficulty in breathing (hyperventilation),
irritation of the eyes, nose, or throat, weakness and extremity numbness are the most frequent complaints.[9]
Differentiating true toxicity from a powerful emotional reaction can be extremely difficult. A large number of
people with emotional reactions can overwhelm the entire emergency response system and hinder timely
treatment of those with true toxic emergencies. Patients must be triaged as toxic emergencies whenever
symptoms are indistinguishable from true toxic effects.
The psychological syndrome is most effectively treated when it is rapidly recognized. Disbanding a group of
patients can diminish symptoms that are exacerbated by the sight and sound of other victims. To alleviate
fears, emphasize the certainties of the incident but never downplay or minimize the patient’s concerns.
Informing the media and public about an incident is important. A credible spokesperson should provide
timely information to the public during an emergency to minimize emotional responses that can occur if
insufficient information is given. [8][63][72] Accurate and timely information will prevent rumors and can
alleviate many fears associated with a toxic exposure.[71]
Special Risks to Rescue Personnel
Recent data indicate that first responders account for many of the victims from Haz-Mat incidents.[35]
Depending on ambient temperature and the physical condition of the rescuer, life-threatening heat illness
can develop quickly when personnel are in fully encapsulated protective equipment.[17][41] Traumatic injuries
may occur during rescue operations. Accidental disruption of the protective suit or respirator malfunction
may lead to serious contamination. Psychologic stress may play a role in rescuer illnesses.[30][69][71]
Aftermath
All patients need a definitive disposition. Those discharged from the hospital need specific reasons to return
for re-evaluation and instructions on expected continued effects, potential long-term effects, and the need for
medical follow-up. Many companies have prearranged follow-up for workplace accidents. ED clean-up
involves disposal of contaminated clothing, equipment, supplies, and water run-off. An industrial hygienist or
an agency such as the health department should certify the entire facility, especially the hot zone area, as
ready to resume normal operations. Prior contractual arrangements with hazardous waste disposal
companies and appropriate agencies will speed these processes. Additionally, all involved prehospital and
hospital personnel should attend a critical incident stress debriefing that also addresses concerns about
health risks from exposure.[8][24][25][73] The debriefing should review lessons learned from the incident and
suggestions for revising the response plan.
Community concerns must be addressed. Questions will arise about contamination of air, soil, food, pets,
livestock, and drinking water. If unanswered, these questions may influence the number of patients seeking
medical attention hours to days following an incident. In addition, community critical incident stress
debriefing is crucial because post-traumatic stress disorder is prevalent following all types of
disasters.[14][69][71] The health department, regional poison center and Environmental Protection Agency can
assist in dealing with many of these concerns.


DEVELOPING THE HAZ-MAT RESPONSE PLAN
Recommendations
The plan should be as simple as possible.[7] Table 14–11 lists issues to address in a response plan.[6] The
task of providing the best care for patients should be reconciled with the burdens of complying with
regulations. The objective is to develop a workable plan with the intent to use it.[22] Define the roles and
priorities and outline the most important tasks within the hospital. Determine resources needed and
resources already available. Departments must solve problems together, in advance, during nonurgent
conditions. A spirit of cooperation and trust, along with a clear mission, will lead to more effective decision
making under urgent conditions.
Table 14-11 -- A Guide to Haz-Mat Preplanning in the Emergency Department

Initial Notification
How is hospital notified of transport of chemically contaminated patients?
Who notifies hospital?
What information is given to hospital regarding chemically contaminated patient?
Is there a process for verification of the notification?
The Plan
Where is the written plan stored?
Is there a specific hazardous material plan?
Is there a specific plan for radiation contamination?
Is there a separate mass casualty plan?
Who is authorized to implement the plan?
Are there specific criteria for activating the plan?
Does the plan include a call list for notification?
Does the plan include a list of information resources?
Safety Issue
Does the hospital have evacuation contingency plans?
Leadership
Does the plan:
Define who is in charge of the incident?
Define the chain of command for reporting and decision making?
Information Management
Does the plan:
Assign a person to be responsible for obtaining additional information regarding the alleged toxin, expected
number of patients?
Assign a person to be responsible for obtaining information (toxic effects, specific treatments and antidotes,
long-term health effects) about alleged chemical exposure?
Assign a person to list all patients and track them through the hospital?
Assign a person responsible for media and public information?
Resource Management
Equipment
Where is the equipment stored?
Is a person assigned to maintain equipment on a routine basis?
Does the stored equipment include:
Decontamination equipment and supplies
Tape barricades
Soap
Soft brushes
Shower nozzle
Containment vessels for water run-off
Containment vessels for contaminated clothing
Personnel
Does the plan define specific staff duties?
Does the plan assign a person to assess health of staff involved in incident?
Does the plan assign a person to assess the health of ambulance crews transporting patients?
Is personnel protective equipment available?
Patient Management
Is there an assigned person to oversee patient flow?
Routine ED patients
Asymptomatic walk-in patients with contamination
Transfer of decontaminated patients into patient care areas
Transfer of patients to wards, ICU, hyperbaric oxygen
Transfer of patients to specialized care facilities (burn center, trauma center, pediatric ICU, hyperbaric facility)
Is there an assigned person to perform follow-up evaluations on patients?
How is documentation handled?
Does the plan have a designated area for potentially contaminated dead victims?
Does the plan have a mechanism for removing the contaminated dead?
Do patients have specific follow-up instructions?
Do patients need a follow-up appointment?
Wrap-Up
Does the plan have specific criteria for “all clear”?
Are all staff decontaminated prior to leaving the hot zone?
Are there provisions for debriefing the staff?
Potential long-term health risks
Critical incident stress debriefing
Is there an industrial hygienist to determine that the facility (specifically the hot zone) is safe for use?
Is there a prearranged agency for facility clean-up?
Is there a prearranged agency to dispose of containment vessels with water run-off and contaminated clothing
and supplies?
Is there provision for critiquing the plan?
Is there a mechanism for feedback to all participants?
Is there a provision for revising the plan?
Information resources must be part of the plan because misinformation is a major pitfall in all Haz-Mat
incidents.[7] A regional poison center should be effectively integrated into the response plan as an
information management resource.[13][40][58][64][75] The poison center can assist in chemical identification
and provide information on the number of patients, toxicity data, and specific decontamination and treatment
recommendations to the scene and to local hospitals. Additionally, the poison center can provide toxicologic
information to the media and public to ensure accurate information regarding the toxicity of chemicals. After
the incident, the poison center can assist public health agencies in long-term care and follow-up of
patients.[40][81]
An effective plan must undergo continual quality improvement by periodic practice, unscheduled testing, and
revision.[3][50] Detailed guidelines for prehospital and ED planning can be found in several
publications.[3][4][6][42][45][61]
Pitfalls
Inertia is the biggest obstacle to having a workable Haz-Mat plan in an emergency department. Other
obstacles include some common misconceptions:
1. Misconception: It will never happen here. At many hospitals, enthusiasm for planning is generated
only following an accident in the community.[7] Unfortunately, even this interest quickly dissipates.
2. Misconception: We already have a disaster plan. The typical hospital “disaster” plan is a document
intended to meet certification requirements. Often the plan is written for a plane crash, but planners
assume it is adaptable to any situation, ranging from a chemical exposure to a tornado.
3. Misconception: The plan must be complex in order to be safe and compliant. Recommendations
for Haz-Mat planning are frequently too complex. Some authorities recommend elaborate equipment,
complicated protocols, and the highest level of personal protective equipment for every situation. These
recommendations derive from military battlefield principles, fire services protocols, hazardous waste
site protocols, and governmental regulations for hazardous chemicals. In reality, the hospital deals with
low levels of contamination compared to those encountered at the site of the spill.[66] Chemical residue
on clothing poses the greatest contamination risk for hospitals, and this risk is significantly decreased
once the clothing is removed. Therefore, clothing removal and a thorough shower will suffice for most.
Rarely will high-level personal protective equipment, multistep decontamination procedures, and
containment of water run-off be necessary. A complex response is costly, time-consuming (both for
training and patient care), and usually unnecessary. Keeping the plan simple and flexible will facilitate
appropriate hospital response.


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Uncited reference
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Washington, D.C., U.S. Department of Health and Human Services, 1994.


Chapter 15 – Drug Testing in the Workplace
SCOTT D. PHILLIPS
Substance abuse costs the citizens of the United States in excess of $200 billion annually in time lost and
overtime for replacement workers.[12][36] Drug testing of workers has resulted from the high prevalence of
abuse and the economic consequences and has rapidly expanded over the past 10 years to cover millions
of workers in the United States. This includes most of the Fortune 500 companies. Increased testing has led
to a dramatic decrease in the number of workers testing positive ( Fig. 15–1 ). Surveys suggest workers in
certain job categories are more prone to abuse alcohol and other drugs. The U.S. Department of Health and
Human Services (DHHS) found that construction workers are the most frequent substance abusers ( Figs.
15–2 and 15–3 ). Workers in public trust areas, including teachers, police officers, and child-care workers,
report the lowest rate of substance abuse.[16]
Figure 15-1 Quest Diagnostics, Incorporated, Drug Testing Index. www.questdiagnostics.com .

Figure 15-2 Percentage of workers reporting use of illegal drugs. (CW, Construction workers; CS, construction supervisors; FP, food
preparation; WW, waiters and waitresses; HL, helpers and laborers; WDAA, writers, designers, artists, and athletes.)[16]
Figure 15-3 Percentage of workers reporting heavy use of ethanol. (AC, All construction; CL, construction laborers; HL, helpers and
laborers; AM, auto mechanics; FP, food preparation; TD, drivers of light trucks.)[16]
Statistics of abuse are difficult to tabulate. Estimates are drawn using severaltechniques, including survey
methods, collateral rates linked to other illnesses. Drug Abuse Warning Network (DAWN), rosters registers,
prescription audits local studies, urine testing results treatment
programs.[6][7][8][13][22][23][25][26][28][29][30][37][42][44][46][48][50][54][57][58] Each method has its own bias, and all are
estimates. Regardless of the source cited, the estimates of adults in the United States who abuse alcohol
and illicit drugs range from 10 to 40 per cent. The absolute number of workers tested is difficult to calculate
but is in excess of 30 million. These include employees in sensitive positions at all agencies of the United
States government; National Collegiate Athletic Association, Olympic, and certain professional athletes; and
workers at businesses throughout the United States who undergo testing at the discretion of their
companies. Athletic drug testing is a complex area not covered in this chapter. Since 1993 the prevalence of
self-reports of illicit drug and alcohol abuse has decreased from 8.4 to 6 per cent in the combined U.S.
workforce ( Table 15–1 ).
Table 15-1 -- Prevalence Rates of Self-Reported Use of Illicit Drugs

Testing Category 1996 1995 1994 1993
Safety-sensitive transportation workforce 3.6% 3.4% 3.5% 2.8%
General workforce 6.4% 7.5% 8.6% 9.8%
Combined U.S. workforce 5.8% 6.7% 7.5% 8.4%
From Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beecham
data shows. Collegeville, PA, SmithKline Beecham Clinical Laboratories, 1996.
DEPARTMENT OF TRANSPORTATION BACKGROUND AND TESTING
The U.S. Department of Transportation (DOT) anti-drug rules apply to agencies involved in the
transportation industry. These include the Federal Aviation Administration, Federal Highway Administration,
Federal Railroad Administration, Federal Transit Authority, Research and Special Projects Administration,
and U.S. Coast Guard. Each may have specific requirements, and the reader is referred to the federal
regulations for appropriate information.
Only certain drugs are to be tested under DOT regulations: amphetamines, cocaine, marijuana,
phencyclidine (PCP), and opiates. Other allowable tests include 6-acetylmorphine (heroin metabolite) and
amphetamine isomers (D-isomer, illegal, vs. L-isomer, legal). They are known as the “NIDA-5.” Recently this
list has expanded to include ethanol breath testing.
The Drug-Free Workplace Act of 1988 requires contractors and recipients of federal grants to certify that
they provide a drug-free work site. Requirements and penalties for noncompliance are specified. In 1990 the
federal government extended urine drug testing to small trucking companies to address a national problem.
The DOT workplace drug testing program, which began in 1988, mandates employers to implement testing
programs for employees in safety-sensitive positions. The DOT put forth 49 CFR part 40, a rule establishing
procedures for urine drug testing. These were modeled after the Mandatory Guidelines for Federal
Workplace Testing Programs issued by the DHHS in April 1988.[14] The procedures, which were outlined in
part 40, were amended in 1994 in response to an earlier 1994 amendment by DHHS and also to include
requirements of the Omnibus Transportation Employee Testing Act of 1991.[15]
The major changes dealt with volume collections for “shy bladder” patients, split specimens, and screening
and confirmation levels for marijuana (discussed later under Laboratory Testing). The volume of urine
currently required is 30 mL for a single collection and 45 mL for a split-specimen collection. With the 1994
amendment, when a donor reports that he or she is unable to provide a specimen, the procedure under DOT
testing calls for the donor to be provided with up to 40 ounces of fluids over a 3-hour time period to produce
a specimen that meets the volume requirement. If a specimen still cannot be provided, the collector reports
this to the employer as a shy bladder and the donor is referred to an employee-designated physician for a
shy bladder evaluation.
A split specimen is a single urine collection divided into two containers, or specimens. If the primary
specimen tests positive, the donor may elect to have the secondary specimen tested. As of August 1994,
split specimen collections, processing, and reporting are mandatory for employees in the aviation, railroad,
and motor carrier industries. As of January 1995, split specimens are required for transit system and
intrastate commercial drivers.


REASONS FOR TESTING
Many reasons exist to test subjects for potential drug abuse.[40] In 1989, a blinded longitudinal study of 5465
job applicants conducted by the Office of Selection and Evaluation of the U.S. Postal Service sought to
determine abuse patterns. Drug-test results in these applicants were compared with rates of absenteeism,
turnover, injuries, and accidents while on the job. After an average of 1.3 years on the job, employees who
had tested positive for any of the illicit drugs had an absenteeism rate 59.3 per cent higher than those testing
negative. The positive group also had a 47 per cent higher rate of involuntary turnover. No relationship exists
between positive drug-test results and rates of accident occurrence.[43] However, another study[51] found a
significant increase in workplace injuries. This study screened 2537 employees and followed each for an
average of 2 years. The authors found that marijuana-positive urine specimens predicted increased
turnover, accidents, injuries, disciplinary actions, and absenteeism. These risks appeared to decrease
during the second year of employment. For those who tested positive for cocaine, increased rates of
turnover, accidents, injuries, disciplinary actions, and absenteeism occurred at levels that did not change
from the first to the second year.
These studies suggest it is beneficial to test employees who work in safety-sensitive areas to decrease the
rates of injury and turnover. Nonetheless, the national debate continues as to the social and legal rights of
those tested. A discussion of that debate is far beyond the scope of this chapter.
Several categories of testing are prevalent ( Table 15–2 ). Pre-employment screening is the most common
reason for testing and encompasses the majority of individuals tested. Random testing, or testing performed
on a random basis after employment, is the second leading category and is a major deterrent to drug abuse.
According to 49 CFR 382.305, randomization can be done with a “scientifically valid method” such as a
random number table or a computer-generated random number list. Although this method detects many
abusers, Dupont and associates[18] suggest that random urine drug tests in the workplace are most effective
in identifying frequent users of illicit drugs. Their study found that 50 per cent of positive test results are from
everyday users and less than 7 per cent of positive results occur in infrequent users of illicit drugs. Other
categories of testing include postaccident, reasonable suspicion of abuse, rehabilitation, and those for
persons on parole or probation. The percentage of positive results is shown in Tables 15–3 and 15–4 .
Table 15-2 -- Categories of Drug Testing by Percentage

Category Percentage of Tests
Pre-employment 90
Random 5
Post-accident
Rehabilitation
Probation and parole 5
Suspicious activity
Table 15-3 -- Positive Drug Test Results by Testing Category, for Safety-Sensitive Transportation
Workforce
Testing Reason 1996 * 1995 1994 1993
Pre-employment 4.3% 4.1% 4.1% 3.4%
Periodic 1.6% 1.7% 1.7% 1.5%
Random 2.9% 3.0% 2.7% 2.4%
Post-accident 3.3% 6.0% 3.4% 3.3%
For cause 11.0% 10.8% 9.5% 9.9%
Return to duty 3.8% 3.7% 2.8% 2.3%
* More than 968,000 tests in 1996.
Table 15-4 -- Positive Results by Drug Category for Safety-Sensitive Transportation Workers, as a
Percentage of all Tests
Drug Category 1996 1995 1994 1993
Marijuana 3.4 3.7 3.5 3.4
Cocaine 1.2 1.4 1.8 2.4
Benzodiazepines 0.38 0.5 0.8 1.1
Opiates 0.46 0.5 0.5 0.8
Barbiturates 0.19 0.26 0.33 0.38


REASONS FOR NOT TESTING
Reasons also exist for not testing individuals, such as the concern over social and legal rights (e.g., invasion
of privacy) previously mentioned.[17] Other reasons include the inability of a urine test to determine the
degree of impairment while at work. As a result of a positive test, one may face job termination, discharge
from the military, denial of employment, or parole violation. Although all DOT-regulated testing programs
require mandatory referral of an employee to the company’s employee assistance program (EAP), at least
for the first positive test result, non–DOT-regulated businesses may not use EAP services. The initial
concern over test accuracy has been effectively eliminated with the use of the gas chromatography/mass
spectrometry (GC/MS) confirmation test.


SPECIMENS TESTED
Several body substances are potential sources for testing for drugs of abuse. Urine is the most common
specimen of choice, but blood, hair, sweat, and breath testing occur in non-DOT testing. Each has
advantages and disadvantages for testing.
Urine testing is the “gold standard” for most drug testing programs. The substance is readily available,
specimen collection is noninvasive, and urine is easily manipulated by laboratory personnel. The
disadvantages are few but include a lack of correlation of test results with impairment or time of drug use.
Also, metabolites rather than the parent drugs are usually measured.
Sweat testing is done by applying an adhesive tamper-proof patch to the skin for 1 week to collect a sample.
This patch is assayed for the NIDA-5 agents. Application and specimen collection are easy. The tamper-
proof adhesive limits intentional adulteration or early removal. Once the patch is removed, it cannot be
reapplied. It also provides for detection of drugs over a longer period of time. Because of its interesting
advantages, sweat testing may replace urine testing in the future.
Blood tests correlate better with recent use, and parent drug concentrations can be measured. A major
drawback of using this substance for testing is the invasive technique necessary for specimen collection,
which requires a certain level of technical expertise as well as stirring the privacy rights issue. Also, all of the
complications of venipuncture apply to this method.
Hair test results have traditionally been difficult to interpret because of environmental contamination. The
advantages of testing hair include its ease in collection and that it provides information about drug use over
a longer period of time than urine.
Breath testing is only useful for volatile compounds such as ethanol. Because of this, breath testing is quite
useful to indicate impairment.


COLLECTION AND HANDLING
Collectors are required to obtain samples and determine if certain forms of adulteration have occurred. In
certain circumstances, witnessed collections may be compulsory. Breath alcohol technicians are trained to
collect breath samples and interpret the results.
The site collector ensures that the specimen is from the correct individual. This is done by using photo
identification (ID) or, if photo ID is unavailable, by using the employer representative as a source. If there is
no photo ID or employer representative, this is documented on the collection and control form. The collector
then requests two forms of non–photo ID bearing the employee’s signature and then proceeds with the
collection. When the donor signs the certification statement on the custody and control form, the collector
compares the signature with that on the non–photo ID. If the signatures appear consistent, the specimen is
processed. If not, the collector notes “signature identification is unconfirmed” on the custody and control
form.
The collector ensures there are no chemicals such as toilet bowel cleaners, soaps, and so on in the donor
room. A coloring agent can be added to the water in the toilet. The sink faucet can be temporarily rendered
nonfunctional by mechanical alteration or by taping the nozzle with tamper-proof security tape, which tears
with attempted removal. After the donation, the collector ensures that the specimen has not been tampered
with by measuring the temperature, observing the color, and looking for any foreign material in the urine.
The temperature of the collection must be within 90°F to 100°F, measured within 4 minutes of donation. The
specimen is sealed with tamper-resistant tape and initialed on the bottle label and dated by the collector and
initialed by the donor. The label is also dated as a further check. Each bottle has a unique ID number.
During specimen collection, the donor is usually allowed to urinate in private. Direct observation of urination
may be required if the donor appears intoxicated, is suspected of specimen adulteration, has previously
submitted an adulterated or tampered specimen, or has abused drugs.
Split-specimen collection requires the use of the same seven-page custody and control form and a collection
kit containing two sealable specimen bottles. The donated specimen is subdivided in the presence of the
donor. The collector may collect the specimen either in a common collection container or in a specimen
container. In the former, 30 mL of the sample is poured into the primary specimen bottle (specimen “A”) and
at least 15 mL into the secondary specimen bottle (specimen “B”) for the split. In the latter method, the
collector pours at least 15 mL into the secondary bottle (specimen “B”) for the split, making sure that a
minimum of 30 mL is maintained in the primary bottle (specimen “A”). Both portions of the split sample are
sent to the initial laboratory. Chain of custody forms are maintained for both portions.
The initial drug testing is performed on the primary bottle. The secondary bottle is stored for several days at
the discretion of the laboratory unless the primary sample is positive, in which case it is kept for at least 60
days. Specimen “A” is kept frozen for a minimum of 1 year. If specimen “A” is positive, the donor may
request within 72 hours to have the split (“B”) analyzed. If requested, the medical review officer (MRO)
makes this request in writing to the laboratory. The initial laboratory then sends the “B” bottle to another
laboratory. Only the metabolite that was found in bottle “A” will be assayed. This assay is done at the limits
of detection (LOD) by GC/MS, rather than the original cutoff values. If positive at any level above the LOD,
the split is positive and reported to the MRO.


TRANSPORTATION
Allowable modes of transporting specimens include the U.S. Postal Service, overnight carriers, or laboratory
couriers.


CHAIN OF CUSTODY
The “chain of custody” requires that each individual directly handling the specimen must sign the seven-part
custody and control form. When the sample is received from the donor, he or she will sign it over to the
collector. The collector signs the form out to the laboratory, where it is then signed that the specimen was
received in good condition.
In 1994 a DOT amendment clarified the chain of custody during transit. Now there is no requirement for
couriers or other shipping personnel to document their participation on the chain of custody form if they do
not directly handle the specimen. Previously, positive tests were invalidated because the couriers did not
enter their names and dates on the chain of custody form.


LABORATORY TESTING
Each laboratory that performs DOT testing must be certified under the Substance Abuse and Mental Health
Services Administration (SAMHSA, formerly NIDA–National Institute for Drug Abuse). For a laboratory to be
SAMHSA certified, the director must have a doctorate or be board certified in toxicology. A list of currently
certified laboratories can be obtained from SAMHSA and can also be found in the Federal Register (updated
monthly). Laboratories are required to review the chain of custody form, inspect the specimen, and analyze it
for illicit drugs. Laboratories are also authorized to screen for adulterants, typically by measuring creatinine,
specific gravity, pH, and nitrite concentration. Testing for illicit drugs is a two-step process. The first step is a
“screening enzyme immunossay” method. Positive samples are sent for the second-step “confirmation” test
by GC/MS.[52] For a specimen to be considered positive, the analyte must be present above the cutoff levels
in both the screening and the GC/MS assays. Specimens testing negative at screening are eliminated from
further analysis.
Initial Screening
In DOT screening, the initial screening procedure uses an immunoassay that meets the requirements of the
Food and Drug Administration for commercial distribution. This is typically an enzyme immunoassay test,
such as the enzyme-mediated immunoassay test, EMIT. It is a relatively fast and cost-effective screening
tool employed by many testing and hospital laboratories. The test is based on the amount of the drug
analyte present being proportional to changes in spectrophotometric absorbance initiated by an enzyme-
substrate reaction.
1. An antibody to a known drug analyte is added to an aliquot of the test urine. If the analyte is present, it
will bind to the antibody.
2. A known amount of the analyte already attached to an enzyme, such as glucose-6 phosphate
dehydrogenase (G6PD), is then added. The analyte, if initially present in the urine, and the analyte-
enzyme complex compete for binding to the antibody. The amount of analyte-enzyme complex left
unbound is directly proportional to the amount of analyte initially present in the urine.
3. The unbound analyte-enzyme complex is active. An enzyme substrate, such as nucleotide adenine
dehydrogenase (NAD), is then added. The unbound, active G6PD reduces NAD to NADH.
4. A spectrophotometer reads the solution absorbance at 340 nm. The absorbance increases
proportionately to the increase in NADH concentration.
A pitfall in this method involves antibody interaction with nontested drug analytes. This may occur with
impure antibodies or with nontested drug analytes that are structurally similar or isomers of tested drug
analytes ( Table 15–5 ).
Table 15-5 -- Drugs That May Interfere with EMIT Screening Immunoassay
Amiodarone
Ciprofloxacin
Griseofulvin
Mefenamic acid
Metronidazole
Salicyluric acid
Sulindac
Sulfasalazine
Tolmetin sodium
The DOT has set specific, positive cutoff levels of the analytes for screening and confirmation ( Table 15–6
). The marijuana cutoff limit has changed since the program began. With the 1994 amendment, the
reportable positive, or cutoff, level for tetrahydrocannabinol (THC) was reduced from 100 ng/mL to 50
ng/mL. Amphetamine remains positive at 1000 ng/mL, morphine and cocaine at 300 ng/mL, and PCP at 25
ng/mL. A 1997 amendment (became effective December 1998) increased the cutoff of screening and
confirmation levels of opiates (see Table 15–6 ).
Table 15-6 -- Laboratory Analytes, and Detection Levels and Times

Drug Level (ng/mL) Common Detection
Drug Target Analyte
Screening Confirmation Times
Amphetamine 1000 500
Amphetamines 500 + =200
Methamphetamine =24 hours
amphetamine
Barbiturates Secobarbital * * 18–29 hours
Benzodiazepines Oxazepam * * 5–6 hours
Cannabinoids Delta-9 THC-acid 50 15 1 day–3 weeks
Cocaine Benzoylecgonine 300 150 2–3 days
Morphine 2000 2000 1–3 days
Opiates and
Codeine 2000
metabolites
6-Acetylmorphine 10 † Hours
Phencyclidine Phencyclidine 25 25 =3 days
Ethanol Ethanol 0.04% (40 mg/dL) Hours
* Non-DOT testing may have variable cutoff levels.
† When morphine concentration exceeds 2000 ng/mL.

Other screening techniques include radioimmunoassay (RIA), fluorescence polarization immunoassay
(FPIA), cloned enzyme donor immunoassay (CEDIA), and kinetic interaction of microparticles in solution
(KIMS). The latter two are more recent techniques, and CEDIA may be done in smaller laboratories,
whereas KIMS is performed in larger laboratories.
Confirmatory Testing
If the screening test is positive, it is subjected to a more specific analytical method. Under DOT guidelines,
GC/MS is the gold standard. In GC, the extracted specimen is vaporized by heat at the injection port and
carried through a column by a steady flow of a heated gas. This specimen can terminate in a detector or be
combined with a mass spectrometer that bombards the specimen with an electron beam, causing fracturing
of molecular bonds. The fracturing pattern is specific for an analyte and results in “molecular fingerprinting,”
which is compared with a known standard. The combined result of the GC/MS is a more sensitive and
specific measurement of drugs of abuse. After abuse, the time period that an analyte can be detected will
vary, depending on the duration and quantity of abuse of substances and on the particular analyte (see
Table 15–6 ). Selected ion monitoring (SIM) is a newer method that may be used in the future.
Confirmation analyte levels are presented in Table 15–6 . For confirmation of methamphetamine, both
methamphetamine and amphetamine are measured. The test is considered positive if a methamphetamine
level at or above 500 ng/mL is found in association with an amphetamine level of at least 200 ng/mL.
Non-DOT Testing
Non-DOT tests are not required to follow the previously presented techniques. They may be single or split
collections, performed on or off site, and may or may not be followed by GC/MS confirmation. An example of
on-site testing is the triage panel for drugs of abuse. In non-DOT testing, barbiturates and benzodiazepines
are frequently added to the traditional NIDA-5. Secobarbital is the analyte of detection for barbiturates. Many
benzodiazepines are metabolized to oxazepam, which is an excellent target analyte to measure.


SPECIMEN INTEGRITY
Specimen integrity may be breached intentionally or nonintentionally during, or before, the collection
process. Adulterants may be added directly to the sample, or various substances may be ingested to alter a
test result. The toilet water in the collection room is typically colored with a colorant agent, so addition of this
will alter the color of the sample. Dilution of the sample with forced oral intake of water is common, and the
specimen’s creatinine and specific gravity may be measured to determine if the sample has been diluted
(specific gravity less than 1.003, creatinine less than 20 mg/dL). Certain teas allegedly alter test results.
Goldenseal tea can mask opiates on thin-layer chromatography screening. However, these substances do
not interfere with GC/MS verification. A variety of substances have been substituted for urine as a specimen.
Artificial urine is available on the street or by mail-order catalogue for substitution into the specimen
container. Recently, the soft drink Mountain Dew has been found as a substitute in drug testing. It caused a
false positive result for ethanol in a non-DOT urine test sample.[24] The substitutes may be preheated or
stored in a body bag to maintain temperature.
Other adulteration methods include the addition of substances that alter the pH or the ionic strength of a
sample, which may inhibit antibody binding or interfere with the method of detection. Glutaraldehyde
interferes with the rate of the enzyme reaction, which may result in a negative test for any of the DOT-tested
drugs. However, glutaraldehyde is usually detected during routine laboratory evaluation. Table 15–7 lists
some of the more common adulterants reported. When a specimen enters a laboratory and appears to have
been adulterated, it is sent to a special area for further evaluation ( Table 15–8 ).
Table 15-7 -- Common Adulterants of Urine Drug Testing

Alkylepoxysulfonate
Apple juice
Ammonia
Bleach
Detergent
Drano (sodium hydroxide)
Glutaraldehyde
Goldenseal tea
Lime-A-Way
MJ Super Clean 13
Mountain Dew
Nitrites
Peroxide
Pyridine (pyridium chlorochromate)
Saline
Saliva
Salt (sodium chloride)
Soap
Sodium bicarbonate
Soft drinks
Vanish
Vinegar
Visine
Water
Table 15-8 -- Common Adulteration Checks Done by Laboratories on Urine Specimens

Temperature
Smell
Appearance (precipitate at bottom or bubbles)
pH
Creatinine
Specific gravity
Electrolytes
Nitrites


REPORTING
Results and records must be maintained under strict confidentiality by all involved. The laboratory must keep
the records in storage. If the specimen tests negative on initial screening, it is a negative result. If the
specimen tests positive by screening assay and negative by the GC/MS confirmation screen, it is a negative
test. If both the screening and confirmation tests are positive, the test is reported to the MRO as being
positive.


MEDICAL REVIEW OFFICER
Under DOT guidelines the MRO must interpret positive results, review the custody and control form for
reported negative results, and manage problems arising from dilute and possibly adulterated specimens. By
definition, an MRO is a licensed physician with training and experience in the diagnosis and treatment of
substance abuse. In Florida and Oklahoma he or she must be certified by either the Medical Review Officers
Certification Council (MROCC) or the American Association of Medical Review Officers (AAMRO), which are
the currently available certifying bodies. As of this writing, no other states currently require certification,
although this may change. MROs act as liaisons between the laboratory and employer and between the
employer and donor. The MRO, or a designated representative, contacts the donor and conducts an
interview to determine if there is an alternate medical explanation for the positive test result. The donor must
provide documentation, such as prescriptions, use of cocaine during a recent nasal procedure, and so on.
The MRO must then determine if the use was medically legitimate. Although the test is positive, it can be
deemed negative by the MRO. It is worth noting that there is no medical indication for PCP or heroin. Finally,
the MRO must be involved when split specimen testing is requested. The DOT does not mandate a formal
role for MROs in alcohol testing. MROs are also not required in non-DOT testing, but they are strongly
encouraged in this litigious field. A list of free Internet information sources for the MRO is given in Table
15–9 .
Table 15-9 -- Internet Sources of Free Drug Testing Information

Direct Contact and Modem Services
Federal Highway Administration (FHWA) Modem download 800-337-3492
Department of Transportation Fax on Demand 800-225-3784 (http://www.dot.gov )
Medical Review Officers Certification Council 847-228-7476 (http://www.mrocc.com )

Internet Addresses *
American Medical Association (http://www.ama-assn.org.ezproxy.med.nyu.edu )
Canadian Centre on Substance Abuse (http://www.ccsa.ca )
National Clearinghouse for Alcohol and Drug Information (http://www.health.org/workpl.htm )

GPO Gate (http://gpo.ucop.edu/search/default.html )
Institute for a Drug Free Workplace (http://www.drugfreeworkplace.org:80/catalog.html )

Join Together (http://www.jointogether.org/news/jto/LatestNews.qry )
Medical Review Officers Certification Council (http://www,mrocc.com/index.htm )
U.S. Navy Statistical Models (http://nprdc.navy.mil:80/nprdc/drug-mod.htm )
U.S. Department of Labor–Substance Abuse Information Database
(http://www.dol.gov/dol/asp/public/programs/drugs/said.htm )
National Association of Collection Sites ( )
SAMHSA Media Services (http://www.samhsa.gov/media.htm )

Department of Labor drug testing information (http://www.dol.gov/dol/asp/public/programs/drugs/facts.htm )
Substance Abuse and Mental Health Services Administration (SAMHSA) (http://www.samhsa.gov )
* Other sources may be found by using Internet search engines.
The certified MRO has completed a course and a certifying examination of the interpretation of drug testing.
Most will have some familiarity with substance abuse, others may not. Those involved with this field are
strongly encouraged to become certified and gain experience in this field. Many MROs will have assistants
initially contact the worker with a positive test for initial information such as prescription drug use. However,
under DOT guidelines the MRO must give the worker an opportunity to discuss the test result with him or
her. Any discussion of positive test results must be done by the MRO—this cannot be delegated.


POST-TESTING EVALUATION AND TREATMENT
The U.S. DOT requires covered employers to use substance abuse professionals (SAPs) to evaluate safety-
sensitive employees who test positive for drugs or ethanol. SAPs are not required to be physicians. They
must, however, have one of the following qualifications:
• A licensed physician with an MD or DO degree with knowledge of, and clinical experience in, the
diagnosis and treatment of ethanol and disorders related to substance abuse
• A licensed or certified psychologist, social worker, or certified employee assistance professional (CEAP)
with knowledge of, and clinical experience in, the diagnosis and treatment of disorders related to ethanol
and controlled substances
• A counselor certified by the National Association of Alcohol and Drug Abuse Counselors


SPECIFIC PROBLEMS WITH ANALYSIS
In non-DOT testing, nonsteroidal anti-inflammatory drugs have been associated with false positive
immunoassays for benzodiazepines. They do not result in false-positive GC/MS results. Oxaprozin (Daypro),
etodolac (Lodine), naproxen sodium (Anaprox), fenoprofen calcium (Nalfon), and tolmetin sodium (Tolectin)
have been reported to cross react with the immunoassay antibodies. These false positive results do not
occur with thin-layer chromatography screening or GC/MS confirmation. Ibuprofen and naproxen (Naprosyn)
have not been shown to cross react on GC/MS.[31][47][49] However, some substances can produce “true”
positives on GC/MS; careful MRO interpretation of these findings is required ( Table 15–10 ).
Table 15-10 -- Substances Causing Positives on GC/MS Confirmation Testing

Test Substance
Vicks Nasal Inhaler *
Selegiline *
Amphetamines Diet pills from other countries:
Chlorbenzorex (Asenlix)
Fenproperex
Benzodiazepines “Black pearls” (Asian product)
Cocaine Coca leaf teas (Health Inca Tea)
Dronabinol (Marinol)
Hemp-containing foods:
Marijuana
Seedy Sweeties
Cranberry Coconut Hemp Bar
Opiates Poppy seeds
* Chiral separation of isomers required.
Cocaine
Several cocaine metabolites cross react with the immunoassay for cocaine. These include benzoylecgonine,
cocaine, cocaethylene, ecgonine methyl ester, and ecgonine. There is no cross-reactivity with any of the
“caine” analgesics, such as lidocaine, benzocaine, or procaine. Health Inca Tea contains cocaine, and
drinking one cup can produce a positive drug test.[21] However, the only legitimate reason for a positive drug
test for cocaine would be from a documented medical procedure in which the use of cocaine can be verified,
for example in otolaryngologic surgery or after topical application of tetracaine-epinephrine-cocaine (TAC)
before laceration repair. Passive inhalation is not a valid reason for a positive test. [4]
Phencyclidine
Phencyclidine (PCP) immunoassays will react with both PCP and certain metabolites and analogs. The
parent compound PCP is easily confirmed with GC/MS. Diphenhydramine and dextromethorphan may
cause false positive fluorescence polarization immunoassay for PCP with levels up to 37 ng/mL.[35] High
doses of thioridazine but not chlorpromazine have been reported to cause false-positive results by EMIT.[56]
There are no medical indications for PCP.
Opiates
Knowing the metabolism of opiates in drug testing is essential for interpretation of positive opiate test
results. Figure 15–4 shows that heroin and codeine are both metabolized to morphine and that morphine is
not metabolized to codeine. In the metabolism of heroin to morphine the intermediate 6-acetylmorphine (6-
AM) is formed. The presence of 6-AM is indicative of heroin abuse, because morphine or codeine
metabolism will not produce this intermediate substance. However, the half-life of heroin is very short, being
completely converted to 6-AM within 10 to 15 minutes. The half-life of 6-AM is 0.6 hour, and the total
morphine half-life is 7.9 hours. The finding of 6-AM in the urine indicates that either heroin or 6-AM was self-
administered within 24 hours of the collection.[11] As shown in Figure 15–4 , the presence of 6-AM is not due
to the metabolism of either codeine or morphine.
Perhaps more confusing is the consumption of poppy seeds found in a variety of salad dressings and baked
goods. The seeds contain varying amounts of morphine and codeine. They may or may not produce an
opiate-positive urine, both on screening and GC/MS confirmation.[4][19] Because of this, MROs do not
confirm a positive urine unless there is also clinical evidence of opiate abuse. An exception to this
requirement is the finding of 6-AM, which arises solely from heroin metabolism.
Figure 15-4 Metabolic profile for heroin, codeine, and morphine.
Perhaps more confusing is the consumption of poppy seeds found in a variety of salad dressings and baked
goods. The seeds contain varying amounts of morphine and codeine. They may or may not produce an
opiate-positive urine, both on screening and GC/MS confirmation.[4][19] Because of this, MROs do not
confirm a positive urine unless there is also clinical evidence of opiate abuse. An exception to this
requirement is the finding of 6-AM, which arises solely from heroin metabolism.
In testing, certain findings may distinguish opiate from poppy seed ingestion:
1. A morphine-codeine ratio of 2 to 3:1 usually rules out poppy seed, and a ratio less than 2 favors
codeine ingestion.
2. Morphine levels greater than 2000 ng/mL without codeine or over 5000 ng/mL with measured codeine
usually rule out poppy seeds as a source.
3. Poppy seeds rarely result in urine positive results more than 24 to 36 hours after ingestion.
4. Very high levels of morphine (> 10,000) with little or no codeine invariably indicate heroin or morphine
use. In the last instance the laboratory must be able to detect codeine at a lower limit of 25 ng/mL.[20]
The MRO must request codeine testing at this level; and, under DOT rules, this request must be written.
However, these guidelines do not negate the MRO requirement to find clinical evidence of opiate abuse
before reporting an opiate-positive urine sample.
Legislation effective December 1, 1998, increased opiate screening and confirmation levels dramatically.
This is an effort to minimize false positive tests for poppy seeds and help with spousal use of codeine
products.
Other opioids do not cross react with current immunoassays for opiates. These substances include
dihydrocodeine, oxycodone, hydrocodone, oxymorphone, hydromorphone, propoxyphene, methadone,
meperidine, and fentanyl.
Marijuana
Cannabinoids are generally not detected in the urine after passive inhalation unless massive exposure has
occurred. Experiments have shown that, to develop a positive urine test for THC secondary to sidestream
marijuana smoke, the donor must have been in almost unrealistic circumstances. Passive inhalation of
marijuana smoke is not an alternative medical reason for a positive test, which should be reported as a
positive test by the MRO.[9][10][34][39][41][45] The only legitimate explanation for a positive THC acid test is from
the prescribed use of dronabinol (Marinol). Dronabinol is approved by the Food and Drug Administration for
use as an antiemetic in chemotherapy and as an appetite stimulant in patients with the acquired
immunodeficiency syndrome (AIDS). Failure to exclude this as a possible explanation may result in litigation
against the MRO.
Clouding the issue, certain consumable products have been formulated with hemp products, including hemp
seeds, hemp oil, and cheeses. Consumption of these products has been offered as an alternative
explanation for a THC-positive urine test. News of this has spread through newspapers, discussion groups,
and over the Internet. Products include Seedy Sweeties (Hungry Bear Hemp Foods, Eugene, OR), and the
Cranberry Coconut Hemp Bar (G&S, Steamboat Springs, CO). A more complicated issue involves state
initiatives passed in California and Arizona in November 1996. In those states, medically recommended or
prescribed marijuana became permissible. The DOT promptly responded by stating that marijuana or hemp
ingestion is not a reason to overturn a THC-positive test.[1] Any individual in a safety-sensitive position
assumes the responsibility for his or her positive test. The federal government considers the prescription of
Schedule I drugs a violation of the law, subject to penalties. Arizona has now introduced recent legislation to
ban the use of substances that the Drug Enforcement Agency regulates as Schedule I.
Amphetamines
Over-the-counter drugs are the most common cause of an amphetamine immunoassay positive urine
sample.[5] More recent immunoassay tests are specific for amphetamine and methamphetamines.
Previously, high concentrations of over-the-counter ephedrine and pseudoephedrine could, under very
specific GC conditions, produce methamphetamine within the instrument. This resulted in a confirmed
positive test for methamphetamine. Because methamphetamine is metabolized in vivo to amphetamine,
methamphetamine levels at or above 500 ng/mL are not reported as positive unless amphetamine is also
detected in concentrations at or above 200 ng/mL.
False positive tests have been reported with the use of drugs containing the L-isomers of methamphetamine
or amphetamine. Pharmacologically the D-isomer produces stimulation of the central nervous system
whereas the D-isomer produces peripheral effects. Vicks Nasal Inhalers contain L-methamphetamine
(desoxyephedrine) as the active ingredient. This noncontrolled substance is less than one tenth as potent as
the illicit D-methamphetamine. Most laboratories will routinely perform chiral separation of the isomers;
others will do so on request. Vicks Nasal Inhalers on chiral separation will show mainly L-isomer, with very
small amounts of the D-form. Illicit methamphetamine has both L and D forms. The DHHS advises MROs
that chiral identification of L-methamphetamine of greater than 80 per cent is consistent with the use of Vicks
Nasal Inhalers.[3] Selegiline (Eldepryl), a drug used in the treatment of parkinsonism and depression, is
metabolized to L-amphetamine and L-methamphetamine. Levels up to 720 ng/mL of amphetamine and
greater than 2000 ng/mL of methamphetamine have been reported with selegiline use.[38] By requesting
chiral separation, the pattern of the stereoisomers will allow one to differentiate selegiline from illicit
methamphetamine use.
Diet pills available in other countries can produce true positive urine tests. A Mexican diet aid, Asenlix,
contains chlorbenzorex. Chlorbenzorex is metabolized in vivo to amphetamine and methamphetamine,[55]
and ingestion can result in measurable urinary amphetamine. Fenproperex, another diet aid, is also
metabolized to amphetamine and methamphetamine.
The following may cross react with the amphetamine screening immunoassay:
amphetamine/methamphetamine isomers, benzphetamine, ephedrine and pseudoephedrine, 3,4-
methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-
methylenedioxyethamphetamine (MDEA), phenmetrazine, phentermine, phenylpropanolamine, and
propylhexedrine.
SUMMARY
Workplace drug testing has changed dramatically over the past decade with millions of workers in both the
government and private sector now being tested. Drug testing is done in accordance with DOT standards, or
as determined by the private employer. The current DOT program has evolved into a very well-organized
and reproducible service. Skills and specific education or certification are necessary for the MRO physician
to deal with this challenging area effectively.
The decision to undertake a drug-detection program must be outcome based. Most employees testing
positive require intervention by an SAP and counseling. The optimal program structure involves an
integrated approach by the employer, employee, laboratory, MRO, and SAP. An organized, integrated
testing program reduces the likelihood of falsely accusing a worker of illicit drug or ethanol use.


REFERENCES
1. Anonymous: Federal response to state marijuana initiatives, and hemp-containing food products. MRO
Update 1997; January:1–5.
3. Autry JH: Technical Advisory to All HHS/NIDA Certified Laboratories, Rockville, MD, Department of
Health and Human Services, March 11, 1991.
4. Baselt RC, Yoshikawa DM, Chang JY: Passive inhalation of cocaine [letter]. Clin Chem 1991; 37:2160-
2161.
5. Baselt RC: Urine drug screening by immunoassay: Interpretation of results. In: Baselt RC, ed. Advances
in Analytical Toxicology, vol 1. Foster City, CA: Bimedial; 1984:81-123.
6. Bonito AJ, Nurco D: Validity of addict self-report in social research. Int J Addict 1976; 11:719-724.
7. Calahan D: American Drinking Practices, New Brunswick, CT, Rutgers Center of Alcohol Studies, 1969.
8. Community Epidemiology Work Group: Epidemiologic trends in drug abuse: Proceedings, December
1989. Rockville, MD, National Institute on Drug Abuse, 1990.
9. Cone EJ, Johnson RE, Darwin WD, et al: Passive inhalation of marijuana smoke: Urinalysis and room air
levels of delta-9-tetrahydrocannabinol. J Anal Toxicol 1987; 11:890.
10. Cone EJ, Johnson RE: Contact highs and urinary cannabinoids excretion after passive exposure to
marijuana smoke. Clin Pharmacol Ther 1986; 40:247-256.
11. Cone EJ, Welch P, Mitchell JM, Paul BD: Forensic drug testing for opiates: I.. Detection of 6-
acetylmorphine in urine as an indication of recent heroin exposure: Drug and assay considerations and
detection times. J Anal Toxicol 1991; 15:1-7.
12. D’Aquila RT, Williams AB: Epidemic human immunodeficiency virus (HIV) among intravenous drug
users (IVDU). Yale J Biol Med 1987; 60:545-567.
13. Dai B: Opium Addiction in Chicago, Shanghai, Commercial Press, 1970. Reprinted Montclair, NJ:
Patterson Smith, 1970.
14. Department of Health and Human Services: Mandatory Guidelines for Federal Workplace Testing
Programs. U.S. Department of Health and Human Services (DHHS) 1988.
15. Department of Health and Human Services: Omnibus Transportation Employee Testing Act of 1991.
U.S. Department of Health and Human Services, 1991.
16. Department of Health and Human Services. Drug Use Among U.S. Workers: Prevalence and Trends by
Occupation and Industry Categories, Washington, DC, U.S. Dept of Health and Human Services,
Substance Abuse and Mental Health Services (SAMHSA), 1996.
17. Drug testing: What’s at stake? Industrial Chemical News 1986; April:61.
18. Dupont RL, Griffin DW, Siskin BR, et al: Random drug test at work: The probability of identifying
frequent and infrequent users of illicit drugs. J Addictive Dis 1995; 14:1-17.
19. Elsohly HN, Elsohly MA, Stanford DF: Poppy seed ingestion and opiates urinalysis: A closer look. J
Anal Toxicol 1990; 14:308-310.
20. Elsohly MA, Jones AB: Morphine and codeine in biological fluids: Approaches to source differentiation.
Forens Sci Rev 1989; 1:13-21.
21. Elsohly MA, Stanford DF, Elsohly HN: Coca tea and urinalysis for cocaine metabolites [letter]. J Anal
Toxicol 1986; 10:256.
22. Feldman HW, Agar MH, Beschner G: Angel dust: An ethnographic study of PCP users, Lexington,
MA, Lexington Books, 1979.
23. Feldman HW, Aldrich MR: The role of ethnography in substance abuse research and public policy:
Historical precedent and future prospects. In: Lambert EY, ed. The Collection and Interpretation of Data
From Hidden Populations, Rockville, MD: National Institute on Drug Abuse; 1990:12-30.
24. Goldberger BA: Unsuspected ethanol ingestion through soft drinks and flavored beverages [letter}. J
Anal Toxicol 1996; 20:332.
25. Greenwood JA: Estimating the number of narcotic addicts, Washington, DC, U.S. Department of
Justice, 1971. Document SCID-TR-3.
26. Harris LS (ed): Proceedings of the 47th annual scientific meeting of the Committee on Problems of
Drug Dependence. Rockville, MD, National Institute on Drug Abuse, 1987; 14:283–289.
28. Hubbard RL, Marsden ME, Rachal JV, et al: Drug abuse treatment: A national study of effectiveness,
Chapel Hill, NC, University of North Carolina Press, 1989.
29. Hughes PH, Jaffe JH: The heroin copping area: A location for epidemiologic study and intervention
activity. Arch Gen Psychiatry 1971; 24:394-400.
30. Hunt LG: Incidence and prevalence of drug use and abuse.
In: Dupont RI, Goldstein A, O’Donnell J, ed. Handbook on Drug Abuse, Rockville: National Institute on Drug
Abuse; 1979:395-403.
31. Jelic-Ivanovic Z, Majkic-Singh N, Spastic S, et al: Interference by analgesics and antirheumatic drugs in
25 common laboratory assays. J Clin Chem Biochem 1985; 23:287-292.
34. Law B, Mason PA, Moffat AC, et al: Passive inhalation of marijuana smoke: Urinalysis and room air
levels of delta THC. Clin Pharmacol Ther 1983; 34:36-41.
35. Levine BS, Smith ML: Effects of diphenhydramine on immunoassay of phencyclidine in urine. Clin
Chem 1990; 36:1258.
36. In: Lierman TL, ed. Building a Healthy America, New York: Mary Ann Liebert; 1987.
37. Lindesmith AR: Opiate Addiction, Bloomington, IL, Principia Press, 1947.
38. Meeker JE, Reynolds PC: Postmortem tissue methamphetamine concentrations following selegiline
administration. J Anal Toxicol 1990; 14:330-331.
39. Moreland J, Bugge A, Skuterund B, et al: Cannabinoids in blood and urine after passive inhalation of
cannabis smoke. J Forens Sci 1985; 30:997-1002.
40. Morgan JP: The “scientific” justification for urine drug testing. Kansas Law Rev 1988; 36:683-697.
41. Mule SJ, Lomax P, Gross SJ: Active and realistic passive marijuana exposure tested by three
immunoassays and GC/MS in urine. J Anal Toxicol 1988; 12:113-116.
42. National Institute on Drug Abuse: Data from the Client Oriented Data Acquisition Process (CODAP),
Rockville, MD, National Institute on Drug Abuse, 1983.
43. Normand J, Salyards SD, Mahoney JJ: An evaluation of preemployment drug testing. J Appl
Psychol 1990; 75:629-639.
44. Pazzaglini M: Street drug use in Delaware. Del Med J 1987; 159:729-732.
45. Perez-Reyes M, DiGuiseppi S, Mason AP, et al: Passive inhalation of marijuana smoke and urinary
excretion of cannabinoids. Clin Pharmacol Ther 1983; 34:36-41.
46. Person Jr PH: Indicators of drug abuse—DAWN. In: Richards LR, Blevens LB, ed. The Epidemiology
of Drug Abuse: Current Issues, Rockville, MD: National Institute on Drug Abuse; 1977:135-137.
47. Pulini M: False-positive benzodiazepine urine test due to oxaprozin. JAMA 1995; 273:1905.
48. Ramos R: Chicano intravenous drug users. In: Lambert EY, ed. The Collection and Interpretation of
Data from Hidden Populations, Rockville, MD: National Institute on Drug Abuse; 1990:128-145.
49. Raphan H: In reply: False-positive benzodiazepine urine test due to oxaprozin. JAMA 1995; 273:1905.
50. Regier D, Meyers JK, Kramer M, et al: The NIMH epidemiologic catchment area program. Arch Gen
Psychiatry 1984; 41:934-958.
51. Ryan J, Zwerling C, Jones M: The effectiveness of preemployment drug screening in prediction of
employment outcome. J Occup Med 1992; 34:1057-1063.
52. Schwartz RH, Hawks RL: Laboratory detection of marijuana use. JAMA 1985; 254:788-792.
54. Snow M: Maturing out of narcotic addiction in New York City. Int J Addict 1974; 18:917-933.
55. Tarver JA: Amphetamine-positive drug screens from use of clobenzorex hydrochlorate [letter]. J Anal
Toxicol 1994; 18:183.
56. Walberg CB, Gupta RC: Quantitation of phencyclidine in urine by enzyme immunoassay. J Anal
Toxicol 1982; 6:97-99.
57. Wesson DR, Camber S: Phenylpropanolamine mentions in the Drug Abuse Warning Network: Numbers
plus interactions. In: Morgan JP, Kagan DV, Brody JS, ed. Phenylpropanolamine Risks, Benefits,
Controversies, New York: Praeger; 1985:362-370.
58. Winick C: Some aspects of careers of chronic heroin users. In: Josephson E, Carroll EE, ed. Drug use:
Epidemiological and Sociological Approaches, New York: John Wiley; 1974:105-124.


Uncited references
Anthony JC, Ritter CJ, Von Korff MR, et al: Descriptive epidemiology of adult cocaine use in four U.S.
communities. NIDA Res Monogr 1986; 67:283.
Hayes LW, Krasselt WG, Mueggler PA: Concentrations of morphine and codeine in serum and urine after
ingestion of poppy seeds. Clin Chem 1987; 33:806-808.
Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beechman
data shows, Collegeville, PA, SmithKline Beechman Clinical Laboratories, 1996.
Johnston LD, O’Malley PM, Bachman JG: Drug Use, Drinking and Smoking National Survey Results from
High School, College and Young Adult Populations 1975–1988, Rockville, MD, National Institute on Drug
Abuse, 1989.
Siddiqi M, McKay CA: Letter to the editor: Passive inhalation of marijuana. MRO Update 1996;
July/August:8–9.


Section II – APPROACH TO THE POISONED PATIENT WITH
Chapter 16 – Central Nervous System Depression
KATHLEEN A. DELANEY PAUL KOLECKI
Essentials
• Treat shock and respiratory failure
• Treat hypoglycemia
• Consider administration of thiamine
• Consider administration of naloxone
• Consider an acute neurosurgical emergency
• Consider acute bacterial meningitis
• Proceed with a thoughtful diagnostic approach directed by the history and physical
examination
INTRODUCTION
Stupor, defined as a state of unresponsiveness from which the patient may be only briefly aroused by
vigorous stimulation, and coma, a deeper state from which the patient cannot be aroused, are
manifestations of central nervous system (CNS) depression.[30] Causes of CNS depression range from
acute life-threatening toxic, metabolic, infectious, or neurosurgical emergencies that require immediate
diagnosis and treatment, to less immediately life-threatening processes that require a thoughtful diagnostic
approach ( Table 16–1 ). This chapter discusses the toxic differential diagnosis of the patient with stupor or
coma, as well as nontoxic considerations. It emphasizes clinical decision making based on the history, the
physical examination, and the readily obtainable laboratory assessments.
Table 16-1 -- Life-Threatening Causes of Coma That Require Immediate Diagnosis and Treatment
Condition Signs
Shock or respiratory
Vital signs, pulse oximetry
failure
Hypoglycemia Low reading on CBG (capillary blood glucose) test
Acute bacterial meningitis Fever, nuchal rigidity, petechiae, purpura, rapid deterioration
Cerebral mass lesion Hyperventilation, focality, fixed pupils, posturing, absent doll’s eyes
Condition Signs
Vertebrobasilar artery
Hyperventilation, fixed pupils, absent doll’s eyes, posturing
thrombosis
Severe thiamine Absent or abnormal doll’s eyes, reactive pupils, history of ataxia, diplopia, history of
deficiency alcohol abuse or nutritional depletion
Cyanide poisoning Severe acidosis, rapid deterioration


INITIAL MANAGEMENT
Basics
The initial management of all patients with coma is the same. The degree of airway management depends
on the judgment of the physician at the bedside as to adequacy of the airway, respirations, oxygenation, and
likely cause of coma. Options range from immediate intubation to observation in a well-staffed area.
Management of the airway is followed by hemodynamic resuscitation. The temperature should always be
measured to detect severe hyperthermia or hypothermia, which may be the cause of the coma (see Chapter
27 ). The patient should be completely undressed and examined for signs of trauma. Continuous monitoring
of the blood pressure, pulse, respiratory rate, cardiac rhythm, and oxygen saturation is initiated.
Coma Cocktail Reconsidered: Naloxone, Glucose, Thiamine, Flumazenil ( Table 16–2 )
Bedside measurement of serum glucose level and treatment of hypoglycemia are essential. Dextrose should
be administered empirically to the comatose patient when reliable blood glucose testing is not available.
Although studies have shown that increased serum blood glucose level is associated with more extensive
ischemic infarction and poorer outcome in brain-injured patients,[42] it seems rational that the risk of
worsening already severe brain injury is less than the failure to prevent severe injury from the completely
reversible condition of hypoglycemia. Although thiamine deficiency is a very rare cause of coma, thiamine
should be routinely administered to any nutritionally depleted or alcoholic adult with altered mental status.
Even when thiamine deficiency is not the cause of coma, the administration of glucose to the thiamine-
depleted patient has been shown to precipitate Wernicke encephalopathy.[41][43] The major indication for the
administration of naloxone in a patient with suspected overdose is respiratory depression (respiratory rate
<12).[16] Although the side effects of naloxone are minimal in the patient who is intolerant of opioids, it may
precipitate severe withdrawal with vomiting and aspiration in the opioid-tolerant patient who is comatose
from another cause, such as a sedative hypnotic, head injury, or hypoxia. It is prudent to begin treatment of
the patient with suspected opioid dependence with an initial dose of 0.1 mg of naloxone, rather than the 0.4
to 2 mg that is commonly recommended.[17]
Table 16-2 -- Empirical Therapies in the Patient with Coma

Treatment Indication Dose Complications
Demonstrated or Adult: 1–2 ampules of D50W Possible exacerbation of ischemic
Hypertonic suspected hypoglycemia (25 g); repeat prn brain injury
dextrose Ped: bolus 0.5–1 g/kg/dose
D25W, repeat prn
Adult: opiate dependence:
Naloxone Respiratory depression Acute opioid withdrawal, aspiration
0.1 mg IV; 0.4–2.0 mg/dose
Ped: Neonate: 0.01–0.03
mg/kg/dose
Treatment Indication Dose Complications
Child: 0.4–2.0 mg/dose
Suspected Wernicke
Thiamine Adult: 100 mg IV None
encephalopathy
Nutritional
Ped: 10–25 mg/day IV/IM
depletion
Alcoholism
Respiratory depression due Adult: 0.2 mg over 30 sec q Seizures due to benzodiazepine
to benzodiazepine 1 min to total of 5 mg withdrawal or effect of a coingestant
Flumazenil
Ped: 0.01 mg/kg q 1 min to
total of 1 mg
D25W, 25% dextrose in water; D50W, 50% dextrose in water; Ped, pediatric.
Flumazenil is a specific benzodiazepine antagonist that rapidly reverses coma associated with
benzodiazepine overdose. Unfortunately, it can precipitate seizures resulting from benzodiazepine
withdrawal in tolerant long-term users and has been associated with seizures when the epileptic effects of
coingestants, such as cyclic antidepressants, are unmasked. It has a limited role in most overdoses because
of these dangerous side effects. It is useful in the pure pediatric ingestion. It may be used cautiously in the
adult without known long-term benzodiazepine use or without coingestion of an epileptogenic toxin, who has
respiratory depression and is deemed likely to require intubation. If uncertainty exists regarding the risk of
seizures, intubation and supportive care may be the better option.[19][23][38]
Dire emergencies requiring very rapid diagnosis are listed in Table 16–1 . These include impending brain
herniation from a mass lesion, basilar artery thrombosis, bacterial meningitis, hypoglycemia, and severe
thiamine deficiency. Cyanide is the only toxin associated with coma as a primary manifestation that requires
immediate intervention to prevent death after the initiation of supportive care (see Chapter 86 ).
Further management, including decontamination, computed tomographic scanning of the head, lumbar
puncture, and other antidotes and antibiotics, depends on the differential diagnosis generated by the history,
physical examination, and laboratory assessment described in the Differential Diagnosis and Clinical
Evaluation sections.


PATHOPHYSIOLOGY
The Neuroanatomy of Consciousness
The following discussion is drawn from the unequaled clinical work of Plum and Posner.[30] CNS depression
occurs secondary to one of two anatomically distinct neurologic processes. The first is global injury to, or
functional impairment of, the cerebral cortex.[30] A myriad of toxic and metabolic disturbances depress global
brain function leading to stupor and coma ( Tables 16–3 and 16–4 ).
Table 16-3 -- Classes of Drugs/Toxins That Cause Central Nervous System Depression
Class Group Examples
Anticholinergic
Antihistamines Diphenhydramine, chlorpheniramine
Agents
Belladonna alkaloids Hyoscyamine, scopolamine
Carbamazepine
Phenobarbital
Anticonvulsants
Phenytoin
Valproate
Cyclic antidepressants Amitriptyline
Imipramine
Selective serotonin reuptake
Fluoxetine
Antidepressants inhibitors
Sertraline
Nonselective serotonin reuptake
Venlafaxine
inhibitors
Cholinergics Insecticides Malathion
War agents Sarin
Sulfonylureas Glyburide
Hypoglycemics
Glipizide
Gamma-hydroxybutyrate (GHB) and related
compounds
Ibuprofen (rare, in large overdoses)
Miscellaneous Isoniazid
Lead
Class Group Examples
Lithium
Phencyclidine (PCP)
Butyrophenones Haloperidol
Phenothiazines Chlorpromazine
Mesoridazine
Neuroleptic Agents
Thioridazine
Dibenzodiazepines Clozapine
Olanzapine
Meperidine, fentanyl, heroin, methadone,
Opioids
morphine
Alcohols Ethanol, ethylene glycol, methanol isopropanol
Barbiturates Secobarbital, phenobarbital
Sedative-hypnotics
Benzodiazepines Diazepam, lorazepam
Miscellaneous Ethchlorvinyl meprobamate
Sympathomimetics Amphetamines, cocaine
Toxic gases Carbon monoxide, cyanide, hydrogen sulfide
Table 16-4 -- Nontoxic Causes of Stupor and Coma

Class Examples
Hematologic disorders Hyperviscosity syndrome, thrombotic thrombocytopenic purpura
Infectious emergencies Bacterial meningitis, meningoencephalitis
Metabolic disorders detected by Hypernatremia, hyponatremia, hypercalcemia, uremia, hyperglycemia,
simple laboratory assessment hypoglycemia
Metabolic disorders suspected on Hepatic encephalopathy, uremia, myxedema, hypertensive
physical examination encephalopathy
Basilar artery thrombosis, brainstem CVA, subclinical status epilepticus,
Neurologic disorders
prolonged postictal state
Subdural and epidural hematoma, subarachnoid hemorrhage,
Neurosurgical emergencies
intracerebral hemorrhage, brain abscess, brain tumor, subdural empyema
Vasculitis Lupus, endocarditis
CVA, cerebrovascular accident.
The second anatomical basis for CNS depression is compression of the brainstem reticular activating
system, which is the cause of stupor and coma in patients with focal brainstem injury or expanding CNS
mass lesions. Injury to the reticular activation system, which begins in the proximal brainstem (thalamus)
and descends through the midbrain and pons to the medulla, leads to depression of consciousness. In the
patient with an expanding supratentorial mass lesion, such as a hematoma, tumor, or abscess, or with
massive cerebral edema secondary to a toxin such as ethylene glycol, or acetaminophen-induced
hepatotoxicity,[24][26] characteristic neurologic changes occur in a rostral-to-caudal pattern as the mass effect
traverses these areas of the brainstem. Pressure on the thalamus results in stupor and an increase in the
respiratory rate manifested as hyperventilation or Cheyne-Stokes respiration. As the pressure effect reaches
the midbrain, deep coma ensues, with continuing hyperventilation and fixation of the pupils in midposition.
Decorticate responses may be present. Compression of the pons is associated with loss of the
oculocephalic, or “doll’s eye” reflex and decerebrate or decorticate posturing. Finally, compression of the
medulla leads to apnea and motor flaccidity. Discrete injury to the brainstem, such as occurs with cerebellar
or pontine hemorrhage or infarct, also causes coma as a result of impairment of the reticular activating
system. Neurologic signs are related to the injured area. For example, isolated injury to the pons is
associated with posturing or rigidity, followed by quadriplegia and loss of the doll’s eye reflex. Unlike the
patient with descending mass effect, the pupils are pinpoint as a result of selective injury to ascending
sympathetic fibers and sparing of the anatomically higher parasympathetic functions of the midbrain.[30]
In contrast to the patient with structural brain injury, a toxic-metabolic cause of coma produces patchy
neurologic impairment. For example, the patient with a barbiturate overdose may have motor flaccidity and
apnea, indicative of medullary dysfunction, but sparing of midbrain-mediated pupillary function.[30]
Drug Effects on the Central Nervous System
Many classes of drugs produce CNS depression when taken in excess. Examples of the more common
classes include the sedative-hypnotics, opioids, and anticholinergics. Specific biochemical mechanisms of
neuronal impairment have been elucidated for some of these classes of drugs.
Agents with sedative-hypnotic properties produce CNS depression by enhancing the effects of gamma-
aminobutyric acid (GABA), an important CNS inhibitory neurotransmitter. The binding of GABA to specific
GABAA receptors opens nearby chloride channels, resulting in an influx of negatively charged chloride ions
into the neuron. The resultant cell hyperpolarization prevents membrane excitation and generation of an
action potential. Sedative-hypnotics bind to the GABAA receptor complex at specific or nonspecific sites,
depending on the agent. Benzodiazepines are one class of sedative agents that have well-defined, specific
binding sites. These agents act indirectly by enhancing the response of chloride channels to binding of
GABA to the GABAA receptor. They do not stimulate GABA receptors directly. In addition to causing CNS
depression through similar facilitation of normal inhibitory mechanisms, other sedative agents such as
ethanol and barbiturates depress membrane function by less well-defined membrane effects.[9][36][44]
Opioids produce their desired analgesic effects by stimulating mu (Mu1 and Mu2), kappa, and delta
receptors in the CNS. Opioids are used primarily for their analgesic effects in clinical practice and
recreationally for their ability to produce euphoria. The analgesic effects of opioids are attributed to
stimulation of delta, kappa, and Mu1 receptors. The characteristic pupillary constriction seen in opioid
poisoning occurs through Mu2,- and kappa receptor–mediated stimulation of the parasympathetic pupillary
enervation. After overdose, opioids produce significant CNS and respiratory depression. Respiratory
depression is mediated predominantly by the Mu2 receptors.[39]
Scopolamine is a classic example of an anticholinergic agent with significant central effects. It produces
confusion, agitation, hallucinations, and coma by interacting with central muscarinic receptors. Atropine, a
drug with similar antimuscarinic properties, has very little CNS effect compared with scopolamine. The
central muscarinic receptors are poorly defined. However, it is believed that the CNS effects of different
agents are related to their ability to penetrate the CNS rather than to their affinity for different receptors. The
usual clinical course is one of CNS stimulation (slight disorientation, agitation, hallucinations), followed by
more significant dose-dependent CNS depression. Anticholinergic agents produce other characteristic
clinical effects by blocking peripheral muscarinic receptors, resulting in dry flushed skin and mucous
membranes, tachycardia, urinary retention, mydriasis, and decreased gastrointestinal motility.[7]
Sympathomimetic agents such as cocaine have been associated with CNS depression.[6] Initially, these
patients present with significant anxiety and agitation, followed by stupor. They assume normal sleeping
postures, may be aroused to full orientation with vigorous stimulation, and then immediately fall back into a
stuporous sleep. This common complication of cocaine bingeing has been attributed to depletion of
neurotransmitters.
Many metabolic disturbances cause stupor and coma through less well-defined mechanisms (see Table
16–4 ).


DIFFERENTIAL DIAGNOSIS
The differential diagnosis of CNS depression resulting from toxins and other causes is extensive (see Tables
16–3 and 16–4 ). The appropriate direction for diagnosis and management is given by the history and
physical examination, which are discussed in detail in the following section on clinical evaluation. The
laboratory also provides useful information.
Toxic Causes
Poisoning, either inadvertent or intentional, is a common cause of mental status depression. In addition to
the sedative hypnotics, anticholinergics, and opioids with well-defined mechanisms mentioned earlier, many
agents cause CNS depression. An extensive list of toxins that may cause coma is found in Table 16–3 . As
noted earlier, of all poisonings that cause coma secondary to direct impairment of brain function, cyanide
poisoning requires the most urgent intervention.
Nontoxic Causes Associated With Drug Use
Mass lesions causing CNS depression are also common causes of coma, and their presence must be
rapidly detected to prevent irreversible brain injury. Head injury can occur in patients who abuse agents that
produce sedation or altered judgment, such as opioids and phencyclidine, so that a patient whose mental
state depression is actually due to brain injury may have a history of possible overdose. Subdural and
epidural hematomas are traumatic neurosurgical emergencies, and they may be historically and clinically
occult in the drug-using patient. Subarachnoid hemorrhage and hemorrhagic cerebrovascular accidents
occur as a consequence of cocaine use and can occur after suicidal ingestion of long-acting anticoagulant
rodenticides.[19][45] These CNS emergencies progress rapidly in previously neurologically normal patients. A
slower onset of neurologic depression occurs in patients with other mass lesions, especially those due to
tumors and abscesses. These patients may have a history of headaches or altered behavior that preceded
the onset of coma. Fatal frontal lobe abscess has been reported after sinus infections in patients who abuse
intranasal cocaine.[34] Mass lesions due to acquired immunodeficiency virus–related toxoplamosis and CNS
lymphoma, or brain abscesses due to endocarditis, occur in intravenous drug users. A history of analgesic
drug ingestion for headache may lead the clinician to attribute mental status depression to the ingested
analgesic, distracting from a search for the cause of the headache.
Mental state depression due to acute bacterial meningitis is a diagnostic emergency.
Vaculitis caused by thrombocytopenic purpura, endocarditis, or lupus may lead to coma. Cerebral vasculitis
has also been reported in association with cocaine abuse.[10][18][25][27][33]
Many metabolic disturbances lead to coma. Severe hypothyroidism,[28] hypercalcemia,[4][29]

hyperglycemia,[2] hypoglycemia,[1] hypernatremia,[15] hyponatremia,[3][15] and uremia[22] are familiar causes
of coma. These frequently occur in patients with suspected or known predisposing medical illness and
premonitory symptoms. Hypoxic encephalopathy characteristically follows resuscitation from a period of
apnea or prolonged severe hypoxia. The initiating event is often related to a toxin. In some cases, neurologic
recovery is followed by recurrence of coma.[31] Hypertensive encephalopathy is rarely a cause of coma. It is
seen in patients with severe or acute elevations of blood pressure, often in patients with known hypertension
and in association with papilledema and diastolic blood pressures above 130 mm Hg. [8] Hypertensive
patients are predisposed to uremia and to CNS hemorrhage. Hepatic encephalopathy is associated with
coma, most often in patients with clinical signs of liver injury and elevation of the prothrombin time and
serum ammonia level.[15][40] Patients with liver failure have coagulation disturbances that predispose them to
CNS hemorrhage, even in the absence of a history of trauma, so this possibility should always be
considered. Seizures cause depression of mental status that often resolves rapidly, aiding in the diagnosis.
Stupor (not coma) rarely is caused by partial complex or nonconvulsive status epilepticus, in which
characteristic motor movements that suggest seizure activity are absent.[11][12][13] Although acute thiamine
deficiency is rarely a cause of coma, it does occur as a near-terminal condition.[41]


CLINICAL EVALUATION
Clues in the History
Information from the family and the scene gives valuable clues to a toxicologic diagnosis. A history of
suicidal intention, or history of recreational drug use, witnessed ingestion, empty bottles from the scene, or
drug paraphernalia support the likelihood of poisoning as the cause of mental status depression.
Determining the available medications or toxicants and the types of medical conditions in family members
assists in identifying specific agents that might have been ingested. Sometimes, a history can be elicited of
premonitory signs and symptoms occurring in poisoned patients before their progression to coma. These
may also be observed in the clinical setting. For example, patients with anticholinergic poisoning may
present with a distinctive mumbling, fragmented speech pattern, in which they speak clearly, then trail off
into unintelligible words. As delirium progresses, these patients exhibit a “picking” behavior. Children with
diphenoxylate-atropine poisoning may initially be hyperactive and babbling incoherently because of an
atropine-induced anticholinergic syndrome. Further absorption of the drug can lead to opioid-induced coma.
This type of deterioration is common in many progressive toxic or disease processes in which agitated
delirium progresses to coma.
The circumstances under which the patient was found also provide clues to the diagnosis. If the patient was
found in a closed space the possibility of carbon monoxide poisoning should be considered. A comatose
patient brought from a gym or a party may have ingested gamma-hydroxybutyrate. The very characteristic
dramatic emergence after a period of observation, with rapid return to a normal mental status, confirms this
diagnosis. Patients found on the street or at the bottom of a flight of stairs should be carefully assessed for
the possibility of a traumatic brain injury. Previous medical illnesses should be carefully explored. A history
of complaints before the onset of CNS depression, such as headache, fever, and abnormal behavior is very
important, as is witnessed seizure activity.
The Physical Examination
The physical examination provides valuable information that directs the management and evaluation of the
unconscious patient ( Tables 16–5 and 16–6 ). When a toxin is suspected, the examination should reveal
findings that would be expected with the suspected toxin ( Table 16–7 ). For example, a patient who is
comatose after the suspected ingestion of an opioid should have some sign of opioid intoxication, such as
miosis, respiratory depression, and CNS depression, that improves after the administration of naloxone.
Conversely, these findings in the absence of a history of opioid exposure suggest the diagnosis of opioid
intoxication. A patient suspected of being comatose because of intoxication with ethanol has mild respiratory
depression and hypotension, in addition to the characteristic odor of ethanol. These patients should improve
steadily with observation. Patients poisoned with anticholinergics typically have some antimuscarinic signs,
such as mydriasis, tachycardia, dry flushed skin and mucous membranes, ileus, myoclonus, and bladder
distention. Cholinergic agents induce the opposite findings: miosis, diarrhea, salivation, and bronchorrhea.
Characteristic odors, such as those of cyanide (bitter almonds) and insecticides (garlic), may be present and
should be noted. Barbiturate-like drugs cause respiratory depression and hypotension, whereas
benzodiazepine poisoning causes much less respiratory and hemodynamic depression, despite significant
CNS depression. As a general rule, for all patients poisoned with sedative hypnotic drugs, pupillary reactivity
is preserved.
Table 16-5 -- The Coma Exam: Pertinent Positives and Negatives

HEENT: trauma, hemotympaneum, icterus, pallor, odors (ketones? hydrocarbons? uremia? fetor hepaticus?)
NECK: thyroid, carotid pulses, rigidity?
CHEST: signs of pneumonia or aspiration
HEART: murmurs (endocarditis?)
ABDOMEN: ascites, character of bowel sounds, bladder distention
EXTREMITIES: cyanosis, petechiae, purpura, splinter hemorrhages, track marks, edema
SKIN: petechiae, purpura, uremic frost, color, moisture, bullous lesions (“barb blisters”)
Table 16-6 -- Neurologic Examination

Finding Suggests
Finding Toxic-Metabolic Structural
Hypoventilation Hyperventilation
Respiration Respiratory acidosis Cheyne-Stokes
Metabolic acidosis Respiratory alkalosis
Reactive Fixed
Pupils
Asymmetric
Flaccidity Posturing
Asterixis Asymmetry
Motor
Myoclonus
Rigidity
Reflexes Clonus, depressed Clonus, Babinski’s
Doll’s eye reflex Present Absent
Skew deviation
Reactive pupils Fixed pupils
Highly predictive coma combinations Normal or decreased tone Posturing
Respiratory acidosis Respiratory alkalosis
Table 16-7 -- Common Findings with Drugs Causing CNS Depression

Decreased GI motility, dry flushed skin, hyperthermia, mydriasis,
Anticholinergics
tachycardia, urinary retention, myoclonus
Opioids Respiratory depression, miosis, hyporeflexia, hypothermia
Cyclic antidepressants Anticholinergic toxidrome, dysrhythmias, hypotension, seizures
Diaphoresis, hypertension, hyperthermia, mydriasis, seizures,
Sympathomimetics
tachycardia
Rigidity, miosis (variable with phenothiazines), hypotension,
Neuroleptic agents
anticholinergic signs
Miosis, bronchorrhea, salivation, emesis, diarrhea, diaphoresis,
Cholinergics
fasciculations, muscle weakness
Lithium Clonus, tremor, myoclonus, ataxia, seizures
Anticonvulsants Nystagmus, ataxia, seizures
Gastritis, nystagmus, familiar odor
Alcohols Fruity breath odor, ketones (isopropanol)
Metabolic acidosis (methanol/ethylene glycol)
Barbiturates Hypotension, “barb blisters,” hypoventilation
Normotensive, minimal respiratory depression when used as single
Benzodiazepines
agent
Bitter almond odor (cyanide)
Toxic gases Rotten egg odor (hydrogen sulfide)
Metabolic acidosis: cyanide, hydrogen sulfide
Gamma-hydroxybutyrate (GHB) and Minimal respiratory depression, normal blood pressure, rapid
related substances emergence, nystagmus, no amnesia
CNS, central nervous system; GI, gastrointestinal.
Less specific signs suggest exposure to certain toxins. Deep Kussmaul respirations due to metabolic
acidosis are associated with severe salicylism or ingestion of a toxic alcohol. Clonus and tremors are
associated with lithium or monoamine oxidase inhibitors. Clonus with neuromotor rigidity suggests the
neuroleptic malignant syndrome or a serotonin syndrome. Cerebral edema can occur with toxicity caused by
salicylates, ethylene glycol, and methanol, and it can occur with hepatic failure caused, for example, by
acetaminophen.
Careful examination should be made for signs of infection that suggest meningitis or other CNS infection.
Fever or nuchal rigidity, which may be absent in the early stages of bacterial meningitis, should always be
assessed. Purpura or petechiae in the comatose patient suggest CNS infection with meningococci or the
possibility of thrombotic thrombocytopenic purpura.[25][27] Heart murmur, track marks, Roth spots, or splinter
hemorrhages indicate the possibility of endocarditis, with associated meningitis, embolic stroke, or brain
abscess as a cause of coma. [10][33]
Certain metabolic disorders have characteristic physical signs that suggest the diagnosis ( Table 16–8 ).
These disorders may be toxin induced. Signs of liver injury include icterus, spider angiomata, and a flapping
tremor. Blood present in the stool may be the precipitating cause of hepatic encephalopathy in patients with
hepatic failure caused by many toxins (see Chapter 21 ). Uremic patients have a dry, “frosty” appearance,
may be hypertensive and tachypneic due to metabolic acidosis, and have an odor that suggests ammonia.
Additionally, these patients have tremor, asterixis, increased motor tone, and seizures. [22] Patients with
diabetic ketoacidosis appear dehydrated, have deep Kussmaul respirations, and the sweet odor of ketosis,
which is not detectable by all examiners. A history of polyuria may be obtained. Diabetes mellitus has been
produced by ingestion of Vacor (N-3-pyridylmethyl-N'-p-nitrophenyl urea). The families of patients with
hypercalcemia may give a history of excessive ingestion of vitamins (hypervitaminosis A or D) or antacids;
use of androgens, glucocorticoids, or thiazide diuretics; or a history of malignancy, bone pain, polyuria, or
constipation. These patients also appear dehydrated with decreased skin turgor. Severe hypernatremia is
associated with toxins that produce diabetes insipidus, such as lithium, with use of osmotic laxatives, such
as sorbitol, lactulose, and glycerol; with excessive intake of sodium salts; or with inadequate access to
water, such as a poorly tended nursing home patient or a homebound elderly person. Myxedema coma is
suggested by diffuse, nonpitting edema; alopecia; loss of the lateral eyebrows; and very characteristic “hung
up” reflexes. Hypothermia and hypoventilation are common. The family may give a history of loss of energy
and constipation. Hypothyroidism can occur in patients taking lithium, although myxedema would be unlikely
to occur,[21] and the diagnosis is also supported by a history of treatment for thyroid disorders or a surgical
scar that suggests thyroid surgery.[28] It is important to consider this diagnosis because routine laboratory
assessment does not give clues beyond the history and physical examination. Severe thiamine deficiency is
characterized by ataxia and ophthalmoplegia. The finding of ophthalmoplegia, manifest as paralysis of the
normal oculomotor, or doll’s eye, reflex in association with sparing of the pupillary response, should prompt
consideration of severe thiamine deficiency as a cause of coma.[41]
Table 16-8 -- Findings Associated with Common Metabolic Causes of Stupor and Coma
Condition Finding Laboratory
Adrenal Hypoglycemia, mild hyponatremia, mild
Hypotension, tachycardia, stupor, fever
insufficiency, severe hyperkalemia, mild metabolic acidosis
Hepatic Icterus, asterixis, spider angiomata,
Elevated prothrombin time, ammonia, bilirubin
encephalopathy ascites
Tenting, polyuria, dehydration,
Hypercalcemia Calcium >14 mg/dL
constipation
Hyperosmolar
Tenting, dehydration Glucose >800 mg/dL
states
Sodium >160 mEq/dL
Hypocalcemia Tetany, hyperreflexia Ionized Ca2 + <2 mg/dL
Coma is unusual unless seizures occur
Seizures, delirium, coma, myoclonus,
Hyponatremia Sodium <120 mEq/dL
asterixis
Dough edema, “hung-up” reflexes, mild
Myxedema Elevated TSH
hypothermia, mild hypercarbia
Condition Finding Laboratory
Thiamine deficiency Diplopia, ataxia, confusion coma,
Metabolic acidosis
(severe) ophthalmoplegia, hypotension
Pallor, seizures, tremor, hyperventilation, Elevated BUN and creatinine, anemia,
Uremia odor of uremia, asterixis, myoclonus, metabolic acidosis, hypocalcemia,
“frost” hyperphosphatemia
BUN, blood urea nitrogen; TSH, thyroid-stimulating hormone.
Findings That Suggest a Structural Cause of Coma
A careful examination should be made for signs of trauma. The neurologic exam provides critical clues to
the more urgent neurosurgical diagnoses. The presence of papilledema is a big clue. However, papilledema
develops in patients who have had an expanding mass lesion for a period of time and is not seen in those
with acute mass effects due to trauma. Patients with a rapidly increasing intracranial pressure do lose
spontaneous venous pulsations, which is a less specific sign. Mass lesions cause other characteristic
findings that speak against the diagnosis of a toxin and give clues to the need for emergent computed
tomographic scanning. Focality, although it may occur transiently in certain kinds of encephalopathy and in
the postical and posthypoglycemic states, strongly suggests the presence of a mass lesion. This includes
the characteristic finding of the “blown pupil,” caused by third nerve compression from uncal herniation.
These neurologic signs of mass effect are straightforward and are not discussed further. Many patients with
traumatic brain injury have no history or physical signs of trauma. Diagnostic errors occur when clinicians fail
to appreciate subtle signs of increased intracranial pressure in patients who do not have discernible focality
and are mistakenly thought to be poisoned. A very early and characteristic sign of increased intracranial
pressure is an elevation of the respiratory rate that results in respiratory alkalosis. This may also be
accompanied by an elevation of the blood pressure. As the mass effect progresses, the pupils become fixed,
usually in midposition. This presentation contrasts with the patient with CNS depression resulting from a
sedative hypnotic agent, where coma is often associated with some degree of respiratory depression and
pupils are spared. The comatose patient with an increased respiratory drive that is not due to metabolic
acidosis should be suspected of having brain injury as the cause of coma. Other causes of a primary
respiratory alkalosis include sepsis, hepatic failure, salicylism, theophylline poisoning, and cardiopulmonary
disorders, such as hypoxia, pulmonary embolism, and tamponade ( Table 16–9 ). Cardiopulmonary
disorders do not cause coma except in the setting of profound hypoxia or shock, although pulmonary
aspiration can occur in patients with coma of other causes. Progression to fixed pupils confirms the
presence of a mass lesion. Unlike the patient with severe anticholinergic poisoning who has widely dilated,
fixed pupils in the setting of other peripheral anticholinergic signs, these patients with progressive brainstem
compression have small or midposition pupils associated with hyperventilation.
Table 16-9 -- Causes of Hyperventilation

Increased intracerebral pressure
Focal brainstem injury
Metabolic acidosis of any cause
Cardiopulmonary disorders
Meningoencephalitis
Sepsis
Hepatic failure
Toxins: e.g., salicylates, theophylline, dinitrophenol
A rare cause of coma that is a diagnostic emergency because it is treatable if it is recognized is an acute
basilar artery thrombosis.[5] These patients often have underlying cerebrovascular disease that has resulted
in previous symptoms of vertigo, diplopia, dysarthria, or drop attacks.[20] Neurologic findings in these cases
suggest brainstem injury, which may be incomplete or asymmetric. The sudden onset of coma with fixed
small or midposition pupils, impairment of doll’s eye reflex, hyperventilation, and posturing are clues to this
diagnosis.[20][30]
A final useful aspect of the clinical evaluation of a patient with CNS depression is the period of observation
that follows the initial evaluation. Patients with seizures or mild intoxications with agents such as gamma-
hydroxybutyrate and ethanol improve with observation. Patients with expanding CNS mass lesions,
untreated meningitis, or severe poisoning deteriorate. Failure to improve or evidence of deterioration in a
patient believed initially to have a minor problem should prompt timely reassessment.


LABORATORY EVALUATION
A computed tomographic scan of the head should be performed immediately after resuscitation in any
patient suspected of having a CNS mass lesion as a cause of coma. This includes the patient with a focal
neurologic examination, fixed pupils (unless there is a clear history of anticholinergic exposure with a
confirmatory toxidrome), papilledema, or unexplained respiratory alkalosis and coma.
The electrocardiogram provides valuable information regarding the possible presence of certain toxins. The
characteristic electrocardiographic changes associated with overdose of a cyclic antidepressant are helpful
in assessing the patient with an anticholinergic syndrome. Minor conduction disturbances that suggest
poisoning occur in patients poisoned with lithium, carbamazepine, and some of the neuroleptics.
Characteristic QT prolongation occurs in patients poisoned with mesoridazine and thioridazine, sometimes
leading to torsades de pointes tachycardia.
The arterial blood gas provides valuable information regarding the differential diagnosis of coma. In the
comatose patient, metabolic acidosis is seen in patients who are postictal or who have ketoacidosis, uremia,
sepsis, or poisoning with a toxic alcohol, iron, cyanide, azide, salicylates, or a biguanide, such as metformin.
Respiratory acidosis is seen in patients with sedative hypnotic or opioid overdose, as well as patients with
spinal cord injury and other structural or intrinsic pulmonary disorders associated with hypoventilation.
Respiratory alkalosis occurs in patients with increased intracranial pressure, sepsis, aspiration, hepatic
failure, or poisoning with salicylates or theophylline (see Chapter 11 for a more extensive discussion of acid-
base disturbances).
Measurement of serum sodium, blood urea nitrogen, calcium, and glucose levels may give information
regarding the primary cause of coma. Mild hypnonatremia and hyperkalemia suggest adrenal insufficiency.
An elevated anion gap indicates certain toxins, as well as the possibility of acidosis from uremia,
ketoacidosis, seizures, shock, or hypoxia. Toxic agents that can cause CNS depression and an anion gap
metabolic acidosis include carbon monoxide, cyanide, azide, ethylene glycol, iron, isoniazid, methanol,
paraldehyde, salicylate, and toluene. Poisoned patients with CNS depression can also be evaluated for an
osmol gap, although a “negative” gap does not eliminate the toxic possibilities (see Chapter 11 ). Toxins that
produce both CNS depression and an elevated osmol gap include ethanol, ethylene glycol, methanol, and
isopropanol. A small increase in the osmol gap is seen in chronic renal failure (<20 mOsm) and significant
lactic and ketoacidosis (<15 mOsm).[35][37]
CNS depression and an anion gap metabolic acidosis accompanied by an osmol gap should immediately
suggest poisoning with ethylene glycol or methanol ( Table 16–10 ). Peripheral metabolic acidosis per se
does not cause alteration of mental status.[30]
Table 16-10 -- Differential Diagnosis of Central Nervous System Depression

Anion Gap Acidosis Osmolar Gap
Carbon monoxide, cyanide, ethylene glycol, iron, ibuprofen (rare,
Ethylene glycol, ethanol,
Toxins large overdoses), isoniazid, metformin, methanol, paraldehyde,
methanol, isopropanol
salicylate, and toluene
Ketoacidosis: diabetic, alcoholic, starvation <15 mOsm
Metabolic Lactic acidosis: Shock, seizures, sepsis, severe adrenal insufficiency,
causes severe thiamine deficiency,
Uremia <20 mOsm
Thyroid-stimulating hormone should be measured in patients in whom myxedema coma is suspected. An

acetaminophen level should be measured in all patients with suspected suicidal ingestion. Elevated
creatinine phosphokinase levels indicate the possibility of rhabdomyolysis due to muscle compression or
compartment syndrome in comatose patients. The demonstration of thrombocytopenia and hemolytic
anemia on the complete blood count is most useful in the diagnosis of thrombotic thrombocytopenic
purpura.[25][27] The white blood cell count is not sufficiently sensitive or specific to rule in or exclude
infections as a cause of coma.
A lumbar puncture is required when meningitis or menigoencephalitis is suspected on the basis of the
history or examination.
A toxicologic screen may give no information, may be helpful, or may mislead. A positive toxicologic screen
for cocaine, opiates, or ethanol commonly occurs in patients with CNS injury or infection but may be an
indicator of remote use and does not necessarily indicate clinical toxicity with the demonstrated drug. In
addition, many intoxicants are not detected by routine laboratory screens. A quantitative level of an agent
such as carbon monoxide (carboxyhemoglobin), lithium, phenobarbital, carbamazepine, theophylline,
salicylate, or ethanol that is sufficiently high to cause coma in a patient suspected of poisoning with that
agent is very helpful. The significance accorded to the results of a toxicologic screen should always be
considered in the context of the history, the physical examination, and the patient’s clinical course.
The electroencephalogram is a useful tool when partial complex or nonconvulsive status epilepticus is
suspected as a cause of coma.[12][13] It is also useful to distinguish patients with psychogenic causes of
coma.[30][32]


DEFINITIVE TREATMENT
The definitive treatment of the comatose patient depends on the cause of the CNS depression. Excellent
supportive care in an intensive care environment is essential in all cases. The importance of early detection
of CNS mass lesions, basilar artery thrombosis, and bacterial infections has been emphasized. Most
patients with CNS depression related to poisoning who arrive alive in the hospital do well with supportive
care and decontamination with activated charcoal. Specific agents may require specific antidotal therapies
or decontamination with whole-bowel irrigation or dialysis. The reader is referred to the specific chapter of
that poison/toxin for more details concerning definitive treatment and to the chapters on decontamination
and extracorporeal therapies (see Chapters 5 and 6 ).


DISPOSITION/NEED FOR CONSULTANTS
Poisoned patients with CNS depression need to be medically treated until they return to their normal mental
status. Patients with prolonged periods of CNS depression should be admitted to an intensive care unit. A
Regional Poison Control Center is an invaluable tool in determining the cause of the CNS depression, in
obtaining treatment recommendations, and in accessing the expertise of a medical toxicologist.


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2. Arieff AI, Carroll HJ: Nonketotic hyperosmolar coma with hyperglycemia: Clinical features,
pathophysiology, renal function, acid-base balance, plasma-cerebrospinal fluid equilibria and the effects of
therapy in 37 cases. Medicine 1972; 51:73-94.
3. Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation
with brain water and electrolytes. Medicine 1976; 55:121-129.
4. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 1992; 26:1196-1202.
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Chapter 17 – Central Nervous System Agitation
LARISSA VELEZ-DAUBON KATHLEEN A. DELANEY
Essentials
• Manage immediate life threats: airway, breathing, and circulation (ABCs)
• Assess core temperature and glucose level
• Control agitation with physical restraints, followed by chemical restraints
° Prevent injury to the patient and health care personnel
° Decrease complications, such as hyperthermia and
rhabdomyolysis
• Examine for specific toxidromes that aid in the differential diagnosis of agitation
• Consider toxic, traumatic, infectious, structural, and metabolic causes before arriving at the diagnosis of
psychiatric disturbances
INITIAL STABILIZATION AND TREATMENT
Life-threatening airway and hemodynamic compromise commonly causes agitation. Hypoxia and shock
need to be diagnosed and treated immediately, followed by detection and treatment of hypoglycemia and
hyperthermia. Diabetic patients whose disease is poorly controlled may have adrenergic and
neuroglycopenic symptoms despite a “numerical euglycemia.” Such patients may have symptomatic
hypoglycemia at plasma glucose levels that are considered to be in the normal range.[6] Also, the
assessment of the hydration status of the agitated patient is important because dehydration is a common
finding. An initial rhythm strip should be obtained to search for arrhythmias and QRS widening.
The presence of agitation should not delay resuscitation and treatment. Studies note that agitation often
interferes with and delays the delivery of medical care.[12] Malnourished or alcoholic patients should receive
thiamine hydrochloride, 100 mg intravenously, during the initial treatment in order to prevent the occurrence
of Wernicke encephalopathy. This therapy has been found to be safe and cost-effective in preventing
delayed deterioration in function of the alcoholic patient. [29] To facilitate evaluation and treatment, initial
management also includes physical restraint, quickly followed by chemical restraint. A combination of
physical and chemical restraints has been found to be the safest and most effective approach to the
management of agitation. Physical control of the patient prevents injury to the patient and to health care
personnel, and chemical restraints prevent the development of complications associated with prolonged
motor agitation. The most important of these complications are rhabdomyolysis and potentially life-
threatening hyperthermia. [11][15][49] The selection of agents for chemical restraint is discussed in Definitive
Treatment.
After treatment of threats to life and adequate sedation, a detailed examination should focus on signs of
injury, infection, endocrine disturbance, hepatic or renal failure, and neurologic deficits. Examination should
include a search for common toxidromes, especially signs of anticholinergic or sympathomimetic poisoning,
which commonly present with agitation. A thorough neurologic examination, including an examination of the
mental status, is essential. When the history or physical examination suggests the possibility of a significant
toxic ingestion, gastrointestinal decontamination with 1 g/kg of activated charcoal is indicated. Gastric lavage
is generally contraindicated in the agitated patient because of the risk of complications, unless a recent
lethal ingestion is suspected (see Chapter 5 ). Because of the risk of aspiration, induction of vomiting is also
contraindicated in any patient with an altered mental status.


In general, the causes of agitation can be divided into toxic, neurologic (structural), infectious, metabolic, and
functional disorders.
Toxins
Toxic exposures that lead to agitation fall into four categories: (1) recreational exposure to illicit drugs, (2)
inadvertent overdose or idiosyncratic response to pharmaceutical agents, (3) suicidal ingestion, and (4)
exposures to environmental agents. Common recreational drugs that result in agitation include cocaine,
amphetamines, phencyclidine, and the hallucinogens. Suicidal ingestion of many medications and drugs
may initially present as delirium, followed by deeper states of depression of consciousness (see Chapter 16
). This group includes agents with anticholinergic properties (e.g., the antihistamines, tricyclic
antidepressants, and neuroleptics), lithium, monoamine oxidase inhibitors, and salicylates. Delirium may
also result from combinations of therapeutic amounts of serotonergic agents, resulting in the serotonin
syndrome (see Chapter 63 ). The elderly are particularly susceptible to central nervous system (CNS) effects
of therapeutic drugs. Numerous agents have been associated with agitated delirium in the elderly,
particularly because of polypharmacy and the elderly’s use of medications with anticholinergic
properties.[14][37][44] Occupational, inadvertent, recreational, or suicidal exposure to many nonpharmaceutical
agents must also be considered. These agents include carbon monoxide, pesticides, hydrocarbons, and
certain mushrooms (see Table 17–1 for agents that can cause agitation).
Table 17-1 -- Toxic Causes of Agitated Delirium

Anticholinergic agents
Antihistamines: diphenhydramine, chlorpheniramine, pyrilamine
Antipsychotics: phenothiazines, butyrophenones, thiothixenes
Antispasmodics: orphenadrine, cyclobenzaprine
Antidepressants: amitriptyline, nortriptyline
Antiparkinsonians: benztropine, amantadine[22]
Antiemetics: prochlorperazine
Atropine, scopolamine
Adrenergic agonists
Cocaine
Amphetamine and its derivatives (methamphetamine, MDMA)
Phenylpropanolamine
Ephedrine/pseudoephedrine
Xanthines (caffeine, theophylline, aminophylline)
Phencyclidine (PCP)
Hallucinogens
LSD
Mushrooms
Aspirin
Lithium
Alcohol
Carbon monoxide
Steroids
Valproate-induced hepatic encephalopathy
Hydrocarbons
Combinations of serotonergic agents (serotonin syndrome)
SSRIs: paroxetine, sertraline
Withdrawal syndromes
Sedative-hypnotics
Gamma hydroxybutyrate (GHB)
Ethanol
Opiates
Amantadine[22]
Unusual: propranolol,[38] ibuprofen[48]
Environmental/occupational
Long-term manganese exposure (“manganese madness”)
Long-term organophosphate/carbamate exposure
Long-term lead, mercury, arsenic, aluminum exposure
LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxymethamphetamine; SSRI, selective serotonin
reuptake inhibitor.
Neurologic/Structural
These patients may have evidence of trauma or focality on neurologic examination, although often they do
not. The most commonly encountered lesions are frontal contusions, subdural hematomas, subarachnoid
hemorrhages, and space-occupying lesions. Spontaneous cerebrovascular accidents are also associated
with acute agitation.[42] Patients at special risk are those with history of alcoholism, chronic hypertension, or
cocaine abuse; the elderly, and patients receiving anticoagulation. Patients with diffuse CNS injury may also
present with agitated delirium that progresses to coma. A postictal state may also be a cause of agitation.
Infectious
Delirium is a common complication of CNS infection. Physical signs of CNS infection include fever and
meningeal irritation. Petechiae or purpura may also be noted, especially when Neisseria meningitidis is the
etiologic organism. Risk factors for these infections include immunosuppression, intravenous drug use,
sinusitis, and cerebrospinal fluid leaks. Many patients experience meningitis or meningoencephalitis without
any predisposing risk factors. In addition, many patients with meningitis, particularly the elderly and children
younger than 2 years, may not show the nuchal rigidity commonly associated with meningeal irritation.
Metabolic
Many metabolic abnormalities can result in agitation. The most commonly encountered abnormality is
hypoglycemia, and the importance of an initial peripheral glucose evaluation cannot be overemphasized.
Patients with hypernatremia, hyponatremia, hypercalcemia, hyperglycemia, or uremia may present with mild
mental status alterations that progress to coma. Encephalopathy due to thrombotic thrombocytopenic
purpura, hepatic failure, thyrotoxicosis, or severe hypertension may also present with extreme agitation (see
Table 17–2 for a differential diagnosis of nontoxic causes of agitation).
Table 17-2 -- Nontoxic Causes of Agitation

Neurologic/structural
Frontal contusion
Subarachnoid hemorrhage
Subdural hematomas
Space-occupying lesions
Normal-pressure hydrocephalus
Seizures/postictal states
Cerebrovascular accidents
Dementia (Alzheimer’s disease, multi-infarct, AIDS)
Rare: Huntington disease[50]
Infectious
Meningitis
Encephalitis
Brain abscess
Sepsis
Metabolic
Hypoglycemia/hyperglycemia
Hyponatremia
Hypercalcemia (malignancy, hyperparathyroidism)
Uremia (renal failure)
Hypercarbia
Hypoxemia (pulmonary embolism, pneumothorax, pulmonary edema, arrhythmias, MI)
Hypothermia/hyperthermia
Hepatic encephalopathy
Vitamin deficiency (thiamine [Wernicke encephalopathy], folic acid, vitamin B 12, niacin [pellagra], pyridoxine)
Porphyria
Rare: Wilson disease
Hypertensive encephalopathy
Pheochromocytoma
Thyrotoxicosis (thyroid storm)/hypothyroidism (“myxedema madness”)
Functional
Schizophrenia
Personality disorder (antisocial, borderline)
Psychogenic (anxiety)
Bipolar disorder (mania)
AIDS, acquired immunodeficiency syndrome; MI, myocardial infarction.


CLINICAL EVALUATION
A thorough physical examination should note the presence or absence of evidence of head trauma,
including an evaluation for hemotympanum and evidence of cerebrospinal fluid rhinorrhea.
Pupil size, symmetry, and reactivity give important information. Small, poorly reactive pupils are commonly
seen with the metabolic encephalopathies, whereas large pupils suggest adrenergic stimulation or
cholinergic blockade. A single dilated and sluggish or fixed pupil in an awake patient suggests an expanding
posterior communicating artery aneurysm.[24] Nystagmus is an important, although nonspecific, ocular
finding that characterizes many toxic-metabolic encephalopathies and, occasionally, structural causes of
agitation. The funduscopic examination, although difficult in these patients, can yield valuable information
regarding chronic medical conditions, such as hypertension and diabetes mellitus. Other significant findings
in the funduscopic examination are the subhyaloid hemorrhages associated with subarachnoid hemorrhage
and papilledema seen in association with chronically increased intracranial pressure. The mouth should be
examined for dehydration, signs of tongue biting, and abnormal odors, such as ketones, fetor hepaticus,
uremia, and hydrocarbons. The presence of cyanosis or jaundice should be noted. Signs of meningeal
irritation suggest meningitis or subarachnoid hemorrhage.
The cardiopulmonary examination should note murmurs, which may suggest endocarditis or cerebral
embolization, and signs of pulmonary congestion, infection, or bronchospasm. The character of the patient’s
breathing gives important diagnostic clues. Hyperventilation in the agitated patient is associated with
metabolic acidosis, anxiety, fever, and poisoning with salicylates, cyanide, carbon monoxide, and
theophylline. It is also an early sign of increased intracranial pressure.
The abdominal examination should include a careful assessment of bowel sounds and evidence of bladder
distention. The clinician should carefully inspect the extremities for needle tracks and the skin for petechiae
and purpura and should also note the presence or absence of moisture. Stigmata of chronic liver disease
include spider angiomas, bitemporal atrophy, ascites, gynecomastia, testicular atrophy, asterixis, and caput
medusae. Table 17–3 shows some specific findings associated with nontoxic causes of agitation.
Table 17-3 -- Findings in Selected Nontoxic Causes of Agitation

Condition Vital Signs History Clues in Examination
Tachycardia, Fine hair, lid lag, exophthalmos,
Palpitations, weight loss,
hypertension (wide stare, enlarged thyroid, proximal
Thyrotoxicosis heat intolerance, frequent
pulse pressure), weakness, tremor, excessive
bowel movements
increased temperature sweating
Nuchal rigidity, +/- altered mental
Meningitis Fever, tachycardia Headache
status, petechiae, purpura
Condition Vital Signs History Clues in Examination
Spider angiomas, bitemporal
Hepatic Tachypnea, atrophy, ascites, gynecomastia,
Ethanolism, hepatitis
encephalopathy tachycardia testicular atrophy, icterus, asterixis,
caput medusae
Flame-shaped hemorrhage, AV
Hypertensive
Hypertension Hypertension nicking, cotton wool patches, disc
encephalopathy
blurring/papilledema
Subarachnoid
Tachypnea Sudden, unusual headache Subhyaloid hemorrhage
hemorrhage
New murmur, needle tracks, Roth
Endocarditis Fever, tachycardia IVDA, fevers spots, Janeway lesions, splinter
hemorrhages
Fever (+/-),
Hypoxemia, acidosis, leukocytosis,
Sepsis tachycardia, Immunocompromise
petechiae
hypotension
Wernicke Normal (+/-),
Ethanolism, malnutrition Ataxia, ophthalmoplegia
encephalopathy tachycardia
AV, arteriovenous; IVDA, intravenous drug abuse.
Neurologic Examination
A complete neurologic examination should focus on evidence of impairment of both focal and global brain
dysfunction. Focal abnormalities suggest a structural lesion and include asymmetry of cranial nerves, motor
strength, and reflexes, as well as aphasia, agnosia, or apraxia. Impairment of orientation and fluctuating
wakefulness suggest the global CNS impairment of delirium. Myoclonus, tremor, diffuse hyperreflexia,
cogwheeling, and rigidity all are seen in patients with various causes of delirium. None of these findings
should be present in the patient in whom a functional psychiatric disorder is considered.
Mental Status Examination
The mental status examination is described in Table 17–4 . The term delirium (also referred to as acute
confusional state) refers to an acute cognitive impairment characterized by an attention deficit and a
fluctuating level of consciousness.[36] The patient can also display disturbances in the sleep-wake cycle,
disturbed psychomotor behavior, emotional disturbances, and impaired judgment.[17][40] Delirium is a readily
reversible condition if a treatable cause is identified early. When it is not recognized and diagnosis and
treatment are delayed, the mortality in patients with delirium is between 15 and 30 per cent.[46][55] It is one of
the most common presentations of medical illness in the elderly.[40][45] In contrast to delirium, dementia is a
chronic, gradual deterioration of the cognitive (intellectual) functions that is not associated with altered level
of consciousness and does not have a fluctuating course. It is usually accompanied by impairment of the
recent memory, even in its early stages.[51] The demented patient who presents with an abrupt deterioration
in the baseline functioning should be evaluated for superimposed delirium.[53] Table 17–5 describes the
differences between dementia and delirium.
Table 17-4 -- Mental Status Examination
Appearance and behavior
Level of consciousness: wakefulness, alert, follows commands
Posture and motor behavior: restlessness, handwringing, singing
Dress, grooming, and personal hygiene
Facial expression: apathy, anger, elation
Manner, affect, and relationship with other persons: appropriate, suspicious
Speech and language
Quantity, rate, volume, fluency
Mood (sad, elated, indifferent, anxious)
Thought process (flight of ideas, loose associations, incoherence)
Thought content (compulsions, obsessions, phobias, hallucinations)
Insight
Judgment
Memory (recent, remote)
Attention (serial sevens, backward spelling)
Mini-Mental State Examination can also be included
Table 17-5 -- Differentiating Between Dementia and Delirium

Dementia Delirium
Normal vital signs Abnormal vital signs frequent
Normal/unremarkable physical examination Multiple clues of organic illnesses
Gradual/insidious onset Acute onset
Prior history usual No prior psychiatric history
Normal alertness Impaired/fluctuating alertness, confused
Difficulty finding words, perseveration Pressured speech
Disoriented, recent memory more affected than Disoriented, immediate memory more affected than
remote remote
+/- Auditory hallucinations, delusions (often absent) Visual or tactile hallucinations (poorly organized)
Stable mood Labile mood
Fragmented sleep Altered sleep-wake cycle
Psychosis is defined as a disorder characterized primarily by well-organized hallucinations or delusions.

Normally, alertness and cognition are not impaired. The differences between agitated patients with an
organic (delirium) and patients with a functional (psychiatric) disorder have been well described in the
literature.[40][44] Delirium is characterized by global impairment of cognitive functions. Disorientation in some
or all spheres (time, date, place, person) is always present, the extent and severity of which depend on the
severity of the delirium. Wakefulness and orientation often fluctuate. The thoughts are disorganized and the
mood is labile. Visual hallucinations are more common in delirium, in contrast to the predominantly auditory
hallucinations of psychosis. Hallucinations are not frequently present in dementia.
Functional (psychiatric) disorders can be differentiated from delirium by the preservation of cognitive
functions in the first group. Orientation is intact, and delusions are very well organized. The mood is also
constant. The most commonly encountered functional disorders causing agitation are schizophrenia, the
personality disorders, and bipolar disorder. If asked, most of these patients give a history of a psychiatric
illness. Although it is always true that disorientation and impairment of wakefulness imply delirium,
apparently “functional” disorders are occasionally associated with organic disturbances, such as brain
tumors and temporal lobe seizures. In this particular group of patients, the age of onset of symptoms may
give clues to an organic cause.[34] Table 17–6 demonstrates the differences between an organic (delirium)
and a functional (psychosis) cause of agitation. A screening study of 1140 patients demonstrated that the
evaluation of four parameters identifies most patients with delirium. These are (1) disorientation, (2)
abnormal vital signs, (3) clouded consciousness, and (4) age greater than 40 without prior psychiatric
history.[21]
Toxidromes
Specific toxidromes that predominantly affect the vital signs, skin, pupils, and gastrointestinal tract
characterize intoxication with certain agents. Table 17–7 summarizes familiar toxidromes seen in poisonings
that present with agitation.
Table 17-7 -- Common Toxidromes Presenting with Agitation

Name Vital Signs Physical Examination Laboratory/Diagnostics
Mydriasis, bladder
QRS (>0.10 sec), suspect TCA; QT
distention, ileus,
Anticholinergic Tachycardia, fever prolonged, suspect trifluoperazine
myoclonus, anhidrosis
(Stelazine) or thioridazine (Mellaril)
(including axillae)
Tachycardia, fever, Diaphoresis, tremor, Metabolic acidosis, hyperglycemia,
hypertension mydriasis hypokalemia, leukocytosis
Sympathomimetic Complications: rhabdomyolysis
(ARF), hyperthermia, myocardial
ischemia
Increased anion gap, respiratory
Tachypnea/hyperpnea,
Salicylates Hyperpnea alkalosis/metabolic acidosis,
fever
ketonuria
Name Vital Signs Physical Examination Laboratory/Diagnostics
Diaphoresis, diarrhea,
Fever, tachycardia, tremor, hyperreflexia,
Serotonin syndrome Nonspecific
hypertension rigidity, ataxia,
nystagmus
Chest pain, headache
Carbon monoxide Tachycardia Increased COHgb levels
disorientation
Phencyclidine Tachycardia, Miosis, hyperreflexia, Complications: rhabdomyolysis
(PCP) hyperthermia nystagmus, ataxia (ARF), hyperthermia
Delusions,
Lysergic acid Complications: hyperthermia,
Tachycardia hallucinations, paranoia,
diethylamide (LSD) rhabdomyolysis (ARF)
distorted perception
Lithium Tachycardia Tremors, hyperreflexia Prerenal azotemia
Sedative-hypnotic Tachycardia, mild Tremors, mydriasis,
Nonspecific
withdrawal hypertension anxiety, seizures
Diarrhea, vomiting,
Opioid withdrawal Mild tachycardia yawning, piloerection, Nonspecific
needle tracks
ARF, acute renal failure; COHgb, carboxyhemoglobin; TCA, tricyclic antidepressant.
Adrenergic agonists include amphetamines and cocaine. Poisoning with these agents is associated with
tachycardia, hypertension, tachypnea, and hyperthermia. The pupils are enlarged, the skin is flushed and
diaphoretic, and gastrointestinal peristalsis is increased.
Anticholinergics include atropine, antihistamines, some antipsychotics, antiemetics, and some

anticonvulsants. Hallucinations, tachycardia, and hyperthermia are seen generally without significant
alteration of the blood pressure or respiratory rate. The pupils are enlarged and may be unreactive. The skin
is hot, dry, and flushed. This anhydrosis, combined with the increased muscle activity, is thermogenic and
may result in significant hyperthermia. Gastrointestinal paralysis that results in ileus and urinary retention
occur.
Withdrawal from opioids, such as heroin, methadone, meperidine, hydrocodone, and oxycodone, causes
characteristic symptoms, the severity of which is inversely related to the duration of the effects of the drug.
Opioid withdrawal does not cause alteration of the mental status. Symptoms of withdrawal may be abrupt
and severe after the administration of
Table 17-6 -- Differentiating Between Delirium and Psychosis

Delirium Psychosis
Abnormal vital signs frequent Normal vital signs; may have tachycardia
Acute onset History of prior similar episodes, recurrent
Delirium Psychosis
No prior psychiatric history History of psychiatric conditions, family history
Impaired/fluctuating alertness, confused Alert, awake
Disoriented, immediate memory more affected than
Oriented, no memory impairment
remote
Well-organized hallucinations, mainly auditory;
Visual or tactile hallucinations (poorly organized)
delusions
the opioid antagonist naloxone or after acute abstinence from a short-acting opioid, such as heroin. These
patients manifest hypertension and tachycardia with normal respiratory rate and temperature. They also have
yawning, lacrimation, piloerection, dilated pupils, nausea, vomiting, and rhinorrhea. Increased gastrointestinal
peristalsis results in diarrhea. This withdrawal syndrome, although extremely uncomfortable for the patient, is
rarely life-threatening. Federal laws prohibit the treatment of opiate withdrawal by the administration of opiates in
the emergency setting.[32]
Physical signs of ethanol withdrawal include mydriasis, tremor, hypertension, tachycardia, tachypnea,
hyperthermia, and diaphoresis. Seizures are common. This may lead to a severe delirium that is life-
threatening (see Chapter 70 ). The withdrawal syndrome associated with long-term use of other sedative-
hypnotics, such as benzodiazepines and barbiturates, is identical to ethanol withdrawal. The time course
and severity are related inversely to the duration of action of the drug involved. These patients lack the
physical findings suggestive of long-term alcohol abuse.
Patients poisoned with phencyclidine often present with very extreme agitation. The severity of agitation
leads to tachycardia, hypertension, diaphoresis, and fever. Pupils are small and reactive. Nystagmus is very
prominent.
Salicylates directly stimulate the respiratory center and cause uncoupling of oxidative phosphorylation.
These patients may be agitated because of CNS impairment, with fever and marked hyperpnea. The
respiratory rate is markedly increased both in frequency and in depth. The lithium-intoxicated patient can be
a diagnostic challenge. Lithium ingestion should be suspected in all the patients with known bipolar disorder.
The most important hallmarks of lithium toxicity are seizures, tremor, hyperreflexia, and altered mental
status.
The serotonin syndrome is an uncommon entity that can cause agitated delirium. The most common findings
are tachycardia, hypertension, myoclonus, diaphoresis, and hyperthermia. In contrast to the neuroleptic
malignant syndrome, the serotonin syndrome tends to be milder, it evolves more rapidly, and the duration of
symptoms is shorter[9][41](see Chapter 63 ).


LABORATORY AND DIAGNOSTIC STUDIES
Quantitative toxicologic studies are useful in the assessment of only a few specific agents, including carbon
monoxide, lithium, salicylates, digoxin, ethanol, ethylene glycol, methanol, many antiseizure medications,
and theophylline.[39] These quantitative tests can be selectively ordered, guided by the history, physical
findings, and substances available to the patient. Acetaminophen should also be included in toxicologic
screens because of our inability to predict toxicity. Qualitative drug screens give information about exposure,
which may be useful in a number of scenarios: substance abusers who may need chemical dependency
interventions, patients exposed to cocaine who present with chest pain or new-onset seizures, and critically
ill patients with unexplained illnesses in whom unsuspected drugs are present.[33] In all other settings,
routine urine drug screens rarely change the patient’s management or affect the patient’s outcome.[8][31][39]
Two studies suggest a more selective use of the urine drug screen, using physical examination and
toxidrome recognition to improve the probability of a positive test result.[31][43] Although drug screens may
help guide therapy in some cases, they can also be misleading. For example, the head-injured ethanol
abuser may be thought to be simply intoxicated, delaying the diagnosis and treatment for a head injury.
Treatment should always be directed at the symptomatology, not at the laboratory results.
Laboratory studies are most useful in the detection of end-organ damage and should address the most
common and important complications in agitated patients, which include alterations of renal and hepatic
function, acid-base disturbances, and rhabdomyolysis. Routine laboratory assessment of electrolytes and
markers for muscle breakdown (e.g., creatinine, creatine kinase, myoglobin, and potassium) is indicated. An
elevation of the white blood cell count is often a nonspecific finding in the agitated patient. Examination of
the cerebrospinal fluid and cultures of the blood and cerebrospinal fluid are indicted if infection is suspected.
If the neurologic examination is focal or suggests increased intracranial pressure or if trauma or
subarachnoid hemorrhage is suspected, a head computed tomographic scan must be performed. In patients
with signs of liver disease, tests of coagulation and ammonia levels are useful. A 12-lead electrocardiogram
can identify dysrhythmias, evidence of sodium channel blockade associated with poisoning, and evidence of
ischemia or infarction that may precipitate delirium in an elderly patient. The chest x-ray study can help in
the diagnosis of pneumonia, congestive heart failure, and pneumothorax.


Most patients who present with agitation due to toxic exposures do well with supportive management
alone.[8][31][39] As previously stated, it is imperative to gain control of the agitated patient. Many studies have
addressed the issue of rapid tranquilization.[20] The goal of rapid tranquilization is to prevent injury, avoid
complications, and allow for evaluation and treatment of the agitated patient. Table 17–8 provides a
summary of the most commonly used agents to control agitation.
Table 17-8 -- Drugs Used to Control Agitation

Drug Dose/Route/Frequency Onset/Duration Side Effects
Haloperidol 2.5–10 mg/IM q 30 min Onset: 5–10 min Dystonia, seizure, hyperthermia, akathisia
5–10 mg/IV q 5–10 min Onset: 1–2 min Sedation, confusion, ataxia
Diazepam Duration: 20–30
min
Onset (IM): 20
4 mg/IM, IV q 20 min Sedation, confusion, ataxia
Lorazepam min
Duration: 4–6 hr
2.5–5 mg/IM, IV q 5 min Onset: 1–2 min Apnea, sedation, confusion, ataxia
Midazolam Duration: 20–30
min
Apnea, hypotension, negative inotropism,
Loading dose: 2.0–2.5 mg/kg Onset: 40 sec
Propofol infections, allergies
Infusion: 5.0–50 µg/kg/min Duration: 4–8 min
2.5–10 mg IM or 1.25–2.5 mg IV Dystonia, seizure, hyperthermia,
Droperidol Onset: 5–10 min
q 30 min orthostasis, akathisia, hypotension
The neuroleptics have been demonstrated to be effective in the control of agitation caused by psychosis in
several studies.[4][12][23][25][35] Droperidol, an analog of haloperidol that lacks antipsychotic properties, has
also been utilized to control agitation.[7][26][47][54] Several studies have suggested the use of combination
therapy to treat the patient with psychotic agitation.[3][5] A multicenter, double-blind trial of 98 patients
concluded that the combination of lorazepam and haloperidol produced faster control of agitation and had
fewer side effects than either drug alone.[3] Side effects and lack of efficacy in treatment of specific disorders
limit the use of neuroleptics in the patient in whom the diagnosis is unclear. In addition to their well-
recognized association with dystonic reactions, neuroleptics such as haloperidol decrease the threshold for
seizures and impair the body’s ability to dissipate heat.[18][20] They have been associated with increased
mortality when used as sole agents in the treatment of sedative hypnotic withdrawal.[27][52]
Benzodiazepines are fast acting and have few side effects.[19] Several authors argue for their use as first-
line agents for the agitated psychotic patient.[3][20] Lorazepam and midazolam can be used both
intramuscularly and intravenously and should be strongly considered if the patient does not have an
intravenous line in place. They have a fast onset and no active metabolites.[30][56][57] Benzodiazepines
decrease heat production by stopping excess motor activity and normalizing vital signs. Another desirable
effect of the benzodiazepines is their ability to terminate and prevent seizures.[28]
Benzodiazepines are the drugs of choice in the management of sedative hypnotic withdrawal.[21] Although
the benzodiazepines are not completely cross-tolerant, they blunt the most important manifestations of
ethanol withdrawal[16](see Chapter 75 ). They are also indicated in the management of agitation caused by
cocaine toxicity.[11][28] Several animal studies of cocaine poisoning have demonstrated significant increases
in morbidity when cocaine-poisoned animals are treated with neuroleptics as compared with
benzodiazepines[10][18] (see Chapter 70 ).
The use of propofol as a sedating agent has also been reported. Propofol is an oil emulsion with a rapid
onset of action and a short half-life. It acts in the gamma-aminobutyric acid receptor, similar to the action of
the benzodiazepines. The main side effect is hypotension. [13]
For certain toxins, antidotes can be used for both diagnostic and therapeutic measures. The chapters
dealing with each specific toxin give a detailed description of the different antidotes and the indications for
their use.


DISPOSITION AND NEED FOR CONSULTANTS
Poisoned patients whose mental status and vital signs do not normalize in the emergency department need
to be admitted.
If a toxin is apparent as the causal agent, the Poison Control Center should be contacted. Some hospitals
also have a toxicology service that may offer specific management recommendations. In general, most
patients require admission, with the exception of uncomplicated insulin-induced hypoglycemia, minor toxic
exposures whose effects resolve quickly, and well-defined seizure disorders with postictal agitation that
resolves in the emergency department. All patients with intentional ingestions should undergo a psychiatric
evaluation before discharge is considered.[2]


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8. Brett A: Implications of discordance between clinical impression and toxicology analysis in drug
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9. Brown TM, Skop BP, Mareth TR: Pathophysiology and management of the serotonin syndrome. Ann
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15. Curry SC, Chang D, Conner D: Drug-and toxin-induced rhabdomyolysis. Ann Emerg
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17. Delaney KA, Goldfrank L: Delirium: Assessment and management in the ICU. Probl Crit
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19. Dietch JT, Jennings RK: Aggressive dyscontrol in patients treated with benzodiazepines. J Clin
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47. Richards JR, Derlet RW, Duncan DR: Chemical restraint for the agitated patient in the emergency
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48. Ritter A, Eskin B: Ibuprofen overdose presenting with severe agitation and hypothermia. Am J Emerg
Med 1998; 16:549-550.
49. Ruttenber AJ, Lawler-Heavner J, Yin M, et al: Fatal excited delirium following cocaine use:
Epidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic
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50. Tardiff K: Unusual diagnoses among violent patients. Psychiatr Clin North Am 1998; 21:567-576.
51. Thal L: Dementia update: Diagnosis and neuropsychiatric aspects. J Clin

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52. Thomas DW, Freedman DX: Treatment of the alcohol withdrawal syndrome: Comparison of promazine
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53. Tueth MJ: Dementia: Diagnosis and emergency behavioral complications. J Emerg Med 1995; 13:519-
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54. Van Leevwen AMH, Molders J, Sterkmans P, et al: Droperidol in acutely agitated patients. J Nerv Ment
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55. Weddington WW: The mortality of delirium: An underappreciated problem?.

Psychosomatics 1982; 23:1232-1235.
56. Wyant M, Diamone BI, O’Neal E, et al: The use of midazolam in acutely agitated psychiatric patients.
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literature. Br J Psychiatry 1984; 145:477-486.


Chapter 18 – Seizures
TAREG A. BEY FRANK G. WALTER
Essentials of Initial Treatment

• Assess the airway. Apply oxygen. Intubate if clinically indicated.
• Monitor. Ensure intravenous access.
• Exclude hypoglycemia.
• Initiate cooling for hyperthermia (=40°C).
• Control seizures (see Table 18–7 ).
Table 18-7 -- Acute Seizure Treatment

Intravenous
Sedation Elimination
Sedation
Onset Half-Life
Antiepileptics Indications Contraindications Dosage *
Diazepam Seizures or withdrawal Inability to manage Adults: 5 mg 0–5 min 43 hours
(first-line drug) hypoventilation over 1 min
Children:
0.1–0.3 mg/kg
Adults: 2 mg
0–5 min 14 hours
Seizures or withdrawal Inability to manage over 1 min †
Lorazepam
(first-line drug) hypoventilation Children:
0.05–0.1 mg/kg
Adults: 2.5 mg
0–2 min 2 hours
Seizures or withdrawal Inability to manage over 2 min
Midazolam
(first-line drug) hypoventilation Children:
0.05–0.2 mg/kg
Adults and
Shock children: 20
mg/kg infusion
at up to 50
Recurrent or prolonged
Porphyria mg/min (in
Phenobarbital seizures (second-line 5–10 min 99 hours
adults or up to 1
drug)
mg/kg/min for
Inability to manage children, for
hypoventilation status
epilepticus)
Intravenous
Sedation Elimination
Sedation
Onset Half-Life
Antiepileptics Indications Contraindications Dosage *
Dosage for
Isoniazid (INH) seizures: 5 g
vitamin B 6
Monomethylhydrazine- empirically in
containing mushrooms adults or 70
Pyridoxine (e.g., Gyromitra spp.) mg/kg in
None N/A 2–3 weeks
(vitamin B6) children. Can
give 1 g vitamin
Hydrazine rocket fuel B6 for each 1 g
of INH ingested,
Theophylline ‡ if ingested dose
known.
Experimental data support the use of pyridoxine in theophylline-induced seizures.[36][88] However, this
is not yet standard care.
* Sedation dosage does not equal the dosage to terminate a seizure and may be insufficient to control seizures (see Tables 18–5
and 18–6 ).
† Lorazepam can also be administered by intramuscular injection until intravenous access is obtained.
‡ In therapy-refractory, theophylline-induced seizures, 5 g of IV pyridoxine can be added as a third-line drug.
• Institute continuous electroencephalographic monitoring in paralyzed patients.
INTRODUCTION
A seizure is an episode of neurologic dysfunction caused by abnormal neuronal electrical discharges. The
Latin word ictus, which literally means “attack,” is used synonymously with seizure. The term convulsion
describes a motor seizure. Epilepsy and seizure disorder are synonymous terms describing chronic
neurologic dysfunction characterized by recurrent, spontaneous seizures. Seizures are also classified as
partial or generalized based on the extent of neuroanatomic involvement and as simple or complex based
on their effects on awareness.[20] Complex seizures alter the level of consciousness, whereas simple
seizures do not. Status epilepticus is defined as more than 30 minutes of continuous seizure activity, or two
or more sequential seizures without full recovery of consciousness between attacks.[90]
Seizures can be induced in any individual by electroconvulsive therapy, drugs, head trauma, withdrawal from
sedative-hypnotics or alcohols, infections, or metabolic disturbances such as hyponatremia, hypocalcemia,
or hypoglycemia ( Tables 18–1 , 18–2 , 18–3 ).[56][69][72][90] Seizures induced by drugs, toxins, or toxicants
are complex and are associated with loss of consciousness and generalized tonic-clonic convulsions.
Metabolic disorders such as hypoglycemia, uremia, and other hyperosmolar states may produce focal
seizures in the absence of detectable focal brain lesions.[9][56] Focal seizures are especially common in
hyperosmolar conditions, because of brain shrinkage that tears small bridging vessels, resulting in
microscopic focal lesions.
Table 18-1 -- Important Causes of Seizures
Toxic
• Tricyclic and tetracyclic antidepressants (including carbamazepine)
• Stimulants (cocaine, amphetamines)
• Anticholinergics, including antihistamines
• Organophosphates/carbamates
• Theophylline
• Isoniazid
• Lithium
• Salicylates
• Sedative-hypnotic, barbiturate, and alcohol withdrawal; with opioid withdrawal in neonates only
• Opioids (propoxyphene, meperidine)
• Gamma-hydroxybutyrate
• Metaldehyde
• Camphor
• Iron
• 4-Aminopyridine
• CO, cyanide, hydrogen sulfide, azides
Metabolic
• Glucose excess or deficiency
• Hypoxia
• Uremia
• Inborn metabolic error (pyridoxine-dependent epilepsy)
• Electrolyte imbalance (hyponatremia, hypernatremia, hypocalcemia)
• Endocrinopathy (thyrotoxicosis)
Infectious
• Meningitis
• Cerebral abscess
• Cerebral cysticercosis
• AIDS-related brain infections
Structural
• Infarct
• Hemorrhage
• Head trauma
• Tumor
Others
• Shock
• Eclampsia
Table 18-2 -- Most Common Causes of Seizures Due to Drug Abuse and Overdose
Drugs n %
Antidepressants (e.g., tricyclics and tetracyclics) 55 29
Cocaine and other stimulants 55 29
Diphenhydramine and other antihistamines 14 7
Theophylline 10 5
Isoniazid 10 5
Cardiodepressant antidysrhythmic agents (calcium channel blockers, mexiletine, procainamide) 4 2
Other (e.g., sedative-hypnotic withdrawal, lithium) 43 23
Total cases 191 100
Modified from Olson KR, Kearney TE, Dyer JE, et al: Seizures associated with poisoning and drug overdose. Am
J Emerg Med 1994; 12:392–395.
Table 18-3 -- Clinical Evaluation and Treatment of Patients with Seizures

Specific
Seizure Differential Physical Exam Diagnostic
Settings Likely Etiologies Diagnoses Clues Studies Definitive Treatment
Airports, Body packers with Cocaine, Sympathomimetic Abdominal x- Benzodiazepines,
ports, train drug-filled amphetamines, toxidromes rays, CT, barbiturates, whole
stations, condoms or intracranial toxicology bowel irrigation,
and packets hemorrhage, screens rarely gastrotomy or
customs head trauma enterotomy
offices
Endoscopy Pulse oximetry, Benzodiazepines,
suites, Benzodiazepine bedside O2, glucose if
Hypoxia and Sympathomimetic
ICUs, and antagonism with glucose check, hypoglycemic,
hypoglycemia toxidromes
recovery flumazenil toxicology phenobarbital for
rooms screens continued seizures
ABG with co-
Carbon
oximetry for CO
monoxide
Specific
Settings Likely Etiologies Diagnoses Clues Studies
oximetry for CO Definitive Treatment
monoxide
Smoke smell, soot, and metHb; 100% oxygen,
and/or cyanide,
Firefighters nasal and oral venous blood endotracheal
airway
and fire Smoke inhalation burns, signs of gas for intubation, hyperbaric
obstruction,
victims hypoxia without elevated O2, oxygen, sodium
simple
cyanosis CN level, thiosulfate for CN
asphyxia, and
lactate level;
head trauma
CT
Other local Local anesthetic
anesthetic injection sites, Benzodiazepines.
anaphylactic or wounds, surgical Pulse oximetry, Treat anaphylactic
Local
Lidocaine toxicity anaphylactoid incisions, cyanosis, lidocaine blood and anaphylactoid
anesthesia
reactions with pallor, hives, levels reactions, if present.
hypoxia and/or diaphoresis, Stop lidocaine.
shock stridor, wheezing
100% oxygen,
Other on-the-job Signs of hypoxia ABG with co-
endotracheal
exposures, food without cyanosis, oximetry for
Mini- Carbon monoxide, intubation, hyperbaric
poisoning with pesticide (garlic) CO;
epidemics organophosphates oxygen, atropine,
mushrooms or odor, cholinergic cholinesterase
pralidoxime,
heavy metals toxidromes levels
chelators
Endotracheal
intubation,
Hypoglycemia,
hyperventilation,
seizure
glucose if
Motor Head trauma, disorder, Stat bedside
Signs of head hypoglycemic,
vehicle myocardial cocaine, alcohol glucose check,
trauma benzodiazepines for
accidents ischemia withdrawal, CT, ECG
seizure disorder or
cardiac
sympathomimetics,
dysrhythmia
antidysrhythmics for
dysrhythmias
Elder abuse,
Stat bedside O2, glucose if
pneumonia,
glucose check, hypoglycemic,
Sepsis, hypoxia, urinary tract or Fever, respiratory
Nursing pulse oximetry, antibiotics,
drug intoxication or other infection, distress, signs of
homes ABG, chest x- benzodiazepines for
withdrawal hypoglycemia, septic shock
ray, cultures, withdrawal, airway
seizure
drug levels management
disorder, CVA
Drug intoxications Drugs of abuse,
Parties and Track marks and Toxicology
and photic-evoked stroboscopes, Benzodiazepines
discos drug paraphernalia screens, CT
seizures head trauma
Drugs of abuse, Drug packets
Drug intoxications, alcohol stuffed in body
Specific
Settings Likely Etiologies Drugs
Diagnoses
of abuse, Clues
Drug packets Studies Definitive Treatment
Drug intoxications, alcohol stuffed in body Benzodiazepines,
Abdominal x-
body stuffers with withdrawal, cavities, track barbiturates, whole
rays, CT,
Prisons drug-filled sedative- marks, bowel irrigation,
toxicology
condoms or hypnotic sympathomimetic rarely gastrotomy or
screens
packets withdrawal, toxidromes, signs enterotomy
head trauma of head trauma
Cerebral gas
Chest x-ray,
embolism, near Abnormal
Scuba Decompression ABG with co-
drowning, funduscopy, cutis Hyperbaric oxygen
divers sickness oximetry for
contaminated marmorata
CO, CT
air (e.g., CO)
CT, cranial computed axial tomography; CO, carbon monoxide; CN, cyanide; O2, oxygen; CVA,
cerebrovascular accident; ABG, arterial blood gas; metHb, methemoglobin; ECG, electrocardiogram; UTI,
urinary tract infection.


PATHOPHYSIOLOGY
Epileptogenesis derives in part from imbalances between excitatory and inhibitory processes in selected
brain regions. Glutamate is the major cerebral excitatory neurotransmitter.[33] It undergoes decarboxylation
by the enzyme glutamic acid decarboxylase (GAD) to form gamma-aminobutyric acid (GABA), the major
cerebral inhibitory neurotransmitter ( Fig. 18–1 ).[22][53][62] Both glutamate receptor agonists and GABA
antagonists elicit local neuronal excitatory responses in animal models of seizures.[53][54][65]
Figure 18-1 Glutamic acid is decarboxylated by the enzyme glutamic acid decarboxylase (GAD) to -aminobuytric acid (GABA). The
enzyme GAD requires the cofactor pyridoxal 5-phosphate (PLP), the active form of pyridoxine (vitamin B6). INH, for example, depletes
pyridoxine, inhibits the formation of pyridoxal 5-phosphate and is metabolized to hydrazones that inhibit pyridoxine phosphokinase.
GABA inhibits neuronal conduction by opening membrane chloride channels, an effect mediated by binding
to specific GABAA receptors ( Fig. 18–2 ). The resultant increased flow of chloride into the neuron lowers the
membrane resting potential and decreases its excitability.[22][53][54][62] The benzodiazepine and barbiturate
anticonvulsants potentiate the effects of GABA by binding at sites adjacent to GABAA receptors on the
neurolemmal chloride ionophore macromolecular complex (see Fig. 18–2 ).[53][54][62]
Figure 18-2 Conceptual diagram of the GABA A receptor-chloride ionophore.
Adenosine, a precursor of the high-energy nucleotide adenosine triphosphate (ATP), is a neuromodulator

that acts as an endogenous anticonvulsant by binding to specific presynaptic adenosine receptors and
decreasing neurotransmitter release.[10][23][24][29][71] Status epilepticus increases cerebral metabolism,
resulting in the increased production and accumulation of adenosine in the extracellular space, where it
exerts a neuroinhibitory effect. Adenosine also causes cerebral vasodilation and increases cerebral blood
flow to meet the higher metabolic demands of the brain during status epilepticus. In animal models,
dipyridamole potentiates the protective neuroinhibitory effect of adenosine while methylxanthines such as
theophylline antagonize it ( Fig. 18–3 ).[10][29]
Figure 18-3 Diagram of proposed mechanism of ictal-interictal cycling due to changes in the interictal adenosine concentration [ADO],
which rises during electroencephalographic (EEG) local activity, causes cessation of ictal activity, and then falls during the interictal
period. Dipyridamole prolongs the interictal phase by inhibiting reuptake of adenosine. Theophylline blocks access of adenosine to its
receptors, allowing ictal activity to continue despite the continuous high concentration of adenosine. (The depicted changes of ADO
are schematic and may not reflect actual trajectories.) (From Eldridge FL, Paydarfar D, Scott SC, et al: Role of endogenous adenosine
in recurrent generalized seizures. Exp Neurol 1989; 103:179.)


SPECIFIC MECHANISMS OF INDUCED SEIZURES
Four major pathophysiologic mechanisms are associated with the biochemical induction of seizures: (1)
impairment of GABA inhibition, (2) excess stimulation of glutamate receptors, (3) defects in systems that
modulate excitatory and inhibitory functions, and (4) defects in neurolemmal ion channels. [31]
Impairment of GABA Inhibition
Substances that inhibit the GABAA receptor-chloride ionophore complex have the potential to cause
seizures. These include cyclic antidepressants, ciprofloxacin, imipenem, penicillin, bicuculline, picrotoxin,
and monamine oxidase inhibitors such as tranylcypromine.[22][54][55][62] Prolonged alcohol use appears to
reduce GABA-mediated inhibition of brain cells by altering the density and sensitivity of GABA receptors.[32]
The benzodiazepine antagonist flumazenil has been shown to precipitate seizures.[14][57][64] In U.S.
premarketing trials, six seizures were observed in 446 overdose patients treated with flumazenil.[74] Four of
these six patients had co-ingested large doses of cyclic antidepressants.[74] Flumazenil is believed to
precipitate seizures when given in mixed benzodiazepine/cyclic antidepressant overdoses because
flumazenil counteracts the anticonvulsant activity of the co-ingested benzodiazepines.[55][81]
Substances or conditions that result in GABA deficiency also cause seizures. The synthesis of GABA by
GAD requires pyridoxal 5-phosphate (PLP), an activated form of pyridoxine (vitamin B6) (see Fig. 18–1 ) that
is formed from pyridoxine by the enzyme pyridoxine phosphokinase. Hydrazines such as isoniazid (INH) or
monomethylhydrazine from the toxic mushroom Gyromitra esculenta inhibit GABA synthesis by blocking the
synthesis of PLP by pyridoxine phosphokinase. They also directly bind and inactivate PLP and enhance its
renal elimination.[40][80] Pyridoxine-dependent epilepsy is an autosomal recessive disease associated with
significantly decreased GAD activity. It presents in infants as seizures unresponsive to standard therapy and
is associated with high concentrations of glutamic acid and low concentrations of GABA in the cerebrospinal
fluid (CSF). High doses of pyridoxine abolish the metabolic derangements and seizures.[7][37]
GABA deficiency may also be caused by conditions that deplete precursors of GABA. Seizures are rare in
diabetic ketoacidosis because of the availability of ketone bodies for energy metabolism.[22] However,
patients with nonketotic hyperosmolar diabetic coma do not produce significant amounts of ketone bodies,
an important source of energy for the brain.[22] This leads to increased cerebral utilization of amino acids
such as GABA and its precursors for energy production via the GABA shunt and the Krebs cycle.[22] The
GABA shunt links GABA metabolism to the Krebs cycle.[22] Under normal conditions, GABA a-oxoglutarate
transaminase (GABA-T), the key enzyme in the GABA shunt, facilitates production of adequate GABA
levels, when sufficient a-ketoglutarate is present.[22] When the concentration of a-ketoglutarate is low, GABA
is converted to succinic semialdehyde, which subsequently enters the Kreb’s cycle as succinic acid,
resulting in GABA depletion.[22][61]
Excess Stimulation of Glutamate Receptors

Febrile seizures in children may be a consequence of increased glutamate production associated with the
temperature-related increase in the brain’s metabolic rate. Studies in animals demonstrate that increased
glutamate levels occur during hyperthermia and predispose to seizures.[65] Substances that stimulate
glutamic acid receptors may also cause seizures. An example of this is domoic acid, a toxin associated with
shellfish poisoning.[84]
Defects in Systems That Modulate Excitatory and Inhibitory Functions: Adenosine Inhibition
Toxic levels of theophylline and other methylxanthines block the inhibitory effect of adenosine, precipitating
seizures that are continuous and refractory to therapy.[29][45] Theophylline also impairs the cerebral
vasodilatory effect of adenosine, resulting in decreased cerebral blood flow and cerebral ischemia during
seizures.[71] These effects of theophylline on the neuroregulatory role of adenosine contribute to the high
morbidity and mortality associated with theophylline-induced seizures.[10][71] Mortality rates as high as 29 per
cent have been reported in patients with theophylline overdoses who develop seizures.[45]
Defects in Neurolemmal Ion Channels
4-Aminopyridine, a drug that has been used to treat multiple sclerosis, can cause seizures in
overdose.[82][92] 4-Aminopyridine has potassium channel blocking properties and increases presynaptic
calcium concentrations and presynaptic release of neurotransmitters.[82][92][94]
Phenytoin and phenobarbital were both protective against 4-aminopyridine lethality in an animal study.[92]
Stork and Hoffman described three patients with 4-aminopyridine intoxication whose drug-induced seizures
were successfully treated with benzodiazepines, phenytoin, and supportive care.[82] One of these three
patients also received phenobarbital. Further study is needed to determine the role of phenytoin in the
treatment of seizures induced by 4-aminopyridine.


Seizures may be caused by a variety of toxic, metabolic, infectious, or structural abnormalities (see Table
18–1 ).[2][9][32][52][56][69][76][86][90] Toxic causes are discussed here. Life-threatening causes that require
immediate diagnosis and treatment such as central nervous system (CNS) infections, hypoglycemia,
hyponatremia, and hypocalcemia should always be excluded. [90] The possibility of eclampsia is indicated by
obvious late-term pregnancy or a history of recent pregnancy.[79] Occult head injury should be suspected,
especially when status epilepticus occurs or the patient’s postictal mental status does not clear rapidly.
Common causes that are not usually life-threatening include chronic epilepsy and alcohol withdrawal
seizures.
Toxic Seizures
A retrospective poison center review of 191 seizures associated with drug abuse or overdose found the most
common causes were due to cyclic antidepressants, cocaine and other stimulants, antihistamines,
theophylline, INH, and antidysrhythmics.[68] Agents associated with toxic seizures in this study are listed in
Table 18–2 .
Seizures related to cocaine and other stimulants, ethanol and sedative-hypnotic withdrawal, and
diphenhydramine tend to be brief and self-limited.[50][68] Although the majority of seizures associated with
cyclic antidepressant overdose are also brief, 20 to 30 per cent were characterized as prolonged, repetitive,
or status epilepticus.[30][68] Seizures associated with theophylline, antidysrhythmics, and INH poisoning
commonly result in status epilepticus.[45][68][69] Patients with large ingestions of cocaine, especially body
packers with leaking packets, may also have status epilepticus. Seizures associated with salicylate, lithium,
carbon monoxide, cyanide, or hydrogen sulfide poisoning indicate life-threatening toxicity.
Meperidine and propoxyphene are opioids classically associated with seizures.[12][78][93] Meperidine and
propoxyphene are hepatically demethylated to proconvulsant metabolites, normeperidine and
norpropoxyphene.[12][93]
Recently, the abuse of gamma-hydroxybutyric acid (GHB) has become commonplace in bars and discos. It
is also touted as an effective body building agent and may be abused by body building enthusiasts.[17] GHB
was synthesized initially as a GABA agonist. When mixed with ethanol or taken in excess, it causes sedation
and seizures, both of which are short lived.[17][27] No deaths have been reported.[16] GHB is metabolized to
CO2 and H2O and cannot be measured with routine toxicology tests; therefore, the diagnosis is usually
based on history.[16][17][27] The mechanism of its toxicity is unclear.[16]
Seizures have also been described after ingestion of the molluscicide metaldehyde.[41][44][63] Metaldehyde
also causes a profound metabolic acidosis. It is suspected that metaldehyde, a polymer of acetaldehyde,
causes seizures through reduction of brain concentrations of GABA.[41]
Anaphylaxis and anaphylactoid reactions precipitated by allergies and adverse drug reactions can produce
secondary seizures due to hypoperfusion and/or hypoxia. Hyperosmolar substances such as radiographic
contrast media can also produce seizures.[50] The incidence of seizures due to adverse drug reactions in
patients hospitalized for other conditions is low. [73] The Boston Collaborative Drug Surveillance Program
reported 17 seizures in 12,617 inpatients (0.1 per cent).[73]
Cocaine Users
Cocaine commonly causes seizures as a manifestation of its toxic effects. Patients who use cocaine also
have an increased incidence of vascular insults such as thrombotic and hemorrhagic strokes. Patients who
use intravenous cocaine are at risk of infectious complications such as meningitis, brain abscess, and
acquired immunodeficiency syndrome–related CNS infections. Cocaine users with status epilepticus may
also have a large gastrointestinal load of cocaine due to body packing or body stuffing (see Chapter 75 ).
Even patients with single, first-time seizures associated with cocaine use should have other underlying
causes excluded because cocaine can lower seizure thresholds in individuals with undetected CNS
lesions.[77] This was demonstrated by a report of two patients with first-time seizures after the use of crack
cocaine who were shown to have previously unsuspected brain tumors on routine head computed
tomography (CT).[77] Every patient with a first-time seizure should have a complete diagnostic evaluation
regardless of the presumed or suspected cause.
The Alcoholic Patient
Alcohol withdrawal and sedative-hypnotic withdrawal are common causes of seizures; however, they rarely
cause status epilepticus. [32][58] In one large series, only 3 per cent of patients with alcohol withdrawal
developed status epilepticus.[86] In a study of 249 patients with status epilepticus and complete diagnostic
workups, only 27 patients (11 per cent) had alcohol withdrawal as their only detectable etiology of status
epilepticus.[2] Clearly, causes other than alcohol or sedative-hypnotic withdrawal must be carefully excluded
in the alcoholic patient who develops status epilepticus or whose mental status does not normalize after a
seizure. Occult head injury is a frequent problem in alcoholics, who often have unreported trauma.[58]
Barbiturate withdrawal can also cause seizures but is less commonly noted, due to the decreased long-term
use of these drugs.
Metabolic Disturbances
Hypoglycemia is associated with intentional or inadvertent overdoses of hypoglycemic drugs. In one study, 9
of 125 hypoglycemic diabetic patients (7 per cent) developed seizures. [56]
Motor seizures occur in 20 to 25 per cent of patients with nonketotic hyperosmolar diabetic coma, 75 per
cent of which are focal.[61] This high incidence of seizures is attributed to reduced availability of ketone
bodies and the increased utilization of GABA and its precursors as cerebral energy sources. Seizures are
rare in patients with diabetic ketoacidosis.[22]
Other metabolic disorders such as hypoxia, hypocalcemia, hyponatremia, and hypernatremia also cause
seizures.[9] Patients with chronic renal failure can have seizures secondary to uremia. Dialysis disequilibrium
syndrome associated with very recent dialysis can also cause seizures.
Brain Injury
Head trauma commonly leads to seizures.[52][69][90] The risk of traumatic seizures rises dramatically with low
Glasgow Coma Scale scores and abnormal cranial CT findings.[52] Seizures can also be caused by
spontaneous intracranial hemorrhages. Of 222 patients with supratentorial intracerebral hemorrhages, 27
patients (12 per cent) had seizures within 24 hours of their strokes and 6 patients (3 per cent) had a delayed
onset of seizures, 2 to 4 months after their strokes. Intracerebral hemorrhages related to underlying vascular
malformations or neoplastic lesions are associated with a much higher incidence of seizures.[89] Although
seizures are more common with intracerebral hemorrhages, any cerebrovascular insult, including
nonhemorrhagic infarction, embolic stroke, or subarachnoid hemorrhage can cause seizures.[28][89]
Febrile Seizures
Fever and high body temperatures predispose to seizures in children. [43][65] Two to 5 per cent of all febrile
children between the ages of 3 months and 5 years manifest simple febrile seizures without underlying CNS
pathology.[20] Although febrile seizures are common in this age group, the possibility of CNS infection should
always be considered. In one study, 25 (13 per cent) of 187 pediatric patients with bacterial meningitis
presented with seizures. Four of these 25 children had no other signs or symptoms of meningitis.[76]


CLINICAL PRESENTATION
The events leading up to a seizure, the setting in which a seizure occurs, and the physical examination are
important clues to the etiology of the seizure (see Table 18–3 ).[50][56][61][69][77][81][86] The prehospital history
obtained from EMS personnel, the family, or other witnesses provides important information when caring for
these patients. When the nature of the prehospital event is unclear, questions should focus on signs that
indicate that a seizure occurred, such as loss of consciousness, tonic-clonic movements, urinary or fecal
incontinence, tongue biting, or evidence of a postictal state. Other important historical clues include suicidal
ideation, available medications, antecedent head trauma, headaches, fevers, or a prior history of seizures.
Family, friends, law enforcement officers, and emergency medical services personnel can assist by
searching the patient’s home, car, and personal belongings for medications, empty pill bottles, illicit drugs,
drug paraphernalia, plants, mushrooms, and open or spilled chemical containers.
The medical and medication histories of both the patient and family members are important. A family history
of seizures, psychiatric disorders, asthma, or tuberculosis indicates the possibility of exposure to
carbamazepine, cyclic antidepressants, lithium, theophylline, or INH. The routine use of antiepileptic
medications indicates that the patient has epilepsy. A recent decrease in the dose or cessation of sedative-
hypnotic agents suggests the possibility of withdrawal seizures. In patients chronically on theophylline
therapy, the recent addition of a macrolide or fluoroquinolone antibiotic, systemic antifungals such as
ketoconazole, or cimetidine can result in decreased theophylline clearance and toxic theophylline blood
levels.[1][18][45]
The past medical history should include a review for antecedent depression, previous suicide threats or
attempts, alcoholism, drug abuse, other psychiatric illnesses, epilepsy, head trauma, neurosurgery, stroke,
diabetes, hypertension, recent pregnancy, renal insufficiency, dialysis, cancer, tuberculosis, and human
immunodeficiency virus infection.[61][69]
The physician should focus on vital signs, perform a complete neurologic examination, and consider signs of
trauma, incontinence, and gingival hyperplasia and cutaneous signs of drug abuse. Recognition of familiar
toxic syndromes (toxidromes) related to cholinergic, anticholinergic, or sympathomimetic toxicants in
patients with seizures will help focus the differential diagnosis on likely causes of drug-induced seizures (
Table 18–4; see Table 18–3 ).
Table 18-4 -- Toxidromes of Toxicants That Can Cause Seizures

Toxicants Toxidromes Other Helpful Signs and Diagnostic Tests
Cocaine and amphetamines Sympathomimetic: a- Usually brief, self-limited seizures
and ß-adrenergic
Track marks
Formication
Ecthyma
Toxicants Toxidromes Other Helpful Signs and Diagnostic Tests
Drug paraphernalia
Often brief, self-limited seizures, however, 20–30%
are status epilepticus
Prolonged QRS complex (>100 msec)
Prominent R wave in aVR
Cyclic antidepressants Anticholinergic
Rightward axis deviation of the terminal 40 msec of
the QRS complex
Hypotension
Coma, convulsions, and cardiovascular collapse
Diphenhydramine, Datura Usually brief, self-limited seizures; uncommonly,
Anticholinergic
species status epilepticus
Usually brief, self-limited seizures
Signs of delirium tremens
Ethanol withdrawal and Signs of alcoholic ketoacidosis such as emesis,
Sympathomimetic: a-
sedative-hypnotic drug dehydration, and ketotic breath
and ß-adrenergic
withdrawal
Stigmata of alcoholic liver disease, such as ascites,
asterixis, fetor hepaticus, palmar erythema, and spider
angiomata
Usually recurrent or continuous seizures (i.e., status
epilepticus) refractory to benzodiazepines and
Isoniazid Status epilepticus barbiturates, but responsive to pyridoxine
Profound lactic acidosis
Cholinergic: muscarinic
Organophosphates Pesticide (garlic) odor
and nicotinic
Usually recurrent or continuous seizures (i.e., status
epilepticus) refractory to conventional doses of
Sympathomimetic: benzodiazepines and barbiturates, possibly
Theophylline predominantly ß- responsive to pyridoxine
adrenergic Anion gap metabolic acidosis, hyperglycemia, and
hypokalemia, in acute theophylline overdoses
Profound lactic acidosis


Specific laboratory studies should be determined by the clinical presentation.[46] Useful diagnostic tests can
include measurement of electrolytes, calcium, magnesium, blood urea nitrogen, and glucose; pregnancy
tests; measurement of arterial blood gases with co-oximeter determination of carboxyhemoglobin and
methemoglobin levels; CSF examination; and qualitative or quantitative urine or serum drug levels,
depending on the toxicants suspected. Pregnancy should be excluded in women with child-bearing
potential.[79] Other useful studies can include cranial CT or magnetic resonance imaging (MRI), chest and
abdominal radiography, electrocardiography (ECG), and electroencephalography (EEG) with neurology
consultation.
The First Seizure
The evaluation of the patient with a first-time seizure is determined somewhat by the history and
presentation. The healthy patient who has normal vital signs and no meningismus or headache and whose
mental status returns rapidly to normal requires an expeditious intracranial imaging study (cranial CT or MRI)
and an EEG at some point. A urine toxicologic analysis for drugs of abuse such as cocaine or amphetamine
may provide valuable information.
More complicated patients with first-time seizures require more extensive and more urgent diagnostic
workups (see Tables 18–3 and 18–4 ). This includes patients with status epilepticus, a possible toxic
ingestion, unexplained fever, persistent or severe postictal headache, a focal neurologic examination,
evidence of increased neuromotor irritability such as clonus or myoclonus, a persistent postictal alteration of
consciousness or confusion, or a history of significant antecedent illness, headaches, weight loss, or fevers.
Measurements of oxygen saturation, glucose, electrolytes, calcium, magnesium, and blood urea nitrogen
can be useful. The use of quantitative levels of toxicants or drugs known to precipitate seizures such as
carbon monoxide, theophylline, lithium, and salicylates should be guided by the history and physical
examination. A qualitative urine toxicology screen for drugs of abuse is particularly helpful in adolescents
and young adults with unexplained seizures, and even in small children who may be exposed to their
parents’ drugs of abuse through parental neglect. An ECG is helpful if cardiotoxic drugs such as cyclic
antidepressants, antidysrhythmics, or neuroleptics are suspected. Abdominal radiography can be useful in
patients suspected of being cocaine body packers. Chest radiography may show mass lesions in patients
suspected of having malignant metastases to the brain.
Emergent head CT scans or MRIs are indicated in the evaluation of patients with antecedent headache,
head trauma, a persistently altered or declining mental status, or a new focal neurologic deficit.[3][28][69][77][90]
Patients who have headache, altered mental status, unexplained fever, or immunosuppression require blood
cultures and a lumbar puncture for CSF analysis, provided there is no suspicion of a focal lesion or
increased intracranial pressure; in these cases, empirical antibiotic therapy is indicated before head CT
scanning. A head CT scan, followed by lumbar puncture if the scan is normal, is indicated when the
diagnosis of subarachnoid hemorrhage is suspected.
Patients with status epilepticus and/or hyperthermia require a dipstick urinalysis for myoglobin and
measurement of serum electrolytes, creatinine, and creatine kinase to screen for suspected rhabdomyolysis.
Neurology consultation and continuous bedside EEG monitoring are indicated in patients who have status
epilepticus requiring neuromuscular paralysis.
Patients With Epilepsy
Studies in unselected groups of seizing patients who presented to emergency departments included high
numbers of known epileptic patients on antiepileptic medications. These studies demonstrated that
measurements of antiepileptic drug levels are very useful tests for determining seizure etiology.[28][46] Known
epileptic patients who are on antiepileptic medications initially require only a stat bedside blood glucose
determination and measurement of antiepileptic blood levels unless a complicating condition is suspected.
Laboratory Abnormalities Due to Seizures
Leukocytosis due to demargination commonly occurs in patients with seizures. Respiratory acidosis is
common, especially during status epilepticus. Lactic acidosis is also common; indeed, its demonstration in
the patient with an unclear prehospital history suggests the possibility of a seizure. Patients with status
epilepticus may have profound lactic acidosis. Lactic acidosis resolves rapidly when motor activity is
controlled. In patients whose acidosis does not resolve significantly within 1 hour of the cessation of
generalized motor convulsions, the possibility of ketoacidosis, uremia, lactic acidosis from sepsis, or
poisoning with toxic alcohols or glycols, salicylates, theophylline, iron, carbon monoxide, or cyanide should
be considered (see Chapter 11 for a complete discussion of the evaluation of the patient with metabolic
acidosis).


MANAGEMENT
Resuscitation
The management of patients with seizures is logical and systematic. Resuscitation requires the immediate
identification and management of life threats such as airway obstruction, hypoxia, hypoglycemia,
hyperthermia, and shock.
The safest practice is to endotracheally intubate all actively seizing poisoned patients. Dronen and
associates found a higher success rate and lower complication rate with orotracheal intubation after
paralysis with succinylcholine than with blind nasotracheal intubation in poisoned patients.[25]
Succinylcholine is contraindicated in patients with hyperkalemia. The use of succinylcholine requires a rapid
but thoughtful risk/benefit analysis when there are significant risk factors for hyperkalemia such as prolonged
status epilepticus, as indicated by a history or the presence of significant hyperthermia. The use of
succinylcholine is also relatively contraindicated in patients who seize after poisoning with an
organophosphate insecticide that inhibits serum cholinesterase, an enzyme required for the reversal of the
drug effect of succinylcholine. Moderately short-acting, nondepolarizing agents such as vecuronium or
atracurium can be used in patients with contraindications to succinylcholine. Because actively seizing
patients may have significant lactic acidosis and hypercarbia, an increased ventilatory rate should initially be
used in paralyzed patients to ensure adequate respiratory compensation for metabolic and respiratory
acidoses.[83]
Control of Seizures in Poisoned Patients
Benzodiazepines
Benzodiazepines are the initial drugs of choice to terminate seizures. Diazepam, lorazepam, and midazolam
have been used successfully. All three drugs have similar mechanisms of action but different
pharmacokinetics ( Tables 18–5 , 18–6 , 18–7 ).[6][19][26][34][38][49][51]
Table 18-5 -- Comparison of Intravenous Diazepam and Lorazepam in Treatment of Status Epilepticus
Diazepam (n = 33) Lorazepam (n = 37)
Dose = 10 mg, IV Dose = 4 mg, IV
Rate = 10 mg/2 min Rate = 4 mg/2 min
First injection seizure control = 19 (58%) * First injection seizure control = 29 (78%) *
Total seizures controlled = 25 (76%) * Total seizures controlled = 33 (89%) *
Latency of action = 0–10 min (median = 2 min) * Latency of action = 0–15 min (median = 3 min) *
Modified from Leppik IE, Derivan AT, Homan RW, et al: Double-blind study of lorazepam and diazepam in status
epilepticus. JAMA 1983; 249:1452–1454.
* Not statistically significantly different.
Table 18-6 -- Comparison of Intravenous and Rectal Lorazepam and Diazepam to Control Seizures
Diazepam Lorazepam
Intravenous n = 34 n = 27
Rectal n = 19 n=6
Total n = 53 n = 33
Patients requiring multiple doses n = 25 (47%) n = 8 (24%)
Patients requiring additional antiepileptic drugs n = 17 (32%) n = 1 (3%)
Patients with subsequent respiratory depression n = 8 (15%) n = 1 (3%)
Intravenous and rectal doses 0.3–0.4 mg/kg 0.05–0.1 mg/kg
IV administration rate 15–30 sec 15–30 sec
Time when second dose of same drug given, if no termination of seizure 7–8 min later 7–8 min later
Modified from Appleton R, Sweeney A, Choonara I, et al: Lorazepam versus diazepam in the acute treatment of
epileptic seizures and status epilepticus. Dev Med Child Neurol 1995; 37:682–688.
Studies comparing diazepam with lorazepam show that diazepam is more lipid soluble and enters the brain
rapidly. However, its receptor binding is weaker and brain concentrations fall rapidly, resulting in a shorter
duration of action than that of lorazepam.[72] One comparative study showed that diazepam distributed into
the brain within 10 seconds and maintained EEG seizure control for 20 to 30 minutes whereas lorazepam
distributed into the brain within 3 minutes and maintained EEG seizure control for up to 3 hours.[26] Clinical
studies have had differing results. A comparison of intravenous and rectal lorazepam with intravenous and
rectal diazepam in children with status epilepticus showed that lorazepam was superior (see Table 18–6 ).[6]
A double-blind clinical study of patients with status epilepticus found both drugs to be equally efficacious
(see Table 18–5 ).[51]
Seizures refractory to diazepam or lorazepam have been successfully terminated with loading doses of
midazolam ranging from 2.5 to 15 mg in adults, sometimes followed by continuous infusions ranging from 1
to 20 mg/hr (0.06–0.39 mg/kg/hr). [19][34][49]
Barbiturates
When intravenous benzodiazepines do not terminate a seizure, if seizures recur after the use of
benzodiazepines, or if seizures occur after flumazenil administration, barbiturates are the next drugs of
choice. INH, theophylline, and other methylxanthines produce status epilepticus more commonly than other
epileptogenic toxicants. Patients with seizures induced by these toxicants will generally require loading with
phenobarbital. There is little scientific information comparing the safety and efficacy of long-acting
(phenobarbital), intermediate-acting (pentobarbital), and short-acting (thiopental) barbiturates in patients with
status epilepticus. In spite of the lack of comparative data, phenobarbital has become the second-line drug
of choice, owing to its longer duration of action (see Table 18–7 ). It is less lipid soluble than the
benzodiazepines, and consequently the onset of therapeutic action is delayed up to 10 minutes.[72] The
recommended dose of phenobarbital is 20 mg/kg of body weight, given at a rate of up to 50 mg/min in adults
or up to 1 mg/kg/min in children, for status epilepticus. Phenobarbital may produce severe soft tissue
necrosis and should be given only intravenously. The treating physician should anticipate and be prepared
to manage the development of respiratory failure and hypotension with the intravenous administration of
phenobarbital.
Phenytoin
Although phenytoin is the second-line agent indicated in the treatment of most causes of status epilepticus,
it is not usually useful in the management of drug-induced seizures. Phenytoin increased the frequency and
duration of episodes of ventricular tachycardia in dogs poisoned with cyclic antidepressants and failed to
prevent imipramine-induced seizures in a rat model.[8][15] It was ineffective in prophylaxis of fatal
theophylline-induced seizures in mice; indeed, the LD50 for theophylline was lower for mice treated with
phenytoin than for controls.[11] Phenobarbital significantly raised the theophylline LD 50 and provided
significant prophylaxis for theophylline-induced seizures in this mouse model.[11] Findings from this animal
study are compatible with a retrospective human study in which 21 of 22 patients with theophylline-induced
seizures failed to respond to phenytoin treatment.[42] Phenytoin is also ineffective in INH-induced
seizures.[11] These data emphasize not only that phenytoin is ineffective for certain drug-induced seizures
but also that phenytoin may increase the morbidity and mortality of seizures in some cases. Seizures
induced by 4-aminopyridine are an exception and have responded favorably in animal experimental studies
and in case reports.[82][92][94]
Pyridoxine
Patients with seizures caused by known or suspected INH, hydrazine, or monomethylhydrazine (Gyromitra
species) toxicity should receive intravenous pyridoxine in addition to benzodiazepines.[80] See Table 18–7
for pyridoxine dosing recommendations. Empirical administration of pyridoxine should also be considered in
overdose patients with refractory status epilepticus because these cases may be due to unsuspected
ingestions of INH. Preliminary observations suggest that pyridoxine may also be of benefit in the
management of patients with refractory seizures due to theophylline or other methylxanthines. This requires
further study.[36][88]
Neuromuscular Paralysis
When standard therapies fail to control status epilepticus, neuromuscular blockade and general anesthesia
are recommended. Neuromuscular blockade prevents rhabdomyolysis, lactic acidosis, and hyperthermia
due to excessive muscle activity, but it does not terminate seizures and does not protect against the brain
injury associated with status epilepticus.[60][75] Irreversible brain damage is a well-recognized consequence
of status epilepticus, even when the motor manifestations of seizures are controlled. The time required for
brain injury to occur is unclear. A teenage girl who was in status epilepticus for 14 hours sustained
permanent cognitive impairment despite neuromuscular blockade.[66] Baboons develop visible
neuropathologic lesions after 82 minutes or more of convulsive status epilepticus.[59] Similar findings were
noted when the animals were paralyzed, but the EEG manifestations of seizures continued.[60] Continuous
EEG monitoring and aggressive therapy for electrical seizure activity is clearly indicated for patients who
require neuromuscular paralysis for control of their convulsions.
Hyperthermia
Status epilepticus may be associated with life-threatening hyperthermia due to increased muscular heat
production. Normally, patients with core temperatures of 41°C (105°F) or higher are at high risk for life-
threatening organ injury; however, temperatures may rise rapidly, and treatment to prevent this should begin
when the body temperature is less than 40°C (104°F). When benzodiazepines do not effectively control
seizures, neuromuscular blockade is indicated to facilitate temperature control. Vecuronium is the drug of
choice in this setting because rhabdomyolysis and hyperkalemia are often present, precluding the use of
succinylcholine.[13]
External cooling should be initiated at the same time as control of seizures. Although evaporative cooling is
most efficacious, it is not always immediately available,[39][47][87][91] and packing in ice is also effective [21]
(see Chapter 27 for a more extensive discussion). During cooling, we recommend continuous temperature
monitoring with both a temperature-probe Foley catheter and a rectal thermistor. The patient should be
cooled until the core temperature reaches 38.5°C to 39°C (101.3°F to 102.2°F).[39]
Specific Toxicologic Treatments
Patients who have ingested epileptogenic toxicants can have the absorption of these toxicants altered.
Syrup of ipecac is absolutely contraindicated because patients who are seizing or postictal are unable to
protect their airways during emesis. Patients with ingestion of toxicants that can cause seizures can receive
activated charcoal (AC). A 10:1, weight:weight ratio of AC to ingested drug is widely accepted as an optimal
value for AC dosing.[4][67] Practically, the amount of toxicant ingested is usually unknown and the AC dosing
is based on body weight, with 1 g/kg AC administered. AC has low binding avidity for lithium, iron, metals,
alcohols, and glycols. Sorbitol may be used at the discretion of the attending physician. However, cathartics
have not been proven to improve the clinical course of poisoned patients. Sorbitol also increases the risk of
emesis and aspiration pneumonitis, and multiple doses of sorbitol have been associated with serious fluid
and electrolyte abnormalities, bowel perforation, ventilatory failure due to distention from intraintestinal
fermentation of sorbitol, and death.[5][70]
Although orogastric lavage is not indicated in all patients who have ingested epileptogenic toxicants, it
should be considered in patients who present within an hour of ingestion or have signs of serious clinical
toxicity on presentation, especially when the ingestant is not bound to activated charcoal.[48]
Antidotes
Glucose
Hypoglycemia should rapidly be excluded in every seizing patient and treated with intravenous D50W in
adults and D25W in children, when demonstrated. The administration of thiamine is recommended in every
adult patient who receives glucose.
Flumazenil
The administration of the benzodiazepine antagonist flumazenil is contraindicated in patients who have
ingested potentially epileptogenic toxicants, even if benzodiazepines were co-ingested. It causes seizures in
mixed overdoses of benzodiazepines and epileptogenic toxicants and may also precipitate seizures in
patients who chronically use benzodiazepines.[14][35][55][57][64][74][81] Its use will also render benzodiazepines
relatively ineffective in treating seizures until the flumazenil receptor blockade has abated.
Naloxone
Naloxone is indicated for reversal of the apnea, hypotension, and mental status depression associated with
opioid overdoses. It will not reverse seizures associated with normeperidine or norpropoxyphene toxicity.[12]
Good experimental data indicate that naloxone is ineffective for meperidine-induced seizures and may
actually exacerbate them. [12][85]
Others
The use of specific antidotes for carbon monoxide, organophosphate insecticides, cyanide, toxic alcohols
and glycols, and iron poisoning depends on the clinical evidence that indicates poisoning with these
substances. See specific chapters for further discussion of the diagnosis and treatment of poisoning with
these agents.
Disposition and Need for Consultants
Most patients with drug-induced seizures require admission to the intensive care unit (ICU). An exception
would be the insulin-dependent diabetic patient with inadvertent hypoglycemia or a stable patient with a
seizure due to cocaine use. The patient with a seizure who is discharged home from the emergency
department must have normal vital signs; a normal neurologic examination including a normal mental status;
no other medical, surgical, or psychiatric conditions that would otherwise warrant hospitalization; appropriate
follow-up; and availability of a safe environment with safe transportation. Consultation with a regional poison
center and/or a medical toxicologist is indicated for patients with toxicant-induced seizures. Patients with
toxicant-induced seizures who require neuromuscular paralysis and continuous EEG monitoring will require
the consultation of a neurologist.
Pitfalls
Pitfalls in the diagnosis and treatment of seizures are detailed in Table 18–8 .
Table 18-8 -- Pitfalls in Caring for Seizure Patients

• Not doing the primary survey and resuscitation (ABCDE) in a timely, systematic fashion.
• Not performing specific toxicology therapy in a timely, systematic fashion.
• Using a neuroparalytic drug whose duration of action exceeds the time it takes to load a seizing patient with
20 mg/kg of IV phenobarbital (i.e., 20–40 minutes). Longer neuromuscular blockade requires continuous EEG
monitoring.
• Failure to serially examine a seizure patient. A patient who does not wake up after a seizure does not
necessarily have a “postictal state” but has status epilepticus or coma due to another serious pathologic
process, until proven otherwise.
• Not checking all seizure patients for hypoglycemia with stat bedside glucose determinations.
• Giving glucose to adult patients without replenishing thiamine.
• Not recognizing isoniazid-induced seizures and treating with pyridoxine.
• Giving flumanzenil to unconscious seizure patients, to epileptic patients chronically taking benzodiazepines
such as clonazepam, or to patients who have ingested potentially epileptogenic toxicants such as cyclic
antidepressants.
• Overlooking head injuries, spine injuries, other injuries, rhabdomyolysis, infection, and/or hyperthermia in
seizing patients.
• Overlooking treatable but life-threatening co-ingestants such as acetaminophen in patients with multiple-drug
overdoses involving epileptogenic drugs.


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Chapter 19 – Peripheral Neuropathy
ROBERT S. HOFFMAN
Essentials
• Obtain a thorough history, including specific aspects of occupation and hobbies that may involve
chemicals associated with peripheral neuropathy.
• Define the neuropathy in terms of:
a. Onset
b. Location
c. System(s) of involvement
Motor
Sensory
Autonomic
Mixed
• Exclude common medical causes for the neuropathy.

• Collect both subjective and objective data to support the presence of a disorder.
• Perform biologic monitoring to confirm the exposure, if possible.
• Remove the patient from the exposure and begin definitive therapy if available.
PHYSIOLOGY/PATHOPHYSIOLOGY
The peripheral nervous system is exquisitely sensitive to injury from diseases and toxins. As summarized in
several excellent reviews, it is the basic structure and function of the peripheral nervous system that creates
this vulnerability.[4][10][51] Transport of electrical impulses across vast distances by single cells is a highly
energy-dependent process. These single cells are often greater than 200,000 times longer than most other
cells in the body, and, despite being configured into very narrow cylinders, the volume of the axon is
substantially greater than that of the cell body. Whereas most synthetic functions of the cell occur in the cell
body, cellular substrate utilization occurs predominately along the axon. Cellular products must be
transported down the axon by an active (energy-dependent) mechanism. Finally, electrical conduction
requires precisely timed opening and closing of multiple ion channels, and active ion pumping is used to
restore the resting potential. All of these functions are energy dependent, with glucose metabolism as the
primary and almost exclusive substrate. Thus, any systemic condition that interferes with either the supply or
utilization of oxygen and glucose or with protein synthesis and transport has the ability to impair peripheral
nerves. In addition, a variety of disorders and toxins can directly damage the peripheral nervous system
through highly selective destruction of certain cellular components.
A number of classification systems can be used to describe peripheral neuropathies. These systems relate
to the number of cells affected, the anatomic distribution of the resulting deficit, the function of the nerve
cell(s) involved, and the histologic site of injury. Because each classification system offers insight into the
disease process, etiologic agents, and the prognosis, it is often customary to describe neuropathies using
terms derived from multiple schemes. A thorough understanding of this terminology and its implications is
essential for the clinician because it serves as the gateway to literature review, consultant referral, diagnosis,
and prognosis. Thus, each of these classification systems is reviewed in some depth. Because this chapter
emphasizes patient evaluation, the discussion of these classification systems will proceed in a fashion that
best follows a patient’s chief complaint.
Number of Cells Affected
A peripheral neuropathy may be subclassified as either a mononeuropathy (involving a single nerve) or a

polyneuropathy (involving multiple nerves). In general, because toxins produce systemic changes that are
often metabolic, most toxin-related neuropathies are polyneuropathies.[10] Clearly, exceptions to this rule
occur. Early presentations of progressive disorders and several unique toxins may manifest as isolated
mononeuropathies, especially those affecting cranial nerves. When a patient presents with stable
involvement of a single nerve, however, trauma and vascular insult are more likely diagnoses. Although the
patient’s chief complaint may suggest a mononeuropathy, this diagnosis should not be entertained until a
thorough evaluation has been completed. A comprehensive examination is essential to detect subtle
abnormalities of which the patient might not even be aware. Once these less-prominent deficits are found,
the diagnosis of a polyneuropathy will be more clear.
Anatomic Distribution of the Affected Area
The simplest description of the anatomic area affected by a neuropathy involves a single distinction between
local and widespread involvement. Thus, a focal neuropathy is one that affects an isolated body part,
whereas a diffuse neuropathy involves a wider anatomic distribution. Similar to mononeuropathies, focal
neuropathies are less common in toxin-mediated injuries. Once again, however, because many patients will
present early in the course of a disorder, it is essential to evaluate them for progressive or subtle dysfunction
of other areas.
Diffuse neuropathies can be further subclassified into symmetric or asymmetric types. As a general rule,
toxin-induced diffuse neuropathies tend to be symmetric. Diffuse neuropathies often take on a characteristic
progression. Because long nerve fibers tend to be more sensitive to injury, patients will often complain of
symptoms that began in their hands or feet and subsequently moved more proximally, or ascend. Although
this progression is common of many neuropathies and is therefore not useful to distinguish toxin-induced
from non–toxin-induced causes, very few toxin-induced peripheral neuropathies occur in descending
fashion. Classic examples of descending neuropathies would be those that result from botulism or
diphtheria.[18][47] Thus, a typical complaint for a toxin-involved neuropathy would relate to symptoms that
began in the fingers or toes of both extremities and progressed to involve the hands and/or feet in a
relatively symmetric distribution.
Function of Cells Affected
The peripheral nervous system is functionally subdivided into motor, sensory, and autonomic divisions. In
addition, the cranial nerves can be considered as a separate division because of their ability to be affected
by a unique subset of toxins. The functional divisions of the peripheral nervous system involved correlate
quite well with the patient’s symptoms. Whereas diseases and toxins are often associated with injury to a
specific subdivision of the peripheral nervous system, many neuropathies demonstrate involvement of
multiple functional divisions. For the purposes of this discussion, diseases and toxins that typically involve
one functional division of the peripheral nervous system are grouped by their primary involvement only.
Those disorders that are usually mixed are listed as such.
Motor
The physiologic correlate of a motor neuropathy is loss of function. Patients will complain of symptoms that
range from weakness to plegia or paralysis of the affected area. Toxins that directly compromise nervous
tissue will usually cause symptoms that begin distally, because the longer nerve fibers supplying distal
muscles are injured first and then move proximally. Lead poisoning is the classic example of a toxin-induced
motor neuropathy. Isolated wristdrop or footdrop might be the only presenting neurologic complaint of a
patient with significant lead poisoning. For unclear reasons, lead neuropathy tends to affect the upper limbs
first in adults and the lower limbs first in children.[44]
The cranial nerves of the eyes are under very rigid control. Subtle muscle weakness from peripheral
neuropathy can produce diplopia, which is a very common finding in motor neuropathies resulting from
impaired impulse or neurochemical transmission. Examples of toxin-induced neuropathy in which diplopia
might be the earliest or sole presenting complaint would include botulism, diphtheria, and elapid
envenomation.[18][22][47] In addition, an isolated lateral rectus (CN VI) palsy is considered the hallmark of
Wernicke’s encephalopathy which is often ethanol-induced.[11] In all of these disorders, ophthalmologic
findings may represent early manifestations of life-threatening illnesses. Therefore, clinicians must evaluate
patients with ophthalmologic findings for other neurologic deficits and observe them for progression of
disease.
Alternatively, toxins that alter neuronal conduction through electrolyte changes (especially potassium and
magnesium) will usually produce more diffuse and precipitous symptoms. Hypokalemia from toluene-
induced renal tubular acidosis or ingestion of soluble barium salts can present as widespread pure motor
weakness that may mimic massive stroke, catatonia, or neuromuscular blockade.[40][50] Common causes of
toxin-induced peripheral motor neuropathies are listed in Table 19–1 .
Table 19-1 -- Toxin-Induced Peripheral Neuropathies: Distribution by System Involved *

Motor Sensory Sensory and Motor Autonomic Cranial
Botulism Acrylamide Arsenic Acrylamide Botulism (early)
Buckthorn Cisplatin Carbon disulfide Alloxan Carbon disulfide
2'3'-Dideoxycytidine
Dapsone Colchicine Cisplatin Diphtheria (early)
(ddC)
Motor Sensory Sensory and Motor Autonomic Cranial
Eastern diamondback Elapid venom
Ethanol Disulfiram Doxorubicin
rattlesnake (rare) (early)
Elapid venom Metronidazole Hexacarbons Ethanol Methanol
Lead Phenytoin Isoniazid Streptozotocin Thallium
Mercury Pyridoxine Organophosphates Taxol Trichloroethylene
Mojave rattlesnake Taxol Thallium
Thallium
Vincristine
* Toxins that cause mixed sensory and motor findings when one type predominates are listed under that particular finding.
When diffuse muscle weakness develops from any cause, it is critical to assess and serially evaluate the
muscles of respiration to determine the need for intubation and mechanical ventilation before the onset of
respiratory failure. Although arterial blood gas analysis and pulse oximetry are fundamental tools for
evaluating the respiratory status, it should be remembered that consequential impairment of respiratory
function can occur long before any depression in oxygen saturation or elevation in the partial pressure of
carbon dioxide can be detected. Consequentially, respiratory muscle function assessment is more important
than assessment of gas exchange. Measurement of the negative inspiratory force is the most rapid,
reproducible objective determinant of respiratory status, in lieu of formal pulmonary function testing. This test
can be accomplished at the bedside with minimal technology or skill.
Sensory
Whereas sensory neuropathies can involve every sense including position, vibration, temperature, taste,
smell, vision, or hearing, the most common complaint of patients with toxin-induced sensory neuropathies
involve touch and two-point discrimination. Patients typically complain of numbness, tingling, and difficulty
manipulating small objects. Classic sensory toxin-induced neuropathies are often described as involving a
symmetric area of the hands or feet in what is know as a “stocking and glove” distribution. This finding of a
nondermatomal distribution implies distal involvement of multiple nerves. A classic example of this type of
neuropathy would result from acrylamide exposure that occurs in the tile or grouting industry.[20] Like other
neuropathies, a stocking and glove distribution may represent the onset of a progressive disorder or the
extent of a stable condition.
Certain other toxins produce sensory neuropathies that take on very characteristic findings. Some of the
metals and metalloids result in a painful sensory neuropathy. Of these, thallium is the most classic with its
tendency to produce an early and rapidly accelerating, exquisitely painful, ascending sensory neuropathy.[28]
Overexposure to pyridoxine (vitamin B6) results in loss of position sense and causes the patient to have a
wide-based, ataxic gait.[45] Other causes of sensory neuropathy are found in Table 19–1 .
Autonomic
Autonomic neuropathies are distinctly uncommon when compared with other forms of peripheral neuropathy
and usually result from diabetes. As such, the diabetic neuropathy caused by toxins such as Vacor, alloxan,
streptozotocin, and similar compounds could be classified as toxin-induced autonomic
neuropathies.[27][32][52] Autonomic neuropathy has also been described with exposures to acrylamide,[46]
cisplatin,[41] doxorubicin,[13] ethanol,[33] taxol,[21] and thallium,[28] as shown in Table 19–1 . Patients may
experience alteration of sweating, heart rate, blood pressure, postural tone, ejaculation, and other functions
normally controlled by the autonomic nervous system.
Histologic Site of Injury
Electrical impulses can be altered or inhibited at any point along the cell. Most impulses originate at the cell
body and result from chemically mediated depolarization of the cell membrane. The impulse travels down
the axon, which is sometimes sheathed in myelin, until it reaches the nerve terminal. When the nerve
terminal is depolarized, ion fluxes allow for release of chemical mediators that affect other nerves or organ
systems. The histologic classification scheme of peripheral neuropathies simply locates the area of the cell
that has been injured. While this classification scheme sheds little or no light on the patient’s symptom
complex, it offers significant information with regard to prognosis. The information necessary to categorize a
patient’s illness into one of these subdivisions cannot be obtained from the history or physical examination.
Rather, it requires sophisticated testing, biopsy, or more commonly a review of the literature once the toxin
has been identified. Peripheral neuropathies are thereby subdivided into four types:
1. Neuronopathies, which are disorders of the cell body
2. Axonopathies, which are disorders of the axon
3. Myelinopathies, which are disorders of the myelin sheath
4. Transmission neuropathies, which are disorders that interfere with the release of neurotransmitters from
the nerve terminal
Neuronopathy
Although toxin-induced neuronopathies are relatively uncommon, they are the most severe. Damage to the
cell body is often permanent. When healing does occur, however, recovery is slow and usually incomplete.
The classic example of a toxin-induced neuronopathy resulted from excessive utilization of pyridoxine
(vitamin B6). Megatherapy with doses of pyridoxine as large as 2 to 6 g/d was recommended either as part
of a body-building regimen or for prevention of premenstrual syndrome. Schaumburg and colleagues
described seven women who chronically consumed this water-soluble vitamin.[45] These patients developed
sensory findings that consisted of numb feet, unsteady gait, numbness in the hands, and, later, perioral
paresthesias. Ultimately, stocking-and-glove sensory deficits developed but motor strength was always
preserved. Testing revealed predominant abnormalities of position and vibration sense, whereas other
sensory findings such as alterations of temperature, pain, and touch were less affected.
This syndrome has been unfortunately reproduced after massive acute overdose with pyridoxine. Albin and
colleagues described two patients who received high-dose pyridoxine therapy for ingestion of Gyromitra
mushrooms.[3] Both patients were given an excess of 100 g (2000 mg/kg) intravenously over a 3-day period
and rapidly developed symptoms similar to the patients with chronic exposure described previously. A milder
form of pyridoxine neuropathy has been described after chronic administration of smaller doses in
humans.[38] In these later patients, symptoms continued to develop after discontinuation of therapy, but
ultimately some recovery was achieved.[38] In both the chronically overdosed and massively acutely
overdosed patients, recovery was slower and often incomplete.[3][45] Rarely, other toxins such as
doxorubicin[13] have been associated with peripheral neuronopathy ( Table 19–2 ).
Table 19-2 -- Toxin-Induced Peripheral Neuropathies: Distribution by Histologic Lesion *

Neuronopathy Axonopathy Myelinopathy Transmission
Doxorubicin Acrylamide Amiodarone Black widow spider venom
Pyridoxine Arsenic Buckthorn Botulism
Cisplatin Diphtheria Elapid and crotalid venom
Colchicine Lead Saxitoxin
Dapsone Trichloroethylene Scorpion venom
2'3'-Dideoxycytidine (ddC) Tetrodotoxin
Ethanol
Hexacarbons
Mercury
Phenytoin
Organophosphates
Taxol
Thallium
Vacor
Vincristine
* Toxins that cause mixed histologic findings when one type predominates are listed under that particular finding.
Axonopathy
Axonopathy is the most common form of toxin-induced peripheral neuropathy. An axonopathy can be viewed
as a chemical transection of the axon. The toxin may attach to and destroy a specific region of the axon. The
distal portion of the axon that is no longer connected to the cell body subsequently dies, and loss of function
results. Alternatively, the toxin may interfere with the transport of nutrients or other essential molecules down
the axon. The axonal remnant located distally to the last region of successful transport subsequently dies.
Even though the symptoms of axonopathies are often devastating, recovery is expected because axons of
the peripheral nervous system have the ability to regenerate, unlike axons of the central nervous system.
This process is often slow, but complete restoration of function is possible.
Classic forms of toxin-induced axonopathy include hexacarbon, acrylamide, organophosphates, and

thallium. Exposure through occupational use or recreational abuse of glues or solvents that contain 6-carbon
straight-chained molecules (n-hexane, or methyl n-butyl ketone) results in a characteristic mixed sensory
and motor peripheral neuropathy. Typical examples come from industries such as the shoe and leather
industry. Abbritti described 122 Italian shoe workers who developed a toxic polyneuropathy as a result of
exposure to n-hexane.[1] Exposed individuals developed dysesthesias followed by symmetric alterations of
touch, perception, and motor function. Diagnostic correlates included findings such as swelling of axons and
accumulation of packed neurofilaments on light microscopy[42] and denervation on electromyography.[8]
Patients typically continued to experience deterioration after removal from exposure but then recovered with
time.
The etiology of this disorder appears to be related to the metabolite 2,5-hexandione (2,5-HD), which has
been demonstrated experimentally to produce lesions identical to those caused by n-hexane and methyl n-
butyl ketone ( Fig. 19–1 ).[37] 2,5-HD has been demonstrated to inhibit phosphofructokinase and
glyceraldehyde-3-phosphate dehydrogenase, which results in impairment of glycolysis.[43] Although this
finding generated a hypothesis that impaired axonal transport and energy production were responsible for
the hexacarbon axonopathy, the concentration of 2,5-HD required to achieve this effect was much greater
than was obtained clinically. 2,5-HD has also been shown to form pyrrole, which interferes with the
interactions between neurofilaments and other proteins; crosslink neurofilaments; decrease phosphorylation
of neurofilaments; and reduce proteolysis of neurofilaments. Although the exact mechanism is unclear, the
most plausible chain of events is described by Abou-Donia as follows.[2] n-Hexane’s metabolism to 2,5-HD
decreases phosphorylation of neurofilaments, which destroys the normal cytoskeletal matrix. Neurofilament
proteins are then transported down the axon where they accumulate, crosslink, and produce the giant
axonal swelling that characterizes this neuropathy.
Figure 19-1 Metabolism of n-hexane.
The use of acrylamide as a polymerizing agent in the 1950s was followed rapidly by human reports and
animal models of acrylamide neurotoxicity.[20][29] Early symptoms may involve skin irritation and generalized
fatigue. Neurologic dysfunction is characterized by symmetric findings of a mixed sensory, motor, and
autonomic dysfunction in the hands and feet. Patients may complain of numbness, weakness, and
excessive sweating. Deep tendon reflexes and vibration sense are also diminished or absent early in the
disease.
The exact mechanism of acrylamide toxicity has not been established, although theories suggest that events
such as a reduction in metabolic energy or an interference with cytoskeletal proteins are responsible.[26]
Histologic findings consist of a classic “dying back” axonopathy.[19] Like other toxin-induced neuropathies
described here, symptoms may progress for several weeks even after the exposure has ceased. Then the
recovery phase begins. The time period for recovery ranges from a few months to a few years, and both the
duration and extent of recovery are largely dependent on the degree of toxicity.
One of the more dramatic examples of axonopathy resulted from an episode that has come to be known as
“Ginger-Jake paralysis.” In the United States in the 1930s, an alcoholic drink prepared from ginger was
contaminated with triorthocresyl phosphate (TOCP). TOCP is an organophosphate compound that has weak
cholinesterase inhibition. Some estimates suggest that as many as 20,000 people were affected, as was
summarized by Le Quesne.[25] Gastrointestinal symptoms were minimal or absent. Motor neuropathy
presented as symmetric distal weakness and wasting. Sensory findings were absent or unimpressive.
Although recovery often occurred, some residual spastic paraplegia was not uncommon. Inhibition of a
specific neuroprotective esterase is thought to be responsible for the neurotoxicity.[25]
Thallium toxicity produces multiorgan failure that is typical of most metal poisonings. As part of this process,
a characteristic ascending, largely sensory, rapidly progressive, and severely painful sensory neuropathy
develops. Although motor and autonomic findings have been described, the sensory findings are so
pronounced they tend to overshadow the other components, except in the most severe of cases. In fact, this
sensory neuropathy is so characteristic that, when combined with the subsequent development of alopecia,
it is almost diagnostic of thallium toxicity. Patients will often have a transient gastrointestinal syndrome that
may involve nausea, vomiting, diarrhea, or constipation.[28][30] Shortly thereafter they will complain of pain in
their feet that is so severe that it prevents walking. Over the course of a few days, these symptoms will
progress and become associated with other organ involvement. Although similar findings may be seen in
patients with arsenic poisoning, the progression of these findings in thallium toxicity is much more abrupt.
Electrophysiologic studies in thallium-poisoned patients show changes consistent with classic axonopathy
and subclinical involvement of multiple neurons.[16]
Although animal studies of thallium toxicity have demonstrated a variety of findings, swelling of axonal
mitochondria seems to be a fairly consistent finding. Again, the exact mechanism of thallium-induced
neuropathy is unclear. Some authors attribute thallium’s effect to its similarity to potassium and suggest
thallium may impair sodium-potassium adenosine triphosphatase.[6] Other toxin-induced axonopathies can
be found in Table 19–2 .
Myelinopathy
Myelin functions to insulate nervous tissue and enhance conduction velocity. Disorders that destroy only
myelin have the unique ability to impair neuronal conduction without altering neuron integrity. Thus, although
the patient may have severe and life-threatening manifestations of nervous system dysfunction, rapid and
complete recovery is expected once the disorder has completed its course. A classic myelinopathy is
Guillain-Barré syndrome (GBS), and, like GBS, respiratory failure is the most severe manifestation of toxin-
induced peripheral demyelinating disorders. The classic example of toxin-induced myelinopathy is
diphtheria.[10][18] Agents such as amiodarone,[39] buckthorn,[9] lead,[49] and trichloroethylene[17] may also
produce demyelination, although reports are conflicting (see Table 19–2 ).
Diphtheria is an infectious disease caused by Corynebacterium diphtheriae and is characterized by fever,
fatigue, headache, sore throat, and a gray or green membrane on the tonsils. Ten to twenty per cent of
patients with diphtheria will develop neurologic symptoms, ranging from cranial nerve palsies to peripheral
neuropathy and frank paralysis that may begin 4 to 8 weeks after the onset of infection. Diphtheria toxin has
the unique ability to directly interfere with myelin synthesis.[18] Recovery is generally complete as long as
other organ damage has not occurred.
Transmission Neuropathy
Unlike the previous categories of peripheral neuropathy, transmission neuropathy involves no damage to the
neuronal cell body, axon, or surrounding myelin. Rather, with transmission neuropathy, the toxin directly
impairs either the propagation of electrical impulses or the release of neurotransmitter molecules from the
nerve terminus. Botulism, tetrodotoxin, saxitoxin, and envenomation by black widow spiders, elapids, some
crotalids, certain scorpions, and other examples of transmission neuropathies are listed in Table 19–2 . In
addition, electrolyte abnormalities such as severe hypokalemia and hypomagnesemia produce similar
findings. Because these derangements involve specific areas of nervous tissue function, the general rule of
thumb is that recovery is relatively rapid and nearly or entirely complete when compared with the disorders
listed earlier that affect other anatomic locations.
The mechanism of botulism toxicity has been well described.[47] The toxin binds irreversibly to the nerve
terminal where it prevents the release of acetylcholine. Patients manifest symptoms of acetylcholine lack as
a pure motor weakness that begins commonly with diplopia or difficulty swallowing and rapidly descends to
produce a flaccid paralysis with respiratory failure. Other manifestations of acetylcholine deficiency include
dilated pupils, dry mouth, and constipation. Administration of antitoxin before the onset of symptoms is
completely protective but only halts the progression of findings once symptoms have begun. Because
binding of toxin to the nervous tissue is irreversible, recovery does not occur until the nerve terminal
regenerates, which may require several months.
Tetrodotoxin is found in puffer fish (fugu), the blue-ringed octopus, and certain newts, toads, and
salamanders. Tetrodotoxin directly binds to the exterior mouth of sodium channels, where it prevents sodium
channel opening and impairs impulse conductance down the axon.[36] After a tetrodotoxin-contaminated
meal, patients may complain of perioral paresthesias, weakness, and shortness of breath. These symptoms
are often followed rapidly by cardiorespiratory arrest and death. With endotracheal intubation and supportive
care, prompt recovery is expected. Saxitoxin has a similar mechanism of action.[36]
The black widow spider (Latrodectus mactans) possesses a complex toxin that reversibly binds to
gangliosides and glycoproteins of the synaptosomal membrane where it opens sodium channels.[5] The net
result is continuous release of acetylcholine and norepinephrine. Patients experience spasm of large muscle
groups with severe pain and autonomic findings such as tachycardia, hypertension, and so on.[7] Because
this binding is reversible, administration of antitoxin results in a rapid and complete restoration of nerve
function.
Scorpion envenomation in the United States is rarely associated with fatality. Rather, a painful neuropathy
develops. Venom of Centruroides species of scorpion binds to sodium channels and incompletely
inactivates them during depolarization to prolong the action potential.[53] An additional action enhances
membrane depolarization.[31] The net result is repetitive and prolonged firing of nerves resulting in enhanced
excitability and pain. Although an antivenin exists, toxicity is usually self-limited and relieved with
conventional supportive care.


SPECIAL SITUATION: THE HUMAN IMMUNODEFICIENCY VIRUS–POSITIVE PATIENT
The human immunodeficiency virus (HIV) epidemic has created a unique problem for clinicians evaluating
patients with peripheral neuropathy in that peripheral neuropathy is associated with both the disease and its
treatment. Comi and colleagues studied 23 patients for the presence of peripheral neuropathy. All 12
patients with the acquired immunodeficiency syndrome (AIDS) and 7 of 11 patients with HIV infection
offered symptoms suggestive of peripheral neuropathy.[14] Clinical or neurophysiologic evidence of
peripheral neuropathy was demonstrated in 6 of the 11 HIV patients and 11 of the 12 AIDS patients. The
most common finding was a distal sensory and motor neuropathy consistent with axonal degeneration.
Other authors estimate a 35 to 40 per cent incidence of peripheral neuropathy (most commonly axonal
degeneration) in AIDS patients. [48][54]
Numerous trials are required to evaluate new antiviral agents. Zalcitabin (2',3'-dideoxycytidine [ddC]) is one
of a number of dideoxynucleosides known to cause peripheral neuropathy. In one study, peripheral
neuropathy was reported as the most common adverse effect of ddC treatment. [35] Dubinsky and coworkers
confirmed that the ddC-induced neuropathy was of an axonal type.[15] Although 2',3'-didoxyinoside (ddI) is
known for its ability to cause pancreatitis, Lambert and colleagues reported that a painful peripheral
neuropathy developed in 8 of 37 ddI-treated patients.[23] Interestingly, when ddC and ddI are combined,
additive or even synergistic toxicity to the peripheral nervous system results. [24] Similarly, early work with
stavudine (d4T) suggests that peripheral neuropathy may also be its most common side effect, occurring in
just under 20 per cent of treated patients.[34]
Because the neuropathies associated with the disease and its treatment are similar, clinicians are often
forced to choose between discontinuing therapy or treating through the disorder. The time course for
developing neuropathy is quite variable,[23] so little correlation can be made between the onset of therapy
and neuropathy.


The differential diagnosis of peripheral neuropathy includes common and rare medical disorders, toxin
exposures, mechanical injury, and a variety of other syndromes. Infectious causes are common. In fact,
leprosy, which causes a demyelinating neuropathy, is believed to be the most common cause of peripheral
neuropathy worldwide. This disorder is distinctly uncommon, however, in the United States, where GBS is
the most common cause of a postinfectious acute demyelinating disorder. Patients typically present with
ascending motor findings associated with a loss of deep tendon reflexes and minimal or no sensory
complaints. Cranial nerves are rarely involved (Miller-Fisher variant), and the most worrisome finding is
respiratory compromise. Other infectious causes include Bell’s palsy, which is now fairly commonly seen
with Lyme disease; the painful neuropathy of herpes zoster; and the descending neuropathy of diphtheria.
A variety of medical illnesses are also responsible for peripheral neuropathy, of which diabetes is clearly the
most common cause. Many varied neurologic lesions have been described in patients with diabetes. The
classic diabetic neuropathy, however, is often termed mononeuritis multiplex, which is characterized by the
sudden loss of single peripheral nerves in an asymmetric distribution. Patients will often have loss of
sensation or burning paresthesias of their feet as a primary finding. Other fairly common neuropathies have
been described with uremia, vitamin B 12 deficiency, AIDS, and paraneoplastic syndromes.
Trauma-related nerve injury is also a common cause of neuropathy. In this category, repetitive motion
injuries such as carpal tunnel syndrome require specific attention when evaluating a patient with hand
complaints. The carpal tunnel is also affected in hypothyroidism, acromegaly, and rheumatoid arthritis.
Peripheral neuropathy can be associated with rare hereditary disorders, endocrine abnormalities, and
exposures to drugs and toxins. Many of the more common etiologic causes for peripheral neuropathy can be
found in Table 19–3 .
Table 19-3 -- Differential Diagnosis of Peripheral Neuropathy *

Mechanical Medical Infectious Toxins Drugs
Vitamin B12
Trauma Botulism Acrylamide Amiodarone
deficiency
Carpal
Diabetes Diphtheria Ethanol Dapsone
tunnel
Guillain-Barré
Hypothyroid Elapid venom Isoniazid
syndrome
Multiple myeloma HIV and AIDS Hexacarbons Phenytoin
Paraneoplastic Leprosy Lead Pyridoxine
Uremia Lyme disease Organophosphates Taxol
Mechanical Medical Infectious Toxins Drugs
Thallium Vincristine
(See other agents in Tables (See other agents in
19–1 and 19–2 ) Tables 19–1 and 19–2 )
* A complete differential diagnosis of peripheral neuropathy is very extensive; this table lists some of the more common causes.


CLINICAL EVALUATION
As always, the evaluation begins with a thorough history and physical examination. The history should
concentrate on the onset, duration, and progression of symptoms as well as hobbies, occupations, and
environmental sources of toxins. A thorough occupational history is essential and must not focus only on a
job title but rather on a description of the type of work, the workplace, and possible chemicals or agents used
by coworkers. Additional inquiry should focus on a family history of inherited disorders listed in Table 19–3 ,
access to medications (including over-the-counter dietary supplements), and the use of alcohol and other
substances of abuse.
Physical examination must include a complete search for medical illness and a comprehensive neurologic
assessment. All distributions of the nervous system should be evaluated, including those modalities rarely
examined (temperature discrimination), and documented. Objective findings such as measurement of two-
point discrimination, responsiveness of deep tendon reflexes, and strength should be quantified and
recorded for comparison with pre-existing medical records and future examinations.


Common Laboratory Tests
The potential for overutilization of the laboratory can easily be appreciated if the clinician elects to
immediately screen for all disorders associated with peripheral neuropathy. This pitfall can only be avoided
by a rational step-wise approach that is guided by the history and physical examination and by a complete
knowledge of the incidence of these disorders. General screening for diabetes and severe electrolyte
disorders such hypokalemia, hypomagnesemia, and hypophosphatemia is a generally indicated first step. In
addition, a complete blood cell count, urinalysis, erythrocyte sedimentation rate determination, and liver
function studies can give excellent clues to the patient’s general level of health, as well as to many systemic
diseases. Although chest radiography and electrocardiography have some potential to detect tumors and
infiltrative diseases, the usefulness of these studies is questionable. Examination of the cerebrospinal fluid is
a required next step in any patient in whom there is a consideration of GBS.
Specialized Laboratory Studies
Biologic monitoring should be obtained to confirm exposure whenever the history suggests the role of toxins
that are known to be associated with peripheral neuropathy. The two major pitfalls of biologic monitoring,
however, are an inability to obtain determinants of exposure to all substances and the lack of a strong
correlation between exposure and neuropathy. Thus, although confirmation of exposure increases the
likelihood of causation, it should never be considered sufficient grounds for establishing a diagnosis of toxin-
related peripheral neuropathy. This commonly occurs during an assessment for metal exposure. Improper
containers, collection methods, and the presence of small amounts of metals in most patients have the
potential to mislead clinicians who are not experienced in metal poisoning.
Electrodiagnostic testing (EDT) should be ordered. The first role of EDT is to confirm the diagnosis of
peripheral neuropathy by distinguishing between primary muscle and neurologic disorders. Subsequently,
EDT can define the location and extent of the disorder (number and distribution of nerves involved). This
helps exclude trauma, diabetes, and a few other disorders such as carpal tunnel syndrome from the
extensive differential diagnosis list. A further characterization can be made between an axonopathy and a
myelinopathy. Because most toxin-mediated disorders are axonopathies and many common medical
disorders are myelinopathies, this distinction can prove most useful. Knowledge of the distribution, extent,
and probable histology of the disorder allows the clinician to correlate the patient’s clinical findings to those
reported in the literature. If such a correlation exists, it will solidify a claim of causation. Finally, EDT has the
ability to characterize effects at the neuromuscular junction. Certain disorders such as botulism, Eaton-
Lambert syndrome, and myasthenia gravis have characteristic findings on EDT that are nearly diagnostic.
A final diagnostic test is sural nerve biopsy. Biopsy is usually reserved for unclear cases where the histology
may prove diagnostic. The sural nerve is typically selected for its accessibility and lack of debility after
biopsy.


Even though antidotal therapy is available for some toxin-induced peripheral neuropathies such as assorted
venoms, metals and metalloids, and botulism, the mainstay of treatment for most patients with toxin-induced
peripheral neuropathy is removal from exposure. The clinician should not be discouraged if the patient’s
condition continues to deteriorate for a period of several weeks after removal from exposure, because this is
a commonly described event. Rather, the clinician should counsel the patient about the duration of illness,
expected recovery phase, the extent of the recovery expected based on the histology of the injury, and the
course of rehabilitation therapy that will be required.


Peripheral neuropathy is rarely a life-threatening disorder. The clinician should recognize those findings that
might suggest the need for immediate intervention or hospitalization.
• The patient is manifesting symptoms of an acute progressive motor neuropathy. It is essential to
recognize rapidly progressive motor neuropathies because of their potential to result in ventilatory
insufficiency. Although this most commonly occurs as a complication of GBS, its toxic correlate could be
considered the patient with botulism or elapid envenomation who presents with diplopia as a sole
finding.
• The peripheral neuropathy is a manifestation of exposure to a toxin with associated life-threatening
manifestations that are not related to the neuropathy itself. A good example would be the ascending
painful sensory neuropathy that might serve as an early marker for a severe case of thallium toxicity.
• There is a potential need to administer an antidote that has intrinsic toxicity. This would include most
antivenins, botulism antitoxin, and the metal chelators.
• The diagnosis is unclear and may be related to a medical illness with consequential indications.
In the absence of these indications, the majority of patients with peripheral neuropathy can be evaluated as
outpatients. Appropriate diagnosis and care will often require a concerted effort between a toxicologist, an
occupational medicine physician, and a neurologist.


REFERENCES
1. Abbritti G, Siracusa A, Cianchetti C, et al: Shoe-makers’ polyneuropathy in Italy: The aetiological
problem. Br J Indust Med 1976; 33:92-99.
2. Abou-Donia MB: Solvents. In: Abou-Donia MB, ed. Neurotoxicology, Boca Raton: CRC
Press; 1992:395-421.
3. Albin RL, Albers JW, Greenberg HS, et al: Acute sensory neuropathy-neuronopathy from pyridoxine
overdose. Neurology 1987; 37:1729-1732.
4. Anthony DC, Graham DG: Toxic responses of the nervous system.

In: Amdur MO, Doull J, Klaassen CD, ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons,
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5. Baba A, Cooper JR: The action of black widow spider venom in synaptosomes. J
Neurochem 1980; 34:1369-1379.
6. Bank WJ: Thallium. In: Spencer PS, Schaumburg HH, ed. Experimental and Clinical Neurotoxicology,
Baltimore: William & Wilkins; 1980:570-577.
7. Binder LS: Acute arthropod envenomation: Incidence, clinical features and management. Med Toxicol
Adverse Drug Exp 1989; 4:163-173.
8. Buiatti E, Cecchini S, Ronchi O, Dolara P, Bulgarelli G: Relationship between clinical and

electromyographic findings and exposure to solvents, in shoe and leather workers. Br J Indust
Med 1978; 35:168-173.
9. Calderone-Gonzalez R, Rizzi-Hernandez H: Buckthorn polyneuropathy. N Engl J Med 1967; 277:69-71.
10. Cavanagh JB: Peripheral neuropathy caused by chemical agents. CRC Crit Rev Toxicol 1973; 2:365-
417.
11. Charness ME, Simon RP, Greenberg DA: Ethanol and the nervous system. N Engl J
Med 1989; 321:442-454.
13. Cho ES: Toxic effects of adriamycin on the ganglia of the peripheral nervous system: A
neuropathological study. J Neuropathol Exp Neurol 1977; 36:907-915.
14. Comi G, Medaglini S, Nemni R, et al: Peripheral nervous system involvement in AIDS and HIV patients:
A comparative neurophysiologic and morphologic study (abstract). Int Conf AIDS 1991; 7:212.
15. Dubinsky RM, Yarchoan R, Dalakas M, Broder S: Reversible axonal neuropathy from the treatment of
AIDS and related disorders with 2',3'-dideoxycytidine (ddC). Muscle Nerve 1989; 12:856-860.
16. Dumitru D, Kalantri A: Electrophysiologic investigation of thallium poisoning. Musc Nerv 1990; 13:433-
437.
17. Feldman RG, White RF, Currie JN, et al: Long-term follow-up after single toxic exposure to
trichloroethylene. Am J Ind Med 1985; 8:119-126.
18. Fisher CM, Adams RD: Diphtheritic polyneuritis: A pathological study. J Neuropathol Exp
Neurol 1956; 15:243-268.
19. Fullerton PM: Electrophysiological and histological observations on peripheral nerves in acrylamide
poisoning in man. J Neurol Neurosurg Psychiatry 1969; 32:186-192.
20. Garland TO, Patterson MWH: Six cases of acrylamide poisoning. Br Med J 1976; 4:134-138.
21. Jerian SM, Sarosy GA, Link CJ, Fingert HJ, Reed E, Kohn EC: Incapacitating autonomic neuropathy
precipitated by taxol. Gynecol Oncol 1993; 51:277-280.
22. Kitchens CS, Van Mierop LHS: Envenomation by the eastern coral snake (Micrurus fulvis fulvis).
JAMA 1987; 258:1615-1618.
23. Lambert JS, Seidlin M, Reichman RC, et al: 2',3'-dideoxyinosine (ddI) in patients with the acquired
immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322:1333-1340.
24. LeLacheur SF, Simon GL: Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine. J
Acquir Immune Defic Syndr 1991; 4:538-539.
25. Le Quesne PM: Neurotoxic substances. Mod Trends Neurol 1975; 6:83-97.
26. Le Quesne PM: Clinical and morphological findings in acrylamide toxicity. Neurotoxicology 1985; 6:17-
24.
27. LeWitt PA: The neurotoxicity of the rat poison vacor: A clinical study of 12 cases. N Engl J
Med 1980; 302:73-77.
28. Lovejoy FH: Thallium. Clin Toxicol Rev 1982; 4:1-2.
29. McCollister DD, Oyen F, Rowe VK: Toxicology of acrylamide. Toxicol Appl Pharmacol 1964; 6:172-
181.
30. Meggs WJ, Hoffman RS, Shih RD, Weisman RS, Goldfrank LR: Thallium poisoning from maliciously
contaminated food. J Toxicol Clin Toxicol 1994; 32:723-730.
31. Meves H, Rubly N, Watt DD: Effect of toxins isolated from the venom of the scorpion Centruroides
sculpturatus on the Na currents of the node of Ranvier. Pflugers Arch 1982; 393:56-62.
32. Monckton G, Pehowich E: Autonomic neuropathy in the streptozotocin diabetic rat. Can J Neurol
Sci 1980; 7:135-142.
33. Monforte R, Estruch R, Valls-Sole J, Nicolas J, Villalta J, Urbano-Marquez A: Autonomic and peripheral
neuropathies in patients with chronic alcoholism: A dose-related toxic effect of alcohol. Arch
Neurol 1995; 52:45-51.
34. Montaner JS, Rachlis A, Zala C, et al: The safety profile of stavudine (d4T) in advanced HIV infection:
Experience from the Canadian expanded access program (EAP) (abstract). Nat Conf Hum Retroviruses
Relat Infect 1995; 2:104.
35. Moyle G, Goll A, Snape S: Safety of zalcitabine (ddC) in zidovudine (ZDV) intolerant individuals: Results
of the European expanded access study (abstract). Int Conf AIDS 1994; 1:210.
36. Narahashi T: Mechanism of action of tetrodotoxin and saxitoxin on excitable membranes. Fed
Proc 1972; 31:1117-1123.
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Pharmacol 1978; 45:269.
38. Parry GJ, Bredesen DE: Sensory neuropathy with low-dose pyridoxine. Neurology 1985; 35:1466-
1468.
39. Pellissier JF, Pouget J, Cros D, et al: Peripheral neuropathy induced by amiodarone chlorohydrate. J
Neurol Sci 1984; 63:251-266.
40. Phelan DM, Hagley SR, Guerin MD: Is hypokalemia the cause of paralysis in barium poisoning?. Brit
Med J 1984; 289:662.
41. Rosenfeld CS, Broder LE: Cisplatin-induced autonomic neuropathy. Cancer Treat Rep 1984; 668:659-
660.
42. Rizzuto N, Terzian H, Galiazzo-Rizzuto S: Toxic polyneuropathies in Italy due to leather cement
poisoning in shoe industries. J Neurological Sci 1977; 31:343-354.
43. Sabri MI, Moore CL, Spencer PS: Studies on the biochemical basis of distal axonopathies. I. Inhibition
of glycolysis of neurotoxic hexacarbon compounds. J Neurochem 1979; 32:683-689.
44. Seto DSY, Freeman JM: Lead neuropathy in children. Am J Dis Child 1964; 107:337-342.
45. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: A new
megavitamin syndrome. N Engl J Med 1983; 309:445-448.
46. Schmidt RE, Plurad SB, Clark HB: Acrylamide-induced sympathetic autonomic neuropathy resulting in
pineal denervation. Lab Invest 1987; 56:505-517.
47. Simpson LL: The origin, structure, and pharmacologic activity of botulinum toxin. Pharmacol
Rev 1981; 33:155-185.
48. So YT, Holtzman DM, Abrams DI, Olney RK: Peripheral neuropathy associated with acquired
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49. Sobue G, Pleasure D: Experimental lead neuropathy: Inorganic lead inhibits proliferation but not
differentiation of Schwann Cells. Ann Neurol 1985; 17:462-468.
50. Taher SM, Anderson RJ, McCarthy R, et al: Renal tubular acidosis associated with toluene sniffing. N
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51. Thomas PK: The peripheral nervous system as a target for toxic substances.
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Uncited reference
Cho ES: Toxic effects of adriamycin on the ganglia of the peripheral nervous system: A neuropathological
study. J Neuropathol Exp Neurol 1977; 36:907-917.


Chapter 20 – Cardiovascular Instability Caused by Drugs or Chemicals
JEFFREY BRENT
Essentials
• For patients with cardiovascular instability secondary to poisoning, standard treatment is appropriate
with a few notable exceptions.
• Cardiovascular instability associated with poisonings may present as hypotension or hypertension,
dysrhythmias, conduction disturbances, or myocardial depression.
• Rapid identification of certain specific toxic syndromes can prompt appropriate antidotal therapy. These
syndromes include those caused by cyclic antidepressants, digitalis glycosides, cocaine, calcium
channel blockers, and ß-adrenergic receptor antagonists.
PATHOPHYSIOLOGY
Most major toxic syndromes have some component of cardiovascular effects. Frequently, the cardiovascular
manifestations of toxins are secondary to metabolic, pulmonary, or neurologic effects of the particular toxin.
The focus of this chapter is on primary, or direct, cardiovascular effects of specific toxic substances. Even
limiting the chapter in this way does not protect us from the remaining prodigious group of cardiovascular
manifestations that can be directly caused by toxic substances. In addition, a primary cardiovascular effect
of a toxin is frequently followed by a series of secondary manifestations on the same organ system. For
example, hypertension caused by excessive amounts of the a-adrenergic receptor agonist
phenylpropanolamine (PPA) can cause reflex secondary bradycardia.[6]
The toxic manifestations of specific substances can be broadly divided into classes that have the following
general effects: (1) agents that affect blood pressure; (2) agents that cause cardiac dysrhythmias and
conduction disturbances; and (3) agents that cause myocardial depression. Subcategories exist within each
of these major classes of toxic effects. The most common ones are considered in this discussion.
Drug-Induced Hypertension
Like all cardiovascular effects of toxins, hypertension can be either primary or secondary. Secondary
hypertension, for example, could result from sympathetic hyperactivity caused by cocaine use. A variety of
agents can have a primary hypertensive effect on the cardiovascular system. These are listed in Table 20–1
along with the mechanism by which they provoke this effect.
Table 20-1 -- Drugs and Chemicals Directly Causing Hypertension

Agent Mechanism
a1-Adrenergic Receptor Agonists Directly stimulate a1-adrenergic receptors
Examples:
Clonidine *
Epinephrine
Ergotamines
Metaraminol
Methoxamine
Naphazoline
Norepinephrine
Oxymetazoline
Phenmetrazine
Phenylephrine
Phenylpropanolamine
Pseudoephedrine
Tetrahydrozoline
Tyramine
Yohimbine
Sympathomimetic Agents Release of catecholamines †
Examples:
Amphetamine
Cocaine
Diethylproprion
Fenfluramine
MDMA ‡
Mescaline
Methamphetamine
Methylphenidate
Pemoline
Phenmetrazine
Other
Latrodectus (black widow spider) Venom Release of catecholamines †
Bretylium Release of catecholamines
Agent Mechanism
Caffeine (early) Release of catecholamines
Cathinone alkaloids Release of catecholamines †
Direct a-adrenergic receptor agonist
Decreased catecholamine degradation
Monoamine oxidase inhibitors Prevent catecholamine degradation
Nicotine Release of catecholamines
Organophosphates Release of catecholamines
Phencyclidine Release of catecholamines
Theophylline (early) Release of catecholamines
* Acts centrally as an a 2-adrenergic receptor agonist but can also act peripherally on a1-adrenergic receptors.
† Also some direct vasoconstrictor activity.
‡ 3,4-Methylenedioxyamphetamine (“Adam” or “Ecstasy”).
Patients with drug-induced hypertension will typically manifest both an elevated systolic and a diastolic blood
pressure, since the mechanism is vasoconstriction. The effects on heart rate can be variable. As noted
earlier, pure a-adrenergic receptor agonists such as PPA can cause reflex bradycardia.[6] Alternatively,
agents that have ß-adrenergic receptor agonist qualities will frequently induce tachycardia from the direct
effect on cardiac ß1 receptors. Cardiac output ranges from normal to increased in drug-related hypertension.
Toxin-Induced Hypotension
Like hypertension, the hypotension seen in association with toxic exposures can be either primary or
indirect. Secondary hypotension may be due to depressed cardiac contractility, a hemodynamically
significant cardiac dysrhythmia, intravascular fluid loss, or decreased sympathetic tone. The latter can be
caused by sympatholytic agents such as barbiturates, opioids, central a2-adrenergic receptor agonists,
benzodiazepines, or other sedative-hypnotic drugs. These agents tend to act by inhibiting sympathetic
outflow from the locus ceruleus. Direct-acting hypotensive agents are vasodilators. Sildenafil, a cyclic
guanosine monophosphate–specific type 5 phosphodiesterase inhibitor, can potentiate the hypotensive
effect of nitroglycerin and other organic nitrates that are nitrous oxide donors. Table 20–2 lists agents that
cause hypotension by vasodilation.
Table 20-2 -- Vasodilators

Angiotensin effector drugs
ACE inhibitors
Angiotensin receptor II antagonists
Adenosine *
Buflomedil †
Examples:
Amlodipine
Bepridil
Cinnarizine
Diltiazem
Felodipine
Flunarizine †
Isradipine
Nicardipine
Nifedipine
Nimodipine
Verapamil
Diazoxide
Flosequinan †
Hydralazine
Minoxidil
Naftidofuryl †
Nitrates/nitrites
Nitroprusside
Phenothiazines
Phenoxybenzamine
Phentolamine
Phosphodiesterase inhibitors
Examples:
Amrinone †
Caffeine
Dipyramidole
Enoximone †
Imazodan †
Milrinone
Pentoxifylline
Pimobendan †
Piroximone †
Theophylline
Prazosin
Sildenafil—nitroglycerin and other organic nitrate interaction
Terazosin
* Short acting.
† Not available in the United States.
Toxin-induced hypotension is characterized by a decrease in systolic and/or diastolic blood pressure.

Tachycardia may be present as a compensatory response unless there is an inhibition of cardiac
sympathetic tone or cardiac conduction by some other process. Because patients with direct drug-induced
hypotension usually have vasodilation, their skin is frequently warm to the touch. Because vasodilation
generally causes a disproportionate drop in diastolic blood pressure, these patients will frequently have a
wide pulse pressure. Cardiac index could be decreased, normal, or increased depending on the status of the
other components of the cardiovascular system. Isolated vasodilation will in general tend to increase cardiac
output.
Toxin-Induced Cardiac Dysrhythmias
The diversity of toxins that can cause cardiac dysrhythmias by any mechanism is prodigious. Like toxin-
related effects on blood pressure, rhythm manifestations may be either primary or secondary. The
secondary, or indirect, cardiac dysrhythmias can result from many mechanisms, including hypoxia,
electrolyte abnormalities, vasodilation, vasoconstriction, or effects on the nervous system. For example,
although cocaine exerts some direct cardiac effects on vasoconstriction of the coronary vasculature[7] and
sodium channel blockade,[5] most rhythm disturbances caused by cocaine are due to the drug’s effect on
autonomic sympathetic activity.[1][2][5] The heightened sympathetic discharge from the locus ceruleus caused
by cocaine is responsible for many of its cardioexcitatory effects, which are a major component of the
cardiovascular manifestations of cocaine toxicity.
Although a variety of agents can cause primary and secondary effects on cardiac rhythm, it is of therapeutic
and diagnostic importance that several agents cause specific and characteristic dysrhythmias. Table 20–3
lists the typical, or common, agents that cause primary cardiac dysrhythmias.
Table 20-3 -- Drugs and Chemicals Causing Primary Cardiac Dysrhythmias

Toxin Dysrhythmia(s)
ß1-Adrenergic receptor antagonists Bradycardia
Calcium channel antagonists Bradycardia
Rapid ventricular rate in Wolff-Parkinson-White syndrome with
atrial fibrillation
Toxin Dysrhythmia(s)
Carbamazepine
Cardiac glycosides Multiple
Examples:
Bufatoxin
Digitoxin
Digoxin
Dogbane
Foxglove
Lily of the valley
Milkweed
Oleander
Ouabain
Supraventricular and ventricular tachydysrhythmias, ventricular
Chloral hydrate
fibrillation
Chloroquine Ventricular tachycardia
Ciguatera toxin Bradycardia, heart block
Cocaine Ventricular dysrhythmias, conduction block
Emetine Ventricular fibrillation
Ethanol Atrial fibrillation
Halogenated hydrocarbons Ventricular fibrillation *
Hellebore Bradycardia
Lithium Bradycardia, sinoatrial or atrioventricular block
Magnesium Bradydysrhythmias, heart block
Potassium Sine wave, ventricular fibrillation asystole
Propoxyphene (norpropoxyphene) Ventricular tachydysrhythmias
Q-Tc interval–prolonging agents (see Table
Torsades de pointes
20–4 )
Thioridazine/mesoridazine Ventricular tachydysrhythmias
Cyclic antidepressants Wide complex supraventricular tachycardias
Type 1A and 1C antidysrhythmics Bradycardia, ventricular tachydysrhythmias
* Theorized to be due to sensitization of myocardium to catecholamines, although hypoxia has not been ruled out.
Among those agents that cause very specific effects on cardiac rhythm are digitalis glycosides, cyclic
antidepressants, and the variety of substances that directly increase the Q-Tc interval and thus predispose
the development of torsades de pointes.
There are two major ways in which toxins can directly induce cardiac dysrhythmias. They may either
increase, or provoke, dysrhythmogenic impulses or they may cause abnormal conduction of action potentials
through the heart.
The aberrant production of arrhythmogenic action potentials can result from abnormal automaticity of areas
of the heart that are usually devoid of rhythm generative impulses. Alternatively, triggering of
afterdepolarizations may cause oscillations in cardiac tissue potentials. If these oscillations occur in the
resting, or phase IV, stage, they may cause the threshold for triggering the opening of voltage-gated sodium
channels to be exceeded. The result ( Fig. 20–1 ) is an action potential that may be propagated, resulting in
a phase 0 upstroke and spread of the action potential from the provoking site. Triggered afterpotentials are a
cause of the characteristic dysrhythmias seen in cardiac glycoside toxicity.[12]
Figure 20-1 Cardiac electrical potentials in a cell that has afterpotentials generated during phase 4. Should one of these
afterpotentials reach the threshold level, an action potential would be generated.
Drugs and chemicals that cause abnormal conduction of impulses tend to be dysrhythmogenic. They may
stimulate re-entrant dysrhythmias or cause abnormalities in the action potentials in the cardiac conduction
tissue. For example, cardiac glycosides inhibit cardiac conduction through the atrioventricular node.[12]
Cyclic antidepressants have a characteristic effect on cardiac conduction distal to the His-Purkinje system
such that impulses are propagated through right-sided fibers in an abnormal fashion, giving rise to the
characteristic terminal rightward QRS forces seen on the surface electrocardiogram (EKG).[10]
Torsades de Pointes Tachycardia

A unique type of ventricular tachydysrhythmia associated with a prolongation of the Q-T c interval is torsades
de pointes ( Fig. 20–2 ). This is a reciprocating ventricular tachycardia because of the sequential and regular
decreasing and increasing magnitudes of the QRS complex on the EKG. This dysrhythmia is triggered by
early afterdepolarizations and results in the axis of the QRS complex rotating in sequential 360-degree
cycles around the baseline of the EKG.[3] Patients with either hereditary or acquired Q-Tc prolongations are
at risk for developing torsades de pointes. Acquired Q-Tc prolongation is generally due either to metabolic
abnormalities or to drugs that affect phase II or III of the action potential. A list of drugs that broaden the Q-
T c interval and predispose to torsades de pointes is provided in Table 20–4 . Class 1A antidysrhythmic
agents (quinidine, procainamide, and disopyramide) are the most typical causes of torsades de pointes. The
class 1A agents, particularly quinidine, can cause torsades de pointes even at therapeutic doses and levels.
Figure 20-2 A 37-year-old female intubated and comatose from a thioridazine overdose who sustained perfusing torsades de pointes
following sinus rhythm with a prolonged Q-Tc interval.
Table 20-4 -- Drugs and Chemicals That Increase the Q-Tc Interval
Amantadine
Arsenic
Astemizole
Bepridil
Butyrophenones
Chloral hydrate
Chloroquine
Cisapride
Citalopram
Emetine
Fluoride (secondary to hypocalcemia)
Fluoxetine
Ketoconazole
Erythromycin
Mercury (organic)
Organophosphates
Pentamidine
Phenothiazines (particularly thioridazine, mesoridazine)
Phosphorus
Pimozide
Scorpion venom
Terfenadine
Tetracyclic antidepressants
Tricyclic antidepressants
Vaughan-Williams Class IA antidysrhythmics
Disopyramide
Procainamide
Quinidine (levels usually therapeutic or subtherapeutic)
Vaughan-Williams Class IC antidysrhythmics
Encainide
Flecainide
Lorcainide
Moricizine
Propafenone
Vaughan-Williams Class III antiarrythmics
Amiodarone
Bretylium
N-Acetylprocainamide
Sotalol
Supratherapeutic levels of astemizole and terfenadine are also associated with torsades de pointes. These
generally occur when these agents bioaccumulate, usually a consequence of the simultaneous
administration of a second agent that competitively inhibits their metabolic degradation by the cytochrome P-
450 isoenzyme 3A4. Other agents metabolized by this isoenzyme include macrolide antibiotics (except
azithromycin), the imidazole antifungals, human immunodeficiency virus protease inhibitors (indinavir,
ritonavir, saquinavir, and nelfinavir), serotonin reuptake inhibitors (fluvoxamine, nefazodone, and sertraline),
zileuton, cisapride, sparfloxacin, mibefradil, and grapefruit juice. Use of these agents is contraindicated with
these antihistamines. Cyclic antidepressants bind to the activated sodium channel [9][13] and thus act
pharmacodynamically like class 1A antidysrhythmic agents. However, they are an infrequent cause of
torsades de pointes. The tendency of cyclic antidepressants to provoke torsades de pointes may be
attenuated by their promotion of increased heart rates. Because the Q-Tc interval is rate dependent, the
relative tachycardia induced by cyclic antidepressants may modulate their effect on the Q-Tc interval.
Chloroquine is related to quinidine and probably exerts a similar effect on the activated sodium channel.
Toxicity from this agent, which is a growing problem in European countries, may be associated with torsades
de pointes.
Drug- or chemical-induced torsades de pointes is an imperfectly understood process. The prolongation of

the Q-Tc interval seen on the surface EKG is a manifestation of the prolonged phase II of the action
potential. Normally phase II is terminated by a rapid outward K+ current, which renders the intracellular
environment negative, a process referred to as phase III rapid repolarization. During the prolonged phase II
(plateau phase) the cell is vulnerable to new further depolarizations that can initiate torsades de pointes.
Thus, any agent that delays phase III repolarization both lengthens the Q-Tc interval and predisposes to
torsades de pointes.[15]
Toxin-Induced Myocardial Depression
Like other toxic cardiovascular manifestations, myocardial depression can be either primary or secondary.
Most often, myocardial depression associated with a toxic exposure is secondary to toxin-induced hypoxia,
metabolic abnormalities, or myocardial ischemia. However, several toxins such as cyclic antidepressants,
scorpion venom, and calcium channel antagonists have a direct depressant effect on the myocardium. A
primary manifestation includes a decrease in cardiac contractility, with resulting decreases in cardiac index,
blood pressure, and ejection fraction. Pulmonary capillary wedge pressure will generally be elevated.
Calcium channel antagonists tend to depress myocardial contractility by blocking phase 2 calcium influx into
the myocardial cell and therefore inhibiting excitation-contraction coupling. Of these agents the
phenylalkylamine class[14] (e.g., verapamil) has more of an effect on the myocardium and therefore
depresses myocardial contractility more than the other classes. However, at higher doses all calcium
channel antagonists can depress myocardial contractility.
Cyclic antidepressants can directly depress myocardial function in addition to causing conduction
disturbances and hypotension due to vasodilation.
Scorpion venom delays the inactivation of voltage-sensitive gated Na2+ channels,[4][8][11] resulting in
depressed myocardial function. Cardiac dysfunction is a major source of morbidity and mortality associated
with scorpion envenomation in certain parts of the world. The effect of scorpion antivenin in preventing or
treating this myocardial depression is unknown.
The differential diagnosis of patients presenting with cardiovascular instability caused by drugs or other
chemical substances is an exercise based on the pathophysiologic principles reviewed herein. Once the
clinician has classified the nature of the cardiovascular instability into one of the small number of categories
reviewed here, both the differential diagnosis and treatment follow naturally from the pathophysiology
already reviewed. Patients should be categorized by whether they are having abnormalities of blood
pressure, cardiac contractility, or cardiac conduction or dysrhythmias. For any of these abnormalities the
next question is whether these abnormalities are primary or secondary.
Blood pressure abnormalities may involve hypertension or hypotension, which may be primary or secondary.
Primary causes of hypotension are restricted to agents that cause vasodilation. Common agents that cause
primary hypotension are listed in Table 20–2 . Secondary hypotension generally will result ultimately from
secondary vasodilation, depression of myocardial function, or volume depletion.
Primary hypertension is generally caused by vasoconstricting agents (see Table 20–1 ). Secondary
hypertension typically results from sympathomimetic effects due to peripheral neuronal effects of drugs such
as amphetamines. Alternatively, secondary sympathomimetic effects may be caused by centrally acting
substances. Agents that cause renal injury may produce hypertension secondary to the toxic effect on the
kidney and activation of the renin-aldosterone system.
Although drugs and chemicals may be associated with a diverse variety of cardiac dysrhythmias, Table 20–3
shows that certain chemical agents are associated with specific dysrhythmias. Similarly, sinus bradycardia
or tachycardia may be due to either direct or indirect effects of chemical agents. The Q-T c interval comprises
ventricular depolarization and repolarization. Any process affecting either of these two events will prolong
this interval. The chemical agents and drugs listed in Table 20–4 prolong the Q-Tc interval. Other causes
include bundle branch block, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, ischemia,
complete heart block, acute central nervous system events, and genetically determined prolonged Q-Tc
syndrome.
Primary myocardial depression can be caused by agents listed in Table 20–5 . Alternatively, myocardial
depression can be secondary to ischemia, hypoxia, metabolic abnormalities, or volume depletion. Other
nontoxicologic and less common causes of myocardial depression include infectious, infiltrative, or
inflammatory diseases of the myocardium.
Table 20-5 -- Agents That Cause Primary Myocardial Depression

Arsenic
ß1-Adrenergic receptor antagonists
Ciguatera toxin
Colchicine
Cyanide
Ethanol *
Iron
Magnesium
Scorpion venom
Syrup of ipecac *
Tetrodotoxin †
Types IA and IC antidysrhythmics
* Cardiomyopathy associated with chronic abuse.
† Found primarily in the puffer fish (“fugu”) and blue-ringed octopus.


CLINICAL EVALUATION
The clinical evaluation of patients with cardiovascular instability related to chemicals or drugs should be
based on the relevant pathophysiology discussed earlier. Determining whether the cardiovascular instability
is due to vasoactive agents, myocardial depression, cardiac dysrhythmias, or conduction disturbances is the
essential primary challenge. Once that has been accomplished, the next goal is to determine the cause. This
is best accomplished by determining whether the cardiovascular instability is primary or secondary.
The clinical evaluation should focus in a very specific fashion on which of the above factors are operative.
This includes, at the minimum, a physical examination to assess the status of the circulation, a
determination of blood pressure and heart rate, and an EKG. On physical examination vascular perfusion
can be quickly assessed by an evaluation of mentation, capillary refill, and the color and temperature of the
skin. Blood pressure determination allows for the diagnosis of hypertension or hypotension; intra-arterial
pressure monitoring may be necessary in cases of severe hypotension or peripheral vasoconstriction. A
reduced diastolic pressure coupled with a wide pulse pressure is a clue to the possibility of vasodilation. In
ambiguous cases, direct measurements of the hemodynamic parameters may be made with the use of a
flow-directed pulmonary artery balloon (Swan-Ganz) catheter.


LABORATORY STUDIES AND INTERPRETATION
The EKG may provide clues that suggest non–drug-related causes of the instability, such as ischemia or
infarction. Rhythm disturbances may also be detected. Specific clues on the EKG suggesting the presence
of a direct toxic effect may be found by assessing the Q-Tc and QRS intervals and looking for specific
dysrhythmias and other conduction disturbances. The Q-Tc interval is considered to be the longest Q-Tc
interval in the limb leads. Causes of prolonged Q-Tc are listed in Table 20–4 .
Cyclic antidepressants have a variety of effects on the electrocardiogram. Prominent among them is a delay
in the propagation of impulses in the right ventricular fibers.[10] As a result, right ventricular depolarization
and subsequent repolarization are delayed. Because of the prolonged conduction time through the right side
of the heart, the EKG shows a rightward shift of the axes of the QRS complex and the Q-Tc interval.[10] This
results in a rightward deviation of the QRS complex manifested by a terminal S wave in leads I and AVL and
a prominent R' wave in lead aVR[10] (see Chapter 62 ). The presence of torsades de pointes on the EKG
suggests one of the agents listed in Table 20–4 .
The various intervals of the EKG can yield important clinical clues to the presence of toxic substances.
Atrioventricular block is seen primarily in the presence of ß-adrenergic receptor antagonists, calcium channel
antagonists, particularly of the benzothiazepine and phenylalkylamine varieties, and cardiac glycosides. The
rhythm and conduction disturbances seen in association with the cardiac glycosides are uniquely a
combination of conduction block and increased automaticity. Thus, a variety of complex dysrhythmias can
occur with these agents. The atrioventricular block may be high grade and associated with a variety of
excitatory rhythms, including atrial tachydysrhythmias, accelerated junctional tachydysrhythmias, and a
variety of ventricular dysrhythmias manifested mostly by premature depolarizations. These last dysrhythmias
give rise to bigeminy and trigeminy, ventricular tachycardia, and ventricular fibrillation.
Chest radiography is useful in evaluating for congestive heart failure, noncardiogenic pulmonary edema, and
other cardiopulmonary processes that may influence hemodynamics. Serum electrolyte determination can
reveal potassium abnormalities as well as metabolic acidosis, manifested by a decreased serum
bicarbonate concentration. Magnesium and calcium levels may be helpful particularly in patients with
prolonged Q-Tc intervals or torsades de pointes.
Serum drug levels may be helpful in evaluating for drug toxicity, but these levels must be interpreted in the
context of the clinical history. Patients taking medications over a prolonged period of time without an acute
increase in dose may show significant clinical toxicity despite relatively modest elevations in serum drug
levels. In contrast, after an acute overdose serum levels may be markedly elevated without significant signs
of toxicity. This latter scenario is true of most medications that follow multicompartment kinetics, where
measured serum levels do not reflect the tissue levels responsible for toxicity.


DEFINITIVE THERAPY
Once the etiology of the cardiovascular problem is ascertained, appropriate therapeutic maneuvers may be
undertaken. In most cases, standard advanced life support therapies are appropriate (see Chapter 3 ). In
certain cases in which cardiovascular instability is induced by particular toxic agents, specific antidotes or
therapies may be indicated. These are listed in Table 20–6 .
Table 20-6 -- Specific Antidotes for Cardiotoxins

Agent Antidote(s)
Arsenic British antilewisite
ß1-Adrenergic receptor antagonists Glucagon
Calcium channel antagonists Calcium, glucagon
Cardiac glycosides Antidigitalis Fab fragments
Cyanide Nitrites, thiosulfate, hydroxycobalamine
Fluoride Calcium, magnesium
Lactrodectus venom Antivenin
Magnesium Calcium
Potassium Calcium, NaHCO3, dextrose + insulin
Scorpion venom Antivenin
Sodium channel blockers Sodium bicarbonate
Cocaine
Norpropoxyphene
Thioridazine/mesoridazine
Class 1A and 1C antidysrhythmics
The treatment of drug- or chemical-induced torsades de pointes involves removal of the offending agent,
enhancing phase III repolarization, and preventing afterpotential generation. Stimulation of rapid
repolarization may be achieved by increasing heart rate, either with ß1-adrenergic receptor agonists such as
isoproterenol or with overdrive ventricular pacing. Class IB antidysrhythmics, such as lidocaine or phenytoin,
enhance repolarization and may also be effective. Suppression of afterpotentials can also be achieved with
type IB drugs. Magnesium may be the single most effective treatment. The mechanism of magnesium’s
effect is unknown, but it probably suppresses afterdepolarizations.[15] It does not stimulate rapid
repolarization and has no effect on the phase II action potential duration or the Q-Tc interval on the EKG.


DISPOSITION
Patients with mild cardiovascular manifestations due to toxins with known self-limited effects on the
cardiovascular system may be observed until the abnormalities resolve. An example is a patient with a mild
sympathomimetic syndrome related to exposure to a sympathomimetic agent such as cocaine. Once the
initial toxidrome has cleared, the patient may be discharged provided there is no concern for delayed or
recurrent toxicity. All patients with moderate to severe, or persistent signs of, cardiovascular instability,
including significantly abnormal vital signs, should be admitted to a monitored unit for treatment and
observation until the drug toxicity resolves. Intensive medical care commensurate to the severity of their
toxicity should be provided.
Some patients with initial cardiovascular instability can be placed in an appropriately monitored observation
unit. This would be particularly pertinent in cases in which minor and self-limited instability is anticipated and
nursing and monitoring capabilities are appropriate to the patient’s toxidrome. In addition, patients with initial
cardiovascular toxicity who responded to treatment, with resolution of the toxic manifestations, may also be
observed in an observation unit. For example, patients with cyclic antidepressant toxicity manifested solely
by sinus tachycardia who are not thought at danger for toxicity progression can be observed until their vital
signs normalize and then be discharged.
In a few cases, as clinical judgment dictates, patients with mild vital sign abnormalities may be discharged.
For example, a patient with persistent mild thyrotoxicosis from excessive thyroid hormone ingestion would
be expected to manifest this state for a period of days, generally beginning many days after the initial
overdose. Such patients may be observed on an outpatient basis once their clinical course suggests no
acute worsening. In all cases of deliberate drug or chemical use, the patient’s psychiatric status must be
evaluated for potential or ongoing suicidal thoughts.


REFERENCES
1. Abrahams TP, Cuntapay M, Varner KJ: Sympathetic nerve responses elicited by cocaine in anesthetized
and conscious rats, 59. Physiol Behav; 1996:109-115.
2. Branch CA, Knuepfer MM: Causes of differential cardiovascular sensitivity to cocaine: II. Sympathetic,
metabolic and cardiac effects. J Pharm Exp Ther 1994; 271:1103-1113.
3. Dessertenne F: La tachycardie ventriculaire à deux foyers opposés variables [Ventricular tachycardia

with 2 variable opposing foci]. Arch Mal Coeur Vaiss 1966; 59:263-272.
4. Dias-Kadambi BL, Combs KA, Drum CL, et al: The role of exposed tryptophan residues in the activity of
the cardiotonic polypeptide anthopleurin B. J Biol Chem 1996; 271:23828-23835.
5. Kloner RA, Hale S, Alker K, et al: The effects of acute and chronic cocaine use on the heart.
Circulation 1992; 85:407-419.
6. Lake CR, Gallant S, Masson E, et al: Adverse drug effects attributed to phenylpropanolamine: A review of
142 case reports. Am J Med 1990; 89:195-206.
7. Lange RA, Cigarroa RG, Yancy Jr CW, et al: Cocaine-induced coronary-artery vasoconstriction. N Engl
J Med 1989; 321:1557-1562.
8. Marcotte P, Chen LQ, Kallen RG, et al: Effects of Tityus serrulatus scorpion toxin gamma on voltage-
gated Na+ channels. Circ Res 1997; 80:363-369.
9. Muir WW, Strauch SM, Schaal SF: Effects of tricyclic antidepressant drugs on the electrophysiological
properties of dog Purkinje fibers. J Cardiovasc Pharmacol 1982; 4:82-90.
10. Niemann JT, Bessen HA, Rothstein RJ, et al: Electrocardiographic criteria for tricyclic antidepressant
cardiotoxicity. Am J Cardiol 1986; 57:1154.
11. Rogers JC, Qu Y, Tanada TN, et al: Molecular determinants of high affinity binding of alpha-scorpion
toxin and sea anemone toxin in the S3–S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
J Biol Chem 1996; 271:15950-15962.
12. Rosen M: The links between basic and clinical cardiac electrophysiology. Circulation 1988; 77:251-
263.
13. Sasyniuk BI, Jhamandas V: Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje
fibers by sodium bicarbonate. J Pharmacol Exp Ther 1984; 231:387-394.
14. Taira N: Differences in cardiovascular profile among calcium antagonists. Am J Cardiol 1987; 59:24B-
29B.
15. Tan HL, Hou CJY, Lauer MR, et al: Electrophysiologic mechanism of the long QT interval syndromes
and torsades de pointes. Ann Intern Med 1995; 122:701-714.


Chapter 21 – Hepatic Failure
ANTHONY ANKER
Essentials
• Treat hypoglycemia and electrolyte abnormalities.
• Correct intravascular volume deficits.
• Treat encephalopathy if present.
• Correct coagulopathy.
• Consider specific therapies such as N-acetylcysteine and hyperbaric oxygen.
• Consider referral for liver transplantation.
INITIAL STABILIZATION/TREATMENT
Hepatic injury is a common sequela of exposure to toxic agents.[20][50] It may be a primary manifestation of
poisoning or part of a toxin-induced multiple organ injury syndrome. The initial treatment of toxic liver injury
should focus on (1) the interruption of ongoing exposure to the toxin; (2) the use of special antidotes such as
N-acetylcysteine for acetaminophen poisoning; and (3) supportive care. In many cases the liver injury
resolves with simple withdrawal of the offending toxin.[39] For the critically ill patient, supportive care in an
intensive care unit setting is crucial. Treatment of fluid, electrolyte, and acid-base abnormalities is essential
to maintain proper cardiovascular function. Patients may require glucose administration and replacement of
coagulation factors. The treatment of hepatic encephalopathy requires the reduction of serum ammonia
concentration by decreasing protein intake and administering lactulose. The mainstay of treatment of
cerebral edema is hyperventilation and oxygen supplementation. It is also essential to maintain adequate
cerebral perfusion while treating cerebral edema. Hemodialysis or intubation for respiratory support may be
indicated when other organ systems are affected. Early consultation with a transplant center is indicated in
critically ill patients with acute hepatic failure.


ANATOMY AND PHYSIOLOGY RELATED TO TOXICITY
Ingested toxins are absorbed from the gastrointestinal tract in a lipid-soluble state and are transported
directly to the liver through the portal system, exposing the liver to the highest concentrations of these
agents. In addition, because of its central role in the detoxification of xenobiotics, the liver is especially
susceptible to toxic injury by metabolites of the toxin. Reactive metabolites produced by the process of
detoxification often cause hepatocellular injury at the site of their formation. The mechanisms by which some
chemicals, pharmaceuticals, and environmental toxins cause injury to the liver are well defined, whereas
those of others are not.
The acinus is the functional unit of the liver ( Fig. 21–1 ). It consists of an hepatic arteriole, a portal venule,
and a bile ductule. Blood flows from the portal triad through hepatic sinusoidal conduits into the central
(terminal) hepatic venule.[38] This anatomic relationship helps to explain physiologic differences between the
different zones of the acinus. Zone 1 cells, which are closer to the hepatic arteriole, portal venule, and bile
ductule, receive blood with a higher oxygen concentration and higher concentration of xenobiotics. They are
less metabolically active than zone 3 cells. The environment of the central hepatic venule (zone 3) is more
hypoxic, and there is increased activity of cytochrome P-450 enzymes, as well as increased detoxification
capacity by other mechanisms (see later). Zone 2 represents a transition area.[3]
Figure 21-1 Anatomy and functional zones of the acinus and associated toxins. The hepatic arterioles travel with the bile ductules and
the portal venules in the portal system (PS). Blood from the terminal hepatic arterioles (THA) and terminal portal venules (TPV) enters
the hepatic sinusoidal (HS) system and is collected in the central venule, otherwise known as the central (terminal) hepatic venule
(CHV). Zone 1 lies closest to the hepatic artery and receives blood with the highest oxygen content but also with the highest
concentration of hepatotoxins, which are often carried by the portal vein. Zone 3 is closest to the terminal hepatic venules and receives
oxygen-poor blood, so this area is most sensitive to ischemic injury. Zone 3 also has the highest cytochrome P-450 MFO activity. Zone
2 is intermediate in all respects. (Adapted from Rappaport AM, Wanless IR: Physioanatomic considerations. In Schiff L, Schiff ER
(eds): Diseases of the Liver, 7th ed. Philadelphia, JB Lippincott Company, 1993.)
Differences in local environment and metabolic activity explain some of the patterns of liver damage seen
with different toxins. Because of its proximity to the portal venule, zone 1 receives the highest concentration
of xenobiotics so that agents directly toxic to the liver, such as iron and yellow phosphorus, cause more
damage in this area. In contrast, agents such as acetaminophen and carbon tetrachloride that undergo
biotransformation by the cytochrome P-450 system cause damage to zone 3.
The cytochrome P-450 system is a gene superfamily with over 300 members, some of which exhibit a
spectrum of catabolic functions and some react with more select xenobiotics.[11][34] The activity of the
cytochrome P-450 enzymes can be enhanced (induced) in certain circumstances. Induction of certain
cytochrome P-450 enzymes will speed the metabolism of some xenobiotics but not others. For example,
phenobarbital therapy[7] and chronic ethanol ingestion[45] appear to induce the enzymes that are also
responsible for acetaminophen metabolism.[34] Patients who chronically ingest these agents may be at
higher risk of hepatotoxicity than the general population after an acetaminophen overdose and perhaps even
after therapeutic doses. There may be a survival advantage that explains this capacity to induce the P-450
function. Previous exposure to xenobiotics at low concentrations can be protective when the individual is re-
exposed to larger doses or higher concentrations.[26]
The biotransformation of xenobiotics by the P-450 system from lipid-soluble parent compounds to water-
soluble metabolites allows elimination of the toxin in the urine.[34][44] The biotransformation of xenobiotics is
mediated by phase I and phase II reactions. Phase I reactions are oxidation reactions that convert lipophilic
xenobiotics to more chemically reactive molecules by adding or exposing a more reactive hydroxyl (-OH),
sulfhydryl (-SH), amino (-NH2), aldehyde (-COH) or carboxyl (-COOH) group. Phase II reactions conjugate
the product of the phase I reaction with another molecule that significantly increases the water solubility of
the resultant compound and renders it chemically unreactive. Sometimes a highly reactive electrophile or
free radical is formed during a phase I reaction. If the phase II conjugation reaction is impeded, these
reactive intermediates may react directly with hepatocyte macromolecules, resulting in damage to the
hepatocyte.[15] Phase II reactions are synthetic and require energy provided by the hydrolysis of high-energy
phosphate compounds such as adenosine triphosphate. They also require electron-rich molecules
(nucleophiles) such as glutathione, S-adenosyl methionine, and uridine diphosphate glucuronic acid. The
most common metabolites are the glucuronidation or sulfation products. [34][44] Phase II reactions may also
take place without a preceding phase I reaction.[34][44]
The most important example of a phase I enzyme system is the microsomal cytochrome P-450 mono-
oxygenase system, or mixed-function oxygenase system. Cytochrome P-450 enzymes are heme proteins
located mainly in the endoplasmic reticulum. The cytochrome gets its name from its spectrophotometric
characteristics. When reduced cytochrome P-450 (Fe2+) binds to carbon monoxide, its maximal absorption
spectrum occurs at 450 nm. These enzymes mediate many different types of oxidation reactions.


DIFFERENTIAL DIAGNOSIS BASED ON MECHANISM ( Table 21–1 )
Free Radical Formation
The mechanism of hepatic injury caused by carbon tetrachloride (CCl4) has been extensively studied. CCl4
is oxidized by the cytochrome P-450 2E1 to the CCl3• free radical.[1] The CCl3• radical forms covalent bonds
with lipid membranes, causing lipid peroxidation, or may spontaneously react with molecular oxygen,
forming the even more reactive CCl3OO• free radical. Low oxygen tensions and high cytochrome P-450 2E1
activity favor CCl3• formation in zone 3, whereas higher oxygen tension favors the formation of the CCl3OO•
radical in zone 1. Although the more reactive CCl3OO• radical would be predicted to cause greater injury to
zone 1, this is not observed because glutathione reacts more rapidly with the CCl3OO• radical in zone 1 than
with the CCl3• radical in zone 3.[9] Therefore, zone 3 is subjected to greater liver injury by CCl4. Hyperbaric
oxygen has been shown to decrease liver injury in animals, possibly by increasing the formation of the
CCl3OO• radical, which is more readily detoxified.[8]
Table 21-1 -- Known Mechanisms of Hepatotoxicity

Rights were not granted to include this data in electronic media. Please refer to the printed book.
Adapted from Kaplowitz N, Aw TY, Simon FR, et al: Drug-induced hepatotoxicity. Ann Intern Med 1986;
104:826–839.
Electrophile Formation
Some xenobiotics undergo phase I biotransformation to a strong electron seeking (electrophilic)

intermediate. Acetaminophen is oxidized to N-acetyl-p-benzoquinoneimine (NAPQI) by the cytochrome P-
450 system, then detoxified and made water soluble by a phase II reaction with glutathione. In the setting of
acetaminophen overdose, the supply of glutathione is depleted and NAPQI reacts directly with cellular
macromolecules, causing liver damage.[37] Because the cytochrome P-450 MFO is concentrated in zone 3,
it is not surprising that most liver damage occurs in this area.
Oxygen Radical Formation
After enzymatic reduction in a phase I reaction, some agents can react directly with molecular oxygen to
form a superoxide anion radical (O2–•). The parent compound is then regenerated. Each molecule of the
xenobiotic generates multiple O2–• radicals, which can then react to form hydrogen peroxide (H2O2) and the
highly reactive hydroxyl radical (OH•). This causes a severe oxidative stress on hepatocytes. Examples of
these agents are nitrofurantoin, paraquat, and doxorubicin.[15]
Iron ions may play a role in the formation of these reactive intermediates.[2]
.
Idiosyncratic
Isoniazid (INH) is the best studied example of an idiosyncratic drug reaction—an hepatotoxic response that
is not dose related and does not have a clear mechanism. There are no animal models of INH toxicity and
only human data are available. Fifteen to 20 per cent of patients who receive INH as a single agent for the
treatment of tuberculosis develop elevated liver transaminase levels. Less than 1 per cent of patients
develop hepatic necrosis, which is often associated with concomitant rifampin use, or chronic alcohol
consumption, both of which induce the cytochrome P-450 system.[18]
Pathologically, INH causes diffuse hepatic necrosis similar to viral hepatitis.[15] People who rapidly acetylate
INH were once thought to be more susceptible to INH hepatotoxicity than were slow acetylators,[27] but on
further investigation this enzyme attribute does not clearly increase the risk of toxicity from INH.[12]
Steatosis
Many agents cause steatosis, generally after chronic exposure to the agent. Common toxins associated with
steatosis include ethanol, amiodarone, valproic acid, and tetracycline. The intracellular accumulation of fat
results from failure of a variety of hepatic functions related to the metabolism of lipids and fatty acids. These
include impairment of lipoprotein synthesis; decreased oxidation of fatty acids; increased production of
triglycerides; decreased binding of triglycerides to lipoproteins; increased peripheral fat mobilization;
increased uptake of circulating lipids; and decreased hepatic release of very-low-density lipoproteins. When
cell injury or death occurs, this reflects underlying metabolic dysfunction and not the presence of fat per se.
Most hepatotoxins that cause steatosis also cause other pathologic changes, such as necrosis,
inflammation, or cirrhosis. Some, like valproic acid, may cause steatosis without other significant associated
pathologic processes.[21][51]
Steatosis that is reversible with abstinence is an early pathologic lesion in alcoholic liver disease. This is
most likely related to the increased NADH/NAD+ ratio that occurs during the hepatic metabolism of ethanol,
resulting in decreased oxidation of fatty acids and the promotion of fatty acid synthesis. Ethanol also
increases the uptake of fatty acids into hepatocytes and decreases lipoprotein secretion.[22]
Recently, steatosis has been reported in HIV-infected patients taking antiviral agents such as zidovudine,
zalcitabine, and didanosine. During experimental treatment of hepatitis B infection the nucleoside analog
fialuridine caused several deaths due to failure of hepatic function. Pathologic examinations showed marked
intracellular accumulation of fat with minimal necrosis and minimal elevation of hepatocellular enzymes and
bilirubin. The severe acidosis seen in these cases suggested that injury was localized to the
mitochondria.[25] Steatosis with extensive hepatocellular necrosis was reported in a fatal case of Bacillus
cereus food poisoning associated with high levels of the emetic toxin cereulide in the bile and liver.[23]
Autoimmune Mechanisms
Halothane and possibly other inhalational anesthetics cause autoimmune hepatitis that is severe and,
fortunately, rare. This generally occurs on re-exposure to halothane and appears even after very small
exposures. This clinical entity has been seen in patients undergoing repeat surgery and in operating room
personnel exposed to low levels of the anesthetic. In these cases, liver damage appears to be due to
autoantibodies that are induced by exposure to halothane. Patients manifest rash, fever, eosinophilia, and
demonstrable autoantibodies in association with acute severe hepatitis.[29][36] Other inhalational anesthetics
(enflurane, isoflurane, desflurane) may also cause a similar illness.[10]
Milder hepatitis that is due to direct hepatotoxic effects also occurs in up to 20 per cent of patients exposed
to halothane. This is often not clinically evident.[29]
Cholestasis
Toxins may cause selective injury to the bile ducts or canaliculi, resulting in cholestasis with little damage to
hepatocytes. An associated inflammatory response with neutrophil migration into the area affected may[26] or
may not[15] contribute to the injury pattern. Specific mechanisms of injury are not well defined. Agents that
have been associated with cholestasis include oral contraceptives, trimethoprim-sulfamethoxazole, rifampin,
and erythromycin. The incidence of this syndrome appears to be rare.[20]
Veno-occlusive Disease
Veno-occlusive disease related to toxins is a pathologic variant of the Budd-Chiari syndrome, which results
in postsinusoidal obstruction to hepatic venous return. Hepatocellular necrosis occurs predominantly in the
zone 3 (centrilobular) areas, damaging sinusoidal endothelial cells and causing obstruction of venous
outflow, hepatic congestion, and portal hypertension.[20][40] The best studied examples of xenobiotic-induced
veno-occlusive disease are caused by plants that contain pyrrolizidine alkaloids.[17][40] These plants are
found throughout the world and have been associated with widespread outbreaks of poisoning as
contaminants in grain or when eaten during famines. Medicinal herbal remedies that contain pyrrolizidine
alkaloids include comfrey (Symphytum officinale), used as a digestive aid, and T’u-san-chi (Gynura
segetum), used for relief of psoriasis. The pyrrolizidine alkaloids are not inherently toxic but are converted to
a toxic form by cytochrome P-450 enzymes.[24]


The etiology of acute hepatic injury includes many toxic and nontoxic causes. The most common cause of
acute hepatic injury is viral hepatitis, with hepatotoxic exposures the second most common.[51] Other causes
of hepatic injury include autoimmune diseases, bacterial and parasitic infections, and tumors. Extrahepatic
causes such as cholecystitis, ascendingcholangitis, pancreatic disease, and hemolysis must also be
considered.[15] Some causes of acute hepatic failure are listed in Tables 21–2 and 21–3 . A thorough history
of ingestion or other exposure to hepatotoxic agents, along with a physical examination and liver enzyme
profile suggestive of hepatic damage, is the best clue to the diagnosis. Frequently, the diagnosis remains in
doubt, and the cause of liver injury in some patients is never learned.
Table 21-2 -- Causes of Acute Hepatic Disease

Viral
Hepatitis virus A, B, C, delta, non-A, non-B, herpes
Other viruses
Yellow fever
Epstein Barr virus—infectious mononucleosis
Exotic viruses: cytomegalovirus, Lassa, Marburg, Rift Valley, Ebola
Other
Acute fatty liver of pregnancy—severe
Wilson disease
Reye syndrome
Infiltration of liver (i.e., cancer)
Hyperthermia
Hypoperfusion syndromes—shock liver
Liver transplantation
Partial hepatectomy
Chronic active hepatitis—multiple causes
Xenobiotics (Partial Listing)
Drugs/chemicals
Cyclopeptide-containing mushrooms (Amanita species)
Plants—multiple classes of toxins
Fatty liver associated with tetracycline therapy
Chronic liver disease caused by xenobiotics
Chronic active hepatitis
Biliary cirrhosis
Alcoholic-like liver disease
Tumor formation
Hepatic veno-occlusive disease (Budd-Chiari syndrome)
From Bernuau J, Rueff B, Benhamou JP: Fulminant and subfulminant liver failure: Definitions and causes.
Semin Liver Dis 1986; 6:97–106.
Adapted from Koff R: Viral hepatitis. In Schiff L, Schiff ER (eds): Diseases of the Liver, 7th ed. Philadelphia, JB
Lippincott, 1993, pp 492–577, and Schiff G: Hepatitis caused by viruses other than hepatitis A, hepatitis B, non-
A non-B hepatitis viruses. In Schiff L, Schiff ER (eds): Diseases of the Liver, 7th ed. Philadelphia, JB Lippincott,
1993, pp 578–585.
Table 21-3 -- Xenobiotics Causing Hepatic Disease

Adapted from Kaplowitz N, Aw TY, Simon FR, et al: Drug-induced hepatotoxicity. Ann Intern Med 1986;
104:826–839; Lee WM: Drug-induced hepatotoxicity. N Engl J Med 1995; 333:1118–1127; and Zimmerman HJ,
Maddrey WC: Toxic and drug-induced hepatitis. In Schiff L, Schiff ER (eds): Diseases of the Liver, 7th ed.
Philadelphia, JB Lippincott Company, 1993, pp 707–837.


CLINICAL EVALUATION
The diagnosis of toxic injury may be delayed when a history of exposure to an hepatotoxic agent is not
obtained. This is often the case when there is a significant time delay from the toxic exposure to the onset of
illness. In addition, the unpredictable and idiosyncratic nature of hepatic injury caused by many agents
makes accurate diagnosis difficult. The clinical spectrum of hepatotoxicity ranges from asymptomatic
elevation of hepatic transaminase levels to fulminant hepatic failure (FHF).[5][18] Early symptoms of liver
injury such as malaise, nausea, vomiting, and abdominal pain are subtle and may be initially attributed to a
more benign disease process. Jaundice, which is not always present, implicates liver injury as a possible
cause of the illness. Jaundice and coagulopathy are predictable manifestations of hepatic failure, sometimes
in association with overt bleeding, and renal failure. FHF is defined by the presence of encephalopathy in
association with acute hepatic failure.[5] It is possible to make some assumptions about the general category
of liver dysfunction based on clinical presentation and simple laboratory data.[35] These are guidelines, and
there is a good deal of overlap among etiologic groups. In acute liver injury, progressive nonspecific
symptoms of general malaise, nausea, vomiting, and abdominal pain are noted by the patient 1 to 3 days
after the inciting toxic exposure. Similar symptoms noted within the first several hours are generally due to
direct gastrointestinal effects of the toxin. Jaundice follows 3 to 5 days after the initial toxic exposure. Liver
enzyme elevation can be seen as early as 24 to 36 hours after exposure to the toxin and often precedes
clinical evidence of hepatic injury. For example, exposure to carbon tetrachloride causes malaise, nausea,
vomiting, and diarrhea for 24 hours, followed by improvement. The onset of clinical manifestations of liver
injury begins 2 days to 2 weeks after exposure. Similarly, acetaminophen poisoning begins with several
hours of gastrointestinal symptoms followed by a clinically quiescent phase of 1 to 2 days, although
transaminase elevations often occur within the first 24 hours.[42] Clinically apparent hepatic injury is evident
within 1 to 3 days after ingestion. The autoimmune form of halothane toxicity has a longer time course with a
systemic inflammatory component. The initial constitutional symptoms include fever, which begins 3 to 5
days after exposure, followed in 3 days by hepatotoxicity. The onset of clinical manifestations of liver injury
in patients exposed to idiosyncratic hepatotoxins such as INH, ethanol, or valproic acid may be indolent and
prolonged.
During the initial evaluation of liver disease it is important to distinguish between acute injury, chronic injury
that is clinically stable, and an acute exacerbation of chronic injury. The rapidity of onset of symptoms and
the presence of known disease are the best evidence of the acuity of the present problem. The acute onset
of abdominal pain, jaundice, liver enzyme elevation, and coagulopathy is a familiar presentation in the
alcoholic patient. In comparison, a previously healthy person with nausea and malaise who is taking INH,
nitrofurantoin, or a-methyldopa offers more of a clinical diagnostic challenge.
Acute hepatocellular necrosis generally causes right upper quadrant abdominal pain, nausea, vomiting, and
jaundice. Laboratory studies include elevation of transaminase and bilirubin levels and sometimes
coagulopathy. The extent of coagulopathy, and the rapidity with which it develops, is indicative of the degree
of hepatic injury.[13][30] Recent introduction of a drug with known hepatotoxic properties is good evidence of a
toxicologic cause. Evidence of an autoimmune process such as rash and eosinophilia may also be related to
a toxic cause of hepatic injury. [15]
Cholestatic jaundice induced by hepatotoxins may be difficult to differentiate from other causes of jaundice.
The onset may be slow and indolent with minimal symptoms. The liver enzyme profile can be similar to that
seen with extrahepatic biliary obstruction, with elevated conjugated and unconjugated bilirubin, moderately
elevated serum alkaline phosphatase, and mild elevation (<1000 IU) of serum transaminases.[15]
Several host factors predispose to the development of more severe liver injury after toxic exposures.
Patients with previous hepatic disease such as chronic active hepatitis are more susceptible to injury by
hepatotoxic agents. The chronic use of P-450 enzyme inducers increases the risk of poisoning by agents
that are bioactivated by the same cytochrome P-450 enzymes. Although increased age has been suggested
as a risk factor for the development of toxic liver injury, it appears that when heart failure and other chronic
diseases are accounted for there is no specific age-related risk.[41]
Hepatic failure leads to compromise of other organ systems, including cardiovascular and circulatory
function. Hypotension results from fluid shifts, cardiac failure, and endothelial damage. Clumps of platelets
and leukocytes plug small arterioles and decrease tissue perfusion. Failure of hepatocellular synthetic
function leads to coagulopathy.[13] The prothrombin and partial thromboplastin times become elevated when
coagulation factors reach about 30 per cent of their normal concentrations. As coagulopathy progresses,
clinical bleeding may become evident. Pulmonary injury occurs by an unknown mechanism, resulting in
noncardiogenic pulmonary edema or adult respiratory distress syndrome.
Fulminant hepatic failure (FHF) occurs with the development of hepatic encephalopathy. Hepatic
encephalopathy is graded as shown in Table 21–4 : the higher the grade, the worse the clinical condition
and the worse the prognosis. The cause of hepatic encephalopathy is only beginning to be elucidated and is
probably multifactorial. Recent work has demonstrated that endogenous benzodiazepine-like substances
are found in the brains of patients with hepatic encephalopathy.[4] Flumazenil may ameliorate mental status
depression in patients with hepatic encephalopathy[28]; however, it does not have a proven therapeutic role.
Patients with hepatic encephalopathy also have elevated serum ammonia concentrations caused by the
inability to excrete the waste products of protein metabolism. Patients with higher grades of hepatic
encephalopathy show progression to irreversible brain disease. Seventy-five per cent of patients with grade
4 hepatic encephalopathy will develop cerebral edema.[31][48]
Table 21-4 -- Grades of Hepatic Encephalopathy

From O’Grady JG, Portmann B, Williams R: Fulminant hepatic failure. In Schiff L, Schiff ER (eds): Diseases of
the Liver, 7th ed. Philadelphia, JB Lippincott, 1993, pp 1077–1090.


LABORATORY STUDIES AND INTERPRETATION ( Table 21–5 )
Laboratory studies are useful in the care of patients with hepatic disease. Their proper interpretation requires
correlation with clinical findings. The extent of acute liver destruction can be estimated with a single
evaluation of serum transaminase concentrations, bilirubin concentration, and coagulation profile, whereas
serial changes show trends in liver injury. While falling transaminase levels often represent recovery, they
can also indicate worsening hepatic failure as enzymes released from dying cells are eliminated from the
body. The ability to maintain euglycemia and to produce coagulation factors is a good indicator of hepatic
metabolic function. Loss of the metabolic function of the liver indicates a poor prognosis. Acute renal
insufficiency or failure as a result of hepatic failure also indicates severe disease and a poor prognosis.
Table 21-5 -- Laboratory Studies in Hepatotoxicity

Serum transaminases
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
Lactate dehydrogenase
Bilirubin
Conjugated
Unconjugated
Electrolytes
Serum glucose
Blood urea nitrogen
Creatinine
Coagulation factors
Prothrombin test (international normalized ratio)
Partial thromboplastin time
Factors V, VIII
Viral studies
Hepatitis A, B, C, viral serologies
Epstein-Barr virus
Cytomegalovirus
Herpes simplex types 1 and 2
Varicella zoster
Serum toxin concentrations
Acetaminophen
Aspirin
Iron
The time course of recovery from toxic liver injury follows a general pattern. Transaminase concentrations
tend to fall first, followed by serum bilirubin concentrations, and finally recovery of coagulation factors to
baseline. There are variations in this recovery pattern between individual hepatotoxins.
Adjunctive laboratory studies are important for definitive diagnosis, but the results are generally not available
for several days and may have limited value in the acute setting. Serum concentrations of specific toxic
agents such as iron, aspirin, and acetaminophen are essential to make the diagnosis and guide therapy.
Screening for markers of hepatitis A, B, and C is standard in the diagnostic evaluation of acute hepatic
injury. When clinically indicated, laboratory tests for the Epstein-Barr virus, cytomegalovirus, herpes simplex
virus types 1 and 2, and varicella zoster may be useful. Radiologic studies to evaluate for bile duct
enlargement, hepatic masses, and an extrahepatic obstructing process such as stones or pancreatic
masses are essential when clinically indicated.


MANAGEMENT
The most important factors in the treatment of toxic liver injury are (1) recognition of the association between
a toxin and the injury, so that ongoing exposure is stopped; (2) recognition of indications for decontamination
and the use of special antidotes; and (3) supportive care.
Definitive Stabilization
Treatment of hepatic disease is similar to that of all other causes of toxic injury in that good general
supportive care is more important than definitive treatment of the specific poison. Specific antidotes exist for
only a few toxins. In general, the treatment of hepatic disease from all causes is similar. Aggressive
treatment of fluid, electrolyte, and acid-base abnormalities, including those of calcium, magnesium, and
phosphate, is essential to maintain proper cardiovascular function. Care must be taken to avoid
overaggressive treatment of metabolic disorders. Patients may require supplementation of the catabolic
activities of the liver such as glucose, blood products, and replacement of coagulation factors. Prothrombin
time values are used to assess the need for liver transplantation (see later). The treatment of hepatic
encephalopathy requires the reduction of serum ammonia concentration by decreasing protein intake and
administering lactulose. It is also essential to maintain cerebral perfusion. The mainstay of treatment of
cerebral edema is hyperventilation and oxygen supplementation, but other more controversial therapies
include mannitol and barbiturate coma.[32] Patients with hepatic failure frequently also have derangements of
other organ systems that require proper management.
Other aggressive therapies have been suggested with varying degrees of success. Prostacyclin improves
oxygen delivery by induction of microcirculatory vasodilation, inhibition of platelet activation, reduction of
leukocyte adhesion, and induction of fibrinolysis. It also displays inherent cytoprotective properties.[6] The
use of vasopressor drugs to treat hypotension associated with FHF may decrease oxygen delivery and
worsen tissue hypoxia. In contrast, epoprostenol, which is similar to prostacyclin and has similar activities,
seems to be of benefit in patients with hypotension and hepatic failure.[47] The treatment of hepatic failure
with charcoal hemoperfusion has been suggested but a controlled trial showed no benefit.[31]
Hepatotoxicity from certain agents can be ameliorated to different degrees by specific antidotal treatments.
N-Acetylcysteine is an effective antidote for acetaminophen poisoning, both for prevention and treatment of
hepatotoxicity.[14][16][43][48] N-Acetylcysteine may be useful in the treatment of other toxins, but further
studies are required to delineate its usefulness. Hyperbaric oxygen has been suggested for the treatment of
carbon tetrachloride–induced hepatotoxicity, based on anecdotal human care reports.[46] There are animal
data and a logical model supporting its effectiveness,[8] but hyperbaric oxygen has not been studied
adequately to elevate it to the status of a routine therapy in management of poisoning.
Disposition/Need for Consultants
The final disposition of a patient with liver injury depends primarily on the severity of the patient’s illness and
on the causative agent. Patients with significant vomiting or electrolyte abnormalities require prolonged
observation for intravenous fluid and electrolyte management. Patients who require prolonged treatment with
specific antidotes, such as the treatment of acetaminophen poisoning, require hospital admission. Any
patient with clinical signs of hepatic failure such as prothrombin time greater than 3 to 5 seconds above
normal, markedly elevated transaminase levels, renal insufficiency, or altered sensorium requires hospital
admission with close observation in a monitored or an intensive care unit.[19]
In the event of FHF, patients who can tolerate the procedure may benefit from liver transplantation. Liver
transplantation has been successful in many cases of FHF from hepatotoxins.[30][33][49] The most important
task of the acute care physician is to identify which patients are at high risk for mortality. This must be done
before their clinical condition deteriorates and the patient becomes too ill to undergo the transplant
procedure. The prediction of who will need transplantation is extremely difficult. Patients who survive acute
hepatic necrosis often recover completely so that one would hope to use transplantation only for those
patients who have little chance for survival without the procedure. A less than 20 per cent chance of survival
is an accepted cutoff point for this risk-benefit decision.[32][33] Currently, well-developed transplant criteria
have been formulated only for acetaminophen toxicity ( Table 21–6 ).[33] Consultation and patient transfer to
a specialty transplant center should occur before the patient’s illness has progressed to the degree
described in Table 21–6 , because the patient must undergo a good deal of preparation for this complex
surgery and complications that make transplantation difficult or contraindicated may develop quickly in toxin-
induced hepatic failure. There are no specific recommendations as to when these transfers should take
place,[30] but early consultation with a transplant center should be initiated when caring for such patients. At
the point that multiple organ failure has developed, only supportive care can be offered.
Table 21-6 -- Transplant Criteria

Acetaminophen Poisoning
pH < 7.30
or PT = 100 sec, creatinine > 3.4 mg/dL (300 µmol/L), and grade 3 to 4 hepatic encephalopathy
or coagulation factor V concentration < 10% of normal with the ratio of factors VIII: V > 30
Causes Other Than Acetaminophen-Induced Hepatic Failure
Prothrombin time > 100 seconds or INR > 6.7,
or any three of the following:
Unfavorable cause (non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reaction)
Duration of jaundice > 7 days before encephalopathy
Age < 10 or > 40 years
Prothrombin time > 50 seconds or INR > 4
Serum bilirubin > 17.5 mg/dL (300 µmol/L)
Coagulation factor V concentration < 20% of normal
INR, international normalized ratio.
From O’Grady JG, Alexander GJM, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure.
Gastroenterology 1989; 97:439–445; and Periera LMMB, Langley PG, Hayllar KM, et al: Coagulation factor V
and VIII: V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: Relation to other
prognostic indicators. Gut 1992; 33:89–102.


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acetylators: Possible relation to hydrazine metabolites. Clin Pharmacol Ther 1975; 18:70-79.
28. Mullen KD, Martin JV, Mendelson WB, et al: Could an endogenous benzodiazepine ligand contribute to
hepatic encephalopathy?. Lancet 1988; 1:457-459.
29. Neuberger J, Williams R: Halothane anaesthesia and liver damage. BMJ 1984; 289:1136-1139.
30. O’Grady JG, Alexander GJM, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure.
31. O’Grady JG, Gimson AES, O’Brien CJ, et al: Controlled trials of charcoal hemoperfusion and prognostic
factors in fulminant hepatic failure. Gastroenterology 1988; 94:1186-1192.
32. O’Grady JG, Portmann B, Williams R: Fulminant hepatic failure. In: Schiff L, Schiff ER, ed. Diseases of
the Liver, 7th ed. Philadelphia: JB Lippincott Company; 1993:1077-1090.
33. O'Grady JG, Wendon J, Tan KC: Liver transplantation after paracetamol overdose.
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34. Parkinson A: Biotransformation of xenobiotics. In: Klaassen C, ed. Casarett & Doull’s Toxicology, The
Basic Science of Poisons, 5th ed. New York: McGraw-Hill; 1996:151-156.
35. Podolsky DK, Isselbacher KJ: Derangements of hepatic metabolism.

In: Braunwald E, Fauci AJ, Isselbacher K, et al ed. Harrison’s Principles of Internal Medicine, 14th ed. New
York: McGraw-Hill; 1997:1667-1671.
36. Pohl LR: Drug-induced allergic hepatitis. Semin Liver Dis 1990; 10:305-315.
37. Potter WZ, Davis DC, Mitchell JR, et al: Acetaminophen-induced hepatic necrosis: Cytochrome P-
450–mediated covalent binding in vitro. J Pharmacol Exp Ther 1973; 187:203-210.
38. Rappaport AM, Wanless IR: Physioanatomic considerations. In: Schiff L, Schiff ER, ed. Diseases of
the Liver, 7th ed. Philadelphia: JB Lippincott; 1993:1-41.
39. Redlich CS, West AB, Fleming L: Clinical and pathological characteristics of hepatotoxicity associated
with occupational exposure to demethylformamide. Gastroenterology 1990; 99:748-757.
40. Ridker PM, Ohkuma S, McDermott WV, et al: Hepatic venoocclusive disease associated with the
consumption of pyrrolizidine-containing dietary supplements. Gastroenterology 1985; 88:1050-1054.
41. Schenker S, Bay M: Drug disposition and hepatotoxicity in the elderly. J Clin
Gastroenterol 1994; 18:232-237.
42. Singer AJ, Carracio TR, Mofenson HC: The temporal profile of increased transaminase levels in
patients with acetaminophen-induced liver dysfunction. Ann Emerg Med 1995; 26:49-53.
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44. Snipes IG, Gandolfi AJ: Biotransformation of toxicants.

In: Amdur MO, Doull J, Klaassen CD, ed. Casarett and Doull’s Toxicology, 4th ed. New York: Pergamon
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45. Tredger JM, Smith HM, Read RB, et al: Effects of ethanol ingestion on the metabolism of a hepatotoxic
dose of paracetamol in mice. Xenobiotica 1986; 16:661.
46. Truss CD, Killenberg PG: Treatment of carbon tetrachloride poisoning with hyperbaric oxygen.
47. Wendon JA, Harrison PM, Keays R, et al: Effects of vasopressor agents and epoprostenol on systemic
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48. Wendon JA, Harrison PM, Keays R, et al: Cerebral blood flow and metabolism in fulminant liver failure.
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49. Woodle ES, Woody RR, Cox KL: Orthotopic liver transplantation in a patient with Amanita poisoning.
JAMA 1985; 253:69-70.
50. Zimmerman HJ, Maddery WC: Toxic and drug-induced hepatitis. In: Schiff L, Schiff ER, ed. Diseases
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51. Zimmerman HJ, Ishak KG: Valproate-induced hepatic injury: Analysis of 23 fatal cases.
Hepatology 1982; 2:591-597.


Chapter 22 – Renal Failure
BRENT MORGAN
Essentials
• Evaluate for hyperkalemia and pulmonary edema and treat if necessary.
• Assess urine output.
• Differentiate between prerenal, intrinsic renal, and postrenal failure.
• Withdraw offending drug or toxin and institute drug or toxin-specific therapy, if available.
• Nephrology consultation for life-treatening complications (e.g., hyperkalemia) or need for definitive
diagnosis via renal biopsy or emergent hemodialysis.
INTRODUCTION
The knowledge of drugs and other toxins that act as nephrotoxic agents has been increasing. It has been
estimated that up to 20 per cent of all cases of renal failure might be secondary to toxic injury.[1][7] The
majority of these toxic nephropathies are produced by drugs. However, potential nephrotoxic substances are
also found in the workplace and in the environment. It has been estimated that nearly 4 million U.S. workers
are exposed to potential nephrotoxic agents.[2] The incidence of renal failure produced by these various
nephrotoxic agents remains unknown.


PATHOPHYSIOLOGY
The renal system is uniquely susceptible to toxic injury. In humans, the kidneys receive 20 to 25 per cent of
the cardiac output despite weighing only 150 g each. Potential nephrotoxic substances in the systemic
circulation are delivered in relatively high amounts because of this high renal blood-flow-to-mass ratio. The
kidney is also metabolically active, containing several enzyme systems capable of bioactivating a nontoxic
substance into a toxic compound. Perchloroethylene, carbon tetrachloride, and acetaminophen are
examples of compounds that are metabolized to a toxic byproduct. The kidney possesses specific transport
mechanisms that allow for site-specific toxicity. For example, substantial aminoglycoside uptake, and
therefore toxicity, is limited to the kidney and the inner ear. In addition, the kidneys concentrate waste
products and nephrotoxic agents to enhance their elimination and to conserve water and electrolytes. This
can produce higher concentrations of toxic substances in the kidney. These properties may explain the
unique susceptibility of the kidney to toxic injury when compared with other organ systems.
Acute renal failure can be divided into (1) prerenal, (2) intrinsic, and (3) postrenal.
Prerenal
Prerenal failure in the poisoned patient can be produced by several mechanisms that lead to hypotension
and a subsequent decrease in renal perfusion.[3] These mechanisms are (1) toxin-induced cardiotoxicity
resulting in a lowered cardiac output, (2) toxin-induced vasodilation, (3) toxin-induced vasoconstriction, and
(4) toxin-induced loss of effective circulatory volume from either diuresis, gastrointestinal fluid loss,
hemorrhage, or third spacing of fluid such as in a chemical burn. Patients with prerenal failure will often have
clinical signs of dehydration.
In addition, several substances can produce intrarenal vascular effects that can lead to decreased
glomerular perfusion ( Table 22–1 ). Renal blood flow represents a balance between vasoconstrictive forces
(catecholamines, angiotensin II) and vasodilatory prostaglandins. Nonsteroidal anti-inflammatory drugs
(NSAIDs) inhibit the formation of the vasodilatory prostaglandins. Patients with compromised renal blood
flow, such as in congestive heart failure, can develop acute renal failure with the loss of prostaglandin-
induced vasodilation. Patients with renal artery stenosis are dependent on angiotensin II–mediated efferent
arteriolar vasoconstriction to maintain glomerular perfusion pressure. Angiotensin-converting enzyme
inhibitors lead to efferent arteriolar vasodilation and a subsequent decrease in intraglomerular pressure.
Table 22-1 -- Substances Known to Cause Renal Failure

I. Decreased glomerular perfusion via intrarenal vascular effects
ACE inhibitors, cyclosporine, radiocontrast agents, NSAIDS, mannitol
II. Glomerulonephritis
Heroin abuse, hydrocarbons, hydralazine, halogenated alkanes, D-penicillamine, methimazole, captopril,
thiopronine, gold, mercurous and mercuric salts, silicon
III. Direct tubular toxicity
Aminoglycosides, cisplatin, mithramycin, ifosfamide, streptozotocin, amphotericin B, diethylene glycol, toluene,
carbon tetrachloride, radiocontrast agents, polymyxin, uranium, arsenic, bismuth, chromium, mercurous and
mercuric salts, mycotoxins, perchloroethylene, hydrocarbons, cadmium, fluorinated anesthetics, diquat,
paraquat
IV. Interstitial nephritis
Allopurinol, ß-lactam antibiotics, cimetidine, NSAIDs, rifampin, sulfonamides
VI. Chronic tubulointerstitial nephritis or fibrosis
Phenacetin, analgesic combinations, cyclosporine, lithium, lead, cadmium, beryllium, NSAIDs, semustine,
carmustine, lomustine, chinese herbal slimming regimen (aristolochic acid)
V. Obstructive uropathy due to tubular precipitation
Ethylene glycol metabolites, acyclovir, methotrexate, sulfonamides
Intrinsic
The most common types of acute toxin-induced intrinsic renal disease are acute glomerulonephritis (AGN),
acute tubular necrosis (ATN), and acute interstitial nephritis. The cortex receives the majority of the renal
blood flow and is more likely than the medulla to be exposed to nephrotoxic agents. The proximal tubule is
very sensitive to ischemia because of its high substrate and energy requirements. In addition, the proximal
tubule is a frequent site of nephrotoxic injury because it contains most of the transport systems. Substances
that are not reabsorbed by the proximal tubule such as acetaminophen and NSAIDs can be concentrated by
the countercurrent mechanism in the loop of Henle. This can produce potential nephrotoxic concentrations in
the deep medulla or papilla.[10]
The location and mechanism of intrinsic renal injury depends on the inciting nephrotoxic agent. AGN is
characterized by proteinuria, salt retention, edema, and hypertension. Toxins can produce AGN through
direct injury or through immunogenic mechanisms. Table 22–1 lists toxins that have been reported to cause
glomerulonephritis. In Europe, intravenous heroin abuse has been associated with the development of
membranoproliferative glomerulonephritis.[9] The development of the heroin-associated glomerulonephritis
appears unrelated to human immunodeficiency virus or hepatitis infection. Possible etiologic agents include
the heroin, adulterants, or bacterial toxins and antigens.
ATN is the most common toxin-induced renal syndrome. It is characterized pathologically by patchy necrosis
of the renal tubules. The proximal tubule is the most frequently involved segment; it is dependent on aerobic
metabolism and is particularly sensitive to hypoxia. Therefore, any toxin-induced reduction in renal blood
flow can cause ATN. The classic clinical presentation of ATN includes oliguria, azotemia, and electrolyte
abnormalities that may necessitate hemodialysis.
The specific pathogenic mechanisms involved in tubular injury are a current evolving area of investigation.
Potential mechanisms include oxidant stress, alterations in cellular energetics, calcium homeostasis, and
enzyme interference.[39] Toxins can undergo intratubular metabolic bioactivation and generate highly
reactive intermediates or possibly increase the production of reactive oxygen species (·OH-). The reactive
intermediates produce oxidative cellular damage by covalently binding to cellular macromolecules or by
initiating lipid perioxidation. Nephrotoxins that may induce oxidative damage include aminoglycosides,
carbon tetrachloride, cephaloridine, cisplatin, and mercuric chloride.[38] Proximal tubule cells are almost
completely dependent on aerobic adenosine triphosphate (ATP) production for cellular homeostasis.
Disruption of cellular energetics by increasing ATP utilization or decreasing production can result in ATN.
Toxins linked to ATP depletion include aminoglycosides, cyclosporine, mercurials, myoglobin, and
phenacetin.[36][38]
Acute interstitial nephritis is usually an allergic phenomenon leading to an inflammatory infiltrate involving
the tubules and interstitium but sparing the glomeruli. Table 22–1 lists the most common agents associated
with interstitial nephritis. Medications, especially penicillins and NSAIDs, are leading causes.[24] Acute
interstitial nephritis usually remits when the offending medication is discontinued.
Some substances require bioactivation by an enzymatic reaction before renal cellular injury can occur. For
example, unmetabolized ethylene glycol is not nephrotoxic and is excreted unchanged by the kidney.
However, when metabolized in the liver by a series of enzymatic reactions, it is converted to a number of
toxic metabolites, including oxalic acid. Oxalic acid combines with calcium to form calcium oxalate crystals
that obstruct the renal tubules, contributing to acute renal failure. Acetaminophen is another example of a
substance that is nephrotoxic after bioactivation. In fact, it is the intrinsic renal metabolism of acetaminophen
that can lead to kidney failure. The renal metabolism of acetaminophen produces both toxic and nontoxic
metabolites. The nontoxic metabolic pathways are rate limited, and increasing renal concentrations of
acetaminophen favor the formation of toxic metabolites through NADPH+-dependent cytochrome P-450
mixed function oxidase and other enzyme systems. When the cellular protective mechanisms,
predominately glutathione, are depleted, the toxic metabolites produce direct tissue damage, followed by the
development of ATN.
Postrenal
Postrenal failure is defined as the retention of nitrogenous waste due to obstruction of urine elimination.
Typically, the continued production of urine in the presence of obstruction leads to collecting system dilation
proximal to the obstruction. Anticholinergic toxins can produce bladder neck obstruction, leading to a
distended bladder. Ergotamine derivatives, such as methysergide, can cause retroperitoneal fibrosis, which
entraps the ureters and leads to urinary obstruction.[33]


The differential diagnosis of acute renal failure is extensive.[7][8] Precipitating factors can include
cardiovascular, infectious, immunologic, hereditary, musculoskeletal, hematopoietic, oncologic, and
toxicologic causes. Because drugs and toxins can produce prerenal, intrinsic renal, and postrenal failure, the
initial evaluation must attempt to differentiate among these three categories of renal failure.
Although the diagnosis of renal failure can be made with laboratory testing, the confirmation of toxic
nephropathy relies on patient history. Information obtained from the patient must include (1) all medications
and therapies, including over-the-counter products as well as “natural remedies”; (2) occupational exposure
to hydrocarbons, solvents, or metals; (3) home exposure to nephrotoxic agents, specifically regarding
hobbies, diet, and water source; and (4) drug abuse, including hydrocarbon huffing and heroin or cocaine
abuse. If nephrotoxic injury is suspected, the clinician should determine drug or toxin dose and length of
exposure.
Patients at increased risk for developing toxin-induced renal failure include patients with an organ transplant
and those receiving chemotherapeutic agents for a malignancy. Cyclosporine is frequently used to prevent
organ rejection. Increasing doses of cyclosporine can result in afferent and efferent arteriolar
vasoconstriction and subsequent acute renal failure. Long-term use of cyclosporine can induce a chronic
interstitial fibrosis. Several chemotherapeutic agents are known to cause renal failure. Obtaining accurate
histories of exposure to these agents is essential.
Prerenal
NSAIDs do not significantly affect renal perfusion in patients with normal renal function and sodium loads.
However, patients with conditions such as congestive heart failure or hypovolemia are more dependent on
prostaglandin-induced vasodilation. In these patients NSAIDs can significantly decrease renal perfusion and
glomerular filtration.[20]
Intrinsic
Patients presenting with an anion gap metabolic acidosis and renal failure should be evaluated for ethylene
glycol ingestion. An osmol gap may or may not be present. The presence of monohydrate calcium oxalate
crystals in the urine can confirm the diagnosis of ethylene glycol ingestion, but the absence of crystals does
not exclude exposure. The ingestion of diethylene glycol can result in acute renal failure that is characterized
by necrosis of proximal and distal tubular cells. In addition, diethylene glycol can cause an osmol gap and a
lactic acidosis.[5]
Gold and mercury exposure can induce immune complexes that deposit in the glomeruli and produce AGN.
These immune complexes activate the complement cascade with resultant inflammation and glomerular
damage. Glomerular injury can also occur when a toxin elicits an antibody response to the pulmonary
basement membrane. Because the glomerular basement membrane is similar in composition to the
pulmonary basement membrane, these toxin-induced antibodies can react with either basement
membrane.[30] Historical clues include the use of gold for treatment of rheumatoid arthritis or a possible
occupational or environmental exposure to mercury. Patients presenting with pulmonary and renal disease
should be evaluated for toxin-induced AGN. Another toxin that can produce extensive pulmonary fibrosis
and ATN is the herbicide paraquat.
Patients with chronic tubulointerstitial nephritis or fibrosis will often have histories of long-term exposure to
offending agents. Analgesic abuse involves the habitual ingestion of analgesic combinations, including
acetaminophen, aspirin, and usually caffeine or codeine over a several-year period. This can lead to
analgesic nephropathy, which is characterized by renal papillary necrosis and interstitial nephritis. Many of
these patients often have a history of upper gastrointestinal complaints.[29]
Histories of analgesic consumption are often inaccurate.[31] Discontinuation of these analgesics can halt the
progression from chronic renal failure to end-stage renal disease. Computed tomographic findings of
decreased renal mass of both kidneys combined with either bumpy contours or papillary calcifications
together with a careful analgesic drug history from the patient and family members were found to be highly
sensitive and specific for analgesic nephropathy.[12]
A recent outbreak of nephropathy occurred in Belgium. This nephropathy was characterized by rapid and
progressive interstitial fibrosis with tubular atrophy. A complete history revealed that these patients had been
consuming a Chinese slimming regimen. Many questions remain unanswered, but the substitution of
Aristolochia fangchi for the prescribed Stephania tetrandra as a component of the slimming regimen has
been hypothesized to be the cause of the nephropathy.[37] Although usually considered a hepatotoxin,
acetaminophen produces acute renal failure in approximately 1 per cent of acetaminophen ingestions.[18]
This nephrotoxicity can occur in the absence of hepatic failure.[6][11] Carbon tetrachloride and amanitine
(Amanita mushrooms) are other toxins that can produce both hepatic and renal failure. [27][32]
Occupational or environmental exposure to many of the metals can cause renal failure. Among the most
common are lead, cadmium, arsenic, and mercurous and mercuric salts. Although usually considered a
chronic nephrotoxin, lead in acute high-dose exposure can cause ATN and a Fanconi-like syndrome with
glucosuria, proteinuria, and phosphaturia. Chronic lead nephropathy is characterized by tubulointerstitial
nephritis and fibrosis with proteinuria and Fanconi-like syndrome. Patients with lead nephropathy may have
other signs of toxicity, including gout, anemia, and hypertension. Cadmium complexes with the metal binding
protein metallothionein in the liver. This metallothionein-cadmium complex is reabsorbed by the proximal
renal tubule and degraded, liberating the cadmium. Once a critical cadmium concentration is reached in the
tubule a progressive tubulointerstitial nephritis can develop.[13]
The patient with acute interstitial nephritis classically develops a low-grade fever, arthralgias, an
erythematous macular papular rash and nonoliguric renal failure shortly after starting the offending agent.
However, exposure to the agent can range from 2 days to 2 months before symptoms develop.[2] Peripheral
eosinophilia and eosinophiluria may be present, but their absence does not exclude the diagnosis of
interstitial nephritis.[35]
Postrenal
Tubular obstruction and acute renal failure have been produced by the precipitation of high-dose intravenous
acyclovir and methotrexate. Ureter obstruction secondary to retroperitoneal fibrosis has developed most
commonly after chronic use of ergotamine derivatives for vascular headaches. Drugs with anticholinergic
effects can induce bladder outlet obstruction even without other signs of anticholinergic toxicity in
susceptible individuals. These drugs include diphenhydramine, doxylamine, and hydroxyzine.


CLINICAL EVALUATION
Patients with prerenal failure often have signs of volume depletion, including dry mucous membranes,
tachycardia, and orthostatic hypotension. Symptoms of intrinsic renal failure include peripheral edema,
lethargy, dyspnea, and decreased urine output. Patients with postrenal failure may complain of hesitancy,
decreased urinary flow, and abdominal pain.
Laboratory Studies and Interpretation
In general, urinalysis and determination of serum electrolytes, blood urea nitrogen (BUN), creatinine, urine
osmolality (UOsm), urine sodium (UNa+), and urine creatinine (UCr) should be obtained in the poisoned
patient with renal failure. A microscopic examination of the urine should be performed looking for red and
white blood cells, casts, tubular elements, and crystals. The appearance of needle-shaped, monohydrate
calcium oxalate crystals in the urine can confirm the diagnosis of ethylene glycol ingestion.[19] The urine
should be stained and checked for eosinophils if acute interstitial nephritis is a consideration.
The BUN/creatinine ratio can help the clinician differentiate between prerenal and intrinsic renal failure. The
clearance of urea is flow dependent whereas creatinine clearance is not flow dependent. Thus, in states of
kidney hypoperfusion the rise in BUN may be more rapid than the rise in serum creatinine. Therefore, a
BUN:creatinine ratio greater than 10:1 suggests prerenal azotemia whereas a ratio less than 10:1 suggests
intrinsic renal failure. These results must be interpreted with caution because other factors such as
gastrointestinal bleeding or a low-protein diet can influence the BUN:creatinine ratio.
A normal kidney with prerenal failure maintains its ability to concentrate urine by reabsorbing sodium and
water. Typically, the poisoned patient with prerenal failure has a urinary sodium (UNa+) level less than 20
mEq/L, urinary osmolality (UOsm) greater than 500 mOsm/kg, and a urine:plasma creatinine ratio (U/PCr)
greater than 40. Patients with toxin-induced ATN have impaired renal tubular concentrating ability indicated
by a UNa+ greater than 40 mEq/L, a UOsm less than 400 mOsm/kg, and a U/PCr less than 20.
When values of these diagnostic studies are overlapping, calculation of the renal failure index (RFI) and the
fractional excretion of filtered sodium (FENa+) can help differentiate between prerenal failure and intrinsic
renal failure. The formulas for calculating RFI and FENa+ are as follows:
A value of less than 1 in either of these measurements is characteristic of prerenal failure whereas values
more than 2 are associated with acute intrinsic renal failure.[26]
In the nondiabetic patient, essentially all glucose filtered at the glomerulus should be reabsorbed in the
proximal tubule. Thus, the presence of glucosuria may represent a toxin-induced dysfunction in tubular
reabsorption. In addition, proteinuria is often an early and sensitive indicator of nephrotoxicity.[34]


NONEMERGENT TESTING
Because the kidneys have a large reserve capacity the typically used screening laboratory test results (BUN
and creatinine) will not be abnormal until creatinine clearance has been reduced by 50 per cent.[22] The
kidney contains several enzyme systems that are found only in specific segments of the nephron.[28] Several
different tests are being developed (enzymuria, renal tubular antigens, anti–glomerular basement membrane
antibodies) to screen for preclinical renal damage.[25] The sensitivity and specificity as well as the potential
clinical uses of these tests remain to be elucidated. Additional applications of enzymuria tests may include a
role in determining the site in the nephron where the toxic insult has occurred.
The anatomic site of the nephrotoxicity can generally be localized if the proteinuria can be classified as
either low molecular weight or high molecular weight. Low molecular weight proteins, such as beta2-
microglobin or retinol binding protein, are freely filtered at the glomerulus and are taken up by the proximal
tubular cells, where they are catabolized. Thus, low molecular weight proteinuria is a highly sensitive index
of proximal tubular dysfunction.[4] In contrast, high molecular weight proteins such as albumin are repelled
from glomerular filtration because of size and charge restraints.[15] Nephrotoxins that produce a loss of
glomerular size selectivity or a loss of the glomerular polyanion can cause albuminuria. The Tamm-Horsfall
mucoprotein is a specific renal protein located in the thick ascending limb of the loop of Henle.[16] It is a high
molecular weight protein whose excretion in the urine can increase when this segment of the loop of Henle
is damaged.


Treatment of prerenal failure depends on the toxin and its underlying pathophysiologic mechanism. Potential
therapies include measures to increase chronotropy and inotropy, vasopressor support, fluid resuscitation,
and blood transfusion. Postrenal failure is treated by relieving the obstruction. This can be accomplished by
Foley catheter insertion or urologic consultation for nephrostomy tube placement.
The causative agent of intrinsic renal failure should be discontinued. The life-threatening complications
include pulmonary edema and hyperkalemia. Pulmonary edema is managed with oxygen, diuretics, and
preload and afterload reducers. Treatment of hyperkalemia may include calcium, insulin and glucose,
sodium bicarbonate, sodium polystyrene sulfonate, furosemide, and albuterol. The majority of patients
presenting with toxin-induced acute renal failure will not need emergent hemodialysis. Emergent
hemodialysis is reserved for severe volume overload and life-threatening metabolic disturbance (e.g.,
profound acidosis or hyperkalemia).
Because nonoliguric renal failure has a better prognosis than oliguric renal failure, an attempt to increase
urine output may be warranted.[23] After correcting volume deficits, loop diuretics and mannitol have been
used to convert oliguric to nonoliguric renal failure. A nephrology consultation should be considered before
these measures are undertaken.


Most patients with acute renal failure should be admitted to the hospital. Patients with mild renal
insufficiency and no underlying medical conditions can be discharged if follow up is arranged. Nephrology
consultation should be obtained in patients with hyperkalemia, pulmonary or cardiovascular compromise,
need for emergent hemodialysis, or renal biopsy for definitive diagnosis. If nephrology consultation and
dialysis are not available, then transfer of the patient is advisable after the patient is stabilized.


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38. Weinburg JM: The cellular basis of nephrotoxicity. In: Schrier RW, Gottschalk CW, ed. Diseases of the
Kidney, Vol 3. Boston: Little Brown; 1993:1031-1237.
39. Zagar RA: Pathogenic mechanisms in nephrotoxic acute renal failure. Semin Nephrol 1997; 17:3-14.


Uncited references
Gault MH, Barrett BJ: Analgesic nephropathy. Am J Kidney Dis 1998; 32:351-360.
Hou SH, Bushinsky DA, Wish JB, et al: Hospital acquired renal insuffiency: A prospective study. Am J
Med 1983; 74:243-248.
Landrigan PJ, Goyer RA, Clarkston TW, et al: The work relatedness of renal disease. Arch Environ
Health 1984; 39:225-230.


Chapter 23 – Hematologic Abnormalities
RICHARD Y. WANG
Essentials of Initial Treatment

• Determine hematologic abnormality present:
° Red cell disorder—anemia, polycythemia
° White cell disorder—leukocytosis, leucopenia
° Bleeding disorder—platelet abnormality, clotting factor
disorder
• Initiate general stabilizing therapies based on disorder and severity of condition:

° Anemia—packed RBCs, hydration, and renal function monitoring for ongoing
hemolysis
° Polycythemia—phlebotomy
° Leukopenia—antibiotics if patient is febrile
° Clotting disorders—platelet infusions for severe thrombocytopenia, blood products for
DIC
• Evaluate the need for specific therapies (e.g., vitamin K for warfarin toxicity, antivenin for crotalid venom-
induced bleeding disorders)
PHYSIOLOGY
The hematopoietic system is one of the most complex structures in the body. It is composed of red cells,
white cells, and platelets and serves to provide nutritional support, defense, and hemostasis for its host.
Oxygen, glucose, and certain products of metabolism are some of the essential cellular substrates
transported in the blood. Thus, disruption of any aspect of the hematopoietic system can lead to disastrous
consequences, including organ ischemia, overwhelming infection, and spontaneous bleeding.
The hemostatic system aids host defense by stopping hemorrhages, which may serve as a conduit for
organisms. Hemostasis is achieved through the concerted efforts of vascular constriction, platelet plugging,
and fibrin clot formation.[47] Fibrin clot formation occurs in two stages. The primary phase occurs when
platelets, with the aid of the factor VII complex, adhere to damaged endothelium to form a platelet plug. At
the same time, the soluble plasma coagulation proteins are activated through a complex cascade of positive
and negative interactions to form a fibrin clot. This secondary phase includes the platelet-dependent intrinsic
coagulation system, the fast extrinsic coagulation system, and the common pathway ( Fig. 23–1 ).
Figure 23-1 Coagulation cascade. Drugs, in boxes, are shown at site of action. = Warfarin sites of action.
The intrinsic system is activated through platelet adhesion and involves factors XII, XI, and IX. Factor X
activation, the last step of this cascade, leads to the common pathway and fibrin clot. The common pathway
can also be activated directly by the extrinsic pathway. Damaged tissue releases thromboplastin, which
activates factor VII of the extrinsic system. This rapidly leads to factor X activation and entry into the
common pathway. Factor VII of the extrinsic system can also activate the intrinsic system through factor IX.
Factor X is the beginning of the common pathway and leads to activation of factor V and then the conversion
of prothrombin to the active enzyme thrombin. Thrombin converts fibrinogen to insoluble fibrin, which is
stabilized by factor XIII. To ensure that the size of the clot is proper and systemic clotting does not occur,
several feedback mechanisms are activated. These involve platelet inhibitors, factor inhibitors, and the
fibrinolytic system. Abnormalities of hemostasis may result from either excessive or deficient activity of the
system and can be congenital or acquired.


PATHOPHYSIOLOGY
Acquired hematologic disorders include drug-induced events that can affect the bone marrow or the mature
cells in the blood. Responsible mechanisms are either immunologic, toxicologic, or idiopathic.[54]
Unfortunately, many of these reactions are poorly studied because of the consequence of rechallenge to the
patient. Aplastic anemia, neutropenia, thrombocytopenia, and hemolytic anemia are some of the disorders
associated with high mortality.
Immune Mechanisms.
These can involve haptens, ternary complexes, or autoantibodies. Clinical drug effects caused by
autoantibodies do not require the drug to be present in the system. Methyldopa is the typical example. The
mechanism for antibody induction is unknown, but the drug probably binds to membrane antigens of
premature cells (e.g., proerythroblasts). The resulting altered membrane may then induce autoantibody
formation.
The drug is, however, necessary for immunologic reactions involving haptens and ternary complexes.
Certain drugs are too small to be immunoreactive unless combined with a cell. When given in large
quantities these drugs can bind to cell membrane proteins and act as haptens. Common agents are
cephalosporins and penicillins. High-dose penicillin therapy (10 to 30 million units/d) can induce hemolytic
anemia through this mechanism, and penicillin sensitivity is not required.[55]
The ternary complex mechanism is so named because the reaction requires the binding of drug, antibody,
and protein located on the cell membrane. Unlike the hapten mechanism in which antibodies are bound to
the drug only, the antibodies formed in the ternary mechanism bind to both drug and cell receptor.
Methyldopa, procainamide, mefenamic acid, and levodopa use the Rh blood group as the receptor
antigen.[40]
Nonimmune Mechanisms.
These drug effects are toxicologic or idiosyncratic. The former is suggested by a slow decline in
hematopoietic cells, dose dependency, and the lack of immediate relapse if the offending drug is
reintroduced in small doses after recovery. An example of a toxic-induced agranulocytosis is the damage
caused by chlorpromazine. This agent is a strong electron donor that affects a number of cellular functions,
including hematopoiesis.[56] Other toxicologic mechanisms are oxidation, chelation, and competitive
inhibition. An example of the latter is methotrexate, a structural analog of folate that inhibits dihydrofolate
reductase to affect DNA and RNA synthesis. At low doses, methotrexate can cause megaloblastic anemia
while high doses may result in pancytopenia.
Idiosyncratic reactions are characterized by the lack of dose-related effects and susceptibility in a small
population. Potential explanations for these occurrences are abnormal drug metabolism or elimination,
genetic abnormalities, and prior cellular damage.


Red Cell Disorders
Anemia
Anemias can be classified in three functional categories ( Table 23–1 ). The first group, hypoproliferation or
impaired red blood cell (RBC) production, is characterized by normocytic, normochromic indices with a
relatively normal reticulocyte count. The red cell morphology on the smear should not show any bizarre
forms or variability, and the red cell distribution width (RDW) should be relatively normal. Examples of these
are aplastic anemia, pure red cell aplasia, myelofibrosis, hematologic malignancy, and marrow infection. A
bone marrow biopsy is necessary to diagnose many of these disorders.
Table 23-1 -- Differential Diagnosis of Anemia

Red Cell
RBC Reticulocyte
Types of Distribution
Morphology Count
Category Anemia Indices Width
Impaired RBC Aplastic anemia Normochromic Normal Normal Normal
production normocytic
Pure red cell
aplasia
Myelofibrosis
Hematologic
malignancy
Marrow infection
Abnormal—microcytic to Abnormal, Normal to
Thalassemia Elevated
macrocytic variable slightly elevated
Ineffective
RBC Iron deficiency
production Megaloblastic
Sideroblastic
Increased
Abnormal
RBC Hemolytic Normal Elevated Elevated
schistocytes
destruction
The second group is characterized as defective or ineffective RBC production. This group demonstrates very
abnormal indices, ranging from microcytic to macrocytic, and markedly abnormal or variable cell
morphology. This variability is usually reflected by an elevated RDW (normal 11.5–14.5 per cent). The
reticulocyte count is not markedly elevated. Examples include thalassemia and iron deficiency,
megaloblastic, and sideroblastic anemias.
The last group are the hemolytic anemias, characterized by increased red cell destruction. The cells may
have relatively normal indices, but there is marked reticulocytosis that increases in proportion to the severity
of the anemia.
Impaired Production
Aplastic Anemia.
Aplastic anemia is defined as peripheral blood pancytopenia with variable bone marrow hypocellularity in the
absence of underlying malignant or myeloproliferative disease.[11] Pathophysiologic mechanisms include
involvement of pluripotential stem cells, failure of the stromal microenvironment of the marrow, impaired
production or release of hematopoietic growth factors, and cellular or humoral immune suppression of the
marrow. The incidence of acquired aplastic anemia increases with age and is attributed to the exposure and
accumulation of toxins over time. The incidence is low before 1 year of age, rises to an intermediate level by
the age of 50 years, and then increases thereafter. Drug-induced causes account for 50 per cent of all
cases.[12]
Drug-induced aplastic anemia can result from either toxic effects or immune-mediated phenomena.
Progenitor stem cells are most commonly affected. Common toxic agents include ionizing radiation,
chemotherapeutic drugs, antibiotics (e.g., chloramphenicol), hydrocarbons (e.g., benzene), antiinflammatory
medications (e.g., phenylbutazone, indomethacin), and metals (e.g., gold) ( Table 23–2 ). Chloramphenicol
is the best studied drug of this disorder. Aplasia has been reported after oral, intramuscular, intravenous,
and topical administration of this drug.[62]
Table 23-2 -- Common Agents Causing Aplastic Anemia

Acetazolamide Ibuprofen
Antineoplastic * Mephenytoin
Alkylating Oxyphenbutazone *
Antimetabolite Paramethadione
Antibiotics Phenothiazines
Benzene * Phenylbutazone *
Captopril Phenytoin
Carbamazepine Propylthiouracil
Chloramphenicol * Quinacrine
Chlorpheniramine Radiation (ionizing) *
Colchicine * Sulfonamides *
Gold salts *
Data from references, 46 , 50 , 53 .
* Toxic mechanism
Benzene is used in the processing of dyes, drugs, and other chemicals. Workers in leather goods and shoe
manufacturing are at risk for disorders associated with this agent, and in one worker cohort the incidence of
aplastic anemia was six times higher than that of the control population.[67] In animal experiments, benzene
metabolites (e.g., quinone) affect committed cells in a cycle-specific fashion.[37] However, in benzene-
treated models, injection of normal bone marrow does not regenerate hematopoiesis. This suggests that the
marrow environment is affected as well. Other agents noted for this dual effect are ionizing radiation and the
antineoplastic agents.
Ionizing radiation can cause aplastic anemia, as was demonstrated when it was used for local therapy of
ankylosing spondylitis.[20] Cellular damage occurs when absorbed energy breaks chemical bonds and form
ions and free radicals.[17] Local irradiation of rats (2000 rads or 2 Gy) causes transient marrow hypoplasia
followed by recovery. At doses of 4000 rads (4 Gy) or more this sequence is followed by a second marrow
aplasia, which is possibly permanent. Neither infusion of normal marrow nor curettage of the marrow
environment causes recovery. However, curettage plus local injection of normal marrow results in
recovery, [43] suggesting that a dose-related effect may produce either stem cell or marrow
microenvironmental disorders.
Antineoplastic agents (e.g., alkylating chemicals, antimetabolites) can also cause marrow depression, and
the effect is usually reversible within weeks on discontinuation of the agent.[11] Alkylating agents form
reactive intermediates that interfere with DNA crosslinking and cause helical breaks. All phases of the cell
cycle are affected, and all bone marrow cells may be involved. Some of the alkylating agents are the
nitrogen mustards, ethylenimine, alkyl sulfonates, nitrosourea, and triazenes. The antimetabolite agents
inhibit the formation of nucleotides necessary for DNA and RNA synthesis. These agents can be classified
as pyrimidine, purine, and folic acid antagonists (e.g., methotrexate). The Vinca alkaloids, colchicine, and
podophyllin derivatives demonstrate toxicity by interrupting microtubular formation to stop cell division at
metaphase. The podophyllin agents may severely depress the bone marrow; the Vinca alkaloids are less
toxic and cause transient leukopenia and thrombocytopenia.
Other drugs with a relatively high risk for aplastic anemia are chloramphenicol, anti-inflammatory agents
(e.g., phenylbutazone, indomethacin, meclofenamate, mefenamic acid, gold salts, oxyphenbutazone),
anticonvulsants (e.g., mephenytoin, phenytoin, carbamazepine), and quinacrine.[46][50][53] Chloramphenicol
is a nitrobenzene derivative whose associated incidence of marrow aplasia is 10 to 50 times higher than that
of the general population.[10] Toxicity results from both chloramphenicol and its metabolite
nitrosochloramphenicol. Nitrosochloramphenicol inhibits DNA synthesis at significantly lower concentrations
than chloramphenicol; and, unlike chloramphenicol, this effect is not reversible when the drug is removed.[65]
Phenytoin and carbamazepine give rise to toxic arene-oxide intermediate metabolites that bind covalently to
macromolecules of stem cells in the marrow and lymphocytes.[29]
Pure Red Cell Aplasia.
Pure red cell aplasia is failure of red cell development in the bone marrow; it rarely occurs. Drugs associated
with this disorder include phenytoin, isoniazid (INH), chlorpropamide, and tolbutamide.[21] The acquired
disorders are typically acute in onset, affect adults, are self-limited on discontinuation of exposure, and are
most commonly caused by immune-mediated mechanisms. Supportive management with transfusion and
immunosuppressive therapy are helpful.
Ineffective Production
Sideroblastic Anemia.
Sideroblastic anemia results from ineffective red cell formation with accumulation of iron in the mitochondria.
The synthesis of heme is affected through the inhibition of enzymes involved in either porphyrin or heme
synthesis. The disorder may be due to hereditary (thalassemia) or acquired causes.[44] Acquired causes
include neoplasm, toxins, certain inflammatory disorders, and drugs. Drug-induced mechanisms include
reduced pyridoxal phosphate in the blood or decreased d-aminolevulinic acid (d-ALA) synthetase
activity.[44][64] Pyridoxal phosphate and d-ALA are both required for protoporphyrin synthesis. Pyridoxal
phosphate is also necessary for the formation of thymidylate involved in red cell DNA synthesis. Common
drugs that cause sideroblastic anemia are INH and pyrazinamide.
Lead and ethanol are directly toxic to enzymes of heme synthesis (e.g., ALA synthetase, ALA dehydratase,
and ferrochelatase). [49][51] Additionally, in lead poisoning, a mild anemia of chronic exposure may result from
either shortened red cell life span due to damaged cellular membranes or concurrent iron deficiency anemia.
Megaloblastic Anemia.
These anemias result from decreased vitamin absorption, impaired metabolism, or both. Vitamin B12 and
folate deficiencies selectively impair cellular DNA synthesis. [14] Because RNA protein production is
maintained, an increased ratio of cytoplasmic to nucleic mass results. All cells are affected, including red
cells, granulocytes, and megakaryocytes. Abnormal cellular maturation leads to premature cellular death.
Decreased absorption usually results from limited nutritional intake or intestinal malabsorptive diseases.
Agents that impair vitamin B12 gut absorption include metformin, colchicine, neomycin, para-aminosalicylic
acid, and slow-release potassium chloride.[46] Causes of folate deficiency include sepsis, pregnancy,
malignancy, chronic hemodialysis, and drugs.
Chronic ethanol ingestion interferes with folic acid intestinal absorption and metabolism. Some
anticonvulsant drugs can lower serum folate concentrations by limiting gut absorption as well. About 50 per
cent of patients on long-term phenytoin therapy have low serum folate concentrations, and about 30 per cent
have red cell macrocytosis and early megaloblastic changes in the bone marrow.[46] Folate replacement
therapy improves the anemia.[14]
Methotrexate, trimethoprim, triamterene, and pyrimethamine inhibit dihydrofolate reductase; and

megaloblastic anemia can develop during long-term and high-dose therapy.[46] Lack of dihydrofolate
reductase activity causes uridine substitution for thymidine in DNA synthesis, resulting in an unstable DNA
strand. Antineoplastic agents that inhibit pyrimidine and purine synthesis also can cause megaloblastosis,
which is not folate responsive.
Acute megaloblastic anemia may also be caused by prolonged nitrous oxide (N2O) anesthesia.[30] This gas
inactivates vitamin B12 through oxidation. This effect on the red cell is usually observed after a cumulative 5-
hour exposure to 50 per cent N2O.
Increased Destruction
Hemolytic Anemia.
Hemolytic anemia is a serious disorder that causes a decreased red cell life span. This situation must be
differentiated from increased red cell loss. Acute blood loss will present as normocytic normochromic
anemia, whereas chronic red cell loss results in depleted iron stores and a microcytic hypochromic anemia.
A reticulocytosis will occur regardless of the cause of diminished red cells.
Hemolytic anemias can be caused by either intracorpuscular or extracorpuscular disorders.[63]

Intracorpuscular disorders consist of red cell membrane defects, abnormal erythrocyte metabolism, and
hemoglobinopathies. Extracorpuscular disorders include immune-mediated destruction, mechanical
fragmentation, infections, and drugs, chemicals, and venoms. These latter agents oxidatively stress the red
cell, causing it to lyse.
When hemoglobin is oxidized, it denatures into particles known as Heinz bodies. These protein units attach
to the periphery of the red cell, from which they are removed by the spleen. The remaining red cell has a
shortened life span. Inherent red cell susceptibilities such as enzyme disorders and unstable hereditary
hemoglobinopathies enhance the ability of certain agents to produce damage. The hexose monophosphate
shunt and the glutathione pathways are the predominant mechanisms by which the red cell handles
oxidative stress. Disorders of either of these can result in oxidative damage to the red cell.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme disorder, and it is
genetically determined.[5] Those prone to this disorder include Africans, Asians, and those of Mediterranean
descent. The Mediterranean variety is the classic form and is the most severe because of lower enzyme
activity. The African variety is unique because only the mature red cells are enzyme deficient. The incidence
of G6PD deficiency in African-American males is about 11 per cent.[5] The susceptibility of a patient with
G6PD deficiency to drug-induced oxidative stress depends on the phenotype of the enzyme disorder as well
as on drug metabolism and excretion. This enzyme regenerates antioxidants (e.g., glutathione) so that
oxidative agents can be continually reduced. Lack of this enzyme allows for the rapid depletion of protective
antioxidants and subsequent denaturation of the hemoglobin unit. Oxidative stressors attack hemoglobin
sulfhydryl groups, releasing heme, whose protein chain then unfolds and precipitates as insoluble
aggregates. Unripened peaches, fava beans, methylene blue, naphthalene, phenazopyridine, and
sulfamethoxazole are agents known to cause hemolysis in G6PD-deficient patients.[5] Salicylates do not
pose a risk for hemolysis, except in high doses.
Another hemolytic mechanism is toxin-induced formation of free radicals that facilitate a glutathione
hemoglobin complex.[5] This unstable complex undergoes structural changes to expose hemoglobin
sulfhydryl groups to oxidative damage. The damaged hemoglobin then denatures and precipitates as Heinz
bodies.
Certain toxins are highly potent oxidants that can hemolyze normal red cells. These toxins include the
sulfones (e.g., dapsone), chlorates, sulfasalazine, primaquine, sulfonamides, arsine, copper salts, and
venoms ( Table 23–3 ).[41][61] The hemolytic effect is dose related and can occur in all subjects. Certain
agents may cause a methemoglobinemia in addition to red cell hemolysis (e.g., naphthalene, chlorates,
phenazopyridine (Pyridium), copper salts). It is unclear whether these two processes represent a continuum
of toxicity or are coincidental.
Table 23-3 -- Common Agents Causing Hemolytic Anemia

Toxic Mechanism Immune Mechanism
Aniline Cephalosporins
Arsine Chlorpromazine
Chlorates Fenfluramine
Copper salts Formaldehyde
Dapsone Insulin
Dimercaprol Isoniazid
Fava beans Levodopa
Methylene blue Mefenamic acid
Nitrite Methyldopa
Peaches (unripe) Penicillin
Phenazopyridine Quinidine
Primaquine Quinine
Stibine Rifampin
Sulfonamides Sulfasalazine
Sulfonylureas
Data from references 46 and 50 .
Arsine (arsenic hydride), a gas found in many industrial processes,[42] is produced when an acid combines
with metal contaminated with arsenic compounds. Exposure can result in severe hemolysis, with abdominal
pain, jaundice, and hemoglobinuria. The mechanism for red cell destruction is unclear but may be attributed
to the disruption of sulfhydryl bonds and the sodium-potassium adenosine triphosphatase exchange that is
necessary for cell membrane stability.
Copper salts have produced hemolysis after oral exposure or hemodialysis with contaminated dialysate
fluid. [41] The mechanism may be due to oxidation of glutathione and inhibition of G6PD by copper.
Chloramine and formaldehyde are other contaminating agents in dialysate that have caused hemolysis.[12]
Other causes of hemolysis include envenomations by arachnids, Hymenoptera, and reptiles and
hyperthermia.[13] Snake venoms contain enzymes (phospholipases) capable of directly lysing red cells.
Environmental heat can stress the red cell and cause hemolysis within 24 hours of exposure. Temperatures
above 47°C have been shown to cause morphologic changes and an increase in osmotic and mechanical
fragility of the red cell.
Polycythemia
Polycythemia is a condition of increased red cell mass per unit volume and is defined as a hemoglobin value
greater than 18 g/dL.[22] This disorder results from either an absolute erythrocytosis (increased red cell
mass) or a relative erythrocytosis (decreased plasma volume). The latter is caused by dehydration, burns,
and use of diuretic agents.
Causes of absolute erythrocytosis include polycythemia rubra vera, a primary disorder, and conditions that
induce an appropriate physiologic erythrocytosis to hypoxia, such as high altitudes or chronic conditions that
include cyanotic heart disease, sleep apnea, chronic obstructive pulmonary disease, and other lung
diseases. The low oxygen tension of these conditions stimulates production of erythropoietin (EPO), a
hormone that regulates hematopoiesis. Smoking, the most common cause of polycythemia, is another
example. Elevated levels of carboxyhemoglobin result in a relative tissue hypoxia that may be the stimulus
for increased red cell mass. Other conditions associated with increased production of EPO include tumors,
renal diseases, and certain endocrinopathies.
Drug causes of erythrocytosis include cobalt, formerly used to treat patients with refractory anemias, and
recombinant human EPO.[23] In normal individuals, EPO administration results in enhanced red cell
production and slight systolic hypertension. Athletes have tried EPO as an alternative to “blood doping” in an
effort to enhance athletic performance. However, life-threatening thromboses have occurred when the
plasma volume decreased with dehydration.[59]
Dyshemoglobinemias
Disorders of the hemoglobin complex leading to cyanosis include methemoglobinemia, sulfhemoglobinemia,

carboxyhemoglobinemia, and abnormal inherited hemoglobins.[36] The toxin-induced dyshemoglobinemias
have varying effects on oxygen binding of existing normal hemoglobin. Methemoglobin and
carboxyhemoglobin will cause a leftward shift of the oxygen dissociation curve. This shift results in an
increased affinity of hemoglobin for oxygen, resulting in decreased tissue oxygen availability. The situation is
reversed with sulfhemoglobin, which shifts the oxygen dissociation curve rightward, resulting in oxygen
being more readily available to tissues.
Methemoglobinemia occurs when the iron molecule in hemoglobin is oxidized from the ferrous (Fe2+) to
ferric (Fe3+) state. In the oxidized state hemoglobin cannot bind oxygen. Common toxins promoting this
oxidation process include nitrites, aniline dyes, naphthalene, Pyridium, quinines, dapsone, sulfonamides,
and local anesthetics (see Chapter 24 ). Sulfhemoglobinemia also results from hemoglobin oxidation and is
not reversible. Sulfonamides, acetanilid, phenazopyridine, nitrates, trinitrotoluene, and phenacetin have
been shown to cause this disorder.
Carbon monoxide is an odorless gas that binds to hemoglobin with an affinity greater than that of oxygen.
Clinical toxicity results from diminished oxygen delivery to tissues, inhibition of aerobic mitochondrial
enzyme activity, and free radical production. Carbon monoxide results from the incomplete combustion of
fossil fuels. Sources include engine exhausts, improperly vented space heaters, and fires.
White Cell Disorders
Leukocytosis
Leukocyte abnormalities result from either the increased release of cellular elements from the storage pool
or alterations in the rate at which these cells are removed from the blood. The causes of an elevated white
cell count are divided into primary and secondary disorders.[7] Primary leukocytosis is an extremely rare
event and is often hereditary. Secondary leukocytosis may occur from stress, infections, inflammation,
endocrinopathies, drugs, and toxins. A leukocytosis of greater than 50,000/mm3 is referred to as a
leukemoid reaction, and malignancies (e.g., chronic myelogenous leukemia) must be considered in the
evaluation.
Leukocytosis after exercise, seizures, and pain results from demargination of mature granulocytes from the
pulmonary circulation.[27] The mechanism by which these cells are released may be either decreased
neutrophil adhesiveness, shearing from altered blood flow, or stimulation of beta-adrenergic receptors
located on the lymphocytes and granulocytes. Identification of cell types may assist in differentiating the
cause of the leukocytosis. Demargination will result in an elevation of neutrophils, monocytes, and
lymphocytes, whereas only the neutrophils will be elevated in an infection. Toxicity from iron, theophylline,
cocaine, and black widow spider venom causes a sympathetic stress to elevate the white cell count by this
process.
Lithium, glucocorticoids, ranitidine, and quinidine are some commonly used agents known to stimulate white
cells.[6] They increase neutrophil release from the bone marrow and prevent neutrophil return to the tissue
pool. Lithium causes a true increase in the total number of mature neutrophils in all body compartments.
Neutrophilia is observed at a serum lithium concentration of 0.3 mEq/L in one week’s time. Cell culture
studies demonstrate that lithium enhances the production of granulocyte colony-stimulating factor (CSF),
which may explain this effect.[6]
Leukopenia
Neutropenia is the most common finding in leukopenia. Agranulocytosis characterized by extremely low
neutrophil counts can be life-threatening. Causes of leukopenia include decreased production, exiting of
circulating neutrophils into tissue pools, and peripheral destruction. Severe neutropenia, repeated infections,
and birth defects may signal an underlying hereditary disorder. Causes of acquired neutropenia include
infections, drugs, and nutritional deficiencies.
Drugs may cause neutropenia by damaging either committed stem cells, proliferating precursors, or mature
granulocytes.[34] If the committed cells are affected, the time period between exposure and clinical
manifestation will be prolonged and the marrow will be hypocellular. Patients on multiple medications, with
high plasma drug concentrations, slow metabolism, or renal impairment are more prone to these
reactions.[38] Phenothiazines, chloramphenicol, and the antithyroid agents are known toxins. Clozapine has
a higher incidence of agranulocytosis during therapy than other antipsychotics, caused by the metabolite
desmethylclozapine. The immune-mediated reactions are similar to those described for red cells and affect
mostly women, the elderly, and those with a history of allergies.[65] Agents demonstrating immune-mediated
neutropenia are amidopyrine, penicillin, phenytoin, propylthiouracil, and quinidine. In previously exposed
individuals, repeated exposure causes a hypersensitivity reaction leading to the disappearance of
neutrophils from the blood within a few hours. Other agents causing leukopenia include colchicine, arsenic,
thallium, nonsteroidal anti-inflammatory agents (NSAIDs), anticonvulsant agents (e.g., valproate,
carbamazepine), antineoplastic agents, and ethanol; leukopenia is also a delayed effect of some Crotalidae
envenomations. Agranulocytosis induced by ß-lactam antibiotics is almost exclusively observed during
hospital treatment, in particular in intensive care units, when high doses are given parenterally over
prolonged periods.[33]
Bleeding Disorders
Excessive bleeding may result from disorders of platelets or coagulation factors.[47] Hypercoagulable states
are less common and attributed to deficiencies of essential antithrombotics such as antithrombin III, protein
S, and protein C; certain disease states; and predisposing factors. The latter category includes malignancy,
trauma, and prolonged immobilization. Corticosteroids and EPO are drug-induced causes of
hypercoagulability. In some patients initially taking warfarin, inhibition of protein C activation can exceed
clotting factor activation, resulting in a hypercoagulable state and skin necrosis.
Platelet Disorders
Qualitative.
Causes of acquired functional platelet disorders include uremia, autoimmune disorders, infections, liver
disease, nutritional deficiencies, and drugs.[28] Salicylates, NSAIDs, and antibiotics are common medications
affecting platelet function. Salicylates prevent thromboxane A2 synthesis by acetylating cyclooxygenase; this
inhibits platelet and megakaryocyte activities. The resulting decreased platelet aggregation causes a
prolonged bleeding time. This process is irreversible, but recovery occurs in 7 to 10 days with the production
and release of new platelets. Salicylates can precipitate hemorrhage in patients with pre-existing hemostatic
defects such as von Willebrand disease, hemophilia A, warfarin ingestion, or uremia. NSAIDs also inhibit
platelet cyclooxygenase. However, in contrast to salicylates, their effects are reversible and generally last
less than 4 hours.
High-dose penicillin and cephalosporin antibiotics can prolong the bleeding time by reducing platelet
adhesion and activation.[25] The serum concentration, drug potency, and lipid solubility of the specific
antibiotic will determine the degree of platelet impairment. This impairment is maximal after 1 to 3 days of
drug administration and may last for several days after therapy. The penicillins may impair the interaction of
von Willebrand factor with the platelet membrane. Patients with coexisting hemostatic defects such as
thrombocytopenia and vitamin K deficiency are at risk for bleeding with use of these antibiotics.
Other agents that affect platelet function include heparin, organic nitrates such as nitroprusside and
nitroglycerin, and fish oils. Heparin’s effects on platelets are multiple,[4] and it can prolong the bleeding time
by inhibiting thrombin, a potent platelet agonist. Organic nitrates are converted to nitric oxide, which
activates guanylate cyclase, resulting in increased intracellular cyclic guanosine monophosphate, which
inhibits platelet aggregation.[45] Fish oils containing eicosapentaenoic acid (omega-3 fatty acid) prolong
bleeding time by reducing the formation of thromboxane A 2 through competitive inhibition of
cyclooxygenase.[32] Black tree fungus, garlic, and cumin have similar antiplatelet effects.
Quantitative.
Drug-induced thrombocytopenia may be the result of either increased destruction or decreased synthesis of
platelets.
Ionizing radiation and chemotherapeutic drugs lower platelet counts through bone marrow depression.[39]
Ionizing radiation releases energy, causing disruption of cellular atoms or molecules with resultant damage.
Gamma rays are a significant external threat to people. They can penetrate up to 50 cm of tissue and
several centimeters of lead. These electromagnetic waves are emitted by radium, cesium 137, and cobalt
60. Common sources of this wave are in medical diagnostic and therapeutic devices.[17] Cytarabine is
extremely toxic with a predilection for platelets and granulocytes. This antineoplastic agent impairs DNA
synthesis by competitively inhibiting polymerase activity and terminating chain elongation. The marrow
effects are noted within the first week of therapy and last 14 to 21 days. Other antineoplastic agents causing
myelosuppression are the alkylating agents, vinblastine, epipodophyllotoxins, antimetabolite agents, and the
anthracyclines. Ethanol decreases platelets by inhibiting the maturation of megakaryocytes.[18] Platelets
normalize in 5 to 21 days after ethanol cessation. Thiazide diuretics also can suppress the bone marrow by
an immune-mediated mechanism.[39] Recovery occurs within 2 weeks after drug discontinuation.
Agents that commonly cause thrombocytopenia through increased peripheral destruction include quinidine,
quinine, heparin, gold salts, penicillin, sulfonamides, and rifampin ( Table 23–4 ).[39] Immune-mediated
mechanisms are responsible. Vaccine-associated thrombocytopenia is presumed to occur by a similar
mechanism.[52] Nonimmune mechanisms are observed in heparin therapy and Crotalidae envenomation.[39]
Heparin causes increased platelet aggregation and thrombi formation, and Crotalidae venom causes a
consumptive coagulopathy.
Table 23-4 -- Common Agents Causing Thrombocytopenia

Increased Destruction or Usage Decreased Production
Amitriptyline Alkylating agents
Amphotericin B Anthracyclines
Amrinone Antimetabolite agents
Asparaginase Cytarabine
Benzene Epipodophyllotoxins
Bleomycin Ethanol
Carbamazepine Procarbazine
Chloroquine Radiation, ionizing
Chlorpheniramine Thiazides
Cimetidine Vinblastine
Cocaine (i.e., DIC)
Colchicine
Crotalidae envenomation (i.e., DIC)
Cyclosporine
Increased Destruction or Usage Decreased Production
Furosemide
Ganciclovir
Glyburide
Gold salts
Heparin
Indomethacin
Meprobamate
Mesoridazine
Methyldopa
Penicillin
Pentamidine
Quinidine
Quinine
Rifampin
Sulfonamides
DIC, disseminated intravascular coagulation.
Acquired thrombocytosis results from increased production or increased release of platelets from storage
pools, such as the spleen. The platelet count typically does not exceed 1 million/µL. Unlike
myeloproliferative disorders, platelet functions are normal in this disorder.[48] Etiologic agents include
vincristine, epinephrine, interleukin, and recovery from thrombocytopenia. Epinephrine causes the release of
platelets from storage depots. This effect is transient, reaching a peak 50 per cent increase within 15
minutes and returning to baseline at 30 minutes. Rebound thrombocytosis usually peaks at 10 to 17 days
after withdrawal of the offending drug.
Clotting Factors
Deficiencies of plasma clotting factors are a common cause of bleeding. Warfarin derivatives inhibit the
recycling of vitamin K by inhibiting vitamin K 2,3-epoxide reductase[57] (see diagram, Chapter 107 ). The
activation of prothrombin and factors VII, IX, and X is blocked, resulting in a prolonged prothrombin time
(PT). The activation of proteins C and S is inhibited as well. A precipitous decrease in activated protein C
may predispose the patient to thrombosis. Increased sensitivity to warfarin sodium may occur in patients
with liver disease, in those on concurrent therapy with a drug that either inhibits warfarin metabolism or
increases free warfarin by competitive plasma protein binding, or in those with decreased vitamin K
availability. Other sources of warfarin analogs include rodenticides and plants (e.g., sweet clover, tonka
beans).
Heparin binds and accelerates the action of antithrombin III, resulting in a prolonged activated partial
thromboplastin time (aPTT) and thrombin clotting time (TCT). Findings supporting a diagnosis of heparin-
induced anticoagulation include correction of the TCT with protamine but not with normal plasma and a
normal reptilase time. The reptilase assay rules out hypofibrinogenemia as a cause of a prolonged TCT.
Bleeding due to heparin therapy may be exacerbated by excessive dosing, pre-existing disorders of
hemostasis, and local lesions such as trauma, malignancy, and vascular malformations. Heparin-like
anticoagulants have been identified in patients with malignancies.[39] These proteins behave like heparin
sulfate, and therapy with protamine sulfate for bleeding has been effective in some of these patients.
The presence of acquired antibodies with anticoagulant properties should be suspected when there is a
prolonged aPTT and no evidence to support its cause, such as heparin use or hemophilia.[24] These
antiphospholipid antibodies inhibit the in vitro coagulation assay and are associated with factor VIII
treatment, systemic infections (e.g., human immunodeficiency virus), and collagen vascular diseases (e.g.,
systemic lupus erythematosus).
False prolongations of the aPTT and PT can result from improper specimen collection. Failure to fill the
collection tube completely will increase the ratio of citrate anticoagulant to plasma, which will delay the
recalcification process of the assay.
Other Causes
Fibrinolysis is demonstrated by elevated fibrin degradation products (FDP).[47] Marked elevation of FDP
(greater than 40 µg/mL) is seen in disseminated intravascular coagulation (DIC) and with the use of
thrombolytic agents. Streptokinase and urokinase will induce a systemic fibrinolytic state, whereas tissue
plasminogen activator has more localized activity and clot specificity. Both intracranial and gastrointestinal
bleeding have occurred with thrombolytic use; precipitating factors include increased age, hypertension, and
the female gender. Severe hyperthermia due to causes such as heat stroke or severe cocaine toxicity can
cause DIC.
Extracorporeal circulation (e.g., heart bypass pumps, hemodialysis, hemoperfusion, plasma exchange) can
result in thrombocytopenia and platelet functional disorders. Platelets can adhere to the surfaces of the
device or undergo mechanical damage, especially with prolonged therapy.


CLINICAL EVALUATION/LABORATORY STUDIES
Red Cell Disorders
The complete blood cell count (CBC) and the peripheral smear are the fundamental tools of assessment for
anemia. Children and gravid patients will have normally lower values than expected because of their
physiological states. Errors in cell counting may be attributed to dilution, mixing, distribution, and
enumeration of the cells. Enumeration errors result from abnormalities in the size or shape of the cells that
are misinterpreted by the automated counter. Severe hyperglycemia (greater than 600 mg/dL) will cause red
cell swelling and cause a false increase in the mean corpuscular volume and hematocrit.[35] Automated
platelet counters may provide spuriously elevated levels by misinterpreting particulate matter in blood, such
as microspherocytes, cytoplasmic fragments of leukocytes, bacteria, cryoglobulin precipitates, and heat-
denatured proteins.
In addition to the CBC, determination of serum iron, transferrin saturation, total iron-binding capacity, serum
ferritin, reticulocyte count, serum bilirubin, and lactic dehydrogenase is helpful in the assessment of the
anemic patient. The reticulocyte count, serum bilirubin value, and lactate dehydrogenase level reflect red cell
turnover. Heinz bodies on the peripheral smear indicate hemolysis; further tests will be necessary to
determine the cause, including but not limited to G6PD activity and hemoglobin electrophoresis.
Anemias
Disorders of the red blood cell present as manifestations primarily relating to decreased oxygen transport
capability. Findings may include dyspnea, lethargy, disorientation, poor exercise tolerance, and
lightheadedness. Underlying cardiopulmonary disease may be exacerbated, and symptoms related to this
may be a primary complaint. The pertinent history should focus on duration of illness, accompanying
complaints, past medical history, recent therapies, and medication use. The clinical examination should
focus on signs and rate of active bleeding and include a search for an underlying medical disease that would
otherwise account for the anemia.
The CBC is the single most important laboratory test. The hemoglobin measures the severity of the anemia
whereas the RBC indices provide parameters by which the disorder may be classified and systematically
evaluated. These indices are the mean corpuscular hemoglobin concentration (MCHC), the mean
corpuscular volume (MCV), and the mean corpuscular hemoglobin (MCH). The RDW evaluates the
variability of red cell size; an increased value represents greater variability. In certain anemias (e.g., iron
deficiency anemia), an abnormal RDW can present before changes occur in the red cell indices. Anemias
can be classified according to the red cell volume: microcytic, normocytic, and macrocytic. Diagnosis based
on these indices can be difficult when concurrent diseases are present. Further testing and consultation with
a hematologist may be necessary.
Normocytic Normochromic Anemias
Hemolytic Anemia.
Hemolytic anemia may present as an acute crisis or as a chronic disease. Intravascular hemolysis presents
in an acute fashion with severe anemia. Abdominal, chest, or back pain may be associated with hemolysis.
Renal failure may develop from shock or toxins of the red cell stroma. Symptom severity depends on the
rate of hemolysis.[63]
In immune-mediated hemolysis, this rate is dependent on the lytic ability, rate of appearance, peak level,
and disappearance from the blood of the antibody. Patients with either the hapten (e.g., penicillin) or an
autoimmune (e.g., methyldopa) mechanism will experience mild to moderate hemolysis with symptoms
developing over days to weeks. These reactions are self-limited and resolve in a few days to weeks on
discontinuation of the agent. Ternary reactions (e.g., cephalosporins, quinidine) may provoke sudden severe
hemolysis with hemoglobinuria. The hemolysis may occur after one dose of the agent if prior exposure has
occurred.
Non–immune-mediated drug-induced hemolysis usually results from oxidative stress and develops within
several hours to days after drug/toxin exposure. Effects may be delayed because the parent compound must
first be metabolized to its toxic intermediate (e.g., naphthalene must be converted to alpha-naphthol, a red
cell toxin). Patients with G6PD deficiency are especially susceptible to hemolysis from oxidative agents.
Laboratory evidence of hemolysis includes hyperbilirubinemia, elevated lactic dehydrogenase levels,

reduced haptoglobin value, and hemosiderinuria. Patients with chronic hemolytic disease usually have less-
pronounced anemia and a marked reticulocytosis. In acute hemolysis, however, reticulocytosis may not be
present because a few days are necessary for the effects of erythropoiesis to be apparent in the peripheral
blood. The presence of spherocytes on the peripheral smear can direct the clinical workup.[63] Disorders
causing fragmented spherocytosis are Heinz body hemolysis and microangiopathic hemolytic anemia. A
smooth appearance on the red cell surface is significant for Crotalidae envenomation as well as hereditary
spherocytosis, immune hemolysis, burns, or sepsis. The direct antiglobulin (Coombs) test will be positive
only for agents causing an immune-mediated hemolysis (see Table 23–3 ). Copper, lead, arsenic, and
arsine gas may cause hemolysis. Basophilic stippling supports the diagnosis of lead toxicity, but this finding
is neither sensitive or specific. Only a minority of lead-toxic patients will have this finding on peripheral
smear, and it may be found in other conditions, including arsenic toxicity, sideroblastic anemias, and some
thalassemias. G6PD activity should be assayed after the patient has recovered to determine an underlying
deficiency. Reticulocytes have intact enzymes, and their increased presence during acute hemolysis may
falsely elevate G6PD activity.
Aplastic Anemia.
Patients present with either bleeding, fatigue, weakness, or an infection. The patient usually remains
asymptomatic until critically low cellular counts are reached or an external stress such as infection exposes
the condition. All blood elements will be diminished, including the reticulocytes. The cells disappearing first
from the peripheral pool will be those with the shortest life span and highest proliferative rate. Neutrophils,
platelets, and red cells will remain in the blood pool for 4, 7, and 120 days, respectively. The presence of
lymphadenopathy and splenomegaly is atypical and suggests another disorder such as infection or
lymphoma. The outcome of patients with aplastic anemia depends on the cause, severity, and, most
importantly, the duration.[11] The absolute neutrophil count is the most important prognostic factor. Patients
with counts of less than 500/µL are at increased risk for infection, and those with counts of less than 200/µL
have an extremely poor prognosis. In cases of exposure to ionizing radiation, the total lymphocyte count is a
sensitive prognostic indicator. Measured at 48 hours after exposure, a lymphocyte count greater than
1000/µL portends a good prognosis for survival, whereas less than 500 lymphocytes/µL indicates a poor
prognosis.
In cases attributed to chloramphenicol, two types of bone marrow response have been reported. A mild and
reversible fall in the blood elements attributed to inhibition of mitochondrial protein synthesis can occur. This
form is dose related, develops during therapy, and may be due to diminished drug clearance. The other type
of aplasia is persistent, occurs weeks to months after treatment, and can be life-threatening. The dose or
route of administration is not a variable in the occurrence of this latter type.
Macrocytic Anemia
Assessment involves taking a thorough history for ethanol dependence, smoking, liver disease, dietary
habits, bowel surgery, neurological disorders, and medication use.[14] Agents associated with
megaloblastosis are anticonvulsants used long-term, oral contraceptives, antimetabolites, antimicrobials,
and ethanol. In severe cases, a bone marrow aspiration confirms the presence of megaloblastosis. In milder
cases, serum assays for vitamin B12 and folate are more practical.
The clinical manifestations of vitamin B12 (cobalamin) deficiency are glossitis, peripheral neuropathy, spinal
cord ataxia, and dementia. Posterior column disorders such as loss of vibratory and positional sense present
early and may occur in the absence of an elevated MCV. The onset of these changes may be delayed
because liver stores of cobalamin can last 1 to 2 years.[15] Dietary cobalamin deficiency is a common cause
for megaloblastosis in vegetarians.
Patients at risk for folate deficiency are the elderly, poor, and ethanol dependent. They can present with
anemia, fatigue, weakness, and no neurologic abnormalities. Symptoms develop sooner compared with
vitamin B 12 deficiency because liver folate stores last for only 2 to 4 months. Folate therapy of 1 to 5 mg/d
will reverse deficient states. When administered in the setting of vitamin B12 deficiency, the neurologic
disorders may progress. If treatment is urgent, then both folate and vitamin B12 should be given together.
Megaloblastosis due to nitrous oxide (N2O) may show red cell changes within 12 to 24 hours.[14] These
effects resolve over several days, and resolution can be hastened with folinic acid or cobalamin treatment.
Other patients at risk for acute megaloblastosis are those seriously ill in intensive care units and patients
receiving extensive blood transfusions, on hemodialysis, on total parenteral nutrition, or receiving weak
folate antagonists such as trimethoprim. Antifolate agents such as methotrexate can cause stomatitis,
ulcerations of the gastrointestinal tract, and alopecia. Treatment consists of folinic acid, which is the
activated form of folate, in usual doses of 3 to 6 mg/d. Larger doses are indicated in methotrexate
overdoses.
Hypochromic Microcytic Anemia
Iron deficiency anemia is a common disorder that can present as decreased MCV and MCH. Iron deficiency
is an important disorder to diagnose because it may represent a significant underlying process, including
occult bleeding, malignancy, gut malabsorption, or lead poisoning. The association between iron deficiency
and lead poisoning is unclear. Socioeconomic factors may play a role, as well as a decrease in the rate of
iron incorporation into lead-toxic red cells.[66] Low serum iron and ferritin levels with an elevated total iron-
binding capacity are found in iron deficiency anemia. The assessment of lead poisoning requires a whole-
blood lead and serum erythrocyte protoporphyrin (EP) level. The EP level serves to diagnose the duration of
lead exposure (elevated for chronic and low for acute) and as an indicator of degree of toxicity. Elevated d-
aminolevulinic acid in a 24-hour urine collection also indicates toxicity. Drug-induced sideroblastic anemia
can be severe but usually improves rapidly on discontinuation of the offending agent and with pyridoxine
administration in certain situations, such as anemia due to INH, pyrazinamide, and cycloserine.[60]
Treatment of Anemias.
General treatment involves stabilizing the patient, discontinuing the offending agent, ensuring adequate
hydration, monitoring renal function, and transfusing with blood components as necessary. Blood transfusion
in the anemic patient is deemed appropriate when there is evidence of blood loss, lack of available specific
therapy, presence of bone marrow suppression, and evidence of hypotension or end organ decompensation
(e.g., myocardial ischemia, disorientation). Young patients with quickly correctable anemia do not require
transfusion. Although blood typing may be difficult in the presence of hemolysis, as long as ABO typing is
compatible, life-saving transfusions should not be withheld. If the offending drug is still present and is a drug
that induces hapten-mediated hemolytic anemia, the transfused red cells may be continuously destroyed.
Glucocorticoids have been demonstrated to prolong red cell survival and improve mortality in severe
immune-mediated hemolytic anemia.[1] Therapy may be initiated with oral prednisone, 60 to 100 mg/d, in
stable patients, or intravenous methylprednisolone, 100 to 200 mg/d in the critically ill.
Immediate therapy for aplastic anemia is directed toward assessing for and stabilizing complications of bone
marrow failure. Blood transfusions should be minimized to limit antibody formation to these elements and
later resistance to such therapy. Protection from infections involves isolation and use of antibiotics.
Antibiotics are indicated when there is an infection confirmed by culture, clinical evidence of infection, or an
absolute neutrophil count less than 500/µL and fever greater than 101°F. Invasive procedures such as
intramuscular injections should be avoided, nutritional deficiencies should be corrected, and oral hygiene
should be maintained. Drugs with potential marrow toxicity should be avoided because continual exposure
of the marrow to these agents may increase damage. Aspirin should be avoided because it depresses
platelet function; acetaminophen may be used. A bone marrow biopsy can differentiate a drug-induced
disorder from infiltrative marrow diseases such as malignancy. Chelation therapy may be indicated in lead or
arsenic exposures (see Chapters 88 and 89 ). When the patient is not responding to initial and supportive
therapy, the initial diagnosis and treatment must be re-evaluated.
Patients with hematopoietic stem cell failure have a better chance of survival with bone marrow
transplantation than conventional therapy regardless of the cause.[9] Marrow transplantation for drug-
induced aplasia has been successful in young patients.[31] Advancing age is associated with decreased
survival because of severe graft-versus-host disease. Accordingly, few transplantations are performed in
patients older than 50 years. Bone marrow transplantation is currently the treatment of choice in children and
young adults with severe aplastic anemia. Without transplantation, supportive care becomes the mainstay
treatment. Androgen therapy is helpful in less severe cases.[2]
Polycythemia
Hemoglobin concentrations above 16 to 17 g/dL may cause sludging in the microcirculation and precipitate
myocardial ischemia and cerebrovascular insufficiency. Hypertension, encephalopathy, seizures, and
thrombosis have been observed in renal failure patients treated with EPO. [23]
Situations presenting with an obvious cause, such as dehydration, require a limited workup. When volume
status is unknown, red cell mass and plasma volume studies are necessary. Assay for plasma EPO is
essential in the evaluation of absolute polycythemia. In polycythemia rubra vera, the EPO level is usually
low, whereas it is elevated in other conditions, such as EPO-producing tumor. Use of EPO by an athlete
should be suspected when an elevated hematocrit is found in the presence of a low EPO level.
Treatment.
There is limited knowledge of the treatment of symptomatic EPO-induced polycythemia. Phlebotomy is the
initial approach in controlling red cell counts. Consultation with a hematologist is recommended for further
recommendations.
Dyshemoglobinemias
Cyanosis from hemoglobin disorders must be differentiated from diseases of the heart and lung. The
dyshemoglobinemias can present as a myriad of symptoms, all related to hypoxia. The measured oxygen
tension of an arterial blood gas can assist in determining the nature of the disorder. In pulmonary edema,
chronic obstructive pulmonary disease, and pulmonary embolus, the partial pressure of oxygen and oxygen
saturation is diminished. However, in either methemoglobinemia or carboxyhemoglobinemia the oxygen
tension will be normal while the measured oxygen saturation will be low. Specific toxin-induced
dyshemoglobins—methemoglobin, carboxyhemoglobin, sulfhemoglobin—can be directly measured. During
the initial evaluation, high flow oxygen therapy is administered and an electrocardiogram and hemoglobin
count are obtained to determine the severity of illness. Specific therapy with methylene blue for
methemoglobinemia, hyperbaric oxygen for carboxyhemoglobinemia, and oxygen for sulfhemoglobinemia
may be indicated.
White Cell Disorders
Drug-induced agranulocytosis is the most important of the leukopenic disorders. Mortality related to
overwhelming infections can be as high as 48 per cent, and the presence of renal failure and prolonged
marrow suppression contributes to worsening outcomes.[34] The frequency of drug-induced agranulocytosis
increases with age older than 50 years and is more prevalent in females. Patients on multiple medications
and those with high plasma drug concentrations, slow drug metabolism, or renal impairment are at
increased risk.[38] Although neutropenia may occur at any time, it usually develops soon after the start of
drug therapy.
Chills and fever are common presenting complaints in these patients. The diagnostic evaluation can be
guided by the history and physical examination. The history should focus on the duration of neutropenia,
past infections and their severity, recent viral illnesses, medications, and family history. A thorough physical
examination should look for evidence of infection and underlying disease processes such as organomegaly
and lymphadenopathy. The maxillary sinuses, perianal region, indwelling venous catheters, and gingiva are
sites of occult infection and should be evaluated.
Specific tests for neutrophilic disorders include the neutrophil count, morphologic appearance, motility,
chemotaxis, phagocytosis, oxidative capacity, and complement assays. Tests for lymphocytes include
absolute count, immunoglobulin levels, lymphocyte subset ratios (e.g., T helper/suppressor), mitogen and
antigen stimulation, and histologic examination of lymphoid tissue. When the cause of neutropenia is not
apparent (i.e., decreased production or increased destruction), a bone marrow examination is necessary to
rule out other disease processes, such as malignancy. The rate of recovery can be roughly predicted by the
degree of marrow hypoplasia. Patients with normal-appearing precursor cells will have neutrophils reappear
in the blood 4 to 7 days after discontinuing the offending agent.[38] Laboratory studies to demonstrate the
presence of drug antibodies are of limited value because of their technical difficulty and unreliability.[50] The
assays are complicated, and false positive results commonly occur in the presence of autoantibodies,
isoantibodies, and myeloma proteins.
Treatment.
Immediate treatment of a febrile neutropenic patient includes identifying the source of infection and starting
antibiotics. All medications taken within the past 2 weeks should be discontinued. Empirical antibiotic
therapy can improve chances for survival when neutrophil counts are below 1000/µL. The absolute
neutrophil count is determined by multiplying the white cell count by the total percentage of bands and
mature neutrophils. Generally, an aminoglycoside and an antipseudomonal ß-lactam antibiotic are adequate
because the majority of these infections are caused by gram-negative organisms. If a skin source is
suspected, vancomycin may be added. The empirical use of antiviral agents such as acyclovir is
recommended if there are skin or mucosal lesions consistent with herpes simplex or varicella-zoster.[3]
Failure to respond to initial measures of support may necessitate specific therapy.
The use of granulocyte transfusions in agranulocytosis has been found to be as effective as a protective
environment in preventing infections.[8][9] Their use is limited in the setting of proven infections. The decision
for using CSF in patients with agranulocytosis is dependent on the severity of neutropenia and anticipated
speed of recovery of the bone marrow.[26] If promyelocytes and myelocytes are present in the bone marrow,
neutrophil recovery will occur spontaneously in 4 to 7 days after the withdrawal of the offending agent.
However, when granulopoiesis is completely absent, neutrophil recovery cannot be expected for at least 14
days. This latter situation can be accelerated by using granulocyte CSF (G-CSF) or granulocyte-
macrophage CSF (GM-CSF).[19] In drug-induced agranulocytosis, the use of CSF when myeloid precursors
are present in the bone marrow can accelerate neutrophil recovery in 1 to 4 days. If myeloid precursors are
absent, neutrophil recovery with CSF therapy would be expected to take comparably longer but still to occur
sooner than without the use of CSF.
Rapid neutrophil recovery after G-CSF or GM-CSF administration has been demonstrated with several drug-
induced disorders.[3][16] When consideration is given to these findings and the high mortality associated with
agranulocytosis, using these agents appears rational. Indications for CSF use are severe neutropenia with
proven infection or when bone marrow recovery is expected to be prolonged. The presence of renal failure,
gram-negative sepsis, or the lack of neutrophil response is an indicator of poor prognosis.[37]
Bleeding Disorders
Patients with bleeding disorders will present either symptomatically or with a laboratory abnormality noted on
screening. A detailed past medical and family history is essential in an attempt to identify the cause.
Questions concerning excessive bleeding with dental extraction, tonsillectomy, and childbirth will assist in
identifying inborn errors.[47] Information on underlying medical illnesses such as liver disease, renal failure or
malignancy, medication use, or other forms of therapy is also important. Anticoagulants, aspirin, or NSAIDs
are the most common causes of acquired bleeding disorders. Symptomatic bleeding disorders are usually
due to decreased plasma clotting factor activity, severe thrombocytopenia, or a combination of both. In
patients with platelet disorders a systemic process such as sepsis or DIC should be excluded. Fever or
persistent platelet disorders for more than 2 weeks after the discontinuation of medications suggest other
causes.
Clinical manifestations suggesting a systemic clotting disorder include unexplained local hemorrhage,
bleeding from multiple sites, purpura, buccal or retinal hemorrhages, and oozing from venipuncture sites.
Platelet disorders may present as purpura, epistaxis, hematuria, or gastrointestinal bleeding. When bleeding
occurs with a platelet count that is not normally associated with this complication (e.g., greater than
50,000/µL), a qualitative platelet disorder should be suspected. Delayed post-traumatic bleeding,
hematomas, and hemarthrosis are indicative of disorders of the plasma clotting factors.
Thrombotic events due to thrombocytosis are uncommon except in primary causes (e.g., myeloproliferative
disorders) and in patients who are susceptible to clot formation, such as the elderly or those with a sedentary
lifestyle or a predisposing disease. Generally, counts of over 1 million/µL are well tolerated in acquired
disorders of thrombocytosis. Heparin-induced thrombotic thrombocytopenia is not dose related and may
present as limb ischemia within the first week of therapy.[4] The etiology is increased platelet aggregability
due to an immune mechanism. Discontinuation of heparin and evaluation of the need for surgical
revascularization of the extremity are recommended.
Essential screening tests include a CBC, peripheral blood smear, aPTT, PT, and bleeding time. More
detailed studies include platelet function tests (e.g., aggregation and adhesiveness), plasma mixing studies
to determine factor inhibitors and deficiencies, and specific factor assays. A common pitfall is to assume that
a normal PT and a normal aPTT exclude a major hemostatic defect. These studies will be normal provided
30 per cent factor activity is present. However, normal factor activity is much higher than this value.
Prolongation of the PT is not observed until the activity of either fibrinogen, prothrombin, or factors V, VII, or
X is reduced to less than 30 per cent.[47] The normal reference range of activity for these agents is 60 to 160
per cent. False prolongation of the PT can result from improper sample collection (especially insufficient
blood quantity) and from sampling blood from above the intravenous site ( Table 23–5 ).
Table 23-5 -- Differential of Coagulation Profile

Increased aPTT, Increased Thrombin Clotting
Increased PT, Isolated Isolated Increased PT/aPTT Time
Factor VII Factor VIII Factor II Fibrinogen
Warfarin therapy
Factor IX Factor V Fibrinogen dysfunction
(therapeutic)
Liver disease (mild) Factor XI Factor X Heparin therapy
Warfarin therapy (high
IV site draw Factor XII Thrombolytic therapy
dose)
Increased aPTT, Increased Thrombin Clotting
Increased PT, Isolated Isolated Increased PT/aPTT Time
Heparin therapy (high
Sample collection Prekallikrein Liver disease
dose)
Kininogen Liver disease (severe) DIC
von Willebrand factor DIC
Heparin therapy
(therapeutic)
Acquired inhibitors
Sample collection
PT, prothrombin time; aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation.
The international normalized ratio (INR) corrects for the response of different PT assays to the effects of oral
anticoagulants. The INR has meaning only for patients on a stable dose of anticoagulants. Therefore, the
risks of bleeding in patients who have not been taking their medications or have other reasons for a
coagulopathy cannot be determined from the INR. When the PT is being used as a screening tool (e.g.,
warfarin overdose), the use of the normal reference range of 11 to 15 seconds is adequate.
Deficiencies of factor VIII, IX, or XI and the presence of acquired inhibitors will cause a prolonged partial
thromboplastin time. The reference range in most laboratories is a mean of 30 seconds plus or minus 6
seconds. The most common acquired inhibitor responsible for an abnormal aPTT is the antiphospholipid
antibody. A mixing study can quickly evaluate for inhibitors.[24] Equal volumes of patient and normal plasma
are combined for 2 hours before performing an aPTT assay. If inhibitors are present, the aPTT will not
normalize.
Treatment.
The rapidity of treatment for bleeding disorders depends on several factors, including hemodynamic stability
of the patient, the site of the bleeding, and the risk for spontaneous life-threatening hemorrhage. Intracranial
hemorrhage is the most common cause of death from thrombocytopenia. Platelet levels below 20,000/µL
are significant, and replacement therapy with blood products may be indicated. Protamine reverses heparin,
whereas vitamin K is the antidote for warfarin and the long-acting anticoagulant rodenticides. DIC due to
Crotalidae envenomation should be treated with antivenin and fresh frozen plasma.
Medications responsible for the hemostatic disorder must be discontinued. Immune mechanisms are largely
responsible for peripheral platelet destruction, and in these cases glucocorticoids should be immediately
started. These agents have not been shown to shorten the duration of thrombocytopenia, but their use
promotes vascular integrity and reduces the incidence of bleeding.[58]
Patients presenting with blood disorders should be initially stabilized and then evaluated for evidence of end
organ damage and risk for bleeding and overwhelming infection. If antidotal therapy is not indicated,
supportive care and treatment of associated medical illnesses are the therapeutic mainstays. When initial
and supportive measures are not successful in managing the patient, consultation with a hematologist will
be necessary to assist in deciding further therapy.


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29. Gerson WT, Fine DG, Spielberg SP, et al: Anticonvulsant-induced aplastic anemia: Increased
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Chapter 24 – Methemoglobinemia
KEVIN C. OSTERHOUDT
Essentials
• Provide supplemental oxygen.
• Eliminate or treat cause of oxidant stress. Decontaminate skin or gastrointestinal tract if appropriate.
• Exclude hemolysis (complete blood cell count with examination of smear); assess for acidosis
(electrolytes, blood gas analysis); and measure methemoglobin levels (blood co-oximetry).
• Institute antidotal therapy with methylene blue 1 to 2 mg/kg (0.1 to 0.2 mL/kg) of a 1 per cent solution.
° Indicated in presence of tissue hypoxia.
° Contraindicated in known glucose-6-phosphate dehydrogenase (G6PD)
deficiency.
The function of hemoglobin in red blood cells is to bind oxygen in the lungs and deliver it to the body tissues.
The ability to reversibly bind oxygen requires that the deoxygenated heme iron be maintained in the ferrous
(Fe2+) state. Methemoglobin, a form of hemoglobin that cannot bind oxygen, is formed when the
deoxygenated heme is oxidized to the ferric (Fe3+) state. Naturally occurring oxidative forces continually
form small amounts of methemoglobin that are rapidly reduced to the ferrous state by cellular enzymes.
Human red blood cells that contain intact methemoglobin reduction pathways typically contain less than 1
per cent methemoglobin.[29] Methemoglobinemia develops when physiologic derangement of this system
favors methemoglobin accumulation.
In addition to a reduction in oxygen-carrying capacity, the presence of methemoglobin also causes an

increase in oxygen affinity of the normal heme moieties in the heme tetramer, leading to decreased release
of oxygen to tissues and a leftward shift of the oxyhemoglobin dissociation curve. Increasing concentrations
of methemoglobin may significantly impair oxygen delivery to tissues, resulting in life-threatening hypoxia in
severe cases.
Methemoglobin Reduction Systems ( Fig. 24–1 )
The maintenance of low levels of methemoglobin requires the availability of high-energy compounds derived
from glycolysis and the hexose monophosphate shunt. Reduced nicotine adenine dinucleotide (NADH)-
dependent cytochrome b5 methemoglobin reductase (also referred to as NADH-diaphorase) is the primary
enzyme system used by erythrocytes to repair the oxidized hemoglobin. In this system, NADH generated
during glycolysis donates its hydrogen ion to cytochrome b5, which in turn reduces methemoglobin to
hemoglobin. Under usual physiologic conditions nearly all cellular reduction of methemoglobin occurs
through this pathway.
Figure 24-1 A, The NADH-dependent cytochrome b5 methemoglobin reductase system (endogenous). B, The NADPH-dependent
methemoglobin reductase system (therapeutic).
A second enzymatic system, reduced nicotine adenine dinucleotide phosphate (NADPH)-dependent

methemoglobin reductase (alternatively referred to as NADPH-flavin reductase or NADPH-diaphorase),
typically plays an insignificant role in maintaining hemoglobin homeostasis. This system, utilizing NADPH
derived from the hexose monophosphate shunt, is activated in the presence of methylene blue. During
antidotal therapy with methylene blue a large percentage of methemoglobin can be reduced by this
pathway.[12]
Cellular antioxidants such as vitamin C (ascorbic acid) and glutathione also reduce methemoglobin. The
availability of glutathione depends on the NADPH-dependent enzyme glutathione reductase. Under normal
circumstances these nonenzymatic reactions add little to the maintenance of ferrous hemoglobin. Enzymes
such as superoxide dismutase, catalase, and glutathione peroxidase probably help limit oxidative damage
from physiologic superoxide radicals[29] but do not reverse inflicted oxidative injury.


Cyanosis unresponsive to oxygen, despite normal arterial oxygen tension, is the hallmark of
methemoglobinemia. The characteristic blue-gray or brown-gray cyanosis is most notable in the skin, lips,
and nail beds. Cyanosis becomes apparent in the presence of 1.5 g/dL of methemoglobin,[17] in contrast to
the 5 g/dL of deoxyhemoglobin required to create recognizable cyanosis in the setting of hypoxia.
Methemoglobinemia is usually quantified as the percentage of hemoglobin existing as methemoglobin.
Cyanosis related to methemoglobinemia becomes notable at levels above 10 per cent. Constitutional
symptoms of malaise, fatigue, headache, dyspnea, and tachycardia ensue as levels approach 30 per cent.
Levels of methemoglobin above 50 per cent are likely to impair consciousness, whereas levels above 70 per
cent are potentially lethal. Clinical interpretation of methemoglobin levels must take into account the total
hemoglobin value, because anemic patients will have proportionately less functional hemoglobin.
Methemoglobinemia that develops rapidly will be clinically more severe than a similar degree that develops
gradually. The acute accumulation of less than 30 per cent methemoglobinemia is usually well tolerated in
the nonanemic patient.[9] Toxins responsible for methemoglobin formation often have other deleterious
physiologic effects. Vasodilators such as nitrites cause tachycardia, hypotension, and circulatory
inadequacy. Oxidants often produce hemolysis or sulfhemoglobin that complicate the clinical presentation.
The clinical implications of any given level of methemoglobinemia must be assessed in light of other
concomitant toxic effects. Neonates and infants often present with nonspecific clinical findings such as
tachycardia, poor feeding, vomiting, irritability, excessive crying, and excessive sleeping. Dusky, “septic-
appearing” infants have repeatedly been observed to have hemodynamically significant levels of
methemoglobinemia.


The differential diagnosis of the cyanotic patient is reviewed in Table 24–1 . Various causes of hypoxia
resulting in cyanosis due to elevated concentrations of deoxyhemoglobin are not discussed in this section.
Abnormal increases in methemoglobin occur in several distinct clinical contexts that include (1) congenital
abnormalities in hemoglobin structure; (2) inherited deficiencies in enzymes responsible for methemoglobin
reduction; (3) oxidative hemoglobin injury in infants, usually as a consequence of diarrheal illness; and (4)
oxidative hemoglobin injury due to poisoning ( Table 24–2 ). Congenital methemoglobinemia is rare.
Transient methemoglobinemia associated with illness is not uncommon in young infants. Indeed, increased
methemoglobin fractions may be present in as many as two thirds of infants younger than 6 months of age
with significant diarrheal enteritis.[45] Among pediatric inpatients of a tertiary children’s hospital, cases of
methemoglobinemia associated with illness equaled the number associated with toxic exposure.[1] The adult
patient with methemoglobinemia is most likely to have encountered an environmental, industrial, or
medicinal oxidant stress.
Table 24-1 -- Differential Diagnosis of Cyanosis

Low Oxygen Tension
Environmental hypoxia
Pulmonary disorders
Airway compromise
Gradient to oxygen diffusion
Ventilation/perfusion mismatch
Vascular shunting
Cardiovascular disorders
Right-to-left shunt
Congestive heart failure
Shock
Vasoconstriction
Polycythemia
Abnormal Hemoglobin
Methemoglobinemia
Sulfhemoglobinemia
Other hemoglobins with low oxygen affinity
Factitious
Discoloration of skin or blood by dyes
Table 24-2 -- Causes of Methemoglobinemia
Congenital
Hemoglobin M
NADH-dependent methemoglobin reductase deficiency
Cytochrome-b5 deficiency
Acquired
Transient, illness-associated methemoglobinemia of infancy
Toxin related
Acetanilid Hydroquinones Phenacetin
Aminophenones Hydrogen peroxide Phenazopyridine
Aniline dyes Hydroxylamines Phenetidin
Antipyrine Local anesthetics Phenylenediamines
Arsine Methylene blue Potassium permanganate
Bismuth subnitrate Metoclopramide Primaquine
Chlorates Naphthalene Propanol
Chloroquine Nitrates Quinones
Chromates Nitrites Resorcinol
Cobalt Nitroalkanes Rifampin
Copper Nitrobenzenes Toluidine
Dapsone Nitroglycerin Trinitrotoluene
Flutamide Nitroprusside Sulfonamides
Hydrazines Petroleum octane booster Vitamin K3 (menadione)
Toxic Methemoglobinemia
Therapeutic use of drugs, environmental exposure to oxidant forces, inadvertent poisoning, and intentional
overdose can all lead to the development of methemoglobinemia. In fact, hundreds of case reports have
been published implicating a vast array of compounds as hemoglobin oxidants. Table 24–2 includes a list of
many such implicated drugs and poisons. The degree to which methemoglobin is induced varies by agent,
dose, and duration of exposure. Individuals with deficient enzymatic reduction systems may be at risk for
more profound methemoglobinemia. Lukens lists four factors that influence the rapidity and extent of
methemoglobin production after toxic exposure[35]: (1) the rate of entry of an oxidant into the circulation and
erythrocytes, (2) the rate of metabolism or biotransformation of the toxin in the body, (3) the rate of excretion
of the toxin, and (4) the effectiveness of cellular methemoglobin reduction systems. Methemoglobin
formation by direct-acting agents such as sodium nitrite is rapid, whereas methemoglobin formation by
bioactivated toxins can be delayed for hours. The biologic fate of some agents (e.g., nitroethane) can lead to
delayed post-treatment recurrence of cyanosis.[43]
Iatrogenic or Intentional Causes of Methemoglobinemia
The iatrogenic induction of methemoglobinemia is an old problem. The increased susceptibility of young
infants to methemoglobin formation has resulted in numerous reports of methemoglobinemia related to the
exposure of infants to chemicals. It was reported in newborn nurseries as a consequence of dermal
exposure to diaper marking ink[23] and dyed blankets [18] and, more recently, to chlorhexidine solutions used
as incubator disinfectants.[28] The topical use of prilocaine for circumcision anesthesia and topical use of
EMLA (prilocaine-lignocaine) cream[19] has been reported to result in low, usually insignificant, levels of
methemoglobinemia.
The therapeutic use of vasoactive nitrites such as amyl nitrite (relatively high potency), isobutyl nitrite,
nitroprusside, and nitroglycerin (relatively low potency) has been associated with the development of
methemoglobinia.[13][54] Cases of severe methemoglobinemia have been reported in infants after
investigational use of inhaled nitric oxide for the treatment of lung disease, although this seems to be an
unusual complication.[15][41] The use of “poppers” of amyl, butyl, and isobutyl nitrites to enhance sexual
pleasure has resulted in death in some cases.[4] Folk remedies containing nitrites have also produced lethal
methemoglobinemia.[7] The ability of nitrites to reliably create methemoglobinemia is at times advantageous,
as in the use of amyl and sodium nitrites to induce methemoglobinemia in the acute treatment of cyanide
poisoning. In another iatrogenic misadventure, silver nitrate used in the treatment of burns has caused
methemoglobinemia.[14]
Unexpected, abrupt cyanosis in an endoscopy suite or similar setting may result from the overzealous use of
topical anesthetic sprays. Three 1-second sprays of benzocaine may deliver up to 600 mg of drug to the
oropharynx.[50] Topical preparations of benzocaine have caused methemoglobinemia in both children[20] and
adults.[21] Methemoglobinemia may occur after recreational use of illicit drugs adulterated with local
anesthestic agents.[38]
Phenazopyridine used for the treatment of genitourinary pain has caused methemoglobinemia.[11] The
sulfonamides used today rarely lead to clinical methemoglobinemia. Methemoglobinemia has been
associated with antimalarial therapy and continues to be a dose-limiting side effect of dapsone therapy. [49]
Environmental, Commercial, and Industrial Causes of Methemoglobinemia
Nitrite contamination of drinking water supplies has caused recent clusters of cyanotic illness.[52] Nitrates,
which are converted to nitrites in the gastrointestinal tract, have also been an important source of
environmental methemoglobinemia. Widespread use of nitrogen-rich fertilizers leads to nitrate contamination
of groundwater and well water.[5] This is both an historical and ongoing public health concern, as evidenced
by the recent reprinting of Comly’s 1945 report of cyanosis in midwestern infants caused by nitrates in well
water as a “landmark article” by the Journal of the American Medical Association. [10] Numerous similar
reports have followed.[16] High nitrate content in spinach, carrots, and beets, in water used to prepare baby
foods, and in other foodstuffs, including sausage, have also led to methemoglobinemia.[2][16]
A wide array of commercial and industrial products may cause oxidative injury to erythrocytes. For example,
inadvertent ingestions of artificial fingernail products containing nitroethane or N,N-dimethyl-p-toluidine by
curious children have led to severely elevated levels of methemoglobin.[43][46]
Congenital Methemoglobinemias
Hemoglobin M is a rare autosomal dominant disorder that leads to lifelong cyanosis in heterozygotes.
Homozygous hemoglobin M is not compatible with life. Several forms of hemoglobin M have been
characterized,[6] each notable for their predilection to stabilize heme iron in the ferric state.
A congenital deficiency in the NADH-dependent cytochrome b5 methemoglobin reductase can be inherited

in an autosomal recessive pattern.[6] Homozygotes may exhibit lifelong cyanosis. They typically exhibit no
cardiovascular symptoms, which may be a result of physiologic compensation for the chronic condition. An
alternative explanation for this lack of symptoms is that older cells have a greater degree of enzyme
deficiency, leaving young erythrocytes with less impairment of their ability to deliver oxygen to tissues.
Several types of this rare disorder have been described. One form that is associated with cytochrome b5
reductase deficiency in tissues other than erythrocytes is accompanied by mental retardation.[53] Both
heterozygotes and homozygotes are highly sensitive to oxidative hemoglobin injury from xenobiotic agents
and may have greater than normal susceptibility to profound methemoglobinemia.[9] Congenital deficiency of
the cytochrome b5 has also been described. [25] It is not known whether many of the sporadic case reports of
methemoglobinemia, after exposure to commonly used drugs and chemicals, may have been observed in
undetected heterozygotes for cytochrome b5 reductase deficiency.
Deficiency in the NADPH-dependent methemoglobin reductase system is exceedingly rare and would not be
expected to lead to clinical methemoglobinemia. When methemoglobinemia occurs due to intoxication, such
patients would not be expected to respond to methylene blue.
Transient, Illness-Associated Methemoglobinemia of Infancy
The hemoglobin of young infants is exquisitely sensitive to oxidative stress. Young infants have deficiencies
of cytosolic NADH-dependent methemoglobin reductase activity that approaches 50 per cent of that found in
adults.[8] Fetal hemoglobin may also be more susceptible to oxidant forces,[37] although this theory has been
disputed.[34] By 6 months of age the fetal hemoglobin level is minimal and methemoglobin reductase activity
reaches adult levels.
Transient methemoglobinemia without obvious oxidant or drug exposure is a frequent finding in septic-
appearing infants with gastroenteritis and severe acidosis. Avner demonstrated that the degree of acidosis
seen in these infants with “endogenous” methemoglobinemia was out of proportion to the degree of
methemoglobinemia, suggesting that methemoglobinemia may be the result of their acidotic illness, rather
than the cause.[1] The underlying mechanism involved in the oxidation of hemoglobin in these infants is not
known but is likely to be multifactorial. Numerous causes have been postulated that include altered intestinal
flora,[24] acidosis,[56] renal tubular acidosis,[51] acidosis with hyperchloremia,[32] organic aciduria,[30] dietary
protein intolerance,[40] and urinary infection.[33]


LABORATORY STUDIES AND INTERPRETATION
The recognition of dark or “chocolate-brown” arterial blood that does not become red with exposure to air
supports the bedside diagnosis of methemoglobinemia. When the presence of methemoglobinemia is
suspected it is useful to place a drop of blood on filter paper (or white paper towel) next to a normal
control.[26] Dark-colored blood from patients with cardiopulmonary disorders that result in hypoxia should
redden with exposure to air; blood darkened by methemoglobin does not.
Pulse-oximetry measurement of the oxygen saturation of hemoglobin does not provide accurate results in
the setting of methemoglobinemia.[48] Pulse oximetry underestimates oxygen saturation at low levels of
methemoglobinemia and overestimates oxygen saturation when methemoglobinemia is severe. Arterial
blood gas analysis will typically reveal a normal arterial oxygen tension (PO 2) and may reveal a metabolic
acidosis proportional to the severity and duration of tissue hypoxia. The profound and disproportionate
metabolic acidosis seen in young infants with diarrheal illness and methemoglobinemia suggests that the
acidosis is a cause or coexisting finding rather than a result of methemoglobinemia.[1] Be aware that many
hospital laboratories do not measure oxygen saturation directly on blood gas analysis but instead derive it
from a nomogram based on the measured PO 2. In this case, the calculated oxygen saturation would be
falsely elevated in the presence of methemoglobinemia. A “saturation gap” is said to exist when the
measured oxygen saturation of blood differs from the oxygen saturation calculated by routine blood gas
analysis. A saturation gap of more than 5 per cent suggests the presence of methemoglobin,
carboxyhemoglobin, or sulfhemoglobin. [44] Measurement of hemoglobin species using a co-oximeter is
required when an abnormal hemoglobin is suspected.
Multiple-wavelength co-oximetry is the accepted standard for confirming and quantifying

methemoglobinemia. Methemoglobin exhibits polymodal spectrophotometric absorbance, with a peak at 630
to 631 nm where little interference occurs from oxyhemoglobin.[36] Hyperlipidemia and intravenous
administration of methylene blue or other dyes may interfere with co-oximetry measurements.
Methemoglobin percentages can only be used to estimate oxygen-carrying capacity when interpreted in
conjunction with the total hemoglobin. Useful laboratory studies include a complete blood cell count with
differential and microscopic examination of the thin smear to evaluate hemolysis, electrolytes, blood urea
nitrogen and creatinine, blood gas analysis, and urinalysis. An electrocardiogram is appropriate in situations
in which myocardial ischemia is of concern. To confirm and quantify the extent of methemoglobinemia it is
necessary to perform co-oximetry analysis of the blood. Urine toxicologic screens for drugs of abuse do not
usually uncover causes of methemoglobinemia. Electrophoresis for hemoglobins M and quantitative tests of
NADH methemoglobin reductase deficiency require specialized laboratory help and are rarely indicated.


Acquired Methemoglobinemia
General principles of supportive care, with attention to removal of the offending agent or process, will suffice
for most identified cases of methemoglobinemia. Infants with illness-associated methemoglobinemia often
appear to respond well to restoration of fluid, electrolyte, and pH balance. Olsen and McEvoy calculated the
half-life of methemoglobinemia induced in a normal individual with a topical anesthetic to be approximately
55 minutes.[42]
Aggressive medical therapy, including administration of methylene blue, should be considered for patients
with overt signs of tissue hypoxia (beyond cyanotic discoloration), central nervous system depression, or
cardiovascular instability. Special consideration should be given to patients with coexisting medical problems
such as coronary artery disease or pulmonary insufficiency who are less able to tolerate decreases in
oxygen delivery. As a general guide, antidotal therapy is recommended for methemoglobin levels in excess
of 30 per cent.
One hundred per cent oxygen should be administered in significant cases of methemoglobinemia, with
prompt attention to the airway, breathing, and circulation. Tachycardia in noninfant patients likely reflects a
reflex response from tissue hypoxia rather than true hypovolemia. Although cardiac monitoring is helpful,
pulse-oximetry may be misleading. Comatose patients should receive intravenous naloxone and glucose.
Activated charcoal may be employed in an effort to decontaminate the gastrointestinal tract when an oxidant
has been ingested. In certain circumstances, decontamination of the skin may be appropriate.
Methylene blue is an effective antidote for methemoglobinemia. When G6PD deficiency is not suspected, 1
to 2 mg/kg (0.1 to 0.2 mL/kg) of a 1 per cent solution of methylene blue can be administered over 5 minutes.
This results in reduction of methemoglobin to hemoglobin within 15 to 60 minutes. Repeat doses may be
administered for persistent or recurrent methemoglobinemia, but the total dose should not exceed 7 mg/kg.
Certain drugs, such as dapsone, create methemoglobin over a long biologic half-life. Some authors prefer
continuous infusions of methylene blue titrated from a starting rate of 0.1 mg/kg/hr, rather than intermittent
bolus therapy in these situations.[3] Methylene blue may discolor skin and mucous membranes, making
visual interpretation of cyanosis inaccurate. It may also interfere further with pulse oximetry readings. After
administration of methylene blue it is prudent to reassess the afflicted patient’s clinical status and to assay
current methemoglobin levels before proceeding with repeat doses.
Methylene blue is excreted primarily by the kidneys. Although side effects are uncommon, large rapidly
administered doses have been associated with nausea, retrosternal chest pain, tachycardia, hypertension,
and anxiety. Urine will subsequently develop a blue-green discoloration. Methylene blue may contribute to
methemoglobinemia in higher than recommended doses,[22] but this complication is unproven in clinical
practice. Methylene blue may also add to oxidative hemolysis, and young infants without G6PD deficiency
have developed Heinz body hemolytic anemia at doses as low as 4 mg/kg.[31] Methylene blue is usually
effective in the treatment of methemoglobinemia. Unexpected treatment failure can occur for several distinct
reasons. These are enumerated in Table 24–3 .
Table 24-3 -- Reasons for Failure to Respond to Methylene Blue

1. G6PD-deficient individuals cannot utilize the NADPH-dependent methemoglobin reductase because of
insufficient production of NADPH.
2. Sulfhemoglobinemia, which is unresponsive to methylene blue, may coexist. Routine co-oximetry may not
differentiate methemoglobin from sulfhemoglobin. Spectroscopic absorbance of light at 620 nm (very close to
the spectral absorbance of methemoglobin), which is stable to exposure to cyanide, can be presumed to be the
result of sulfhemoglobin. Isoelectric focusing methods to differentiate sulfhemoglobin from methemoglobin also
exist.[44]
3. Continuing drug absorption, or persistent methemoglobin formation, may make response to methylene blue
clinically inapparent.
4. NADPH methemoglobin reductase deficiency or hemoglobin M may be present. These conditions are
extremely rare.
5. High doses of methylene blue may create factitious cyanosis or might add to the oxidative stress.
Known or suspected G6PD deficiency is a contraindication to the use of methylene blue. G6PD is a key
enzyme in the formation of NADPH. In G6PD-deficient individuals, insufficient NADPH is generated to
efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the
NADPH-dependent methemoglobin reductase system. G6PD-deficient individuals are also prone to
methylene blue–induced hemolysis. A number of therapies have been recommended in this scenario, but
none is completely satisfactory. Hyperbaric oxygen therapy may temporarily increase the delivery of
dissolved oxygen, but transport and monitoring of critically ill patients is problematic. Once the oxidant
compound has dissipated, exchange transfusion can replenish oxyhemoglobin content if heroic measures
are required.[39] Ascorbic acid, 300 to 1000 mg/day intravenously in three to four doses, provides
nonenzymatic methemoglobin reduction but is slow. Vitamin E (alpha-tocopherol) has been investigated[47]
but does not seem promising as a treatment for acute poisoning. Wright has demonstrated in vitro efficacy of
N-actetylcysteine in reducing methemoglobinemia,[55] an intriguing approach that requires more study.
A number of drugs require bioactivation before they can oxidize hemoglobin to methemoglobin.[9] For
example, dapsone is oxidized to hydroxylamines before exerting its toxic effects in humans. Agents that
inhibit this bioactivation step may be useful in the prevention of drug-induced methemoglobinemia.
Cimetidine has been used successfully to decrease methemoglobin formation and hemolysis, thereby
increasing tolerance to dapsone therapy.[49]
Congenital Methemoglobinemia
Physiologic compensatory mechanisms leave most enzyme-deficient individuals asymptomatic despite

significant cyanosis. Methemoglobin levels can be reduced significantly by the administration of oral
methylene blue (100 to 300 mg/day in adults).[6] Ascorbic acid (200 to 500 mg/day in adults)[25] or
riboflavin[27] may be useful as alternative therapies in patients with G6PD deficiency. There is no beneficial
therapy for individuals with M hemoglobins; fortunately, these patients are not usually symptomatic.


Patients with acute, acquired methemoglobinemia warrant hospital admission. Clinical and laboratory
parameters should be monitored for evidence of escalating or rebound methemoglobinemia, worsening
oxygen delivery, or possible concomitant hemolysis. Young infants with illness-associated
methemoglobinemia are likely to need prolonged hospitalization.[1] Consultation with a hematologist may be
warranted when an enzyme deficiency or congenital hemoglobinopathy is suspected.


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46. Potter JL, Krill Jr CE, Neal D, et al: Methemoglobinemia due to ingestion of N,N-dimethyl-p-toluidine, a
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Pediatr 1982; 100:415-418.


Chapter 25 – Pulmonary Abnormalities
TIMOTHY E. ALBERTSON BRENT VAN HOOZEN GREGORY P. MARELICH ROBLEE P. ALLEN
Essentials
• Clear airway of foreign materials.
• Establish and secure an airway.
• Evaluate and support ventilation/oxygenation.
• Reduce or eliminate further drug or toxin exposure.
• Perform clinical assessment for pulmonary manifestations of a toxidrome.
INTRODUCTION
Pulmonary manifestations of drug or chemical exposures can be acute, subacute, or chronic. They can be
the consequences of direct toxicity of the compound or the result of indirect effects. Although the focus in
this chapter is on acute direct and indirect pulmonary effects of toxic exposures, also included is some
material on subacute and chronic manifestations. A discussion of the pathophysiology, clinical presentation,
prevention, and treatment of acute chemical-induced pulmonary toxicities is also presented.
Patients exposed to toxic substances frequently present with respiratory complaints. The clinician treating
the poisoned patient must appreciate the signs and symptoms of toxic respiratory exposures, as well as the
current respiratory treatment modalities available. Table 25–1 is an outline of the various categories of
potential acute and chronic drug- or toxin-induced respiratory system abnormalities. Initial evaluation of an
acutely poisoned or symptomatic patient should include a survey of the respiratory symptoms and
physiologic parameters. Inquiries as to the presence of breathlessness, cough, or chest pain combined with
objective measures of oxygenation and ventilation are basic to any medical evaluation.
Table 25-1 -- Categories of Potential Drug-Induced Pulmonary Toxicities

Airway Abnormalities and Irritants
Airway burns
Bronchiectasis
Bronchiolitis obliterans
Bronchitis
Bronchospasm/air trapping
Emphysema with/without bullae
Foreign body aspiration
Vocal cord paralysis/upper airway edema
Barotrauma
Pneumomediastinum
Pneumopericardium
Pneumothorax
Central Drive and Neuromuscular Diseases
Impaired central respiratory drive
Neuromuscular weakness or fatigue of respiratory muscles
Oxygen Delivery and Use
Altered cellular use of oxygen
Altered hemoglobin
Hemolysis
Reduced cardiac output
Anemia/reduced hemoglobin
Pleural and Mediastinal Disease
Barotrauma
Empyema
Hematomas
Mediastinal adenopathy
Pleural effusions
Pleural thickening/reactions/plaques
Malignancy
Pulmonary Parenchymal Disease
Atelectasis
Bronchiolitis obliterans with/without organizing pneumonia (BOOP)
Cancer
Cardiogenic pulmonary edema
Emphysema
Eosinophilic pneumonia/allergic alveolitis
Fibrosis
Pneumoconiosis
Pneumonia/Pneumonitis
Pulmonary granulomatosis
Pulmonary Vasculature Disease
Foreign body embolism
Pulmonary embolic disease
Pulmonary hypertension
Pulmonary vascular granulomatosis
Pulmonary veno-occlusive disease
Vasculitis


INITIAL STABILIZATION/TREATMENT
Removing the patient from an environment with continued drug exposure is an obvious first concern.
Specific treatment of the poisoned patient with drug-induced pulmonary manifestations centers around
supporting ventilation and oxygenation. Clinical evaluation begins with observational assessment of level of
consciousness, airway patency, respiratory drive, air movement, and oxygenation status. Physiologic
parameters such as the respiratory rate and pulse oximetry should be immediately noted.
For an obstructed upper airway, establishing a secure airway by intubation or by inserting an artificial airway
may be sufficient treatment. Upper airway foreign body removal followed, if necessary, by laryngoscopic or
bronchoscopic removal of lower airway foreign bodies will usually improve ventilation. It is important to
prevent aspiration of gastric contents. Early endotracheal intubation, left lateral decubitus positioning of the
patient, elevating the head of the bed to 30 degrees, and nasogastric tube placement to suction are
important maneuvers to reduce the risk of aspiration. A focused physical examination including auscultation
of the neck, heart, and lungs and evaluation of the nail beds for cyanosis and clubbing can be rapidly
performed. Further studies such as continuous pulse oximetry, arterial blood gas sampling with possible co-
oximetry determination, calculation of the serum anion gap, measurement of the serum lactate level, and a
chest radiograph can follow, depending on the signs, symptoms, and specific drug exposure. Co-oximetry
should be requested on the arterial blood samples to evaluate for methemoglobinemia and for
carboxyhemoglobin if carbon monoxide exposure is suspected or if either pulse oximetry or estimated
arterial saturation appears spuriously high for the clinical condition of the dyspneic or symptomatic patient. A
peak flowmeter or spirometry should be used acutely to evaluate and quantitate air flow in patients with
drug-induced asthma or bronchospasm.


PATHOPHYSIOLOGY AND DIFFERENTIAL DIAGNOSIS
Pathophysiology
The role of the respiratory system is the maintenance of appropriate and physiologic cellular environments.
This process ultimately involves the cellular consumption of oxygen, the metabolic production of carbon
dioxide, and the physiologic mechanisms for ensuring appropriate delivery and removal of these gases. The
relatively narrow window that makes up the cell’s appropriate physiologic environment is controlled
homeostatically at a number of levels. Central nervous system cells located primarily in the medulla
oblongata control respiratory drive. Cells in this area and in other peripheral sites normally respond to
circulatory levels of carbon dioxide, oxygen, and the pH of arterial blood. Sensory feedback systems then
increase or decrease the tonic rate and depth of breathing in an attempt to maintain the narrow
physiologically acceptable environment. Local and systemic physiochemical alterations (e.g., pH shifts of the
oxygen-hemoglobin dissociation curve) ( Fig. 25–2 ) and local vascular changes (e.g., pulmonary vascular
shifting of deoxygenated blood to areas of alveoli rich in oxygen) can further refine the homeostatic controls
of the respiratory system.
Figure 25-2 These curves demonstrate the relationship between hemoglobin saturation and dissolved oxygen (Po2) in blood.
Alterations in pH, temperature, and the partial pressure or dissolved arterial carbon dioxide (Paco2) have immediate effects on the
oxygen dissociation curve. Increases in hydrogen ion concentration (acidemia), temperature, and Paco 2 (hypercarbia) as well as
sulfhemoglobinemia promote release of oxygen from hemoglobin and enhance tissue oxygen delivery. Toxins, such as salicylates,
capable of generating an increased temperature and metabolic acidosis would shift this curve to the right, enhancing tissue oxygen
delivery. Alternatively, decreases in hydrogen ion concentration (alkalemia), temperature, and Paco 2 (hypocarbia) along with the
presence of carbon monoxide (CO) or methemoglobinemia decrease the release of oxygen from hemoglobin. The effect of naturally
inducible 2,3-diphosphoglycerate (2,3-DPG) is also to increase oxygen delivery; it is not shown, as its effects occur mainly in the
setting of chronic hypoxemia. (Modified from West JB: Gas transport to the periphery. In West JB [ed]: Respiratory Physiology: The
Essentials, 4th ed. Baltimore, Williams & Wilkins, 1990.)
The resulting complex respiratory process that controls the cellular environment begins with air movement
into and out of the lungs.[38] This step is dependent on coordinated respiratory muscle activity, low airway
resistance, and normal lung compliance. Next, diffusion of gases across the alveoli and pulmonary capillary
membranes must take place. Gases are then dissolved in the blood or in the case of oxygen or carbon
monoxide also carried on the hemoglobin molecule for transportation to or from the lungs and tissues.
Alterations in the configuration or amount of hemoglobin can thus alter oxygen delivery. Changes in
cardiovascular function such as cardiac output can alter the amount of hemoglobin, and therefore oxygen,
being delivered. Finally, both local tissue blood flow and local tissue buffering characteristics can regulate
gas deliveries to and away from individual cells.
Although simplified in description here, each step of the respiratory process potentially can be affected by a
toxic drug exposure. For example, toxic drugs can impact the mechanical bellows function of the muscles of
respiration. Central respiratory drive is vulnerable to perturbations by poisons. Most commonly, respiratory
drive is decreased, but with some exposures it can be augmented. Most patients with drug-induced
respiratory failure have a combination of type I (hypoxic) and type II (hypercapnic) respiratory failures.
Development of barotrauma, pleural disease, or neuromuscular blockade of respiratory muscles can alter
the mechanical function of the lungs. Airway abnormalities such as gastric contents aspiration or chemical
burns can lead to blocked or damaged airways or the development of bronchospasm. This can result in
reduction of air movement into, or more commonly out of, the lung. The oxygen-carrying capacity and
buffering abilities of blood can be altered by toxin or drug exposures such as development of
methemoglobinemia from nitroglycerin exposure during the manufacture of explosives. Drug exposures may
directly or indirectly reduce the efficiency of gas exchange, altering ventilation/perfusion (

) ratios of lung segments. Foreign body pulmonary artery emboli, postobstructive pneumonias, or drug-
induced pulmonary alveolar edema are examples of conditions that can be associated with drug use in
which gas exchange can be severely altered. Toxin-induced causes are but one of many stimuli that can
result in these pathologic changes.
Table 25–2 offers a differential diagnosis based on clinical effects of specific acute and chronic drug-
induced pulmonary toxicities. Mechanisms for these alterations may be directly related to the effect of the
drug exposure or to indirect consequences of the drug on the lung. Examples of indirect or secondary effects
include the development of a pneumomediastinum or pneumothorax as the result of intravenous drug use in
which the “shooter” may use a transjugular approach and inadvertently penetrate the pleural space. Another
example of indirect pulmonary drug-induced toxicity includes agents such as the cyclic antidepressants,
which can cause multiple organ system failure. Severe overdoses with cyclic antidepressants are associated
with a high risk of gastric aspiration and with severe hypotension and shock, both of which are known
triggers for adult or acute respiratory distress syndrome (ARDS). Thus, exposure to a drug can create an
environment or situation resulting in pulmonary toxicity without the drug being directly toxic to the lung.
Table 25-2 -- Differential Diagnosis of Drug-Induced or Drug-Associated Pulmonary Toxicities

Central Respiratory Drive Airway Abnormalities
Decreased Airway Burns/Sloughing
Antidepressants Inhalation of strong acids/bases (e.g., hydrofluoric acid)
Antihistamines Inhalation of superheated gases (e.g., cocaine)
Antipsychotics Bronchiolitis Obliterans with Organizing
Baclofen Pneumonia/Obliterative Bronchiolitis
Benzodiazepines/barbiturates/other sedative-
Amiodarone
hypnotics
Clonidine, other central a2-agonists Bleomycin
Ethanol Cocaine
General anesthetics Cyclophosphamide
Lidocaine Gold
Opioids Methotrexate
Increased Mitomycin-C
Doxapram Nitrogen dioxide
Progesterones Penicillamine
Theophylline Radiation
Neuromuscular Weakness, Fatigue or
Blockade, and Myopathies of the Respiratory Sauropus androgynous plant
Muscles
Aminoglycoside antibiotics Sulfasalazine
Amiodarone Thionyl-chloride
Angiotensin-converting enzyme inhibitors Welding fumes
Calcium channel antagonists Zinc chloride inhalation
Clofibrate Bronchitis/Bronchiectasis/Bronchorrhea
Corticosteroids Cholinergic agents
Cyclic antidepressants Inhaled marijuana
D-Penicillamine Inhaled/smoked cocaine
Diuretics (induced hypocalcemia/hypokalemia) Intravenous heroin
Epsilon-aminocaproic acid Isopropanol aspiration
Gold Smoke inhalation
Isoniazid Emphysema With/Without Bullae
Macrolide antibiotics Intravenous drug abuse
Magnesium sulfate Marijuana
Neuromuscular blockers Talcosis (intravenous magnesium trisilicate)
Nicotine Tobacco
Perhexiline Toxic oil syndrome (denaturalized rapeseed oil)
Phenytoin Foreign Body/Aspiration
Polymyxin B Convulsant agents
Procainamide Inhalation of drugs of abuse (e.g., cocaine)
Vaccines Potent sedating agents
Vincristine Reversible Airway/Asthma/Cough
Pleural and Mediastinal Diseases Adenosine
Pleural/Pleuritis Allergic/anaphylactoid drug reactions
Asbestosis (exudative effusion/pleural
plaques/pleural cancers)
Dantrolene Animal danders
Empyema (intravenous drug abuse, direct
Antibiotics (e.g., penicillins including airborne exposure)
penetration or blood borne)
Ethchlorvynol (exudative effusion) Aspirin
ß-Adrenergic receptor antagonists (systemic and ophthalmic,
Hydralazine (drug-induced lupus syndrome)
includes sotalol)
Interleukin-2 Blood transfusions
Isoniazid (drug-induced lupus syndrome) Cholinergic agents (systemic and ophthalmic)
Mephenytoin (drug-induced lupus syndrome) Cotton smoke
Methotrexate Diisocyanates
Methysergide (pleural fibrosis) Dipyridamole
Phenytoin (drug-induced lupus syndrome) Drugs that increase gastroesophageal reflux (e.g., ethanol)
Procainamide (drug-induced lupus syndrome) Enflurane
Pneumothorax/Barotrauma Indomethacin (systemic and ophthalmic)
Amphetamine Inhaled verapamil
Bleomycin Interleukin-2
Carmustine (BCNU) Latex allergy
Cocaine Leather protectors (aerosolized)
Heroin Marijuana
Iron Methylphenidate
Intravenous drug abuse (jugular or subclavian Metals (e.g., galvanized steel, nickel, aluminum fluoride,
veins) aminoglycosides)
Marijuana Nebulized agents (e.g., pentamidine, beclomethasone)
Nitrous oxide Nonsteroidal anti-inflammatory drugs
Opioids Calcium channel antagonists
Oral contraceptive agents Colloid and crystalloid
Pituitary snuff Daunorubicin hydrochloride
Plastic/epoxy resins Doxorubicin hydrochloride
Eosinophilic Pneumonia/Allergic Alveolitis/Hypersensitivity
Polymer fumes
Lung
Polymyxin/colistin Bleomycin
Propafenone Cocaine
Propellants and inhaler additives Cromolyn
Propofol Dantrolene
Protamine Hydralazine
Proteolytic enzymes (e.g., subtilisin) Isoniazid
Radiographic contrast media L-Tryptophan (eosinophilic myalgic syndrome)
Saxamethonium Methotrexate
Smoked cocaine Methylphenidate
Sodium metabisulfite preservative (systemic and
Nitrofurantoin
ophthalmic)
Triamterine/hydrochlorothiazide Penicillin
Vaccines/serums Phenytoin
Vinblastine/mitomycin-C Procarbazine
Vitamin K Sulfonamides
Vocal Cord Paralysis/Upper Airway Edema Thermophilic actinomyces
Noncardiogenic Pulmonary Edema/Acute Respiratory
Distress Syndrome (ARDS)
Drug-induced allergic/anaphylactoid reactions
Acrolein
(e.g., laryngeal edema)
Intravenous drug abuse (e.g., damage to
Amiodarone
recurrent laryngeal nerve)
Intravenous drug abuse (e.g., abscess formation
Amphetamines
occluding airway)
Pulmonary Vasculature Disease Amphotericin B
Pulmonary Embolic Disease Bleomycin
Cocaine Blood products
Dextran-40 Cadmium (high exposure levels)
Ethiodized oil/lymphangiography Chlorine
Foreign body (e.g., material injected during IV
Cocaine
drug abuse, talc)
Oral contraceptives Cyanide
Therapeutic embolization/migration (e.g.,
Gelfoam, silicone spheres)
Pulmonary Hypertension Cyclosporine
Amphetamine/aminorex
Cytarabine
fumarate/dexfenfluramine
Cocaine Dextran-70
Fat emulsion (Intralipid) Epinephrine
Paraquat Ethchlorvynol
Ethiodized oil with radioactive iodine (pulmonary
Pyrrolizidine alkaloids (e.g., monocrotaline)
hemorrhage)
Sodium morrhuate (e.g., esophageal variceal
Fentanyl (epidural)
sclerosis)
Pulmonary Vascular Granulomatosis Flurazepam
Cocaine (e.g., snorted and intravenous) Heparin (with or without pulmonary hemorrhage)
Cotton fibers (e.g., heroin filter wadding) Hydrochlorothiazide
Intravenous use of crushed oral drugs (e.g.,
methadone, hydromorphone, methylphenidate, Interleukin-2
phenmetrazine)
Talc and cellulose (e.g., intravenous drug abuse) Leukocyte transfusions
Pulmonary Veno-occlusive Disease Methotrexate (intrathecal and systemic)
Bleomycin Methyl chloride (inhalation/combustion)
Carmustine (BCNU) Mitomycin-C + 5-fluorouracil
Cyclophosphamide Mitomycin-C + leukocyte transfusions
Etoposide Moxalactam (pulmonary hemorrhage)
Mitomycin-C Nitrofurantoin (acute)
Vasculitis Nitrogen dioxide
Amphetamines Nitroprusside/nitric oxide
Cocaine Opioids/heroin
Foreign material (e.g., material injected during
Oxygen (high concentrations, prolonged exposures)
intravenous drug abuse)
Hydralazine Paraquat
Nitrofurantoin D-Penicillamine (pulmonary hemorrhage)
Penicillins Phenothiazines
Procainamide Phosgene
Sulfonamide Protamine
Pulmonary Parenchymal and Alveolar
Pyromellitis dianhydride inhalation (pulmonary hemorrhage)
Disease
Alveolar Proteinosis Radiation
Busulfan Radiographic contrast material
Silica/silicates Salicylates
Cardiogenic Pulmonary Edema Pulmonary Fibrosis
Antidysrhythmics Aluminum oxide
ß-Adrenergic receptor antagonists Asbestosis
Sclerotherapy Busulfan
Smoke inhalation Carmustine (BCNU) + cyclophosphamide
Streptokinase High oxygen concentration exposure, prolonged
Sulfur dioxide Methylphenidate (talc)
Trichloroethylene (welding-induced inhalation) Nitrofurantoin
Trimethoprim-sulfamethoxazole Paraquat
Tocolytic agents (e.g., beta agonists—terbutaline
Shark oil
and ritodrine)
Tumor necrosis factor/endotoxin Silica/silicates
Zinc chloride smoke (inhalation) Talc (intravenous)
Pneumonia/Pneumonitis/Pneumoconiosis Vinblastine + mitomycin-C
Acrylic resin pneumoconiosis Pulmonary Granulomatosis
Amiodarone Green tea (aspirated)
Beryllium Methylphenidate (talc granulomas)
Bleomycin Nitrofurantoin + methotrexate (low dose)
Bromine compounds Talc
Cemented tungsten carbide Oxygen Delivery and Use
Cobalt Reduced Cardiac Output
Cocaine Agents producing bradycardia (e.g., digitalis)
Corneal moisturizer (e.g., Lacrilube leading to Antidysrhythmic agents (e.g., quinidine, procainamide,
lipoid pneumonia) propafenone)
Flecainide ß-Adrenergic receptor antagonists (e.g., propranolol)
Gold + naproxen Cyclic antidepressant overdose
Gold salts Iron
Hydrogen peroxide (inhalation) Altered Hemoglobin/Cellular Oxygen Use
Intravenous drug abuse (e.g., hematogenous
Altered cellular use of oxygen (e.g., cyanide, sodium azide,
organisms forming pulmonary abscess or
salicylates, hydrogen sulfide)
pneumonia)
Altered-hemoglobin carrying capacity (e.g., carbon
Liquid paraffin
monoxide)
Methotrexate (low dose) Aplastic anemia (e.g., chemotherapeutic agents)
Drug-induced hemolysis (e.g., nonimmune-mediated:
hypophosphatemia, glucose-6-phosphate dehydrogenase
Mexiletine
deficiencies and oxidative drugs; immune-mediated:
penicillin, quinidine, and methyldopa)
Megaloblastic anemia (e.g., antifolinic
Nitrofurantoin agents—methotrexate, triameterene, trimethoprim, nitrous
oxide, anticonvulsants)
Methemoglobin or sulfhemoglobin forming agents (e.g.,
nitrites, nitrates, aniline derivatives, nitroglycerine,
Penicillamine primaquine, mafenide, acetate, sulfonamides, phenacetin,
hydrogen peroxide, ferrocyanide, benzocaine, chlorates,
dinitrophenol)
Red cell aplasia (e.g., gold salts, azathioprine,
Quinidine
chloramphenicol, thiouracil)
Radiation
Silica/silicates
Sulindac
Tocainide
Vinblastine + mitocycin-C
Pulmonary Cancer
Arsenic
Asbestos (including mesothelioma)
Bischloromethyl ether
Chromium (hexavalent)
Nickel
Polycyclic aromatic hydrocarbons
Tobacco smoke (chronic)
Radon progeny from uranium


CLINICAL EVALUATION
Neuromuscular/Central Nervous System Alteration
Both acute and chronic toxicity of agents can be manifested in respiratory failure.[3] Table 25–2 outlines a
number of agents associated with central respiratory depression. In addition, agents associated with
myopathies and neuromuscular weakness that can lead to respiratory compromise are listed. In its pure
form, this results in a type II or hypercapnic respiratory failure with impaired ventilation as the primary defect.
Marked elevation in dissolved arterial carbon dioxide levels (PaCO2) with relative preservation of oxygenation
is classically noted. Lowered PaO 2 (dissolved arterial oxygenation content or partial pressure of oxygen) can
occur in severe cases of pure type II respiratory failure. The reason for this is that the partial pressures of
alveolar oxygen (PAO2) and carbon dioxide (PACO2) are linked by the alveolar air equation:
where PACO2 is assumed to be equal to

the arterial partial pressure of carbon dioxide (PaCO2), R is the respiratory quotient (usually assumed to be
0.8), and PIO2 is the partial pressure of inspired oxygen at sea level. The PIO2 is obtained by multiplying the
percentage of oxygen concentration (21 per cent or 0.21 in room air) by the difference of atmospheric
pressure (760 mmHg) minus the vapor pressure of water (47 mmHg). Thus, at sea level: PIO2 = (760 - 47
mmHg) × 0.21 150 mmHg. Equation A simplifies at sea level on room air as:
A normal alveolar-arterial (A-a) gradient for oxygen (PAO2 - Pa O2) is approximately 10 mmHg and increases
only slightly with age. Thus, an acute rise in PaCO2 from 40 to 70 mmHg will result in a drop in PaO2 from 90
to 52 mmHg.
For the busy clinician this effect can be estimated by using the Wasserman number, in which on room air at
sea level the PaO 2 and the PaCO2 normally should add up to 110 to 130 mmHg. With type II (hypercapnic)
respiratory failure, a normal Wasserman number and a normal alveolar-arterial PO2 difference or gradient
should be found. If the sum is less than 110 mmHg on room air, then reduced inspired oxygen
concentration, mismatch, diffusion impairment, or a right-to-left shunt must also be

contributing to the hypoxemia. Although acute exposures to agents such as morphine can acutely diminish
ventilatory responses to hypoxia and hypercapnia, resulting in acute respiratory acidosis,[39] the
neuromuscular-induced toxicities often occur over longer periods of time. This allows some metabolic
compensatory actions such as retention of bicarbonate by the kidney to blunt the pH changes of
hypercapnia.
Pleural and Mediastinal Disease

The most common pleural and mediastinal manifestations of drug-induced pulmonary toxicity are
pneumothoraces and barotrauma. Intravenous drug users often eliminate accessible superficial veins due to
scarring with repeated use. Eventually, they may turn to the use of central veins such as the internal jugular
(“pocket shot”) or the subclavian veins. This can be attempted by the abuser or by another individual and
may result in unilateral or bilateral pneumothorax with or without pneumomediastinum.[42] Usually, evidence
of a puncture site with or without superficial abscess is noted. In addition, hemothorax, tension
pneumothorax, empyema, or pyopneumothorax has been reported.[15] Patients will often present with acute
respiratory failure, and emergent chest tube thoracostomy can be lifesaving. Transient pleural or mediastinal
enlargement probably from hematomas or infections has been reported, and mediastinal hematomas and
abscesses can even produce extrinsic obstruction of the trachea or mainstem bronchi ( Fig. 25–1 ).[35]
Figure 25-1 A known intravenous drug abuser presented to the emergency department complaining of pain in the area of the right
sternoclavicular joint. He admitted to central venous injections. Upon his return to the clinic 3 days later, a large neck mass was seen
extending medially to the sternal notch (A). On chest radiograph, a right upper lobe peritracheal anterior mass was seen, with soft
tissue neck swelling (B). On CT scan (C), a large anterior mediastinal abscess was noted. This required surgical drainage and
prolonged antibiotic administration. Although not seen in this case, tracheal compression and resulting airway obstruction can occur in
this type of infection.
Inhalation of cocaine, amphetamine, and marijuana has been associated with barotrauma, owing in part
from coughing episodes and the prolonged ritualistic Valsalva maneuvers used.[15][33] Intravenous heroin
use is also associated with barotrauma from coughing.[15] These patients may present with shortness of
breath, pleuritic chest pain, subcutaneous emphysema, and Hamman’s crunch sign. Hamman’s crunch sign
is heard on auscultation of the heart as a crunching sound accentuated with systolic activity of the heart from
a pneumopericardium.[33] In one review, patients with drug-associated barotrauma responded to
conservative measures, including observation and supplemental oxygen. [33] Rarely, chest tube
thoracostomy was required.
Direct exudative pleural effusions are rare but have been reported after toxic exposures of ethchlorvynol and
as a result of chronic asbestosis.[13] More commonly, drug-induced lupus erythematosus has resulted in
pleural pulmonary involvement with pleuritis and pleural effusions (see Table 25–2 ).[9][34][42]
Pleuropulmonary involvement occurs more frequently with drug-induced lupus erythematosus than with
idiopathic lupus.[9] Procainamide, hydralazine, and isoniazid account for the majority of cases of drug-
induced lupus syndromes.[9] Eliminating further drug exposure is the treatment of choice in these cases.
Airway Abnormalities
Significant premature air trapping or emphysema can result from long-term pulmonary exposure to some
agents. Chronic tobacco and marijuana abuse and intravenous drug abuse with or without talc adulterants
have been associated with premature emphysema and upper lobe bullae formation.[12][13][15][36] Early
cessation of further respiratory exposure is the best treatment. Further symptomatic therapy including
antibiotics, oxygen, and bronchodilators may be useful. Obstructive airway changes of emphysema have
also been reported 4 years after accidental ingestion of edible oil adulterated with denaturalized rapeseed oil
(toxic oil syndrome).[11]
Inflammatory response of the airway with and without signs of infection and bronchorrhea has been reported
with smoking of tobacco, marijuana, and cocaine.[31] A chemical-induced tracheobronchitis can be seen
after smoke inhalation or aspiration of irritants such as isopropyl alcohol. Bronchitis and symptomatic
bronchiectasis have been noted in intravenous heroin abusers, particularly after episodes of overdose.[15]
The mechanism for the development of this altered airway is unknown, but gastric aspiration and pneumonia
or local fungal colonization or infection have been postulated.[15][35] Smoking marijuana contaminated with
fungi has been associated with the development of allergic bronchopulmonary aspergillosis[15] and, in a
transplant patient, invasive aspergillosis. [24] Bronchorrhea associated with wheezing and reversible airway
spasm has been noted with inhaled or systemic toxic exposure to agents such as carbamates and
organophosphates that increase acetylcholine effects by inhibiting acetylcholinesterase.
A bronchial disorder that overlaps with parenchymal disease is bronchiolitis obliterans with organizing
pneumonia (BOOP). Drug-induced BOOP is pathologically characterized as patchy destruction of the
terminal bronchiole and alveolar filling with inflammatory cells and loose connective tissue. Exposure to
several agents including cocaine, gold, antineoplastic agents, welding fumes, and amiodarone (see Table
25–2 ) have been associated with the development of BOOP.[2][8][31][36] Reports have suggested that when
the normally highly nutritious vegetable Sauropus androgynous is consumed in large amounts as a health
food in Taiwan, it is associated with obstructive pulmonary function changes and histologic changes
consistent with BOOP or other proliferative changes.[23][25] The histologic morphology of drug-induced
BOOP is indistinguishable from that of idiopathic BOOP.[31] The patients have patchy air-space opacities on
chest roentgenograms. Treatment includes limiting further drug exposure and initiating corticosteroid
therapy.
Upper airway obstruction can be an indolent condition or a medical emergency that may be rapidly fatal.
Vocal cord paralysis from intravenous drug abuse and neck venous injection attempts has been reported.[15]
In one series, nine patients presented with hoarseness, upper-airway obstruction, or both after heroin
injections in the neck.[14] Although surrounding cellulitis and neck abscess formation were seen in some of
these patients, direct neurologic injury (mechanical or drug-induced) to the recurrent laryngeal nerve was the
postulated mechanism of the unilateral or bilateral vocal cord paralysis.[14] Acute management of the airway
required intubation or tracheotomies in most of these patients along with antibiotics and surgical treatment of
any cellulitis or neck abscess. Laryngeal edema associated with allergic or anaphylactoid drug reaction
requires immediate airway establishment. In addition, supplemental oxygen, epinephrine, antihistamines,
and corticosteroids are given.
Upper airway swelling and edema can also result from direct exposure of caustic materials such as
hydrofluoric acid.[7] Upper and lower airway burns can occur with any inhalation or aspiration of strong acids
or bases. This can lead to edema, necrosis, and sloughing of the airway. Securing an airway early in these
patients by endotracheal or tracheotomy tube placement is important. Nebulized 2.5 to 3 per cent calcium
gluconate for hydrofluoric acid or bicarbonate for other acid exposures has been advocated with little or no
experimental support.[7] Frequent mechanical airway clearing of sloughed epithelial cells and mucus plugs
by bronchoscopy is critical.
Airway aspiration of foreign bodies has been seen with convulsant agents or agents that are significant
depressants. Foreign body aspirations can result in a variety of presentations, ranging from immediate large
airway blockage and ventilation abnormalities to minimal ventilatory symptoms. Postobstructive pneumonias
can develop. Foreign body aspiration has also been associated with the local anesthetic effects of cocaine,
including a report of an accidental hypodermic needle aspiration by a freebase user.[20] Bronchoscopic
removal of the foreign body will correct the airway obstruction, and antibiotics will be required for treating
postobstructive pneumonias.
Table 25–2 outlines a number of chemical agents associated with asthma or reversible airway disease
exacerbations.[16][26][40][42] The mechanism of drug-induced asthma can be receptor mediated (e.g., beta-
adrenergic receptor antagonists), inflammatory, or allergic/anaphylactoid mediated. Exposures to these
agents can be by inhalation, parenterally, by ingestion, or by ophthalmic routes.[16][26][27][40] The clinician
often is challenged to identify the inducing agent. Leather protectors have been reformulated to eliminate
trichloroethane. The resulting products contain solvents such as isobutane, iso-octane, ethyl acetate, and n-
heptane mixed with fluoropolymer resins or carbonyl fluoride.[6][21] Aerosolized exposures to these products
has resulted in cough, shortness of breath, and bronchospasm with wheezing.[6][21] In contrast, angiotensin-
converting enzyme (ACE) inhibitor antihypertensive use is associated with a dry cough, typically without
associated bronchospasm. [17] A 4-day trial off the ACE inhibitor with resolution of symptoms is diagnostic of
the drug-induced cough.[17] The related angiotensin II receptor antagonists are significantly less likely to
cause cough in patients with previous ACE cough.[28] Irritant-induced airways disease known as reactive
airways dysfunction syndrome (RADS) is a postchemical injury asthma-like syndrome.[1] Table 25–3 outlines
chemical exposures associated by case reports with the development of RADS. Key criteria for the
diagnosis of RADS include an absence of preceding respiratory disease in a nonatopic person with abrupt
onset of persistent asthma-like symptoms within minutes to hours of a documented exposure to excessive
concentrations of corrosive or irritating gas, vapor, fumes, or dust.[1][5] A reversible air flow pattern on
spirometry with the presence of moderate to severe bronchial hyperreactivity on methacholine challenge
testing and the lack of minimal lymphocytic inflammation without eosinophilia on histopathologic study have
also been included as criteria for the diagnosis of RADS.[1][5]
Table 25-3 -- Chemical Exposures Associated with Reactive Airway Dysfunction Syndrome
Acetic acid Lithium bromide
Acids Locomotive exhaust
Ammonia fumes Metal coat remover
Bleaching agents Metam sodium (sodium N-methyldithiocarbamate)
Burnt paint fumes Methylene chloride (phosgene)
Butadiene Perchloroethylene
Calcium oxide Phosphoric acid
Chlorine gas Silicon tetrachloride
Diphenyl methane diisocyanate Silo gas
2-Diethylaminoethanol Sodium hydroxide
Ether vehicle (used in freebasing cocaine) Spray paint
Ethylene oxide Sulfur dioxide
Fire/smoke Sulfuric acid
Floor sealant/cleaner Tear gas
Formaldehyde Toluene diisocyanate
Fumigating fog Trochlorusilane
Heated acid Uranium hexafluoride
Hydrazine 35% Welding fumes
Hydrochloric acid Zinc chloride
Hypochlorite sodium
Data from references 1 and 2 .
Acute bronchodilators (anticholinergics and beta-agonists) often reverse most drug- or irritant-induced
bronchospasms. Self-injectable epinephrine is available and should be prescribed for patients with life-
threatening bronchial hyperreactivity to prevalent antigens or irritants. Anti-inflammatory agents such as
corticosteroids may be useful. Corticosteroids are given systemically for acute exposures and by inhalation
when possible for chronic unavoidable exposures. Reducing further exposure by removing the patient from
the offending agent is important. When life-threatening bronchospasm accompanies anaphylaxis, then
immediate airway management, oxygen, epinephrine, corticosteroids, and antihistamines are needed.
Pulmonary Vasculature Disease

The pulmonary vasculature is an extensive surface that is at risk for drug-induced damage. General types of
pulmonary drug-induced vasculature alterations are outlined in Table 25–1 . Table 25–2 gives specific drugs
associated with these toxicities. Pulmonary embolic disease can be the consequence of a hypercoagulable
state causing deep vein thrombosis, or it can be the direct effect of the drug or its contaminants. Oral
contraceptives are an example of the first situation, and foreign particle embolism from intravenous drug
abuse represents an example of the second mechanism.[10][19][22][30][37] Manifestations of pulmonary
embolism include chest pain, dyspnea, oxygenation alterations, hypotension, and possible chest
radiographic and electrocardiographic changes. Treatment includes anticoagulants, thrombolytics for severe
cases, oxygen, and, occasionally, the placement of inferior vena cava filters.
Pulmonary vasculitis, pulmonary hemorrhage, pulmonary hypertension, disrupted pulmonary capillaries

leading to alveolar edema, pulmonary veno-occlusive disease, and pulmonary vascular granulomatosis are
additional reported drug-induced vascular toxicities.[2][18][19][22][29][30][31][35][37][41] Many of these conditions
are difficult to treat and can lead to the development of cor pulmonale and death from progressive
respiratory failure.
Pulmonary Parenchymal and Alveolar Disease
Acute or adult respiratory distress syndrome (ARDS) is a noncardiogenic pulmonary edema caused by
increased pulmonary capillary permeability.[29] Drugs and toxins are relatively rare causes of ARDS
compared with other stimuli such as trauma and sepsis. Table 25–2 outlines agents associated with drug-
induced ARDS.[2][8][9][13][19][29][30][31][41][42] This list is extensive but contains many agents based on a single
case report. As discussed previously, ARDS can be triggered directly by primary lung toxicity or indirectly by
neurogenic mechanisms or by initiation of the systemic inflammatory cascade (e.g., inducing prolonged
systemic hypotension). Like most parenchymal/alveolar disorders, ARDS is associated with type I
(hypoxemic) respiratory failure. Specifically, ARDS increases shunt fraction, or the amount of blood relative
to the total cardiac output that passes through nonventilated portions of the lung. Computed tomographs of
the lungs demonstrate patchy air space involvement, with a greater degree of alveolar filling in gravity-
dependent regions. Because pulmonary capillary blood flow is greatest in the dependent portions of the
lung, the shunt fraction is increased. Whereas mismatching can be compensated by

100 per cent oxygen administration, the hypoxemia associated with a shunt fraction of 30 per cent or more,
which is common in ARDS, will not significantly improve without the addition of mechanical ventilation and
positive end-expiratory pressure (PEEP).
Drug-induced pulmonary hemorrhage has frequently been associated with ARDS (e.g., Dextran 70) but has
also occurred without ARDS.[4][19] Cardiogenic pulmonary edema can be associated with drug exposure.[19]
Beta-adrenergic receptor antagonists and calcium channel antagonists are most commonly associated with
drug-induced cardiogenic pulmonary edema in the acute setting.
A wide range of drug-associated parenchymal and alveolar conditions have been noted and outlined in
Table 25–2 , including lung cancer, pneumonia, pneumonitis, pneumoconiosis, pulmonary fibrosis, alveolar
proteinosis, eosinophilic pneumonia, hypersensitivity pneumonitis, and pulmonary
granulomatosis.[2][30][31][32][41][42] Treatment of these drug-induced disorders includes limiting further
exposure to the causative agent, oxygen, anti-inflammatory agents for most cases, and surgery and
chemotherapeutic agents for cancers. Diuresis is the first-line therapy in cardiogenic pulmonary edema and
is even encouraged if hemodynamically tolerated in ARDS.
Oxygen Delivery/Cellular Use
The final goal of the respiratory system is to support cellular metabolism and oxygen consumption. Drugs
that have negative inotropic and chronotropic effects can reduce oxygen delivery by reducing cardiac output
(see Table 25–2 ). Because of the importance of hemoglobin in oxygen delivery, any agent that alters the
function, amount, or configuration of hemoglobin can also reduce oxygen delivery (see Table 25–2 ).
Because a hemoglobin molecule can bind four oxygen molecules, each gram of hemoglobin is capable of
transporting 1.36 mL of oxygen when fully saturated. The oxygen content of blood (CaO 2) is the sum of
dissolved and hemoglobin-bound oxygen and at 1 atmosphere of pressure and 37°C is:
where SaO 2 is the hemoglobin oxygen

saturation and hemoglobin (Hgb) is measured. In the absence of severe anemia or hyperbaric conditions,
dissolved oxygen is a minor contributor to total oxygen delivery (DO 2), which can be calculated by the
simplified equation:
where Qt is cardiac output in liters per minute, usually measured by a right

heart catheter. When oxygen delivery does not globally or locally meet cellular oxygen demand, the cells
convert from aerobic to the less efficient anaerobic metabolism, with resultant formation of lactate.
Uncoupling of cellular oxidative phosphorylation by cellular toxins such as cyanide, salicylates, or sodium
azide can also block cellular oxygen metabolism and thus affect overall cellular respiration or metabolism.
Cardiac output may increase to temporarily compensate for the effects of mild anemia or altered hemoglobin
conditions on oxygen delivery. When cardiac output can no longer compensate for altered hemoglobin,
hypoxemia, occupied hemoglobin (e.g., carbon monoxide), or increased oxygen consumption, then cellular
hypoxia and lactic acidosis ensue.


LABORATORY VALUE INTERPRETATION
Laboratory studies useful in evaluating the respiratory manifestations of a poisoned patient can be classified
as either imaging studies or functional studies. Imaging studies include chest radiographs, chest computed
tomography (CT), magnetic resonance imaging (MRI), nuclear medicine scans, and,
most recently, positron emission tomography (PET). Functional studies measure air movement, lung
volumes, exercise capabilities, diffusion capacities, oxygenation, pH, and ventilation. A detailed review of the
interpretation of pulmonary imaging and functional studies is beyond the scope of this chapter, but some
aspects of these studies that are altered in the poisoned patient deserve emphasis.
Acutely poisoned patients will be primarily evaluated with chest radiographs. Evidence of barotrauma,
pulmonary edema, air trapping, and parenchymal diseases can often be seen. Radiographic manifestations
of acute pulmonary edema, especially noncardiogenic ARDS, can have a delayed onset and resolve more
slowly than the alveolar-arterial oxygen gradient. Chest CT tends to be more useful in evaluating chronic
manifestations of poisoning when better imaging of the mediastinum, upper airway, or parenchymal
structures is required. Thin-section CT of the chest can aid in the diagnosis of interstitial and parenchymal
lung diseases. Although chest radiographs and CT are very useful for evaluating mediastinal, pleural, and
parenchymal disease, the upper and lower airways are best evaluated by direct visualization (e.g.,
laryngoscope or bronchoscope) when burns, swelling, or foreign bodies are considered.

scans are particularly useful in the diagnosis of pulmonary emboli when perfusion defects are found in the
absence of ventilation defects. Chest MRI and PET imaging have had limited utility in evaluating the
poisoned patient.
Spirometric measures including peak flows, forced expiratory volumes, and lung volume measurements can
be useful in confirming the presence of obstructive (e.g., asthma or emphysema) or restrictive (e.g. fibrotic)
lung disease. These studies are commonly employed to evaluate the possible subacute or chronically
exposed patient. Diffusion capacity measurement reflects the relative amount of alveolar-pulmonary capillary
interface. Diffusing capacity measured using a single breath or carbon monoxide is reduced in lung fibrosis
and pulmonary vascular abnormalities.
Measurements of arterial oxygen hemoglobin saturation can be done indirectly using pulse oximetry. This
technique passes bands of light through, for example, the fingernail bed and estimates the percentage of
hemoglobin saturated. Pulse oximetry readings are decreased in the presence of hypoxia and
methemoglobinemia. However, pulse oximetry will not detect carbon monoxide because it cannot
differentiate oxyhemoglobin (the percentage of hemoglobin saturated with oxygen) from carboxyhemoglobin
(that saturated with carbon monoxide). Other problems such as nail bed pigment, nail coverings, and poor
circulation can limit the usefulness of this diagnostic tool. Co-oximetry can be performed on arterial blood
samples to directly measure the percent of oxyhemoglobin and carboxyhemoglobin. If co-oximetry is not
obtained, then the hemoglobin oxygenation saturation is estimated ( Fig. 25–2 ) from the PaO2 and the
patient’s temperature. Pulse oximetry saturation and hemoglobin saturations estimated from PaO 2 will be
artificially high with carbon monoxide poisoning. The use of co-oximetry will allow accurate diagnosis of
carbon monoxide and methemoglobinemia poisoning. Hemoglobin saturations estimated from venous
oxygen partial pressure (PvO2) are not accurate because of the steepness of the hemoglobin saturation/PO2
curve at low PO 2 (see Fig. 25–2 ). Co-oximetry again should be used in cases for which accurate venous or
arterial hemoglobin saturations are needed.
Other studies that can be useful in evaluating possible toxic patients with pulmonary consequences include
pulmonary exercise testing and bronchoprovocation challenge testing. About 5 per cent of patients with
interstitial lung disease, including some patients with toxic exposures, present without chest radiographic
evidence of disease. Exertional widening of the alveolar-arterial oxygen gradient may be all that is
demonstrable. Bronchial provocation challenge testing with specific compounds may be useful to confirm
hypotheses suggested by history or to disprove false claims.


As discussed briefly under Initial Stabilization/Treatment, support of oxygenation should be addressed in a

timely fashion in the poisoned patient. The patient with type I hypoxic respiratory failure is the classic
example. Supplemental oxygen is the most common therapy.[38] mismatching is

corrected by increasing the inspired oxygen concentration, whereas pure right-to-left pulmonary or cardiac
shunts will be minimally improved. Oxygenation can be increased in the nonintubated patient by using nasal
prongs, face mask, a hyperbaric chamber, or continuous positive airway pressure (CPAP) administration. By
using noninvasive ventilation devices that allow setting inspiratory positive airway pressure (IPAP) and a
separate expiratory airway pressure (EPAP), oxygenation and ventilation can be supported in some patients
without intubation and mechanical ventilation. Bronchodilators and corticosteroids frequently improve
ventilation in patients with drug-induced bronchospasm. Chest tube insertion to evacuate a pneumothorax
can dramatically improve ventilation.
Greater inspired oxygen concentrations can be delivered via endotracheal tubes than by using masks or
nasal cannulae. Endotracheal intubation increases the ability to flush out nitrogen from the lung and
prevents ambient air leak into the system with high flow rates during inspiration. Ventilation can be
supported directly with mechanical ventilators after intubation or tracheostomy. Table 25–4 summarizes
indications for and examples of drug-induced states that may require mechanical ventilation. Assessing the
need for mechanical ventilation in the poisoned patient can be made by clinical evaluation alone, particularly
in the emergent situation (e.g., clinical evidence of apnea, cyanosis), or it can be made by obtaining
laboratory values (e.g., arterial blood gases, spirometry) in conjunction with the clinical evaluation. Although
a full discussion of the use of mechanical ventilators is beyond the intent of this chapter, the goal of
maintaining an appropriate minute ventilation that allows a physiologic pH and PaCO2 with low peak
inspiratory pressures (usually < 40 cm H2O) should be remembered. Mechanical ventilation alone will
correct type II hypercapnic respiratory failure in its pure form. Correction of a respiratory acidosis usually
follows correction of ventilation abnormalities, but occasionally short-term bicarbonate use will be needed in
the presence of a severe respiratory acidosis.[38]
Table 25-4 -- Drug-Induced Indications for Mechanical Ventilation

Airway Protection
Acute hemoptysis from corrosives
Airway burns
Airway obstruction (e.g., foreign body aspiration)
Aspiration risk from central nervous system depression
Hypoxia Refractory to Supplemental Oxygen
Adult or acute respiratory distress syndrome
Pleural effusions
Pneumonitis and pneumonia
Pneumothorax
Pulmonary vascular disease (e.g., embolic disease, pulmonary hypertension)
Severe interstitial lung disease
Intentional Hyperventilation
Cyclic antidepressant overdose
Reduction of cerebral edema
Reduction of intercranial pressure
Metabolic Acidosis with Insufficient Respiratory Compensation
Altered hemoglobin (e.g., carbon monoxide, methemoglobin)
Cellular toxins (e.g., cyanide, sodium azide)
Respiratory Acidosis
Central nervous system depression (e.g., opioid, sedative-hypnotics)
Central nervous system injury (anoxic event)
Respiratory muscle fatigue
Increased work of breathing (e.g., bronchospasm, increased A-a gradient)
Neuromuscular blocking agent
PEEP, like CPAP, increases functional residual lung capacity and tends to improve oxygenation in many
hypoxemic conditions such as pulmonary edema. However, PEEP and positive-pressure ventilation can
adversely reduce venous return, which can then diminish oxygen delivery by severely reducing cardiac
output. Severe cases of drug-induced pulmonary edema requiring intubation and PEEP will frequently
necessitate right-sided heart catheterization to precisely determine cardiac output and volume status.
Hyperbaric oxygen therapy has been recommended in severe carbon monoxide poisoning, resulting in
increased tissue oxygen and reduced half-life of carboxyhemoglobin. Its use in other poisonings such as
cyanide, sodium azide, carbon tetrachloride, and hydrogen sulfide remain controversial.
Other techniques to improve oxygenation should be considered. Diuresis and inotropic support can
potentially reduce pulmonary edema fluid and improve oxygenation and oxygen delivery. Drug- or toxin-
induced immunologically mediated diseases (e.g., hypersensitivity pneumonitis, eosinophilic pneumonia)
may show dramatic improvement with corticosteroid therapy. Oxygenation abnormalities from intravenous
foreign body-induced pulmonary emboli may partially respond to systemic anticoagulation therapy.[8]
Secondary pneumonias will improve with removal of obstructing material (foreign body or mucus) and
antibiotics. Bacteremia from infected right-sided heart valves, as the result of intravenous drug use, may
result in continued showering of septic emboli to the lungs. Replacement of the valve with long courses of
antibiotics may be necessary for successful treatment. Neck and mediastinal abscesses from intravenous
drug use will require surgical drainage and antibiotics.
Subtle airway hyperresponsiveness may be diagnosed by inhalation challenge tests (e.g., methacholine or
specific allergen) followed by spirometry.[40] Full pulmonary function testing including lung volume
determinations, spirometry, and carbon monoxide diffusion capacity (DLCO) followed by pulmonary exercise
testing may be required for the complete evaluation of some subacute or chronic consequences of a drug
exposure.


Hospital admission is required for any poisoned patient manifesting or at risk for significant abnormalities of
oxygenation or ventilation. Furthermore, any documented deterioration or potential for rapid deterioration of
oxygenation or ventilation will require intensive care unit monitoring and support. Early consultation is
needed with specialists in critical care or pulmonary medicine for most severely ill patients with drug-induced
respiratory symptoms. Important outpatient consultations may include occupational medicine specialists,
otolaryngologists, toxicologists, public health providers, and pulmonary specialists.


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Proc 1990; 65:521-529.
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pulmonary perfusion. Intensive Care Med 1988; 14:25-29.
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Hypertens 1995; 5(Suppl):S51-S54.
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Chapter 26 – Hypersensitivity Reactions
WILLIAM J. MEGGS
Essentials
• A history of exposure is usually evident.
• Urticaria, angioedema, or flushing is noted.
• Pruritus is generally present.
• Hypotension exists along with warm skin.
• Tachycardia is present.
• Bronchospasm and bronchorrhea may occur.
• Laryngeal edema is a major cause of death.
• Gastrointestinal symptoms include nausea, vomiting, diarrhea, bloating, and pain.
INTRODUCTION
Hypersensitivity is a body reaction to a foreign protein or chemical. Some individuals are prone to these
reactions, such as those with an atopic tendency. Some chemicals such as penicillin or sulfa drugs and
animal proteins such as horse serum or Hymenoptera venom are particularly antigenic and more likely to
incite a reaction. Some of the mediators have been identified ( Table 26–1 ), but the exact mechanisms and
the ability to predict which individuals will have a reaction are incompletely understood.
Table 26-1 -- Mediators of Inflammation Released by Mast Cell and Basophil Degranulation
Preformed Mediators
Histamine
Tryptase
Chymase
Carboxypeptidase
Cathepsin G–like protease
Heparin
Chondroitin sulfates A, E
Mediators Produced by Metabolism
Tumor necrosis factor alpha
Interleukin-4
Prostaglandin D2
Leukotriene C4
Leukotriene D4
Leukotriene E4
Adapted from Schwartz L, Huff T: Biology of mast cells and basophils. In Middleton E Jr, Reed CE, Ellis EF, et al
(eds): Allergy Principles and Practice. St. Louis, CV Mosby, 1993, p 135.


There are both immunologic and neurologic pathways leading to hypersensitivity reactions.
Immunologic Inflammation
Initial exposure to either a protein (antigen) or a chemical (hapten) bound to a protein leads to sensitization,
with the production of IgE antibody to the antigen. The IgE is produced by plasma cells that differentiate from
B lymphocytes. This IgE binds with great avidity to the surface of basophils (found in the bloodstream and
sometimes the tissues) and mast cells (found in tissues in proximity to blood vessels and sensory nerves).
When an antigen crosslinks a pair of IgE molecules on the surface of basophils or mast cells, the cell
releases preformed chemical mediators contained in cytoplasmic granules and metabolically produces other
mediators (see Table 26–1 ). These mediators interact with receptor cells to produce inflammation in
tissues. Mast cell degranulation has radical effects on multiple organ systems ( Table 26–2 ). Chemotactic
factors are released by mast cells and lead to tissue infiltration with neutrophils and eosinophils. The most
common allergens causing allergic reactions in humans are protein aeroallergens (pollens, mold spores,
dust mite feces, animal danders), venoms (insect stings, snake bites), antivenoms (horse serum), foods, and
drugs as haptens ( Table 26–3 ).[16]
Table 26-2 -- Major Manifestations of Immediate Hypersensitivity Reactions

Skin Cardiovascular
Flushing Hypotension
Pruritus Tachycardia
Angioedema Cardiac dysrythmias
Urticaria Myocardial infarction
Heat Gastrointestinal
Respiratory Nausea
Rhinorrhea Vomiting
Sneezing Diarrhea
Postnasal drip Abdominal bloating
Sinusitis Crampy abdominal pain
Pharyngitis
Laryngeal edema
Hoarseness
Bronchospasm
Bronchorrhea
Cough
Hypoxia
Table 26-3 -- Examples of Substances Known to Produce Immediate Hypersensitivity Reactions in

Humans
Foods Nonsteroidal Anti-inflammatory Medications
Peanuts Aspirin
Cottonseed meal Naprosyn
Shrimp Ibuprofen
Egg Indomethacin
Milk Venoms
Potato Honey bee
Carrot Wasp
Antibiotics Hornet
Penicillin Yellow jacket
Ampicillin Rattlesnake
Cephalothin Aeroallergens
Tetracycline Tree pollen
Streptomycin Weed pollen
Autologous Serum Grass pollen
Horse serum Dust mite antigens
Enzymes Cat saliva proteins
Penicillinase Mouse urinary protein
L-Asparaginase Mold spores
Chymotrypsin Cockroach antigens
Chymopapain Diagnostic Agents
Nutrient Injections Iodinated radiocontrast material
Vitamin E
Iron dextran
Neurogenic Inflammation
Sensory nerve C-fibers contained in subepithelial tissues have chemoreceptors on the nerve fiber surfaces.
Chemical irritants bind to chemoreceptors and trigger an inflammatory response. Examples of chemical
irritants are cigarette smoke, gases such as sulfur dioxide and chlorine, solvents such as toluene
diisocyanate and formaldehyde, and some fragrances, perfumes, and pesticides. When the irritants bind to
the nerve fiber chemoreceptors, chemical mediators including substance P, calcitonin gene-related peptide,
and neurokinin A are released. These substances produce vasodilation and edema. In addition, the binding
of irritants to the chemoreceptors initiates a nerve impulse that travels to the central nervous system.[14][15]
The immunogenic pathway and the neurogenic pathway are related in a crossover network. Mast cells
contain receptors for substance P, and the binding of substance P to mast cells triggers mast cell
degranulation and the release of mast cell mediators. Sensory nerve C-fibers have surface receptors for
histamine, and when histamine binds to the nerve fibers, substance P is released and an impulse is
transmitted up the nerve fiber.[1] Figure 26–1 depicts the relationship between nerve fibers and mast cells.
Figure 26-1 Relationship between type 1 immunogenic (immediate hypersensitivity) and neurogenic inflammation. Neurogenic
inflammation is triggered by chemical irritants binding to chemoreceptors on sensory nerve C-fibers, with substance P release.
Immediate hypersensitivity is triggered by antigen molecules cross-linking IgE antibody molecules on mast cell surfaces, with the
release of histamine and other mediators. These processes are linked by substance P receptors on mast cell surfaces and histamine
receptors on C-fiber surfaces.
Neurogenic Switching
Clinical symptoms typically appear at the site of inoculation with an antigen or chemical irritant, but
sometimes the site of response can be switched to another site. [11] Examples include systemic anaphylaxis
to ingestions of food and drugs, in which there is a rapid development of signs and symptoms in many organ
systems. Food allergy most commonly causes gastrointestinal symptoms of diarrhea, nausea, vomiting,
abdominal bloating, and cramping, but it can result in urticaria, asthma, laryngeal edema, and systemic
anaphylaxis. The site switching is thought to occur in the central nervous system, with the response to the
sensory nerve signal from the site of inoculation being rerouted to another peripheral location, leading to
substance P release at the second location, as depicted in Figure 26–2 . In animals, systemic anaphylaxis
can be blocked by ablating nerve pathways, even though histamine release still occurs at the inoculation
site.[4][5]
Figure 26-2 Schematic diagram showing how the site of inflammation is switched from the site of inoculation to the site of stimulation
by a process known as neurogenic switching.
Allergic Diseases
Asthma, rhinitis, sinusitis, urticaria, conjunctivitis, migraine headache,[17] and systemic anaphylaxis are
diseases associated with allergy. These conditions may be acute or chronic and can sometimes go into
remission with removal of the offending agents. Individuals who have one of the diseases have an organ
system abnormality in addition to the hypersensitivity. For example, if a group of individuals who
manufacture IgE to egg proteins are fed eggs, a variety of responses may be seen. A person with a
predisposition to asthma might develop wheezing, and a person with a predisposition to urticaria might
develop hives. Individuals who have an allergic disease can have exacerbations by stimuli other than
allergens and chemical irritants. In the case of asthma, cold dry air, stress, respiratory infections including
influenza,[2] and exercise[8] can trigger attacks in some individuals.
Chemical Sensitivity
Some individuals have a heightened response to chemical irritants such as the products of combustion
(cigarette smoke, wood fires, gasoline and diesel vehicle exhaust), perfumes, fragrances, cleaning products
such as ammonia and disinfectants, and pesticides. This heightened response is called chemical sensitivity.
Chemical sensitivity is different from allergy in that chemical irritants interact with chemoreceptors on
sensory nerves rather than with IgE antibodies on mast cell surfaces.[13] Respiratory symptoms are very
prominent in these individuals,[9][10] and the majority of individuals with asthma or rhinitis have some degree
of chemical sensitivity.[9][14] Although chemical sensitivity is not as well understood as allergy, neurogenic
inflammation is thought to play an important role in this type of sensitivity.[9][12][13] Dysregulation of
neurogenic inflammation is under investigation as a cause of chemical sensitivity.
Late-Phase Reactions
Immediate hypersensitivity reactions occur within minutes of exposure to an antigen. The immediate
symptoms are caused by mast cell degranulation with release of histamine and other mediators. Symptoms
can resolve and then recur after 4 to 8 hours. This late response is known as the late-phase reaction and is
characterized by infiltration of the tissue with eosinophils and neutrophils. Neutrophils release factors that
degranulate mast cells. Late-phase reactions have been documented for urticaria, asthma, and systemic
anaphylaxis. Corticosteroids block late-phase reactions and should be given after a severe hypersensitivity
reaction, including all cases of systemic anaphylaxis, even if the immediate symptoms have resolved.[3]
Anaphylactoid Reactions
Some substances directly degranulate mast cells rather than by binding to an antibody. The term
anaphylactoid reaction is reserved for reactions caused by these substances, whereas anaphylactic reaction
refers to reactions mediated by IgE. Examples of substances causing anaphylactoid reactions include
opioids, iodinated radiocontrast media,[7] and nonsteroidal anti-inflammatory agents, including aspirin.
Clinically, the symptoms and treatment of anaphylactoid and anaphylactic reactions are identical. An
anaphylactic reaction only occurs after an initial exposure with sensitization, but an anaphylactoid reaction
can occur the first time a person is exposed.


Multiple organ systems (see Table 26–2 ) are involved in the presentation of hypersensitivity. Patients are
frequently uncomfortable; and if the discomfort is due to difficulty breathing or hypoxia, the cause should be
corrected immediately. Laryngospasm is a major cause of death and presents as difficulty breathing and
hoarseness. Bronchospasm can be caused by a hypersensitivity reaction, with wheezes heard on
auscultation of the chest. In allergic asthma, bronchospasm is often accompanied by cough, bronchorrhea,
conjunctivitis, and rhinitis. Sputum is thin and watery and can be copious. A family history of asthma or hay
fever may be present, and there may be a history of recurrent episodes that may flare with seasons. When
hypotension and shock occur, the skin is typically warm and flushed and there is usually a secondary sinus
tachycardia. Urticaria is the most common skin manifestation and can be seen with flushing or angioedema.
When edema occurs in the airway, rapid intervention is needed. Pruritus is usually present but may be
variable. Nausea, vomiting, bloating, and crampy abdominal pain typically occur with food allergy and may
occur at the same time.


Urticaria is most commonly associated with a hypersensitivity reaction, but other conditions can mimic
urticaria such as vasculitis ( Table 26–4 ). A biopsy is needed to distinguish vasculitic urticaria from that due
to mast cell degranulation. Angioedema can result from a hypersensitivity reaction, but other causes of
angioedema include trauma, infiltration of intravenous fluids, and hereditary angioedema. Hereditary
angioedema is a condition in which there are recurrent attacks of angioedema, often with gut involvement
and severe abdominal pain, due to a deficiency of the enzyme C1q esterase inhibitor. Cold and vibration can
precipitate urticaria in some individuals, and persons with cold-induced urticaria are at risk for systemic
anaphylaxis in situations such as swimming in cold water.
Table 26-4 -- Differential Diagnosis of Hypersensitivity Reactions

Shock or Cardiovascular Collapse
Sepsis
Cardiogenic: acute myocardial infarction, aortic aneurysmal dissection
Hypovolemia
Neurogenic shock
Pulmonary embolus
Tension pneumothorax
Pulmonary
Pneumonia
Bronchitis
Reactive airway disease
Pulmonary edema
Dermal
Angioedema
Vasculitis
Trauma
Causes of bronchospasm to be considered in addition to asthma induced by a hypersensitivity reaction

include foreign body aspiration, viral or bacterial infections, and chronic obstructive pulmonary disease.
Cardiac asthma refers to individuals with heart failure who present with dyspnea and wheezing. The
bronchospasm associated with pulmonary edema is thought to result from irritation of the airways by
pulmonary edema fluid. Clues to cardiac asthma include a history of heart failure, physical findings of rales
and gallops, signs of pulmonary edema on a chest roentgenogram, and elevated blood pressure. With a
severe asthma attack the blood pressure may appear to be elevated, owing to the presence of a paradoxical
pulse, with auscultation of Korotkoff sounds over a peripheral artery at a high systolic pressure on expiration
that disappear with inspiration.
Differential diagnosis of anaphylactic shock includes septic shock, cardiogenic shock, capillary leak
syndrome, pulmonary embolism, hypovolemic shock, neurogenic shock, and shock induced by poisoning.
Septic shock is associated with fever, elevated white blood cell count, hyperventilation, and localized signs
of infection, such as pneumonia, cellulitis, signs of an acute abdomen, or pyuria. Cardiogenic shock usually
occurs in the setting of a large acute myocardial infarction, with electrocardiographic changes of ischemia or
injury, cardiac dysrhythmias, and a history of risk factors for coronary artery disease such as cigarette
smoking and hypercholesterolemia. In cardiogenic shock, the skin is typically cold and clammy and
diaphoresis may be present. Capillary leak syndrome is a condition of unknown etiology in which there are
recurrent episodes of shock due to fluid leaking from capillaries into extravascular compartments. An
opening of the junctions between endothelial cells is thought to be responsible for these attacks. During an
attack, the hematocrit rises precipitously as fluid leaks from the vascular compartment. Treatment is support
of the circulation with infusions of isotonic fluids and plasma, and requirements may be huge. A massive
pulmonary embolism may present as immediate dyspnea and circulatory collapse. A history of recent
surgery, immobilization of an extremity, or reduced physical activity for medical or other reasons predisposes
to pulmonary embolism and can be a clue to the diagnosis. Hypovolemic shock occurs with hemorrhage or
fluid loss due to vomiting, diarrhea, or urinary diuresis. Neurogenic shock occurs when damage to the
sympathetic branch of the autonomic nervous system leads to a loss of vascular tone and most commonly
occurs with spinal cord trauma. Toxins can produce shock through hypovolemia (arsenic poisoning),
suppression of myocardial inotropy (calcium channel blockers and ß-adrenergic receptor antagonists), or
massive cardiovascular collapse (colchicine, hydroxychloroquine).


LABORATORY STUDIES
Systemic anaphylaxis is a clinical diagnosis that cannot be verified by a definitive laboratory study. Plasma
histamine levels rise with anaphylaxis, but histamine levels are not widely available and have not been
verified as a reliable marker of anaphylaxis. Blood cultures can be used to rule out sepsis as a cause for
shock, ventilation-perfusion scans and chest roentgenograms can support a diagnosis of pulmonary
embolism, and electrocardiograms can verify cardiogenic causes of shock. In capillary leak syndrome, the
hematocrit rises with an acute attack and there is marked edema on examination.
Allergic asthma is a condition with distinct pathology seen on lung biopsy. Findings include thickening of the
basement membrane, desquamation of the epithelium, cellular infiltrates of neutrophils and eosinophils, and
mucus plugging. Lung biopsy is not used in the diagnosis of asthma but may be helpful in the research
setting and the medical examiner’s office in the evaluation of sudden respiratory death. Pulmonary function
tests show an obstructive pattern of decreased forced expiratory volume in 1 second (FEV1) with normal or
increased vital capacity that is reversible with bronchodilators.[6] Pulmonary function tests can be useful in
quantitating the degree of bronchospasm and ruling out restrictive disease. Other forms of obstructive lung
disease such as chronic bronchitis secondary to cigarette smoking may not be distinguishable from allergic
asthma. Sputum examination can aid in the diagnosis of allergic asthma if characteristic findings of
eosinophils, Curschmann’s spirals, and Charcot-Leyden crystals are present, but the expertise to interpret
sputum smears is not widely available.
Urticaria due to hypersensitivity has a characteristic pathology on skin biopsy that can be distinguished from
urticarial vasculitis. This test is seldom necessary in the absence of a strong suspicion of vasculitis.
Studies can be undertaken after the acute episode to determine the etiology of a hypersensitivity reaction.
The gold standard is a double-blinded provocative challenge, in which the patient is challenged with the
substance and monitored for the development of symptoms and signs of disease. These tests are
expensive, time consuming, and dangerous and have greatest utility in research. The most sensitive method
to detect allergy is skin testing. A small drop of a solution containing an antigen is placed on the skin and a
prick made in the center of the drop (prick test), or a small quantity of a solution containing an antigen is
injected into the skin (intradermal test). Skin tests are inexpensive, give immediate results, and are very
sensitive. Skin testing reagents are readily available from several suppliers to a variety of antigens, including
Hymenoptera venoms, pollens, molds, dust mites, and animal danders. Rare incidences of anaphylaxis
have occurred from skin tests, so these should be performed by knowledgeable practitioners equipped to
treat untoward reactions. Techniques for in vitro measurements of serum IgE such as radioallergosorbent
(RAST) assays are done by a variety of techniques but are not as sensitive as skin tests. Indications for
RAST include patients who cannot discontinue medications such as antihistamines and cyclic
antidepressants that negate skin test results.


TREATMENT
Hypersensitivity reactions can affect both the cardiovascular and the respiratory systems, leading to
cardiopulmonary compromise and, in extreme cases, cardiopulmonary arrest. Aggressive management
must be instituted ( Table 26–5 ). Epinephrine is the emergency drug of choice for the initial management of
any severe hypersensitivity reaction. It should be given in the field if possible, and individuals at risk for
anaphylactic or anaphylactoid reactions should carry epinephrine kits for self-administration.
Table 26-5 -- Treatment Essentials of Hypersensitivity Reactions

1. Intubate and ventilate as needed.
2. Administer oxygen 100%.
3. Administer
a. Intravenous (IV) fluids: normal saline or lactated Ringer’s for blood pressure support
b. Pressors: 1 : 1000 epinephrine 0.01 mg/kg up to 0.5 mg SQ or endotracheal (1 : 10000 epinephrine 0.01
mg/kg IV if patient is in extremis)
c. H1 antihistamine: diphenhydramine, 1 mg/kg up to 50 mg IV
d. H 2 antihistamine: cimetidine, 300 mg IV
e. Corticosteroids: methylprednisolone, 1 to 2 mg/kg up to 125 mg in adults IV
4. Remove stingers attached to the skin.
5. Discharge with 3-day course of H1 antihistamine and prednisone.
6. Advise to have self-administered epinephrine available at all times.
7. Avoid high-risk situations.
a. Walking barefoot outside
b. Brightly colored clothes
c. Perfumes
d. Orchards and flower gardens
8. Refer to allergist for desensitization injections.
Laryngeal edema is a major cause of death in hypersensitivity reactions. If the edematous vocal cords can
be visualized, it is usually possible to pass an endotracheal tube through the cords. An emergency surgical
airway may be necessary.
Bronchospasm and bronchorrhea may compromise respirations and should be treated emergently with
epinephrine and oxygen. Further treatment with bronchodilators such as nebulized albuterol (0.1 to 0.15
mg/kg/dose up to 5.0 mg in children, 2.5 to 5.0 mg in adults), and theophylline (5.6 mg/kg intravenous
loading dose, and 0.5 mg/kg/hour intravenous infusion) may be necessary. A corticosteroid such as
methylprednisolone (1 to 2 mg/kg intravenously) should be given.
Tachycardia, hypotension, cardiac dysrhythmias, and cardiac arrest may be present. The drug of choice for
hypotension is epinephrine (0.01 mg/kg in children, 0.3 to 1.0 mg in adults). Epinephrine can be given
subcutaneously (1:1000), by endotracheal tube, or intravenously (1:10,000). Subcutaneous administration is
the preferred route in most patients, and the intravenous route is reserved for patients in severe shock
because of the increased risk of myocardial infarction and ventricular fibrillation with intravenous epinephrine
administration. Supplemental oxygen and intravenous fluids should be given. Both H1 and H2 antihistamines
should be given by the intravenous route. The most commonly used H1 antihistamine is diphenhydramine (1
mg/kg in children, 50 mg in adults), and cimetidine (300 mg in adults) is used as an H2 antihistamine. A
corticosteroid such as methylprednisolone (1 to 2 mg/kg intravenously) should be given.
In any patient with a clinical syndrome associated with hypersensitivity, emergency management of
symptoms should be followed by a vigorous attempt to determine the cause. Some causes of
hypersensitivity reactions are given in Table 26–3 . General categories include foods, pharmaceuticals,
envenomations, aeroallergens such as pollen, dust mite products, molds spores, animal danders, and
iodinated radiocontrast agents. Immunotherapy injections to desensitize the individuals to exposures that
cannot be avoided have been scientifically shown to be efficacious for anaphylaxis secondary to
Hymenoptera envenomations, as well as asthma and rhinitis secondary to aeroallergen exposure.
Prophylactic medications such as antihistamines, bronchodilators, and corticosteroids should be prescribed
as indicated. Individuals with a history of life-threatening hypersensitivity reactions should carry a form of
injectable epinephrine. Epi-Pen is an autoinjectable form of epinephrine that fires when the device is
pressed against the thigh. Ana-Kit contains a vial of epinephrine that must be drawn up in a syringe before
injection.


DISPOSITION
Patients with severe anaphylactic reactions that are not readily reversed in the emergency department are
admitted to the intensive care unit for further treatment. Patients with severe reactions that reverse with
treatment in the emergency department should be admitted to a monitored observation bed for 24 hours.
Patients with severe reactions on discharge should have prescriptions for two injectable forms of
epinephrine, one to be kept at home and one to be carried when they are away from home, which in many
cases can be kept in the glove compartment of their car. Patients with severe reactions to Hymenoptera
envenomation should be referred to an allergist for further evaluation and desensitization with
immunotherapy if indicated. Patients with severe anaphylactic-like attacks of unknown etiology should also
be referred to an allergist for evaluation of occult causes and for medical conditions such as systemic
mastocytosis and hereditary angioedema.


SEQUELAE
Most individuals who recover from an acute hypersensitivity reaction are sensitized and at risk for future
reactions with repeat exposure. Patients may suffer long-term disability from the clinical effects, such as
prolonged hypoxia and shock.


REFERENCES
1. Cavagnaro J, Lewis RM: Bidirectional regulatory circuit between the immune and neuroendocrine
systems. Year Book Immunol 1989; 4:241-252.
2. Kava T: Acute respiratory infection, influenza vaccination and airway reactivity in asthma. Eur J Respir
Dis 1987; 150:1-38.
3. Kaliner MA: Late phase reactions. N Engl Regional Allergy Proc 1986; 7:236-240.
4. Leslie CA, Mathe AA: Modification of guinea pig lung anaphylaxis by central nervous system (CNS)
pertubations. J Allergy Clin Immunol 1989; 83:94-101.
5. Levy RM, Rose JE, Johnson JS: Effect of vagotomy on anaphylaxis in rat. Clin Exp
Immunol 1976; 24:96-101.
6. Li JT, O’Connell EJ: Clinical evaluation of asthma. Ann Allergy Asthma Immunol 1996; 76:1-13.
7. Lieberman P: Anaphylactoid reactions to radiocontrast material. Clin Rev Allergy 1991; 9:319-338.
8. McFadden Jr ER: Exercise-induced airway obstruction. Clin Chest Med 1995; 16:671-682.
9. Meggs WJ, Cleveland Jr CH: Rhinolaryngoscopic examination of patients with the multiple chemical
sensitivity syndrome. Arch Environ Health 1993; 48:14-18.
10. Meggs WJ: Health effects of indoor air pollution. NC Med J 1992; 53:354-358.
11. Meggs WJ: Neurogenic switching: A hypothesis for a mechanism for shifting the site of inflammation in
allergy and chemical sensitivity. Environ Health Perspect 1995; 103:54-56.
12. Monro J: Food-induced migraine. In Brostoff J, Challacombe SJ (eds): Food Allergy and Intolerance.
London, Bailliere Tindall, p 633.
13. Nadel JA: Neutral endopeptidase modulates neurogenic inflammation. Eur Respir J 1991; 4:745-754.
14. Nielsen GD: Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev
Toxicol 1991; 21:183-208.
15. Schwartz L, Huff T: Biology of mast cells and basophils. In: Middleton Jr E, Reed CE, Ellis EF, et
al ed. Allergy Principles and Practice, St. Louis: CV Mosby; 1993:135.
16. Shim C, Williams Jr MH: Effect of odors in asthma. Am J Med 1986; 80:18-22.
17. Vaughn R, Lyndon E: Neurologic reactions to foods and food additives.

In: Metcalfe DD, Sampson HA, Simon RA, ed. Food Allergy, Oxford: Blackwell Scientific; 1991.


Chapter 27 – Disorders of Thermoregulation: Hyperthermia and Hypothermia
KATHLEEN A. DELANEY
HYPERTHERMIA
Essentials
• If the core temperature is at least 41.1°C (106°F) begin external cooling with ice or tepid water plus fans
until temperature reaches 38.3°C (101°F) ( Table 27–1 ).
Table 27-1 -- Treatment of Hyperthermia: Temperature >41.1°C (106°F)

Initiate simultaneously
Control airway as needed.
Put patient on cardiac monitor.
Remove clothing. Cool with ice, ice-water immersion, or fans plus tepid water spray.
Control agitation, rigidity, or seizures with diazepam, 5–10 mg IV q5–10min, or lorazepam, 2–4 mg IV
q15–20min, titrated to effect.
Time to cooling: =30 minutes. Stop at 38°C (101°F).
Use rectal thermocouple to monitor temperature.
Exclude hypoglycemia.
Infuse normal saline. Place a Foley catheter. Maintain urine output at 1–2 mL/kg/hr.
Anticipate DIC, rhabdomyolysis, myoglobinuric renal failure, hepatic failure, and hyperkalemia.
Diagnose and treat encephalitis and meningitis when clinically suspected.
Avoid cooling blankets, antipyretics, phenothiazines, and butyrophenones.
• Control shivering and agitation with intravenous benzodiazepines titrated to effect (see Table 27–1 ).
• Anticipate myoglobinuric renal failure, hyperkalemia, hypoglycemia, hepatic injury, and coagulopathy.
• Fever due to infection rarely raises the temperature above 41.1°C (106°F). Consider infection if the core
temperature is less than 41.7°C (107°F).
Initial Stabilization and Treatment
Rapid Cooling in Severe Hyperthermia (Temperature is above 41.1°C [106°F])

Rapid external cooling should be instituted concurrently with other critical resuscitation procedures. The goal
of treatment is a temperature of 38.3°C (101°F) within 30 minutes of the patient’s arrival in the emergency
department. The ideal way of cooling a severely hyperthermic patient avoids intense cooling of the skin,
which stimulates shivering and vasoconstriction. An effective technique, espoused by the physicians who
treat the hundreds of heatstroke cases that occur during the yearly pilgrimages to Mecca, Saudi Arabia,
utilizes tepid water sprays and fanning of naked patients suspended in nets to minimize vasoconstriction and
shivering and maximize evaporative cooling.[25][160] Unfortunately, the sophisticated equipment necessary to
institute this type of cooling is not available in most institutions. Most limiting is the lack of the ability to
expose the entire body surface area when the patient is lying on a stretcher. All hospitals, however, have ice.
Despite the clear drawbacks related to the use of ice and ice-water immersion for cooling, military
experience has proved this alternative to be life-saving, significantly reducing the mortality of heatstroke in
basic training.[11][32][134] The resultant shivering can be effectively controlled with intravenous
benzodiazepines. Standard cooling blankets are not adequate. Antipyretics have no role, as they work by
lowering the hypothalamic set-point in febrile patients, a mechanism that has no relevance to the patient with
hyperthermia.[13]
Measures for Decreasing Ongoing Heat Production
Hyperthermia cannot be effectively treated without addressing the sources of excess heat production.
Agitation must be controlled, preferably with intravenous benzodiazepines, such as diazepam or lorazepam,
titrated to effect. Phenothiazines and butyrophenones are contraindicated in these patients, owing to their
interference with thermoregulation, their effects on blood pressure, a tendency to lower the seizure
threshold, and their lack of efficacy in treating delirium tremens. Restraint alone is detrimental. The patient
struggling in restraints without chemical sedation can suffer dramatic rises in body temperature.
Treatment of Hypotension
Several studies of patients with acute onset of heatstroke associated with exertion showed that the average
volume of fluid required for resuscitation ranged between 1000 and 1400 mL.[4][34][106][126] A much greater
volume deficit is seen in hyperthermic patients who become slowly dehydrated during prolonged heat
waves. [142] Vasopressors should be avoided during the period of hyperthermia because of the effect of
vasoconstriction on cooling.[29][142] Right heart catheterization may be necessary to guide the management
of heatstroke patients with persistent hypotension after cooling.[34][142][152]
Essential Laboratory Studies
All patients with severe hyperthermia require initial laboratory evaluation for coagulopathy, rhabdomyolysis,
hepatic injury, and hypoglycemia. Liver tests should include alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and bilirubin. The initial evaluation for coagulation disturbance should include
prothrombin time (PT), partial thromboplastin time (PTT), and a platelet count. Evaluation of the urine for the
presence of myoglobin, and a serum creatine phosphokinase (CPK), should be sent to detect
rhabdomyolysis. Electrolytes, blood urea nitrogen (BUN), calcium, phosphate, and glucose as well as a
chest radiograph and electrocardiogram are also indicated. Temperatures in excess of 41.1°C (106°F) are
rarely associated with fever due to infection. Although clinical judgment is always required, severe
hyperthermia is not an indication for routine blood cultures and evaluation of cerebrospinal fluid unless
infection is suspected. Toxicologic screening may reveal the presence of a toxin that requires specific
treatment (salicylates or lithium), but is not indicated in every case (see section on differential diagnosis and
Table 27–2 ).
Table 27-2 -- Differential Diagnosis of Hyperthermia: Drugs and Toxins Associated With Hyperthermia
Class or Specific Agent Mechanism Examples
a-Adrenergic agonists Vasoconstriction Amphetamines, cocaine, PPA,
ephedrine, pseudoephedrine
Increase muscle heat production
due to agitation
Increase serotonin release
First-generation antihistamines,
Anticholinergics Impair sweating Belladonna alkaloids,
antiparkinsonism agents
Limit cardiac output Propranolol, metoprolol
Calcium and ß-adrenergic receptor
channel blockers Impair ability to increase skin blood
Verapamil, nifedipine, diltiazem
flow
Imipramine, nortriptyline,
Anticholinergic effects amitriptyline, doxepin, clomipramine,
Cyclic antidepressants trazodone
Block serotonin reuptake
Limit cardiac output Furosemide
Diuretics Impair sweating Hydrochlorothiazide
Metolazone
Severe extrapyramidal rigidity
following withdrawal of medication Amantadine
Dopamine agonist withdrawal in Parkinson patients
Bromocriptine
Agitation, neuromotor irritability,
Lithium (severe hyperthermia seizures in overdose
usually in combination with
haloperidol or carbamazepine) Increases postsynaptic serotonin
receptor sensitivity
Increase agitation and muscle heat Phencyclidine, amphetamines,
CNS stimulants
production cocaine
Isocarboxazid, phenelzine,
Decrease CNS serotonin
Monoamine oxidase inhibitors tranylcypromine, moclobemide,
catabolism
(MAOIs) selegiline
Muscular rigidity
Chlorpromazine, haloperidol,
Hypothalamic dysfunction thioridazine, metoclopramide, all
Class or Specific Agent Mechanism
Hypothalamic dysfunction Examples
thioridazine, metoclopramide, all
classes of neuroleptics
Neuroleptics
Impair sweating
Cause rigidity
Uncouple oxidative
Methyl salicylate
Salicylates phosphorylation
Cause agitation Aspirin
Ethanol, barbiturates,
Increase heat production by
Sedative hypnotic withdrawal benzodiazepines, meprobamate,
muscle
ethchlorvynol
Fluoxetine, paroxetine, sertraline,
Selective serotonin reuptake Block reuptake of serotonin
venlafaxine
inhibitors (SSRIs)
Increase CNS serotonin
Strychnine Increases muscle activity
Synthetic opioids (in combination Tramadol, dextromethorphan,
Block serotonin reuptake
with MAOI, SSRI) meperidine
Uncouple oxidative
Pentachlorophenol
Wood preservatives phosphorylation
Severe muscular rigidity
CNS, central nervous system; PPA, phenylpropanolamine hydroxide; SSRIs, selective serotonin reuptake
inhibitors.
Differential Diagnosis of Hyperthermia
Introduction
The medical literature describes three types of heatstroke, the most severe form of heat injury related to
hyperthermia. The first is exertional heatstroke, which occurs in athletes and laborers exercising in warm
environmental conditions. A form of exertional heatstroke also occurs in agitated patients. The second is
seasonal, or nonexertional, heatstroke, seen during prolonged elevations of environmental temperatures.
The third type, nonseasonal heatstroke cases, occurs in the absence of environmental heat stress,
commonly in patients who are exercising or agitated. Many different drugs and medications predispose heat-
stressed patients to heatstroke. In overdose, various drugs and medications may also cause hyperthermia
that is not life-threatening, depending on the degree of associated exertion, agitation, or environmental
exposure. Severe hyperthermia associated with neuromuscular rigidity is not called “heatstroke” in the
literature but has the same clinical effects, severe end-organ damage by hyperthermia. The drug-induced
rigidity syndromes, neuroleptic malignant syndrome (NMS), malignant hyperthermia, and serotonin
syndrome are discussed in the following sections.
The effect of a drug or toxin on the physiologic responses that mediate thermoregulation may have a
significant impact on the development of hyperthermia ( Table 27–2 ).[92] Impairment of sweating by
anticholinergic agents and cocaine-induced vasoconstriction are familiar examples. Production of intense
muscle heat due to severe agitation, seizures, delirium tremens, or rigidity induced by drugs or toxins is
commonly associated with hyperthermia. Impairment of judgment or physical immobilization that prevents a
person from taking shelter in an adverse environment may also result in hyperthermia.
The temperature disturbance may simply provide a clue to the presence of the toxin or it may be more life-
threatening than the toxin itself. For example, a mild elevation of temperature in a patient with an
antihistamine overdose is a clue to the presence of an anticholinergic agent, while severe hyperthermia in an
agitated patient poisoned with phencyclidine may cause far more morbidity than the toxin.
A life-threatening elevation of body temperature occurs when (1) exposure to environmental heat
overwhelms the body’s thermoregulatory capacity, (2) endogenous heat production exceeds the body’s
capacity to dissipate heat, or (3) significant thermoregulatory dysfunction leads to poikilothermia. With the
exception of the drug-induced muscular rigidity syndromes, most patients with drug or toxin exposure who
become severely hyperthermic have experienced excessive exposure to environmental or endogenous heat
production, in addition to the presence of a toxin. As a general rule, the morbidity and mortality of patients
with severe hyperthermia are related to the duration of hyperthermia and the absolute temperature elevation.
In this chapter, an elevation of the body temperature that occurs in the setting of excessive endogenous heat
production or environmental exposure will be referred to as heatstroke, regardless of the presence or
absence of a toxin. Life-threatening elevations of temperature that occur as a result of exposure to toxins
that cause muscular rigidity will be discussed separately; however, it should be noted that the
pathophysiologic effects of heat injury are common to all etiologies.
Pathophysiology
A complex interaction between the hypothalamus and the internal and external environment allows the
human body to maintain a constant temperature despite wide ranges of environmental temperature
exposure.[67][90] A rise in the core temperature stimulates vasodilation and sweating via efferent
hypothalamic responses. Sweating facilitates evaporative cooling, while vasodilation results in increased
skin blood flow, exposing heated blood to convective, conductive, and evaporative cooling
mechanisms.[29][69][72][123]
Both therapeutic and excessive doses of pharmacologic agents that block the normal thermoregulatory
responses to increases in the core temperature have been associated with the development of life-
threatening hyperthermia or heatstroke, usually in the setting of exercise or significant environmental
exposure to heat.[5][9][77][143][158][169] Drugs with anticholinergic effects, particularly the cyclic
antidepressants, antihistamines, and chlorpromazine, impair sweating ( Table 27–3 ) and have been
associated with heatstroke in the exercising or environmentally exposed patient.[9][143][169] Drugs with
peripheral a-adrenergic agonist effects, such as cocaine and amphetamines, prevent normal cutaneous
vasodilation and have also been associated with life-threatening elevations of body temperature in the
agitated or exercising patient.[57][77][158] Beta-adrenergic receptor antagonists and calcium channel
antagonists depress cardiac contractility and impair the ability to increase skin blood flow during heat
exposure. Although hyperthermia is not seen in patients poisoned with these medications, therapeutic doses
place these patients at an increased risk for hyperthermia during heat waves. Diuretics impair sweating and,
by causing volume depletion, limit the body’s ability to increase cardiac output. Volume depletion
significantly increases the risk of hyperthermia in the exercising or environmentally exposed person.[37][59][80]
Table 27-3 -- Differential Diagnosis of Hyperthermia: Physiologic and Disease Processes Associated
With Heat Intolerance
Mechanism Condition
Decreased cardiac output Valvular, ischemic, hypertensive heart disease
Cor pulmonale
Dehydration
Drug effects (see Table 27–2 )
Autonomic dysfunction: diabetes, old age
Extensive psoriasis, scars
Decreased sweating
Hypothalamic injury
Autonomic dysfunction: diabetes, peripheral vascular disease, drug effects
Decreased vasodilation
(see Table 27–2 )
Status epilepticus
Thyrotoxicosis
Psychotic agitation
Increased endogenous heat
Hypothalmic injury
production
Parkinson’s disease
Fever
Neuromotor abnormalities, such as tremor, myoclonus, and rigidity induced by pharmacologic effects and by
other pathologic neurologic processes, are associated with hyperthermia that may be severe.
Neuromuscular rigidity with hyperthermia has been described in patients poisoned with a monoamine
oxidase (MAO) inhibitor[87] or following occupational exposure to pentachlorophenol, a wood preservative.
The hyperthermia in pentachlorophenol exposures results from uncoupling of oxidative phosphorylation.[167]
Severe hyperthermia associated with neuromuscular rigidity occurs in approximately 1 to 2 in 1000 patients
receiving neuroleptic medications (NMS).[40] The severe hyperthermia seen in NMS ( Table 27–4 ) is
thought to result from both increased muscular heat production from severe extrapyramidal rigidity and
altered hypothalamic function resulting in the inability to dissipate heat.[1] Most patients with severe
hyperthermia associated with neuroleptic agents do not have NMS. The therapeutic use of neuroleptic
agents results in an increased risk of heatstroke during heat waves.[80] Neuromuscular rigidity is absent and
the hyperthermia is attributed to both the anticholinergic effects and the central hypothalamic depression by
these drugs.[9][169] Lithium has been implicated in cases of severe hyperthermia in exercising or exposed
patients only when it is used in combination with antidepressants or neuroleptic agents.[5][60] Although mild
temperature elevations are seen in lithium-toxic patients with neuromotor hyperactivity, a clear association of
lithium, used alone, with life-threatening hyperthermia has not been satisfactorily demonstrated.
Table 27-4 -- Differential Diagnosis of Hyperthermia by Temperature
Causes of Temperatures >41.7°C (107°F)
Severe neuromuscular rigidity Neuroleptic malignant syndrome
Serotonin syndrome
Pentachlorophenol
Exertional heatstroke (rare)
Exertion (± drug effects) (see Table 27–2 )
Exertional heatstroke Exertion + severe heat exposure
Exertion + predisposing medical condition (see Table 27–3 )
Environmental exposure (± drug effects)
Nonexertional heatstroke Environmental exposure + predisposing medical condition (see
Table 27–3 )
Psychosis (± drugs, toxins)
Agitation or pathologically increased motor Delirium tremens

activity Status epilepticus
Thyrotoxicosis
Causes of Temperatures <41.7°C (107°F)
All etiologies above plus
Infection
Tumor
Hypersensitivity reactions
Exogenous pyrogen reactions
Salicylate toxicity can produce hyperthermia that is usually not life-threatening. The proposed mechanism is
excessive metabolic heat production due to uncoupling of oxidative phosphorylation.[135]
Underlying disease processes cause thermoregulatory dysfunction that increases the risk of heat injury
during environmental exposure or exercise.[80] Any type of heart disease that limits cardiac output decreases
the body’s capacity to dissipate heat by increasing skin blood flow.[47] Diabetic patients with peripheral
neuropathy or patients with peripheral vascular disease also have a limited capacity to vasodilate and
sweat.[48] Extensive skin disease or skin occlusion (e.g., by restraints) limits evaporative and convective
cooling and may predispose an agitated or heat-exposed patient to hyperthermia.
Heatstroke
Heatstroke is the most severe form of heat injury. The onset of heatstroke requires a temperature high
enough to cause generalized tissue injury. Mental status alteration due to heat injury is required for the
diagnosis of heatstroke. The clinical diagnosis of heatstroke may be confusing when the hypethermic patient
is intoxicated with drugs that alter the sensorium, especially if cooling has occurred prior to the first
temperature measurement. The lowest body temperature compatible with the development of thermal injury
has been difficult to determine clinically, as many reported cases appropriately were cooled prior to
determination of the temperature.[128] Animal studies of heatstroke have determined a core temperature
median lethal dose (LD50) of 41.5°C (106.7°F) as the threshold for heatstroke.[69] The initial rectal
temperatures of most patients who suffer heatstroke are greater than 41.1°C (106°F) at
presentation.[29][106][107] The rectal temperature does not reflect the temperature of vital organs such as the
brain and liver, which may be even higher. Based on available data, it appears that protein coagulation and
lipid membrane breakdown begin to occur at a tissue temperature near 42°C (107.5°F) and that the amount
of tissue damage is related to the absolute elevation of the temperature and to its duration. Heatstroke
results in a spectrum of physiologic disturbances caused by thermal injury to vital organs. Recent studies
also implicate endotoxins and tissue cytokines, such as interleukins, tumor necrosis factor, and interferon, in
the etiology of multiorgan failure and hemodynamic collapse in patients with severe hyperthermia.[17]
Increases in hypothalamic serotonin levels have recently been associated with the development of
heatstroke in an animal model. Interleukin-1 appears to increase serotonin release in the hypothalamus
during heatstroke.[27] Infusion of interleukin antagonists offers protection in a rat model of heatstroke.[28]
Pathologic examination of tissues in autopsied patients who die of heatstroke demonstrates cellular
swelling, coagulation necrosis, and hemorrhage in all vital body tissues.[26][93][130] The end-organ damage is
similar regardless of the initial etiology of hyperthermia. The hyperthermia produced by increased muscle
activity in a patient with cocaine poisoning, delirium tremens, or NMS has the same deleterious effects as
those seen in an athlete or a laborer with heatstroke. The elderly diabetic or hypertensive patient on a
diuretic who develops heatstroke during a heat wave also has a similar spectrum of end-organ damage.
Fever
Fever is distinguished from hyperthermia by both its magnitude and its mechanism. Only rarely are
temperatures above 41.1°C (106°F) due to fever.[44] Fever is caused by a resetting of the hypothalamic
setpoint following exposure to pyrogens, usually in the setting of infection, although tumors, collagen-
vascular disorders, and exogenous pyrogens also cause fever. Febrile patients manifest shivering,
vasoconstriction, and piloerection as the temperature rises to meet the new hypothalamic set-point, while
hyperthermic patients are usually sweating and vasodilated, as the body attempts to return to the lower
hypothalamic set-point.[13][67] Exceptions include the hyperthermic patient poisoned with cocaine, who does
not vasodilate, or the patient poisoned with an anticholinergic agent, who does not sweat. Patients with
heatstroke often lose the capacity to sweat, regardless of the etiology.
Meningitis, encephalitis, thyroid storm, sedative hypnotic withdrawal, delirium tremens, and sepsis should
always be considered in the differential diagnosis of hyperthermia in the patient with altered mental status. It
should be remembered that patients who abuse drugs are at risk for serious infectious etiologies for fever,
including meningitis, endocarditis, and infections related to acquired immunodeficiency syndrome (AIDS). In
these cases, a positive toxicology screen may be misleading.
Neuromotor Abnormalities and Hyperthermia
The differential diagnosis of toxin-related neuromuscular rigidity with hyperthermia includes neuroleptic-
induced extrapyramidal rigidity, serotonin syndrome, poisoning with MAO inhibitors, and occupational
exposure to pentachlorophenol. Other toxic neuromotor disturbances that may be associated with
hyperthermia include opisthotonos (strychnine), tremors (lithium, sympathomimetics), and myoclonus
(lithium, anticholinergics). Severe rigidity with hyperthermia may follow the abrupt withdrawal of
antiparkinsonian medications.[51][148] Severe rigidity is occasionally seen as a manifestation of exertional
heatstroke in healthy persons.[93] Malignant hyperthermia is a rare disturbance associated with congenital
abnormality of calcium flux in the sarcoplasmic reticulum in which life-threatening hyperthermia associated
with neuromuscular rigidity follows induction of general anesthesia. In rare cases, it is reported to be
precipitated by exercise.[12][91][134]
Delirium and Hyperthermia
The differential diagnosis of hyperthermia in the setting of agitation includes sedative hypnotic and
barbiturate withdrawal, agitated psychosis (called “lethal catatonia” in the older literature),[24][132]
meningoencephalitis, and thyroid storm. Heatstroke, itself, in the absence of toxic effects, is associated with
delirium. Common drugs that are associated with delirium and agitation in the overdose setting include
anticholinergics, such as first-generation antihistamines and cyclic antidepressants, and also phencyclidine,
cocaine, and amphetamines.
Serotonin Syndrome
The serotonin syndrome results in hyperthermia associated with altered mental status and neuromotor
symptoms, such as rigidity, seizures, myoclonus, tremor, and hyperreflexia. This syndrome is seen in
patients taking agents that raise central nervous system (CNS) serotonin levels and may be a consequence
of excess serotonin receptor stimulation. Selective serotonin reuptake inhibitors (SSRIs) are commonly
implicated, often in combination with other drugs that alter serotonin levels, such as monoamine oxidase
inhibitors (MAOIs), cyclic antidepressants, or synthetic opioids, such as tramadol, meperidine, and
dextromethorphan. [95][139] The mechanisms by which various agents affect serotonin levels in the
intersynaptic space include (1) blockade of reuptake (cyclic antidepressants, SSRIs, synthetic opioids); (2)
increased release of presynaptic serotonin (amphetamines, cocaine), (3) increased synthesis (tryptophan),
(4) decreased catabolism (MAOIs), (5) receptor agonists (buspirone), increased postsynaptic serotonin
receptor sensitivity (lithium).[100] A long-recognized version of this syndrome occurs when patients on MAOIs
develop severe hyperthermia following administration of drugs such as meperidine or dextromethorphan.[20]
The CNS side effects seen after poisoning with tramadol, a new synthetic analgesic agent with opiate and
noradrenergic effects, have been attributed to increased serotonin levels.[137] The combination of selegiline,
a selective MAO B-receptor blocker used in the treatment of Parkinson’s disease, with antidepressants has
resulted in symptomatology consistent with the serotonin syndrome.[118] Although combinations of drugs are
most frequently involved, single agents have also been implicated in the development of serotonin syndrome
in the overdose setting.[74][111] Although the symptoms are frequently mild,[118][137] they may result in severe
hyperthermia and have resulted in death.[20][50][53][100][114]
Neuroleptic Malignant Syndrome
The neuroleptic malignant syndrome (NMS) is a rare disorder, occurring in an estimated 1 to 2 patients per
1000 receiving neuroleptic medications.[40] Most agents that block the D2 dopamine receptor have been
associated with NMS.[1][62] The definition of NMS is currently debated. It has traditionally been defined as a
syndrome characterized by hyperthermia and intense muscle rigidity attributed to the D2 receptor–blocking
effects of neuroleptic agents.[1][62] The rigidity, itself, may also contribute to the hyperthermia. In addition to
hyperthermia, other manifestations of autonomic instability, such as fluctuating blood pressure, tachycardia,
and severe diaphoresis, occur at the same time or follow the onset of rigidity. Debate about the definition of
“NMS” has taken place in the literature since this syndrome was first described. Is NMS a discrete entity
independent of the more common and familiar extrapyramidal syndromes associated with neuroleptic
medication,[86] or is it a spectrum of disorders ranging from mild extrapyramidal symptoms (EPS) to severe
EPS with fever?[24][61][116] Can a manic dehydrated hyperthermic patient without rigidity be diagnosed with
“incipient” NMS?[151] For the clinician who is not intent on classifying and studying the disorder, it is
reasonable to recognize a spectrum of extrapyramidal disturbances that may herald the onset of this life-
threatening form of extrapyramidal disturbance. Cogwheel rigidity, altered mental state, or increased muscle
tone even in the absence of fever should raise concerns regarding the possibility of progression to NMS.[151]
Malignant Hyperthermia
Malignant hyperthermia is a rare disturbance associated with a congenital abnormality of calcium flux in the
sarcoplasmic reticulum. Life-threatening hyperthermia associated with neuromuscular rigidity follows
induction of general anesthesia. In rare cases, it is reported to be precipitated by exercise.
Clinical Evaluation
Hyperthermia
The clinical evaluation of the hyperthermic patient should focus on an assessment of the vital signs,
including the absolute level of the temperature. Temperatures above 41.1°C (106°F) are rarely
manifestations of fever due to infection or other pyrogen reactions.[44] The physical examination may reveal
the presence of a toxidrome, with pupillary dilatation, active bowel sounds, diaphoresis, and tremor evident
in the patient with cocaine poisoning or sedative hypnotic withdrawal; or dry hot skin, pupillary dilation,
myoclonus, absent bowel sounds, and bladder distention in the patient with anticholinergic poisoning.
Tachycardia is a common and nonspecific finding in the patient with severe hyperthermia. Signs suggestive
of serious infection include petechiae or purpura, nuchal rigidity, icterus, flank or abdominal tenderness,
murmurs, thrush, track marks, or signs of pulmonary consolidation. Erythroderma suggests a
hypersensitivity reaction. The neurological examination should focus on the assessment of reflexes and
motor tone and a search for tremor, myoclonus, clonus, or rigidity. Marked nystagmus in an agitated
hyperthermic patient suggests poisoning with phencyclidine. Focal findings should alert the physician to the
possibility of focal CNS infection, including brain abscess and toxoplasmosis.
Heatstroke
The clinical diagnosis of heatstroke requires evidence of thermal injury to the brain. Neurologic
manifestations range from confusion and psychosis to seizures and coma.[29][106] Temperature is usually
greater than 41.1°C (106°F), unless the patient underwent cooling prior to the measurement of temperature.
The absence of sweating, which suggests thermoregulatory failure, has been noted in as many as 80 per
cent of patients with heatstroke and has been used as a diagnostic criterion for heatstroke. It is clear,
however, that many patients who develop heatstroke are sweating profusely at the time of
collapse.[29][81][93][130] Patients who develop heatstroke related to the use of phenothiazines or other
anticholinergic medications do not show evidence of sweating.[2][9][169] Most patients with NMS sweat
profusely.[1][41][70]
Neurologic Findings
Confusion, psychosis, seizures, and coma reflect the extent of brain impairment by heat.[11][23][31][130] Coma
that lasts longer than 3 hours is associated with significantly increased mortality.[128][130] Patients who die
rapidly following the onset of heatstroke have extensive cerebral edema with gross and microscopic
hemorrhages at autopsy.[26][130]
Muscular rigidity is associated with neuroleptic-related extrapyramidal effects, the serotonin syndrome, or
poisoning with MAO inhibitors. It also occurs in occupational exposures to pentachlorophenol, a wood
preservative.[167] Severe extrapyramidal rigidity that resembles NMS has been reported in patients with
Parkinson’s disease following abrupt withdrawal of bromocriptine and levodopa. [51][148] Rigidity may be seen
as a manifestation of exertional heatstroke in the absence of drug effect, but it is not common. [93] Tremor,
myoclonus, and hyperreflexia may also be observed in patients poisoned with lithium or MAO inhibitors, and
as a manifestation of the serotonin syndrome.
Cardiac and Hemodynamic Effects
Examination of the heart in fatal cases of heatstroke shows petechiae, subendocardial hemorrhages, and
necrosis.[75][93] This diffuse myocardial injury manifests clinically as nonspecific electrocardiographic ST and
T wave changes and elevation of myocardial enzymes.[31][75][81] In one case series, QT c prolongation
occurred in 50 to 60 per cent of heatstroke patients.[2][31] Right-sided heart failure has been reported, with
right ventricular dilation noted at autopsy.[75][81][93][106][168]
Two types of hemodynamic patterns are described in the patient with heatstroke. Most commonly, patients
present with vasodilation and a wide pulse pressure.[31][106][130] Studies of these patients using right heart
catheterization demonstrate low systemic vascular resistance, normal pulmonary capillary wedge pressure
and pulmonary vascular resistance, and elevated cardiac output.[34][152] Up to 60 per cent of these patients
are hypotensive at presentation.[93] Significant volume depletion is uncommon in this group.[34][106][126] Less
commonly, patients with heatstroke present with low cardiac output, hypotension, and increased peripheral
resistance, associated with significant volume depletion and cardiac dysfunction.[106][142][152] Heatstroke
patients also poisoned with cocaine or amphetamine would be expected to have high peripheral vascular
resistance at presentation. This has not been studied invasively; however, clinical evidence of intense
vasoconstriction with cool, clammy skin despite a high core temperature has been described in
amphetamine poisoning[57] and has also been observed frequently by the author in unreported cases of
severe cocaine-related hyperthermia.
Renal Effects of Thermal Injury
Increased muscular activity or muscular rigidity is a prerequisite for the development of acute renal failure in
most cases of heatstroke. Renal failure occurs in up to 10 per cent of heatstroke cases associated with
increased muscular activity, usually in association with rhabdomyolysis and hypoperfusion.[130]
Hyperthermia is not always reported in the agitated poisoned patient who develops acute myoglobinuric
renal failure[18][122]; although in one study, 69 per cent of patients who developed acute myoglobinuric renal
failure in the setting of cocaine poisoning had temperatures greater than 40°C (104°F).[122] Rarely, in severe
cases of heatstroke, autopsy studies show evidence of direct thermal injury to the renal parenchyma in
addition to deposition of myoglobin.[26]
Gastrointestinal Effects of Thermal Injury
Vomiting and diarrhea commonly occur secondary to thermal injury to the gastrointestinal mucosa.[93][130]
Gastrointestinal hemorrhage develops secondary to heat-induced coagulopathy or disseminated
intravascular coagulation (DIC). Hepatic injury is heralded by a very early elevation of hepatic enzymes
(within hours), followed by clinical and pathologic evidence of hepatic injury 2 or 3 days after resuscitation
and cooling.[76]
Pulmonary Effects of Thermal Injury
Noncardiogenic pulmonary edema (NCPE) was found in 58 per cent of fatal cases in one series.[93] NCPE in
association with DIC in heatstroke carries a high mortality.[46] In several studies, excessive fluid
administration during resuscitation has contributed to the development of NCPE.[4][126]
Laboratory Value Interpretations
Several laboratory abnormalities are commonly observed in patients with heat injury, none of which are
pathognomonic. Respiratory alkalosis and metabolic (lactic) acidosis are common and expected.[31][141][144]
Hypophosphatemia has been attributed both to renal phosphate losses due to hyperventilation and to renal
tubular injury.[81] Coagulation disturbances result in elevation of the prothrombin time (PT), partial
thromboplastin time (PTT), fibrin split products, and depression of the platelet count. Elevation of the lactate
dehydrogenase level reflects general tissue injury and is expected in all cases. [78] Elevations of the levels of
creatine phosphokinase (CPK), alanine aminotransferase (ALT), and aspartate aminotransferase (AST),
reflecting injury to muscle and hepatic tissue, occur commonly.[78][81][130] Myocardial specific enzymes are
less commonly detected.[31][75] Significant elevations of the serum potassium, phosphate, creatinine, and
CPK, along with hypocalcemia, may be noted when rhabdomyolysis is present.[33] Hypocalcemia in the
setting of rhabdomyolysis has been historically attributed to extensive calcium binding to injured muscle
tissue.[98] More recently, decreased production of 1,25(OH)2-vitamin D has been described.[131] The
measurement of serum glucose is important, as hypoglycemia is reported in up to 40 per cent of patients
with exertional heatstroke.[31] A chest radiograph may show the presence of NCPE. Examination of the CSF
may yield normal results or may reveal mild elevations of protein and mild pleocytosis.[93] The urinalysis may
also show evidence of myoglobinuria.
Temperatures above 41.1°C (106°F) are rarely manifestations of fever due to infection.[44] When the history
and physical examination suggest the possibility of infection, particularly when the temperature is in the
range consistent with fever, cultures of blood, urine, and CSF and examination of the CSF are indicated.
Electrocardiographic Effects
Nonspecific ST and T wave changes on the electrocardiogram reflect the presence of diffuse myocardial
injury. QTc prolongation has been observed in 50 to 60 per cent of heatstroke cases. This is reversible and
may be related to metabolic disturbances.[3][31] Older patients with coronary artery disease may also
manifest evidence of myocardial injury specific to the distribution of a single coronary artery.[3] In patients
with extensive rhabdomyolysis, the ECG effects of hyperkalemia or hypocalcemia can be evident. In the
poisoned patient, the electrocardiogram may reflect the cardiac effects of a toxin. Lithium and the more
cardiotoxic neuroleptic agents, such as thioridazine and mezoridazine, cause conduction disturbances that
are nonspecific and may be indistinguishable from the effects of hyperthermia. The characteristic ECG
conduction disturbances associated with tricyclic antidepressant poisoning are discussed in Chapter 62 .
Coagulation Disturbances
Coagulation disturbances are common and attributable to a number of different factors.[103] It has been
postulated that early thrombocytopenia is caused by increased clearance of platelets injured by heat.[10][103]
In severe cases in which extensive vascular intimal injury has occurred, thrombocytopenia may be related to
DIC.[26][136] Direct heat-injury to coagulation factors may account for some early coagulation disturbances.
Primary fibrinolysis has been attributed to platelet activation.[55] Hepatic injury results in coagulation
disturbances detected 2 to 3 days into the patient’s course.[76][103]
Toxicologic Testing
Toxicologic testing in hyperthermic patients may confirm the presence of a drug or drugs already suspected
on clinical grounds, such as cocaine, amphetamines, phencyclidine, antihistamines, cyclic antidepressants,
or salicylates. Lithium should be specifically sought in patients with neuromotor irritability. The presence of
MAOIs or SSRIs is normally suspected on the basis of the history and clinical presentation. The finding of
meperidine or dextromethorphan on extensive toxicologic testing of a hyperthermic patient on an MAOI
inhibitor suggests the diagnosis of the serotonin syndrome.
Heatstroke
For the patient with severe hyperthermia in which heatstroke is the primary diagnosis, definitive stabilization
follows rapid cooling and blood pressure resuscitation. Ongoing care requires (1) detection of significant
rhabdomyolysis and prevention of myoglobinuric renal failure; (2) observation for clinical hepatic failure,
which occurs 2 to 3 days following the initial heat injury; (3) diagnosis and management of coagulation
disturbances; and (4) diagnosis and management of significant toxic exposures. If a significant toxic
exposure has occurred, gastrointestinal decontamination should be considered. Significant toxic exposures
requiring decontamination are unusual in the case of heatstroke. The cocaine body packer and lithium- and
salicylate-poisoned patients in status epilepticus are exceptions. For the patient with rhabdomyolysis at risk
for myoglobinuric renal failure, the most important preventive measure is the establishment of a steady
output of urine. Both urinary alkalinization and mannitol administration have been advocated to impede renal
tubular precipitation of myoglobin. Their efficacy independent of volume administration has not been
established.[120] In individual cases, the clinician must decide whether the risk of worsening hypocalcemia by
bicarbonate loading, for example, is worth the theoretical benefit of urinary alkalinization.
Dantrolene
Dantrolene, which blocks calcium fluxes in the sarcoplasmic reticulum of striated muscle, has demonstrated
anecdotal efficacy in the treatment of patients with muscle rigidity and hyperthermia due to malignant
hyperthermia, a rare disorder associated with a congenital disturbance of muscle calcium regulation ( Table
27–5 ).[12][91][134] It has also shown some anecdotal efficacy in decreasing the rigidity associated with
NMS.[30][66][79][96] Despite the absence of pharmacologic rationale, dantrolene has been recommended for
use in heatstroke cases in which muscle tone is not increased.[89] In one human study of heatstroke,
patients treated with dantrolene cooled faster, although the volume effects of its mannitol vehicle were not
controlled for.[25] A recent study in piglets suggested that the volume effects associated with administration
of the mannitol vehicle of dantrolene contributed to improved cooling rates.[171] Dantrolene was not effective
in a dog model of heatstroke, [6] nor in a prospective human study.[18] Its use as sole therapy in hyperthermic
patients with amphetamine poisoning resulted in cooling delays of up to 90 minutes.[158] Dantrolene should
never be used as sole therapy for heatstroke and has no pharmacologic value in cases of heatstroke not
associated with neuromotor rigidity. The efficacy of this drug appears to be due to the effects of its mannitol
vehicle on volume.
Table 27-5 -- Treatment of Severe Rigidity Syndromes Associated with Hyperthermia: Neuroleptic
Malignant Syndrome (NMS), Severe Serotonin Syndrome, Malignant Hyperthermia, and Others
Stop all neuroleptic or serotoninergic medication.
Temperature: >41.1°C (106°F):
Treat as in Table 27–1
Initiate neuromuscular paralysis with intubation if rigidity does not respond to benzodiazepines.
Administer dantrolene, 3 mg/kg IV, if rigidity does not respond to neuromuscular paralysis. *
Temperature: <41.1°C (106°F):
Initiate cooling with ice or fans plus tepid water spray.
Treat rigidity or agitation with intravenous diazepam or lorazem titrated to effect.
If rigidity is unresponsive to benzodiazepines, administer dantrolene, 3 mg/kg IV.
NMS:
Avoid anticholinergics.
Administer amantidine, 100–200 mg PO b.i.d., or bromocriptine, 2.5–10 mg PO t.i.d.
Serotonin syndrome:
Supportive care.
Consider: Cyproheptadine, 4 to 8 mg PO q1–4h (maximum 32 mg).
* Not studied for severe serotonin syndrome.
Hyperthermia
The patient who is hyperthermic but does not have severe elevation of body temperature should be
evaluated as described previously for toxic and infectious causes of fever. The patient with an altered mental
state and fever for whom the diagnosis of meningitis or sepsis is considered should have appropriate
cultures and antibiotic therapy initiated.
Treatment of the Neuroleptic Malignant Syndrome

Emergent Therapy
The most important initial therapy in the treatment of the NMS is to stop the administration of neuroleptics
and control hyperthermia using the external cooling measures described earlier. Again, cooling blankets and
antipyretics are not useful. Intravenous benzodiazepines should be used to control agitation and may also
decrease rigidity. Adequate fluids must be given to prevent myoglobinuric renal failure. Neuromuscular
paralysis with intubation should be considered in any case in which rigidity results in severe hyperthermia
that does not respond rapidly to standard interventions.
Specific Drug Therapies
Therapeutic interventions for this rare disorder have been evaluated only in anecdotal case reports. Specific
drug therapies have been selected on the basis of pharmacologic rationale in attempts to decrease rigidity
and counteract the presumed inciting dopamine-blocking effects of the neuroleptics.[62][121] Benzodiazepines
decrease the extrapyramidal neuromotor effects and should be given intravenously as initial therapy for
rigidity and agitation.[70][79] The dopamine agonist agents amantadine and bromocriptine (see Table 27–5 )
may aid in the resolution of the NMS. [41][63][70][97][102][153][171] Reported doses for bromocriptine range from
2.5 to 10 mg PO t.i.d., and for amantadine they go from 100 to 200 mg PO b.i.d.[62] Dantrolene, given in
divided doses of 1 to 3 mg/kg/day, has also been reported to decrease the severe rigidity associated with the
NMS.[30][66][79][96] Anticholinergic agents, the mainstay of treatment of milder extrapyramidal syndromes,
have been used extensively in reported cases of NMS without demonstrated efficacy. [79][97][153] Their
adverse effects on thermoregulation should be considered contraindications to their use in hyperthermic
patients.
Treatment of the Serotonin Syndrome
Most cases of the serotonin syndrome are mild and respond to simple supportive care measures. Rarely,
severe cases may resemble NMS. Treatment should include external cooling, intravenous benzodiazepines,
and neuromuscular paralysis with intubation if indicated. The use of dantrolene has not been studied, but it
would be reasonable to use it in the patient who has failed other therapies for rigidity. There is no
pharmacologic rationale for the use of the dopamine agonists bromocriptine and amantadine.
Cyproheptadine, a 5-HT1 serotoninergic receptor agonist, has been reported to be useful in anecdotal
cases. Doses have ranged from 4 to 8 mg PO every 1 to 4 hours to a maximum of 32 mg in adults or until a
therapeutic response occurs.[100][139]
Disposition and Need for Consultants
All patients with heatstroke require intensive care admission until stabilized, as do other critically ill patients
regardless of the degree of hyperthermia. Patients with delirium tremens, status epilepticus, and
neuromuscular rigidity require admission to an intensive care unit. Patients with noncritical temperature
elevations related to exertion or mild stimulant poisoning may be observed and discharged if they are stable
and there is no evidence of rhabdomyolysis.


HYPOTHERMIA
Essentials
• Patients with cardiac arrest due to hypothermia may benefit from prolonged resuscitation with rapid core
rewarming.
• All patients should receive 100 per cent oxygen and intravenous fluid support.
• Hypoglycemia and opioid poisoning are common causes of hypothermia, while thiamine deficiency is a
rare cause. D50W, naloxone, and thiamine are indicated in the initial management of the hypothermic
patient.
• Diagnostic etiologies that require urgent consideration include toxins, infection, and endocrine
disturbances.
• Patients with significant underlying illness or poisoning rewarm very slowly (<1°C/hr) or not at all, while
healthy patients rewarm rapidly.
• Most clinical thermometers do not record temperatures below 34°C (93.2°F). An indwelling rectal
thermistor with the capacity to measure lower temperatures is required to accurately determine core
temperature.
Initial Stabilization and Treatments
Cardiac Arrest: Temperature Less Than 30°C (86°F)
Patients with cardiac arrest secondary to hypothermia have an excellent prognosis owing to the protective
effects of hypothermia on the brain. Ventricular fibrillation due to myocardial irritability occurs at
temperatures below 30°C (86°F), with an increasingly significant risk below 28°C (82.4°F). Asystole related
to hypothermia occurs as the temperature drops below 23.9°C (75°F).[84][166] Prolonged cardiopulmonary
resuscitation followed by rewarming of patients with hypothermic cardiac arrest has repeatedly resulted in
intact survival of patients with circulatory arrest times that lasted for as long as 4 hours.[65][138][156] The most
effective means of rapid core rewarming are cardiopulmonary bypass and femorofemoral bypass, which
facilitate rapid core rewarming with ongoing support of circulation.[8][43][65][104][138][154][156][157] It is important
to note that in cases in which bypass was not available, successful resuscitation of arrested patients using
the means readily available in most emergency departments is frequently reported. Appropriate measures
include prolonged cardiopulmonary resuscitation (CPR) and aggressive rewarming by external application of
heat to the trunk,[44][49][82] warm gastric and bladder lavage, warm humidified oxygen, and warm peritoneal
lavage.[71][85] A recent report described the successful resuscitation of a patient with cardiac arrest at 22°C
(71.6°F) using prolonged CPR and closed chest lavage via thoracostomy tubes.[164]
CPR maintains adequate cerebral blood flow in the hypothermic patient and should be done in the standard
manner.[94][155] A routine advanced cardiac life support (ACLS) approach to cardiac resuscitation is not
useful in the hypothermic patient. Cardioversion is often unsuccessful until the body temperature is above
30°C (86°F), although it is worth trying because it is occasionally successful.[82] When several attempts at
cardioversion have failed, CPR should be continued with aggressive rewarming until the body temperature is
above 30°C (86°F), at which point attempts at cardioversion should be reinstituted.[117][138] One dose of
bretylium, 5 mg/kg, is recommended prior to the second attempt at cardioversion, as bretylium has been
anecdotally reported to be useful in the treatment of the ventricular fibrillation associated with
hypothermia.[35] Repeated administration of cardiac drugs should also be avoided during CPR, as drug
metabolism is altered during hypothermia, with the possibility of toxic drug effects being manifested after the
patient is rewarmed.[83][117]
Cardiac Arrest: Temperature Above 30°C (86°F)
The absolute temperature above which the patient with cardiac arrest will not benefit from rewarming is not
clear; however, for most patients with temperatures above 30°C (86°F) cardiac arrest is due to other
disturbances, such as anoxia, shock, or poisoning, rather than hypothermia. A standard ACLS approach is
appropriate for these cases. Other therapies may also be beneficial, such as alkalinization for cyclic
antidepressant myocardial toxicity, or overdrive pacing to treat thioridazine-induced torsades des pointes.
Hypothermic Patients Without Cardiac Arrest: Temperature Below 28°C (82.4°F)
There is some controversy in the literature regarding the best approach to rewarming the patient with deep
hypothermia who has not experienced cardiac arrest, defined as a temperature less than 28°C (82.4°F). At
this temperature, myocardial irritability is high and shivering is suppressed, so the body cannot rewarm
itself.[56][58][127][166] Unnecessary physical stimulation should be avoided, as it may convert an effective sinus
bradycardia to ventricular fibrillation.[88] Although intubation has occasionally been reported to precipitate
ventricular fibrillation, it is essential to maintain adequate oxygenation, and ventilation and should be used
when clinically indicated.[36][39] Although femorofemoral or cardiopulmonary bypass has been advocated for
these patients,[154] no outcome studies have been done to support this approach. External rewarming with
application of warm blankets, a Bair Hugger, or warm water bottles has been demonstrated to be successful
in patients with this degree of hypothermia.[7][44][49][82][105][133][150] In these cases, the choice of rewarming
modalities depends on the resources of the treating hospital and on the cardiovascular stability of the
patient. All patients should receive heated oxygen and active external rewarming by application of warming
blankets or a Bair Hugger to the trunk. The failure to rewarm indicates the need for more invasive core
rewarming, such as peritoneal lavage, closed thoracostomy lavage, or bypass.
Nonarrested Hypothermic Patients: Temperature Above (80°F)
These patients initially require 100 per cent oxygen, volume support with intravenous fluids, exclusion of
hypoglycemia, and administration of naloxone if clinically indicated. Ongoing heat loss should be prevented
by removal of wet clothing and application of blankets. More active rewarming with warm inspired oxygen
and application of warm blankets to the trunk is indicated at lower temperatures. The airway should be
managed as clinically indicated. Unnecessary physical stimulation should be avoided until the temperature is
>86°C (90°F). For the patient with mild hypothermia— temperature above 32.2°C (90°F)—the primary
concern is the cause of the hypothermia, not the hypothermia per se. Initial management should include
treatment of hypotension, hypoglycemia, and suspected opioid poisoning. Diagnostic etiologies that require
urgent care include significant drug overdose, hypothyroidism, shock, and sepsis. Aggressive attempts to
rewarm the significantly poisoned, hypothyroid,or septic patient with mild hypothermia will not alter the
underlying condition or improve the prognosis.
Toxin-Specific Therapies
Hypothermia due to poisoning is usually mild unless concomitant environmental exposure has occurred. The
decision to initiate gastrointestinal decontamination, dialysis, or specific toxic therapies should be based on
the specific agent as determined by the history, laboratory screening, and physical examination (see the
section on differential diagnosis).
Laboratory Studies
All patients with moderate to severe hypothermia require measurement of the uncorrected arterial blood gas
values,[39] electrolytes, and glucose and an electrocardiogram. When poisoning is suspected, toxicologic
screening is indicated. Evaluation of sepsis is assisted by the measurement of the white blood cell count,
and cultures of blood, urine, and cerebrospinal fluid (CSF). Measurement of thyroid-stimulating hormone
(TSH) will provide evidence of hypothyroidism, but it is not indicated in every case.
Differential Diagnosis of Hypothermia
Introduction
Simple environmental exposure to extreme cold results in hypothermia in healthy persons. Exposure to
toxins that alter thermoregulation may result in hypothermia. In most cases, the degree of hypothermia is
mild to moderate unless environmental exposure has occurred, and provides a clue to the presence of the
toxin or other underlying condition. In other cases, the temperature disturbance may be more life-threatening
than the toxin itself. For example, a profoundly hypothermic patient who fell asleep in a snow bank while
intoxicated with ethanol would be treated primarily for hypothermia, while hypothermia that occurred in a
patient in the intensive care unit who had severe barbiturate or opioid toxicity does not require significant
attention beyond treatment of the poisoning itself. The mortality of profound hypothermia related to exposure
in healthy persons is influenced by the cardiac rhythm at rescue (ventricular fibrillation carries a better
prognosis than does asystole) and by whether or not asphyxia preceded the onset of hypothermia. [155] The
mortality of the patient with mild to moderate hypothermia—35°C (95°F) to 28°C (82.4°F)—is related
primarily to the significance of the underlying poisoning or medical condition that led to the
hypothermia.[36][99]
Many toxins have been associated with hypothermia in the overdose setting ( Table 27–6 ). These include
agents that cause coma, such as alcohols, all sedative hypnotics, barbiturates, opioids, and carbon
monoxide. Phenothiazines, which depress hypothalamic function, have also been associated with
hypothermia in exposed patients, as have organophosphate insecticides, ß-adrenergic receptor antagonists,
and centrally acting a-adrenergic agonists, such as clonidine and guanabenz.
Table 27-6 -- Drugs and Toxins Associated With Hypothermia

Class Mechanism Examples
Alcohols Behavioral impairment Ethanol
Hypothalamic depression Isopropanol
Vasodilation
Class Mechanism Examples
Altered glycogenolysis,
ß-Adrenergic receptor Propranolol
lipogenolysis
antagonists
Decreased cardiac output Metoprolol
Central a-adrenergic Hypothalamic depression Guanabenz

agonists Clonidine
Organophosphate, carbamate insecticides,
Diaphoresis
Cholinergic agents cholinesterase inhibitors
Impaired glycogenolysis
Hypothalamic depression Phenothiazines
Neuroleptic drugs Piperidines
Butyrophenones
Behavioral impairment Barbiturates
Hypothalamic depression Meprobamate
Sedative hypnotic drugs
Ethchlorvynol
Chloral hydrate
Patients with an overdose of hypoglycemic agents, such as sulfonylureas, insulin, or Akee fruit ingestion,
may also present with hypothermia that is a manifestation of concomitant hypoglycemia.
Medical conditions causing thermoregulatory impairment that commonly lead to hypothermia include sepsis,
shock of any etiology, hypoglycemia, hepatic failure, and hypothyroidism. Thiamine deficiency has been
associated with mild hypothermia. Patients with conditions that cause autonomic disturbances (diabetes,
spinal cord injury) and patients with injuries to the hypothalamus also are intolerant of cold and predisposed
to developing hypothermia. A recent series reported relapsing hypothermia in multiple sclerosis patients with
hypothalamic lesions demonstrated at autopsy.[161]
Pathophysiology
The body defends itself against hypothermia through shivering and vasoconstriction, hypothalamic
responses that are initiated by stimulation of cold-sensitive skin receptors. Shivering increases muscle heat
production, while vasoconstriction conserves heat by shifting blood flow away from the cold skin to the
central areas of the body. Piloerection also occurs; however, it is most useful in improving the insulation of
furry mammals and is probably a vestigial response in humans.[67] Behavioral responses are also important
in temperature regulation in that they guide the exposed person to seek shelter or put on protective clothing.
Behavioral, pharmacologic, and environmental factors contribute significantly to the development of
hypothermia in the poisoned patient ( Table 27–7 ). Adverse environmental conditions may promote
significant heat loss through the processes of conduction and convection. The major determinants of
convective heat loss are wind velocity and air temperature. Water immersion or contact with wet clothing can
result in significant conductive heat loss.
Table 27-7 -- Physiologic and Disease Processes Associated With Hypothermia
Mechanism Condition
Decreased shivering Old age
Hypoglycemia
Hypothalamic dysfunction
Spinal cord injury
Spinal cord injury
Decreased vasoconstriction Hypothalamic dysfunction
Psychiatric disorders
Behavioral dysfunction Dementia
Sepsis
Liver failure
Hypoglycemia
Decreased endogenous heat production
Hypothyroidism
Shock of any etiology
Many pharmacologic agents alter specific mechanisms of thermoregulation and result in hypothermia, even
in moderate environments. Drugs with a-adrenergic receptor–blocking effects, such as chlorpromazine, or
direct-acting vasodilators, such as hydralazine or ethanol, prevent vasoconstriction.[92] Beta-adrenergic
receptor antagonist drugs impair mobilization of glucose and increase hypothermia in animal models.[92]
Drugs with central a-adrenergic receptor agonist effects, such as clonidine and guanabenz, have been
associated with hypothermia in the overdose setting owing to postulated depression of central
thermoregulation.[113] The intense diaphoresis seen in patients with organophosphate poisoning may result
in lowering of body temperature, augmented by the depressant effects of cholinergic stimulation on
mobilization of fat and glucose stores.[92] Physical immobilization caused by ethanol and other sedative
agents commonly leads to exposure hypothermia. In addition, many sedative agents depress the shivering
response to cold exposure and result in hypothermia.[56][58][112]
In the patient who does not have thermoregulatory suppression, skin cooling precipitates shivering, which
becomes violent and then stops when body temperature nears 27°C (80.6°F). Shivering is depressed or
absent in the patient with significant depression of thermoregulation.[112] Central shunting of blood by
vasoconstriction results in a significant diuresis and volume depletion, possibly mediated by stimulation of
atrial stretch receptors. The metabolism declines at a rate of approximately 6 per cent per degree centigrade
decrease in body temperature, resulting in a decreased oxygen requirement.[68][166] Although the observed
protective effect of hypothermia on vital organs has been most often attributed to this metabolic sparing
effect, recently other mechanisms have been elucidated. Hypothermia has been shown to prevent the
normal decrease in intracellular ATP seen in animals on low-flow cardiopulmonary bypass[145] and to
increase the time to ischemic contracture of the oxygen-deprived myocardium.[165] Hypothermia also inhibits
the release of excitatory neurotransmitters in ischemic brain [22] and increases intracellular pH in brain
tissue.[145]
Effects of Hypothermia on the Heart
The earliest effect of hypothermia on the heart is tachycardia associated with shivering. As the body
temperature falls below 29°C (84.2°F), progressive bradycardia ensues.[38][166] Asystole is seen as the
temperature drops below 23°C (73.4°C).[166] In patients with profound hypothermia, very low blood
pressures may provide adequate tissue perfusion owing to the protective effects of hypothermia.[125][145]
Human fatalities in uncomplicated hypothermia are the result of its cardiac effects. Death from hypothermia
in humans is usually attributable to the failure of myocardial conduction or to ventricular fibrillation, which is
often iatrogenically precipitated by movement of the patient.[88] Despite a demonstrated ATP-sparing effect
of hypothermia on myocardial tissue,[165] myonecrosis has been observed in both accidental and induced
cases of hypothermia.[54][138] The failure of hypothermia to protect the heart from ischemia has been
attributed to the following observations: (1) failure of coronary autoregulation,[21] and (2) normal or increased
myocardial contractility and stroke volume, so that an oxygen-sparing effect of hypothermia depends on a
decrease in the heart rate.[21][109][115] Elevated intracellular calcium concentrations may be responsible for
the observed preservation of myocardial contractility.[115][129]
The risk of ventricular fibrillation increases significantly as the patient’s temperature falls below 28°C
(82.4°F).[84][166] Myocardial irritability in hypothermia has been historically attributed to myocardial
temperature gradients, which alter the rate of conduction in different parts of the myocardium.[88][101] More
recent investigations show that hypothermia decreases the magnitude of the phase 1 inward sodium current,
decreases the diastolic resting membrane potential, and increases the action potential duration.[14][15][129]
These effects are related to an alteration of the integrity of the protein and lipid components of membrane
ion channels, changes in electrolyte gradients, and dysfunction of the ATP-dependent sodium-potassium
pump.[14][15] It is probable that regions of intramyocardial temperature variability lead to reentry dysrhythmias
by creating different areas of refractoriness and conductivity.[14] Anecdotally, patients intoxicated with
ethanol have been reported to be at a lower risk for ventricular fibrillation.[161a] While this may be related to
the absence of significant underlying disease in the intoxicated hypothermic patient, suppression of
shivering may theoretically result in decreased catecholamine release and more uniform cooling of the
myocardium. Electrocardiographic abnormalities reflect the extent of conduction disturbance caused by
myocardial cooling. The Osborne, or “J,” wave, a characteristic elevation of the initial ST segment, is
pathognomonic of hypothermia. Atrial fibrillation is common, usually resolving with rewarming.[108][110][149]
Effects of Hypothermia on the Brain
Hypothermia confers a protective effect from ischemic injury to the brain. Full recovery of a child following
complete submersion in ice water for 66 minutes has been reported.[16] In addition to decreasing the
metabolic demand of cerebral tissue, it decreases the synthesis of stimulatory neurotransmitters[22] and
facilitates the maintenance of intracellular pH and ATP stores.[145] Preservation of autoregulation in the
cerebral vasculature facilitates further protection against ischemic injury in low-flow states.[125]
Neurologic depression is a direct function of brain temperature. Slowed mental responses, difficulty in
walking, clumsiness, and dysarthria occur as the temperature drops below 32.2°C (90°F).[52] Significant
depression of mental status in patients with temperatures above 89°F should suggest a complicating
condition, such as exposure to a drug or toxin, head injury, or meningitis. Purposeful motor responses have
been noted at temperatures as low as 20°C (68°F).[52] Patients below this temperature who appear to be
dead may still be living and salvageable. [65]
Other Physiologic Effects
Lactic acidosis is common in patients with hypothermia. It may be the result of shivering, ischemia, or
washout of lactate during resuscitation. It has no predictive value with regard to mortality.[36][65][99][133]
Hypothermia increases the binding of oxygen to hemoglobin, resulting in a leftward shift of the oxygen-
hemoglobin dissociation curve.
Hypothermia inhibits coagulation and is associated with a bleeding diathesis that is not measured in the
normal laboratory tests of coagulation. (All blood samples are warmed to body temperature in the
hematology laboratory before the PT and PTT are measured, thereby correcting the disturbance.) Trauma
surgeons have been aware of the clinical effects of hypothermia in the patient who requires surgery for many
years.[73][119] Severe hypothermia may be associated with DIC,[65] which is a major complication in dogs
cooled below 10°C (50°F).[64]
The best method of evaluating the acid-base status of the hypothermic patient has been debated
extensively.[39] Hypothermia decreases the dissociation of water to free hydrogen ions, so the pH rises as
cooling occurs. It also decreases the pressure of gases dissolved in the blood, lowering the partial pressure
of carbon dioxide (P CO2) and PO 2, even though in a closed system the content of those gases remains
unchanged.[39] When the blood gas is corrected, it means that the blood gas values obtained after warming
the blood to normal body temperature in the laboratory are corrected mathematically to reflect the predicted
chemical changes that cold induces in the blood. An example that illustrates the meaning of correction of the
arterial blood gas is that of a man walking in the cold. His core temperature is 37°C, with an arterial blood pH
of 7.40 and PCO2 of 40 mmHg. The blood flowing through the skin capillaries is 25°C and has a corrected
pH of 7.6 and a corrected PCO2 of 22 mmHg.[162] The content of carbon dioxide is the same in each of these
areas of the body. The uncorrected blood gas values of the blood at 25°C, measured in the laboratory at
37°C, are pH 7.40 and PCO2 40 mmHg. The uncorrected blood gas values demonstrate that the acid-base
state in the skin is the same as in the core. If the corrected value of the pH is used to ventilate a hypothermic
patient, significant carbon dioxide retention may result, in addition to alveolar collapse and hypoxia due to
the degree of hypoventilation needed to sustain a PCO2 of 40 mmHg at very low temperatures. As another
example, a patient at 17°C with corrected blood gas values of pH 7.47 and PCO2 40 mmHg has uncorrected
values of pH 7.18 and PCO2 111 mmHg at 37°C.[147] The use of the uncorrected arterial blood gases to
assess pH and PCO2 provides a clinically meaningful assessment of the acid-base state. For a more detailed
discussion, see Delaney and associates.[39]
Clinical Evaluation
The physical examination of the hypothermic patient should focus on mental status, vital signs, and physical
evidence of illness or poisoning. In the patient with non–toxin-related hypothermia, neurologic depression is
a direct function of brain temperature. Significant mental status depression in patients with temperatures
above 31.7°C (89°F) should suggest a complicating condition, such as a drug or toxin, head injury, or
meningitis.
In uncomplicated hypothermia caused by exposure, tachycardia is associated with shivering until the body
temperature falls below 29°C (84.2°F) and a progressive bradycardia ensues.[38][166] In experimental
animals, the arterial blood pressure rises with progressive hypothermia until the temperature declines to
27°C (80.6°F).[94][109] Patients with hypothermia related to exposure maintain normal blood pressures at
temperatures as low as 25°C (77°F).[49][150] Patients with significant poisoning or medical illness often have
abnormalities in vital signs, such as tachycardia, bradycardia, or hypotension, that are disproportionate to
the body temperature. For example, mildly hypothermic patients who are poisoned with a beta-adrenergic
blocker or calcium channel blocker have bradycardia and hypotension out of proportion to the decrease in
temperature. Poisoning with a barbiturate, chloral hydrate, or an opioid that is significant enough to cause
hypothermia often results in hypotension out of proportion to the degree of hypothermia.
Other findings give clinical clues to the presence of a toxin. Miotic pupils suggest poisoning with an opioid,
central a-adrenergic agonist, or organophosphate. Diaphoresis, diarrhea, and pulmonary congestion
suggest organophosphate toxicity. Large cutaneous blisters are associated with barbiturate overdose.
Seizures may occur in the hypothermic patient poisoned with a ß-adrenergic blocker, an organophosphate,
carbon monoxide, or a hypoglycemic agent.
The clinical signs of medical illness associated with hypothermia include signs of sepsis, such as focal
infection, purpura, petechiae, nuchal rigidity, icterus, or other signs of liver disease. Alopecia, doughy
edema, and delayed reflexes suggest myxedema.
An important part of the clinical evaluation involves observation of the response to therapy. A rapid rate of
rewarming in the patient with mild to moderate hypothermia is a sign of the absence of significant underlying
illness as a cause of hypothermia, while the failure of the body to rewarm suggests significant
thermoregulatory suppression. Patients with significant intoxication or underlying illness rewarm very slowly
(<1°C/hr), or not at all.[161a] Patients with uncomplicated, readily reversible causes of hypothermia, such as
opioid overdose or hypoglycemia, rewarm as quickly as 10°F/hr following the administration of naloxone or
glucose.
Laboratory Value Interpretation
The hemoglobin is often elevated in hypothermic patients owing to hemoconcentration. The white blood cell
count is often elevated in patients with significant hypothermia due to the sympathetic effects associated
with shivering. It has no predictive value with regard to underlying infection.
Potassium disturbances are common in hypothermia. The hypothesis that intracellular shifts of potassium
cause hypokalemia in hypothermic patients was prompted by the observation that correction of hypokalemia
results in postrewarming hyperkalemia in a rat model.[140] Dramatic elevations of the serum potassium (>10
mEq/L) have been associated with the failure to resuscitate victims of accidental hypothermia.[65][124] Except
in the hypothermic patient with an explanation for severe hyperkalemia, such as significant crush injury or
renal failure, it is likely that potassium levels of this magnitude represent membrane failure and irreversible
death.[65][84][124]
Hypoglycemia is not caused by hypothermia but is a common cause of hypothermia. The serum glucose
should always be assessed on presentation of the hypothermic patient.
Electrocardiographic abnormalities reflect the extent of conduction disturbance caused by myocardial

cooling. Osborne, or “J,” waves are pathognomonic of hypothermia. Atrial fibrillation is common, usually
resolving with rewarming.[108][110][149] Such abnormalities may also reflect specific effects of cardiotoxic
drugs in the poisoned patient who is also hypothermic. Sedative agents that may alter myocardial
conduction include chloral hydrate, carbamazepine, neuroleptics such as thioridazine and mesoridazine and
propoxyphene. Patients with shock and hypothermia due to overdoses of calcium channel or ß-adrenergic
blocking agents manifest characteristic ECG changes.
Measurement of the PT and PTT reflects intrinsic coagulation disturbances that are not related to
hypothermia unless disseminated intravascular coagulation (DIC) is present. DIC may be associated with
sepsis or profound hypothermia.
Determination of arterial blood gases allows assessment of the adequacy of oxygenation and ventilation.
The use of these uncorrected values to guide ventilation in the hypothermic patient appears to result in
improved myocardial function and decreased oxygen utilization.[68][146][163]
Hemodynamic Support
Although many patients who present with temperatures above 25°C (77°F) have normal blood pressures,
they require volume administration during rewarming ( Table 27–8 ). Attempts to raise the blood pressure by
fluid administration should be guided by continuous assessment of oxygenation and pulmonary function.[117]
Pharmacologic or electrical attempts to increase heart rate theoretically increase myocardial oxygen
demands, so that cardiac pacing has not been recommended in the patient with a temperature below 29°C
(84.2°F) in whom bradycardia is a consequence of hypothermia. It may be useful in patients with milder
degrees of hypothermia and inappropriately low heart rate. A recent study of healthy young dogs with deep
hypothermia showed a significant increase in the rewarming rate when the heart was paced.[42] The risk of
this approach in humans has not been determined.
Table 27-8 -- Treatment of Hypothermia

Core Hemodynamically Hemodynamically
Temp Cardiac Arrest Unstable Stable
<28°C Intubate, 100% O2 Intubate/100% O2 Intubate if
(82.4°F) indicated/100% O 2
Prolonged CPR IV normal saline IV normal saline
Bretylium, 5 mg/kg Rewarm as for patient with Start with least invasive
cardiac arrest active rewarming:
Core Hemodynamically Hemodynamically
Temp Cardiac Arrest Unstable Stable
Attempt defib ×2 External trunk
rewarming
Rewarm as rapidly as possible: Warm, humidified
oxygen
Cardiopulmonary or fem-fem bypass Upgrade rewarming per
response
Peritoneal lavage
Closed mediastinal lavage with tube
thoracostomy
Aggressive external rewarming of trunk
Intubate, if indicated,
100% O2
IV normal saline
<30°C
External trunk rewarming
(86°F)
Warm, humidified oxygen
Upgrade to invasive
modalities if no response
Intubate if indicated, 100%
Standard ACLS approach in most cases 100% O2
O2
Consider rewarming if hypothermia appears
to be causative: clear environmental
IV normal saline IV normal saline
exposure, not significantly poisoned, ill, or
>30°C asphyxiated
(86°F)
Passive rewarming or
External trunk rewarming
external trunk rewarming
Treat hypotension,
dysrhythmia per standard
approach
Standard approach to
Standard ACLS approach Passive rewarming
>32°C unstable patient
(90°F) Consider special toxic therapies: Determine etiology of Determine etiology of
alkalinization, overdrive pacing hypothermia hypothermia
fem-fem, femorofemoral; ACLS, advanced cardiac life support.
The utility of pressor agents in the management of hypothermia has not been clearly demonstrated.
Theoretical contraindications to pressors in the profoundly hypothermic patient include the accumulation of
unmetabolized pharmacologically active agents, and aggravation of frostbite injury due to vasoconstriction.
Vasopressors are indicated in the volume-resuscitated patient with mild to moderate hypothermia, where
hypotension is unexpected and is probably related to poisoning or sepsis.
Rewarming
Most patients with mild to moderate hypothermia related to exposure or exposure plus mild sedative
hypnotic toxicity where the temperature is higher than 28°C (82.4°F) will respond to simple measures that
decrease heat loss, such as the removal of wet clothing and insulation with blankets. Patients with
hypothermia at the colder end of the spectrum regarded as “moderate” and patients with more significant
intoxication may require more active interventions, such as core rewarming with warm humidified oxygen or
active external rewarming of the trunk.[84] The choice of the rewarming modality depends on the resources
of the medical care setting and the stability of the patient’s cardiovascular status.
Patients with core temperatures below 28°C (82.4°F) have profound hypothermia. The choice of the
rewarming modality depends on the resources of the medical care setting and the stability of the patient’s
cardiovascular status. All of these patients require active rewarming, by applications of warm blankets to the
trunk and core-rewarming techniques, such as warmed, humidified oxygen. These simple measures may
suffice in stable patients. More invasive methods of core rewarming have been previously described, and
include peritoneal lavage, gastric and bladder lavage, and mediastinal lavage via tube thoracostomy. [164]
Cardiopulmonary or femorofemoral (fem-fem) bypass with CPR is the method of choice for the patient with
cardiac arrest.[155]
Respiratory Support
The uncorrected arterial blood gas measurement is most useful for the management of ventilation in the
hypothermic patient. Patients with significant hypoxia or hypercarbia (hypercapnia) require intubation, based
on standard clinical indications.
Dispositions and Need for Consultants
Patients with mild hypothermia who rewarm quickly and have normal examinations after rewarming do not
require hospital admission. Hospitalization for 23-hour observation should be considered for patients with
temperatures lower than 32.2°C (90°F), regardless of their appearance following rewarming unless the
temperature disturbance was due to a readily reversible cause, such as hypoglycemia or opioid intoxication.
All patients require cardiac monitoring until the temperature reaches 30°C (86°F). Patients with hypothermia
related to shock, hypothyroidism, or infection all require hospital admission.


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167. Wong KC: Physiology and pharmacology of hypothermia. West J Med 1983; 138:227.
168. Wood SD, Rom WN, White Jr GL, Logan D: Pentachlorophenol poisoning. J Occup
Med 1983; 25:527.
169. Zahger D, Moses A, Weiss AT: Evidence of prolonged myocardial dysfunction in heatstroke.
Chest 1989; 95:1089.
171. Zubenko G, Pope HG: Management of a case of neuroleptic malignant syndrome with bromocriptine.
Am J Psychiatry 1983; 140:1619.


Uncited references
Brody SL, Wrenn KD, Wilber MM, Slovis CM: Predicting the severity of cocaine-associated rhabdomyolysis.
DuBois EF: Why are fever temperatures over 106°F rare?. J Med Sci 1949; 217:361.
Weaving EA, Berro VE, Kew MC: Heatstroke during a “run for fun.”. S Afr Med J 1980; 57:753.
Zellman S, Guillan R: Heatstroke in phenothiazine-treated patients: A report of three fatalities. Am J

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Zuckerman GB, Singer LP, Rubin DH, Conway Jr EE: Effects of dantrolene on cooling times and
cardiovascular parameters in an immature porcine model of heatstroke. Crit Care Med 1997; 25:135.


Chapter 28 – Ocular Abnormalities
RICHARD L. MANKA
Essentials
• Immediate irrigation is the first priority.
• Check for foreign bodies and injury below the lids.
• Conjunctival necrosis and corneal opacification correlate with poor outcome.
INTRODUCTION
The eye and the visual system are potential targets of a wide variety of toxic substances, both by direct and
by systemic exposure. Injuries by direct exposure of the eyes to toxic chemicals are a common problem in
societies that depend on chemicals for everyday industrial, agricultural, and home use.[34] Eyes are
particularly vulnerable to contact injuries because of their exposed location.
The scope of this chapter and the context in which it will be used allow for only a sampling of some of the
more common or serious toxic problems. References such as Grant’s Toxicology of the Eye[20] or
Fraunfelder’s Drug-Induced Ocular Side Effects [17] provide an encyclopedic listing of the agents known to
have ocular side effects or actions. It is not important to know every substance with possible ocular toxic
effects, but it is important to be aware that the eyes can be damaged by both direct contact and systemic
exposure to toxins. With that awareness, it is possible to access the pertinent information for managing each
particular exposure. This chapter outlines general principles, with emphasis placed on the practical clinical
information most valuable in emergency and acute care settings. Information about common situations and
specific toxins is presented in detail.


INITIAL STABILIZATION AND TREATMENT OF DIRECT OCULAR EXPOSURE
General Principles[34][36][45][49][62][63]
The goals of managing patients with direct toxic exposure of the eye are as follows: (1) minimization of
ocular damage, and (2) facilitation of healing, with preservation of maximal ocular function. To accomplish
this, the most important principles are (1) to remove quickly the toxic material from the eye; (2) to establish
an environment conducive to re-epithelialization; and (3) to avoid further ocular damage from ulceration,
infection, glaucoma, and other sequelae.
It is important to understand the structural and functional anatomy of ocular and periocular structures in
order to appreciate the mechanism of eye injuries ( Fig. 28–1 ). Because of the delicate nature of ocular
tissue, exposure to seemingly innocuous substances may produce devastating effects in the eye. For
example, the eyelid is essential for protecting the globe, conditioning the surface of the globe through
blinking, providing good tear function, and lubricating the globe via oil glands in the lid. A burn on an
extremity may leave a scar, but the function of the affected limb is usually not seriously impaired. Scar
formation in the eyelid, however, often destroys essential lubricating glands and leaves the eyelid thickened,
with loss of the smooth surfaces necessary for providing surface conditioning. The lacrimal apparatus may
also be damaged or destroyed, resulting in inadequate tear function. The sequelae of an eyelid burn can
impair ocular function and even lead to loss of the eye.
Figure 28-1 Anatomy of the eye. (From Ignatavicius DD, Workman ML, Mishler, MA: Medical-Surgical Nursing Across the Health
Care Continuum, 3rd ed. Philadelphia, WB Saunders, 1999, p 1154.)
The most exposed portion of the ocular system, after the lids, is the superficial epithelium of the conjunctiva
and cornea. This delicate layer is highly susceptible to injury from direct contact with a variety of substances
and is the most commonly damaged ocular tissue. Modest injury produces patchy and incomplete damage.
The underlying structures remain intact, and the epithelium quickly heals without intervention. However,
damage to underlying tissue structures impairs the ability of these superficial tissues to support the regrowth
and reattachment of the surface epithelium necessary for re-epithelialization. If this does not occur, the eye
is subject to chronic problems, including the potential for blindness. It is therefore extremely important to
provide an environment conducive to re-epithelialization immediately after the injury. Occlusion therapy with
patching or surgical closure of the lids, and use of adequate lubrication, may be necessary. Adjunctive
medications and surgical techniques will be discussed later.
Treating the occasional patient exposed to toxic substances can be challenging, but managing a sudden
and massive influx of such patients from a disaster can be overwhelming and is best handled by formulating
and implementing a disaster plan. Industrial accidents, terrorism, chemical spills, the use of tear gas on
rioters, and other situations can produce large numbers of patients with eye injuries that require rapid
treatment. An ocular disaster plan should include strategies for triage, starting treatment and irrigation in the
field, and continuing it nonstop during transport of patients to a medical facility. The plan should address
triage procedures, availability of irrigation supplies, adequacy and availability of trained personnel and
ophthalmic equipment, space provisions, and accessibility of reference materials on the toxic substances
involved and the techniques to be used in treatment. [21]
Emergency Treatment
History.
A detailed history elucidating the nature of the accident and the chemicals involved will optimize treatment.
Ocular irrigation should not be delayed; the history can be obtained simultaneously. Any exposure details,
including the possibility of retained foreign bodies or a ruptured globe, need to be elicited. Any preexisting
eye problems or the use of corrective lenses and the type of prehospital treatment should be determined.
Irrigation.
The emergency treatment of external ocular toxins is based on prompt removal of the toxin and
neutralization of any acidity or alkalinity. Immediate irrigation and removal of particulate material are the
mainstays of treatment. Irrigation can be started at the site of injury with water or some bland fluid. Normal
saline is ideal, being sterile, isotonic, pH neutral, and, most important, readily available. Irrigation with hand-
held intravenous tubing is simple and effective but may be tedious. Irrigation may be facilitated by the
instillation of topical ophthalmic anesthetics, such as tetracaine 0.5% or proparacaine 0.5% for comfort, and
should be continued until litmus paper testing of the cul-de-sac shows a pH of between 7 and 8. Testing of
the pH should not interfere with continued irrigation of the eye. Once irrigation is started, an irrigation lens
may be added, but the use of any system should never delay treatment. Irrigating contact lenses are unlikely
to be any more effective than hand-held tubing, but they may be more convenient if personnel are limited,
because prolonged irrigation for 2 hours or longer may be required, especially in alkali burns. Irrigation
should be at a rate of at least 3 to 4 liters per hour. Irrigation must continue until all toxic substance is
removed and the pH remains neutral (between 7 and 8) when retested 10 minutes after cessation of
irrigation. Particulate matter or material that does not irrigate easily from the eye can be removed with a
cotton-tipped applicator, either plain or coated with a lubricant such as an antibiotic ointment.
Clinical Evaluation.
A careful physical examination should be performed with the use of topical anesthetics to relieve pain or
photophobia. Initially evaluate and document visual acuities in both eyes. Snellen charts or near vision cards
can be used in adults, while children’s visual acuity can be tested with pictures or familiar objects. If the
patient’s vision is markedly decreased, simply ask the patient if he or she can count fingers, see hand
motion, or perceive light. Examine the lids for redness and swelling, epithelial defects, lacerations, and any
evidence of penetration, embedded substances, or necrotic tissue. Chemical injury to the conjunctiva can be
difficult to evaluate because the initial irrigation may cause redness and swelling and produce iatrogenic
epithelial defects. A significant portion of the conjunctiva is hidden under the lids and is more difficult to
examine. Have the patient look in all directions while the lids are spread and fixed with fingers or cotton-
tipped applicators. The lids can be everted with a cotton-tipped applicator if there is no globe rupture. If a
penetrating globe injury is suspected, pressure on the lids or globe should be avoided. Retraction or double
eversion with a Desmarres retractor may be necessary for adequate examination. Subconjunctival
hemorrhages may indicate trauma beyond simple chemical exposure.
Check the cornea for clarity as well as for a clean and sharp light reflex. Any cloudy or opaque areas, as well
as an uneven light reflex, should be noted. Fluorescein applied via sterile strips will highlight epithelial
defects of the conjunctiva and the cornea. Blue light from a slit lamp or a Wood’s lamp will further illuminate
the fluorescein staining. Intraocular pressure can be severely elevated, especially in alkali burns, and should
be evaluated after irrigation. Intraocular pressure is accurately determined with the use of applanation
tonometry on a slit lamp or a Perkins hand-held tonometer. Schiøtz tonometry can be used but is typically
more damaging to corneal epithelium. Either method is adequately accurate in the presence of corneal
epithelial defects. A Tonopen can also be used. The anterior chamber depth and clarity are determined, as
is the integrity of the iris. This is best accomplished with a slit lamp. If one is not available, a penlight used
from the side can be substituted. Examination of the lens, vitreous, fundus, and optic nerve is carried out in
the usual manner with an ophthalmoscope. Dilation of the pupil may be necessary for adequate examination
of the fundus and optic nerve. Any opacity or blood in the anterior chamber or vitreous, or damage to the
retina, may indicate penetrating or blunt trauma.
Since alkali burns can cause shrinkage of collagen in the globe as well as damage to the intraocular fluid
outflow mechanisms, it is particularly important to monitor intraocular pressure in the post–alkali burn phase.
Elevated intraocular pressure can be lowered with the use of topical beta-blockers such as 0.5% timolol, 1
drop twice a day, or 0.5% apraclonidine three times a day or acetazolamide, 500 mg sequels (the sustained-
release form preferred by ophthalmologists) orally every 12 hours or intravenously at the same or lower
dosage, depending on the response).
Medications
Mydriatics.
The eye often is inflamed for some time after the injury; thus, the pupil should be dilated with either atropine
1% twice a day if long-term dilation (longer than 1 week) is anticipated, such as in severe burns with
expected long-term inflammation, or with homatropine 5% or cyclopentolate 1% or 2% twice a day if short-
term dilation is needed, as for milder burns. The dosage is the same in adults and children. Scopolamine
drops are absorbed systemically in sufficient quantities to cause significant central nervous system effects
and should be avoided. The use of mydriatics improves comfort and prevents scarring of the iris to the
central part of the lens.
Antibiotics.
Topical antibiotics should be applied whenever epithelial defects are present. They should provide broad
spectrum coverage without impeding healing. Aminoglycoside antibiotics provide good coverage but are
mildly toxic to the epithelium. Topical ciprofloxacin and other fluoroquinolones treat most organisms,
although resistance is increasing. Bacitracin, sulfonamide, polymyxin, neomycin, or trimethoprim, or
combinations of these and others, are also good choices for prophylactic use early in the course of the
healing process. Allergic reactions, especially with neomycin, can occur with long-term use of topical
antibiotics. Itching and follicular reaction in the conjunctiva and redness and scaliness of the lids can
develop. Antibiotic ointments provide some protection from exposure and drying of the external ocular
surface and may be useful when lid damage causes exposure or when the eye is to be patched.
Anti-inflammatory Medications.
The inflammatory response to injury should be suppressed by medication, since large quantities of
destructive enzymes are released by polymorphonuclear leukocytes and other inflammatory cells in the
immediate postinjury period. Topical corticosteroids (e.g., prednisolone 1%, dexamethasone 0.1%,
fluorometholone 0.1% or 0.25%), as well as systemic corticosteroids and nonsteroidal anti-inflammatory
drugs (NSAIDs), will suppress this response. Dosages need to be titrated to inflammation level and
response. Topical and systemic corticosteroids are associated with glaucoma, so intraocular pressures need
to be monitored with long-term (more than 2 weeks) use of these medications.
Surgery
Removal of necrotic tissue from the conjunctiva and cornea in the early postinjury period can also
significantly reduce the inflammatory response. In severe burns of the eye, the inflammatory response can
continue for up to a year. Since corneal transplant graft survival diminishes in an inflamed environment,
transplantation is often deferred for at least 1 year.[4] However, corneal stem cell transplantation may be
necessary for re-epithelialization and thus may be performed in the first 1 to 2 months after the injury.
Glaucoma surgery is also more successful in an uninflamed environment, but it can be performed any time
the intraocular pressure is uncontrollable with medication or laser therapy and is threatening the optic nerve.
Disposition/Need for Consultants
The decision of whether to admit a patient to the hospital or to treat him or her on an outpatient basis
depends on the immediate need for ongoing treatment and the intensity of such treatment. Telephone
consultation with an ophthalmologist is helpful in planning the disposition. Superficial burns consisting of
some epithelial loss requiring only topical antibiotic and mydriatic therapy are often amenable to outpatient
treatment. Follow-up with an ophthalmologist within the next 24 hours should be arranged. Burns that
require more intensive treatment, or situations in which the extent of injury is not immediately apparent, as is
the case in many alkali burns, may require hospitalization of the patient for optimal care. Pain management,
the need for frequent around-the-clock or intravenous medications, inability of the patient to self-administer
medications, and bilateral visual disability as well as other factors all are considerations in the decision to
admit.


SPECIFIC SUBSTANCES ( Table 28–1 )
Alkali Burns[9 ] [15 ] [33 ] [41 ] [42 ] [43 ] [48 ] [50 ]
Alkali burns can produce devastating chemical injuries to the eye. Burn severity results from rapid and deep
penetration of many alkaline substances into ocular tissue. The alkali typically combines with cell membrane
lipids, resulting in disruption and breakdown of barriers to penetration, allowing damage to the inner eye as
well. As the alkali reacts with ocular tissue, hydroxyl ions are consumed at high pH and then regenerated
when the reaction is allowed to reverse at lower pH, which can occur during irrigation of the eye. This slowly
reversible reaction with gradual regeneration of hydroxyl ions presumably accounts for the observation that
alkali-exposed eyes only slowly regain neutrality despite copious irrigation with water. [19 ]
Table 28-1 -- Clinical Manifestations and Management of Common or Severe Toxic Substances
Affecting the Eye by Direct Contact
Alkalis
Ammonia
Copious irrigation
Lubricants
Mild: superficial epitheliopathy
Mild: Good
Rapid deep penetration
Lye
Remove particulates
Occlusive therapy
Severe: Corneal opacification limbal/conjunctival ischemia deep-tissue penetration
Severe: Very poor
Massive tissue destruction
Sodium hydroxide
Check pH
Ascorbate 10%
Protracted recovery phase

Potassium hydroxide
Goal is pH >7–8
Sodium ascorbate orally
Lime
May require extended (>1–2 hr) irrigation
Sodium citrate 10%
Cleaners
Recheck pH 5 min after irrigation finished and every 10 min for 1 hr
Corticosteroids
Antibiotics
Surgical repair
Acids
Sulfuric
Manage as alkali
Lubricants
Mild: Superficial epitheliopathy
Typically quite good for mild and moderate burns
Coagulation of surface tissue
Hydrochloric
Occlusive therapy
Moderate or Severe: epithelial coagulation tissue penetration
Typically limited penetration

Hydrofluoric
Antibiotics
Blunt and penetrating trauma common in automobile battery explosions

Acetic
Corticosteroids
Solvents
Acetone
Irrigate
Promote re-epithelialization
Epithelial defects
Good
Methylethylketone
Gasoline
Paints
Thinners
Glues
Detergents and Surfactants

Cleaners
Copious irrigation
Manage as alkali
Mild: Superficial damage
Variable
Substances vary widely
Manage as alkali
Severe: Alkali-type burn
May contain alkalis, solvents, and surfactants

Chemical Warfare
Nerve gas
Irrigate
Late, persistent corneal ulceration in mustard injuries
ALL: Irritation
Mustard: Poor
Decontamination of clothing and body may be necessary
Mustard and nitrogen mustard
BAL ointment to skin and eyes for lewisite
Nerve Gas: Miosis

Others: Good
Avoid self-contamination
Lewisite
Mustard: 8-hr latent period
Corneal decompensation starting 8–24 hr
Lacrimators
Tear gas
Irrigate
Superficial epitheliopathy
Good
Occasionally may produce severe corneal damage in high concentrations
Mace
Topical anesthetic
Look for mechanical damage from propellant
Pepperspray
Herbicides and Insecticides

Agricultural chemicals
Irrigate
Conjunctival hyperemia
Good
May contain surfactants, oils, organophosphates, etc.
Superficial epitheliopathy
Miosis: Organophosphates
“Superglues”
Cyanoacrylate
Irrigate
Treat epithelial defects
Lids/lashes glued together
Good
Cyanoacrylate is typically nontoxic, but may require microscopic removal
Remove particulates
Foreign substance
BAL, British antilewisite (dimercaprol).

Management: Management: Clinical
Examples Immediate Extended Manifestations Prognosis Comments
Clinical Manifestations ( Figs. 28–2 , 28–3 , 28–4 )
In mild burns, the external eye demonstrates a hyperemic conjunctiva with normal vascular pattern, and the
cornea is clear but may have some surface staining of the epithelium with fluorescein. In more severe burns,
the conjunctiva may actually appear white and vascular in some areas, giving the mistaken appearance of
being undamaged. In actuality, the conjunctival vessels are destroyed and the white appearance is due to
coagulated tissue. The cornea may also appear white (see Fig. 28–3 ). Any whitening of the cornea or
ischemia of the conjunctiva, as indicated by a whitened vascular appearance at the limbus or elsewhere,
indicates severe damage with a much poorer prognosis.
Figure 28-3 Right cornea from the man in Figure 28–2 , 2 months later. Although re-epithelialization has occurred, extensive corneal
scarring is present, with peripheral vascularization. A corneal transplant could be done, but it would be at high risk for rejection.
Figure 28-2 One week after exposure to liquid alkali, this man’s face and eyes show extensive burns. Facial and eyelid burns of this type
can cause scarring, which interferes with proper eyelid function. Note the opacification of the corneas.
Figure 28-4 A young woman working in a hospital kitchen was injured when a cleaner containing NaOH splashed into her eye. Despite
immediate and copious irrigation, the pH did not return to normal for more than 2 hours. Note the peripheral corneal opacification. Since no
ischemia of the conjunctiva is present in this area, the conjunctival vascular pattern is retained, indicating a better prognosis than if it had
appeared avascular.
Within 2 to 3 minutes of exposure, the pH of the inner eye can rise dramatically, with resultant damage to
the iris, trabecular meshwork, lens, ciliary body, and even retina. Collagen shrinkage can acutely increase
intraocular pressure, and the surface and inner eye damage as well as this acute pressure rise can result in
severe pain. Paradoxically, the more severe alkali and acid burns may be relatively painless because of the
widespread destruction of sensory nerves.
Evaluation of the severity and the prognosis in these burns depends on assessment of the degree of
damage. By using the degree of corneal and conjunctival opacification as well as other indicators, numerous
grading systems have been developed for evaluating the extent of damage in an effort to direct treatment
and determine prognosis ( Table 28–2 ).[61 ] [62 ] [63 ] In addition, monitoring the inflammatory response in the
anterior chamber over the ensuing days may help to direct treatment and determine the final outcome.
Table 28-2 -- Thoft’s Classification of Chemical and Thermal Injuries

Grade I
Conjunctival hyperemia, with no more than diffuse superficial punctate keratitis
Grade II
Conjunctival hyperemia, with partial corneal epithelial loss
Grade III
Conjunctival hyperemia or areas of necrosis, with total corneal epithelial loss
Grade IV
More than 50% perilimbal conjunctival necrosis, with total corneal epithelial loss
The healing process is short in grades I and II. In grade III and IV injuries, however, it can be very prolonged, with
repeated epithelial breakdown and intraocular damage, including damage to the iris, filtration angle, and lens.
Clinical Course
The natural history of alkali burns depends on the degree of damage, which, in turn, depends primarily on
the pH and concentration of the agent and the duration of exposure. Higher concentrations and longer
exposure allow the alkali to lyse the cell membranes and penetrate to deeper tissue layers. The damage can
range from epithelial injury to deep destruction of the cornea, the conjunctiva, and even the retina.[42 ] [60 ]
In severe alkali burns, the aqueous humor fills with necrotic debris and inflammatory mediators. The ensuing
inflammatory response can extensively scar the inner eye. Damage to the trabecular meshwork, which
functions as the outlet for intraocular fluid, can occur either from direct chemical injury or as a consequence
of this inflammatory process. Collagen shrinkage secondary to alkali denaturation can also occur, resulting
in elevated intraocular pressure and glaucomatous damage to the optic nerve. Conversely, the ciliary body,
which produces the aqueous fluid that continually flows into the eye, may be so badly damaged that
aqueous humor production effectively ceases and the eye becomes soft and nonfunctional.
Mild burns heal by movement and regeneration of undamaged epithelium, in a manner similar to the repair
of a corneal abrasion. Healing typically requires several days. More severe burns with underlying scleral
and/or corneal stromal damage and with extensive destruction of surface epithelium usually cause epithelial
defects that may not heal for weeks or months—or not at all. The epithelial defects may appear to be healing
initially, and then may deteriorate into a frank corneal ulceration that may not heal for an extended period of
time. The damage may be exacerbated by the release of destructive enzymes by inflammatory cells.[42 ]
Typically, these epithelial defects heal when revascularization or neovascularization of the ocular surface
has taken place. In severe alkali burns, the best outcome to be expected is a totally vascularized cornea with
no persistent epithelial defects and without resultant glaucoma or phthisis.
Treatment
Irrigate the eye immediately and copiously, as described earlier. Topical anesthetics should be used only to
allow irrigation—and not for pain control after the acute stage, since they are themselves quite toxic to the
eye when used injudiciously. Repeated applications of topical anesthetics delay epithelial healing, increase
the permeability of the cornea to drugs and chemicals by breaking down the epithelial barrier, and promote
physical or chemical damage by preventing discomfort and reducing the blink reflex. Sensitization also
occurs, resulting in inflammatory infiltrates and scarring of the cornea. Topical anesthetics should be
discontinued after the initial irrigation ceases.
Ocular epithelialization should be promoted by the use of lubricants, bandage soft contact lenses (a specific
thin and highly permeable protective lens), or occlusion by patching to protect the surface. Surgical closure
of the lids is indicated if the ocular surface is exposed as a result of lid damage.
Medications
The use of topical corticosteroids remains controversial. However, these medications can limit inflammation-
mediated damage following a severe burn. This beneficial effect must be balanced against their
disadvantages, which include retardation of wound healing and a predisposition to infections. With longer
term corticosteroid use, some patients will also develop glaucoma and cataracts.
Other medications used to prevent or heal corneal ulcers after alkali burns include ascorbate 10%, applied
topically every hour, plus 2 grams of ascorbate, given orally four times a day for the first week and tapered
thereafter. Sodium citrate 10% may be useful in reducing ulceration and perforation of the cornea.[45 ] [64 ]
Surgery to débride necrotic tissue and repair associated lid wounds is often necessary in the immediate
postinjury period. However, corneal transplantation should be deferred until the eye has healed and the
inflammation has resolved. [4 ]
Acids[28 ] [34 ] [44 ] [58 ]
In acid burns, the extent of ocular damage is determined by the pH change caused by the hydrogen ion and
the damage to the tissue proteins caused by the anion. Different anions elicit different reactions. Those
anions that have a higher protein affinity produce more severe damage, although their greater tissue binding
may limit penetration. Severe acid injuries are more commonly associated with exposure to heavy metal
acids, such as chromic acid, or mineral acids, such as sulfuric, sulfurous, and hydrofluoric.
Acid injuries differ distinctively from alkali injuries. Acids tend to cause less damage to ocular tissue because
acids coagulate and precipitate proteins. Proteins buffer the effect of the acid while the coagulated
epithelium acts as a mechanical barrier to penetration. Therefore, while alkalis saponify membranes,
damaging tissue barriers against penetration and thus facilitating rapid spread through tissues, acids in mild
and moderate strengths create a self-limiting barrier to penetration. However, in severe acid burns, the
tissue damage can extend into the deeper tissue layers.
Evaluation and treatment of acid injuries are similar to the strategies outlined for alkali burns. The extent of
damage dictates further therapy with antibiotics, lubricants, or anti-inflammatory medication or surgery. The
prognosis is typically better than that in alkali burns, but severe burns or those combined with blunt trauma
or foreign bodies, as occur in automobile battery explosions, can result in suboptimal outcomes.
Hydrofluoric acid (HF) burns require special consideration. A weak acid, HF readily crosses cell membranes
and penetrates deeper tissues. There, it releases fluoride ions, which form insoluble complexes with tissue
calcium and magnesium, resulting in tissue damage that can be severe. Ocular exposure may de-
epithelialize the cornea and conjunctiva and cause corneal edema, conjunctival necrosis, and damage to
anterior chamber structures.[26 ] Anecdotal cases of successful treatment with the use of irrigation with
calcium gluconate or other fluoride ion–binding substances have been reported.[6 ] [30 ] [51 ] McCulley and
colleagues[29 ] evaluated the toxicity and therapeutic value of numerous agents applied to rabbit eyes. They
evaluated topical ointments of 25% and 50% magnesium oxide or magnesium sulfate; irrigation with water,
isotonic saline, magnesium chloride, lanthanum chloride, 0.2% benzethonium chloride, 0.03% and 0.05%
benzalkonium chloride, and an isotonic divalent ion mixture; and 10% calcium gluconate subconjunctival
injections. They concluded that “quaternary ammonium compounds and 10% calcium gluconate are far too
toxic for use in ocular tissues. Zephiran Chloride caused additional ocular damage and had no beneficial
therapeutic effect. Likewise, topical ointments containing magnesium oxide or magnesium chloride are
excessively toxic to the eye. The only therapeutic procedures evaluated that were nontoxic and had
beneficial effects were simple irrigations with water, normal saline, or isotonic magnesium chloride. More
recently, Beiran and associates [5 ] found no significant improvement with 1% calcium gluconate drops or with
subconjunctival injection in rabbit eyes that had HF injury.[5 ] Immediate and copious irrigation appears to be
more important than neutralization in ocular HF injuries.
Solvents and Hydrocarbons
Toluene, xylene, benzene, n -hexane, alcohol, acetone, and amyl acetate are found in household products
such as paint thinners, lacquers, glues, and polishes, and are used extensively in industry. Gasoline,
kerosene, motor oil, and other hydrocarbons are also commonly used. Ocular exposure to these substances
from vapors or from splashes is typically accidental but may be intentional, as in cases of “glue sniffing.”
Fortunately, ocular exposure to these substances usually causes mild superficial epithelial damage, which
heals quickly. Initial treatment is prompt irrigation, usually for only a few minutes, since solvents and
hydrocarbons do not bind chemically to tissues. Significant ciliary spasm or pain from exposure to these
substances rarely occurs, and mydriatics are not usually necessary.
Detergents and Surfactants
Numerous household and industrial cleaning agents contain detergents and surfactants, either alone or
combined with other substances such as acids or alkalis. Damage to the eye from these substances varies
widely. Household hand soap may cause stinging without ocular damage, while Hibiclens, a presurgical skin
antiseptic containing a detergent as well as 4% chlorhexidine gluconate, may cause permanent corneal
opacification.[46 ] Some detergents and surfactants can break down tissue barriers, exposing deeper layers
to other substances present in these combination products.
Treatment consists of immediate irrigation. The duration of irrigation is difficult to predict, given the wide
variety of these substances and multiple combinations of ingredients. However, since some of these
substances have delayed effects, irrigation as for an alkali injury is recommended.
Methyl Isocyanate
Because of the large number of people affected by the release of methyl isocyanate (MIC) on the night of
December 3, 1984, in Bhopal, India, much data are available on the ocular effects of exposure to MIC. The
signs and symptoms of exposure included foreign body sensation, redness, lid swelling, watering,
photophobia, and decreased vision. The most common effects were superficial epithelial keratopathy of the
conjunctiva and cornea. Less common were involvement of the corneal stroma and iritis. Epithelial healing
was complete in 5 days and corneal stromal opacification cleared within 2 to 3 days. Treatment consisted of
topical antibiotics and cycloplegics, as well as topical corticosteroids in patients with stromal involvement or
iritis. In a study that included a 3-year follow-up, Andersson found an increased risk of trachoma and other
lid infections and an increased risk of persistent irritant symptoms after exposure.[1 ] [14 ]
Chemical Warfare Weapons
Chemical warfare weapons have been in existence for many years and through many wars.[40 ] These
agents may have been deployed militarily as recently as 1988[23 ] and by terrorists in a nonmilitary setting in
a Japanese subway attack in 1995.[39 ] Large stockpiles of these agents exist in many countries, and they
are easily producible from readily available industrial chemicals.
Nerve Agents[13 ]
These agents include tabun (code name GA), sarin (GB), soman (GD), and VX (a methylphosphonothiolate
compound).[10 ] They are typically dispersed in a vapor or microdroplet phase and can be absorbed through
the respiratory system or transdermally. The eyes can be affected either via direct contact or by secondary
response to systemic absorption. Ocular effects include miosis, conjunctival redness, pain (especially on
focusing), slight dimness of vision, headache, and lacrimation.[49 ] These ocular signs, if present after a
chemical assault, may indicate the use of an anticholinesterase inhibitor. For example, following the use of
sarin in a terrorist attack in a Japanese subway, some emergency medical personnel treating the victims,
initially unaware of the causative agent, noted dim vision and severe miosis along with other systemic
symptoms, indicating secondary exposure to the sarin.[39 ] Miosis from direct ocular exposure to these
substances may be relatively unresponsive to systemic atropine, whereas miosis due to systemic effects
does respond.
Mustard and Nitrogen Mustard[10 ] [12 ] [18 ]
Mustard gas is an oily straw-colored fluid with a garlic-like odor used in either vapor or microdroplet form.
Systemic toxic effects of mustard compounds include bone marrow depression and cellular DNA damage.
Dichlorodiethyl sulfide (mustard gas) penetrates the skin and cornea in about 10 minutes. Thus,
decontamination is most effective if begun during this 10-minute interval. Conjunctival necrosis and vascular
occlusion may start within 30 minutes after exposure and increase over the first 24 hours. Small vessel
endothelial damage begins about 24 hours after exposure and produces subsequent hemorrhagic changes
in the conjunctiva. Within a few days, healing of the conjunctiva commences. Corneal changes develop
more slowly than conjunctival ones and begin with surface irritation, followed by a clinically latent period of
about 8 hours. Then, corneal edema, infiltration, and epithelial loosening from Bowman’s membrane may
occur. Regeneration of corneal epithelium starts within 24 to 48 hours or more, depending on the severity of
injury. The iris becomes edematous, hemorrhagic, and necrotic, and the lens opacifies. Inhibition of cellular
mitosis may last for weeks. Late persistent corneal epithelial defects may be present for years, with
vascularization and opacification causing permanent visual disability. A delayed keratopathy can develop
decades later. The delayed keratopathy is preceded by a conjunctivitis, after which the cornea begins to
cloud. Progressive clouding, vascularization, and calcium deposition cause a marked decrease in vision.
Topical EDTA (ethylenediamine tetraacetic acid) can be used to remove the calcium. Corneal
transplantation is necessary in cases of severe clouding.[4 ]
There are no specific antidotes for ocular mustard poisoning. Treatment consists of copious irrigation,
followed by antibiotics, and topical atropine until the inflammation subsides and the corneal epithelium is
intact.[7 ] [10 ] [18 ]
Lewisite
Lewisite, or dichloro (2-chlorovinyl) arsine, binds sulfhydryl groups of structural proteins and enzymes.
Lewisite may immediately affect the eye by causing redness, edema, and a burning sensation, with corneal
damage and iritis. Permanent blindness may result if the eye is not decontaminated within 1 minute.
Phosgene
The agent phosgene causes violent conjunctival irritation, redness, and edema with lacrimation as well as
severe corneal involvement. Ocular treatment consists of irrigation followed by supportive therapy.
Lacrimators
A wide variety of substances that go by various names, including tear gas, Mace, pepperspray (which
contains capsaicin), and others, cause intense irritation, lacrimation, pain, photophobia, and
blepharospasm.[2 ] Typical ingredients may include chlorobenzylidenemalononitrile (code named CS),
chloroacetophenone (CN), dibenoxazephine (CR), and others. Damage is usually limited to minimal
superficial epithelial toxicity with no lasting residual, although more extensive damage has been reported. [3 ]
[8 ] [59 ] The propellant may cause mechanical damage to the ocular surface or propel solid objects at the
eye. Treatment consists of copious irrigation and analgesia, followed by examination for mechanical
damage.
Metallosis
Traumatic injury to the eye often involves metallic intraocular foreign bodies that can incite chemical and
toxic reactions as well as cause mechanical damage. The biochemical reactions of various metals have
been described.[37 ] The site, shape, size, and type of metal involved determine the severity of reaction and
the clinical course. A copper-containing foreign body may remain suspended in the vitreous cavity for years
without causing problems, yet the same foreign body in contact with the retina or choroid can elicit a
massive cellular infiltration.[37 ]
Copper is the most reactive of the commonly encountered metal foreign bodies. [47 ] With copper intraocular
foreign bodies, the clinical course often consists of fulminant inflammation starting within a few days of
entry.[31 ] [54 ] A foreign body with a copper content of more than 85% produces a more pronounced acute
reaction. Low copper content and small size can lead to a more chronic chalcosis. Copper-containing foreign
bodies with a high copper content should be surgically removed as soon as possible.
Iron-containing ocular foreign bodies are common. Intraocular ferrous compounds are much less reactive
than are cupric compounds, and the clinical course is often determined more by the mechanical damage
than by the chemical reaction. When the ferrous foreign body remains in the eye for a prolonged time,
however, iron can deposit in the cornea, lens, iris, ciliary body, and retina, leading to heterochromia iridis,
mydriasis, cataract, retinal dysfunction, and optic nerve atrophy.[22 ] [32 ] Iron-containing macrophages can be
found in the trabecular meshwork and may lead to glaucoma. Superficial ferrous foreign bodies of the lids,
conjunctiva, and cornea should be removed as soon as practical, and intraocular ferrous foreign bodies
should be removed surgically, if possible, or the eye closely observed for inflammation or siderosis.[37 ]
Intraocular gold is quite nonreactive.[25 ] A 22-carat gold particle remained in the anterior chamber of a
goldsmith’s eye for 9½ years without causing problems.[56 ] Intraocular silver has also been well tolerated.[53
] [55 ] In general, however, most intraocular foreign bodies can and should be removed when possible.
Miscellaneous
Reports of chronic and acute exposures to many other substances in either the work environment or
elsewhere reveal widely different exposures, depending on the geography and local culture. For instance,
among fishermen and fish industry workers in the coastal regions of Norway, 56 per cent of all occupational
eye traumas due to chemicals were caused by fish bile splashed in the eye.[11 ] Countries with civil unrest
may have a high percentage of lacrimator incidents during riots or demonstrations.[24 ] [27 ] Local industrial
facilities may have the potential for accidents, such as the one that happened in Bhopal, India,[14 ] and local
economies may involve businesses that use toxic chemicals prone to causing eye injuries.[16 ] [38 ] [52 ] [57 ]
[61 ] It is important to be familiar with local common chemical eye injuries and to be appropriately prepared to
evaluate and treat them.
Ocular exposure to cyanoacrylate glue is common. Cyanoacrylate produces damage by strongly adhering to
superficial ocular structures, such as the lids and cornea. While cyanoacrylate is not chemically harmful (in
fact, it is used therapeutically to close holes in the cornea), it causes mechanical damage to tissues, such as
lid skin, lashes, and corneal epithelium, when removed. Careful removal, best done under magnification,
minimizes this trauma. Irrigation is not helpful, since cyanoacrylate is not water-soluble. Therapy after
removal of the glue consists of treating the epithelial defect or other subsequent trauma.


OCULAR EFFECTS OF SYSTEMIC SUBSTANCES
The ocular and visual effects due to systemic exposure to most substances do not typically present as
isolated ocular emergencies. Most of these effects are chronic or asymptomatic, as in the talc retinopathy
seen in intravenous drug abusers, but rarely do they cause ocular symptoms or problems. [35] However,
patients with systemic exposure to methanol and quinine, among others, may present with acute ocular
symptoms. Recognition and treatment of these toxicities may prevent or minimize damage to the eye or
visual system. As mentioned previously, encyclopedic listings of ocular toxins exist and are recommended,
but a few of the more common or severe of these substances are presented in Table 28–3 .[17][20]
Table 28-3 -- Substances Commonly Affecting the Visual System via Systemic Exposure
Visual Optic Nerve and Visual
Corneal Deposits Lens Changes Disturbances Retinal Changes Pathway Changes
Amiodarone Amiodarone Acetazolamide Benzene Carbon monoxide
Amodiaquine Chlorpromazine Botulinum toxin Canthaxanthin Corticosteroids
Chloroquine Copper Digitalis Carbon dioxide Ethambutol
Copper Corticosteroids Hallucinogenics Carbon monoxide Ethylene glycol
Gold Dinitro-o-cresol Methylmercury Chloroquine Isoniazid
Hydroxychloroquine Dinitrophenol Sulfonamides Hydroxychloroquine Lead
Isotretinoin Iron Epinephrine Methanol
Mercury Mercury Methanol Nalidixic acid
Silver Methyldichlorarsin Optoquine Quinine
Tamoxifen Silver Oxygen Tetracycline
Trinitrotoluene Quinine Vitamin A
Tamoxifen
Thioridazine
Pupil Abnormalities
Miosis Mydriasis Nystagmus Partial/Total Vision Loss
Anticholinesterases Amphetamines Ethanol Carbon disulfide
Glaucoma medications Anticholinergics Isoniazid Carbon monoxide
Nerve gases Antihistamines MAOIs Carbon tetrachloride
Organophosphates Cocaine Phencyclidine Chloroquine
Opioids Parasympatholytics Phenytoin Ciguatoxin
Parasympathomimetics Sympathomimetics Sedative-hypnotics Cyanide
Deferoxamine
Hexane
Hydrogen sulfide
Mercury
Methanol
Methyl bromide
Neurotoxic shellfish
poisoning
Quinine
MAOIs, monoamine oxidase inhibitors.


SYSTEMIC EFFECTS OF OCULAR MEDICATIONS
Systemic effects of ocular medications are due to their absorption via the mucous membranes of the eye
and nasal passages. Beta-adrenergic blockade may occur with the use of ocular beta-adrenergic receptor
antagonists.[20] The use of timolol, levobunolol, carteolol, and metipranolol can adversely affect patients with
asthma, congestive heart failure, or bradycardia, and these agents are also implicated in causing or
exacerbating depression. Even betaxolol, a cardioselective beta-adrenergic blocker, can produce such
effects. Any topical ocular medication can also cause a local allergic reaction, typically manifested by
swollen, reddened, itching lids and conjunctival injection. Severe systemic allergic reactions have been seen
in patients exposed to topical medications containing substances such as sulfonamide. Miotics such as
pilocarpine frequently cause headaches, especially during the initiation of therapy, which resolve over the
first few weeks of treatment. Carbonic anhydrase inhibitors such as acetazolamide and methazolamide can
cause numbness and tingling in the hands and feet, a metallic taste in the mouth, acid-base and electrolyte
abnormalities, kidney stones, and sulfonamide allergies.


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Section III – TOXINS IN DEPTH:
Chapter 29 – Acetaminophen
ANTHONY ANKER
Essentials
• Acute ingestion:
° Nausea and vomiting occur or may be asymptomatic initially
° Elevation of hepatocellular enzymes occurs within 36 hours after
ingestion
° Treat with N-acetylcysteine within 8 hours of ingestion
• Chronic ingestion of more than 4 g/day

° Treat if aspartate transaminase (AST) is elevated. Consider treatment of “at risk” patients if
acetaminophen (APAP) is detectable
• With any acute hepatic injury, suspect acetaminophen
INTRODUCTION
Acetaminophen, also known as paracetamol, a popular and widely available over-the-counter analgesic, is a
frequently reported medicinal agent associated with toxic ingestions. [37] Injury to the liver following the
ingestion of acetaminophen is the most common cause of serious morbidity and of death, although organ
systems other than the liver may also be affected. The prevention of hepatic injury requires early diagnosis
and treatment. Extensive clinical experience has demonstrated that the development of hepatotoxicity can
be predicted and its occurrence prevented by the timely administration of N-acetylcysteine
(NAC).[50][59][66][68]


PHARMACOLOGY/PATHOPHYSIOLOGY
Pharmacology
Most forms of acetaminophen are rapidly absorbed following ingestion. In one study, 97 per cent of a
supratherapeutic 5-g dose of elixir was absorbed after 2 hours.[57] Peak levels occur at 30 to 60 minutes
following a therapeutic dose of uncoated tablets.[1][51] The newer extended-release acetaminophen
preparations have a pharmacokinetic pattern of absorption similar to that of regular-release formulations,
with peak levels occurring less than 4 hours after ingestion but with decreased maximal concentration and
area under the curve.[9][15][70][71]
Acetaminophen is metabolized almost exclusively in the liver. More than 90 per cent is directly converted to
nontoxic glucuronide and sulfate conjugates and less than 5 per cent is excreted unchanged in the urine.
The rest (approximately 5 per cent) is oxidized by various cytochrome P-450 enzymes, including P4502E1,
P4501A2, and P4503A4. Metabolism via these enzymes produces the reactive electrophile N-acetyl-p-
benzoquinoneimine (NAPQI) ( Fig. 29–1 ).[11][13][36] Under most circumstances, NAPQI combines
immediately with glutathione to form a nontoxic mercaptide conjugate. Cytochrome P-450 enzymes are also
found in the kidney, and some NAPQI is formed there.[44]
Figure 29-1 Acetaminophen metabolism and NAPQI formation. Sulfate, glucuronide, cysteine, and mercaptide conjugates are
nontoxic metabolites that are excreted in the urine. 1NAC is converted to cysteine, which is then converted to glutathione within
hepatocytes[31] (the major mechanism of NAC action). 2NAC acts as a direct substitute for glutathione, reducing NAPQI[24](minor
mechanism of NAC action). 3NAC acts as a sulfur donor in the formation of the nontoxic sulfate metabolite of acetaminophen[65]
(minor mechanism of NAC action). 4NAC reduces NAPQI directly back to acetaminophen in animals, but this mechanism may not be
active in humans.31 5NAC appears to reduce liver injury by a variety of mechanisms.[8][20][25] (Modified from: Mitchell JR,
Thorgeirsson SS, Potter WZ, et al: Acetaminophen-induced hepatic injury: Protective role of glutathione in man and rationale for
therapy. Clin Pharmacol Ther 1974; 16:678–684.)
Pathophysiology
Glutathione depletion occurs in acetaminophen overdose when the rate of utilization of glutathione exceeds
its rate of formation, or in states of nutritional depletion when glutathione stores are inadequate. If
glutathione levels fall below 30 per cent of normal, the highly reactive NAPQI can bind instead to cellular
macromolecules that contain cysteine.[13][43][48][55] Histochemical staining has demonstrated binding of
NAPQI to cysteinyl sulfhydryl groups in the hepatic centrilobular area that precedes hepatocellular
necrosis.[55] This covalent binding of NAPQI causes hepatocellular damage at many sites in the liver,
although centrilobular necrosis predominates.[13][16][55][72] Renal injury may also occur owing to the
production of NAPQI by P-450 enzymes in the renal parenchyma.[12][44][49] How the binding of the NAPQI-
cysteine protein adduct causes injury to cells is not clear. Proposed mechanisms of injury include inhibition
of mitochondrial function; inhibition of NADH and Krebs’ cycle enzymes; and disruption of the normal
calcium gradients that regulate ATP production and intracellular catabolic enzymes.[39] A cellular or humoral
immune response directed against the adduct-hepatocyte complex is not the cause, as injury occurs in
hepatocyte tissue culture independent of cellular immunity mechanisms.[13]
Previously healthy, nonfasting patients who acutely ingest more than 150 mg/kg (children) or 7.5 g (adults)
are at risk for developing acetaminophen toxicity. Following chronic ingestion of quantities greater than the
recommended dosages, those at increased risk for developing acetaminophen-induced hepatotoxicity
include children with acute febrile illnesses,[21] patients with preexisting liver disease, and patients who
chronically ingest agents that induce P4502E1, such as ethanol and isoniazid.[7][13][30][32][62][74][76] A recent
study has suggested an increased risk of hepatotoxicity when fasting precedes acute acetaminophen
overdose or chronic ingestion, even at doses only modestly above the recommended daily dose of 4
g/day.[74] The mechanism of this effect is unclear, although it is postulated to be due to decreased
glutathione stores.[32] The prevalence and significance of these findings require clarification by further
studies.


Early recognition of an acute acetaminophen overdose is essential, as the prognosis is best when antidotal
treatment is initiated within 8 hours of the overdose. Early signs of toxicity may include malaise, nausea, and
vomiting, with few findings on physical examination. Many patients with toxic acetaminophen levels and a
significant potential for hepatotoxicity are initially asymptomatic following acute ingestion (stage I in Table
29–1 ).[36] Signs of liver injury, such as abdominal pain, persistent vomiting, icterus, and right upper quadrant
tenderness, only become apparent 24 to 48 hours after an acute ingestion (stage II). Serum transaminases
begin to rise as early as 16 hours following a significant ingestion and are always elevated at the time that
the clinical signs of hepatotoxicity initially manifest. [64]
Table 29-1 -- Clinical Stages of Acetaminophen Toxicity

Stage Time Following Characteristics
Ingestion
I 0.5 to 24 hr Anorexia, nausea, vomiting, malaise, pallor, diaphoresis
Resolution of the above characteristics; right upper quadrant abdominal pain and
II 24 to 48 hr
tenderness; elevated bilirubin, prothrombin time, INR, hepatic transaminases, oliguria
Peak liver function abnormalities; anorexia, nausea, vomiting, malaise may reappear;
III 72 to 96 hr fulminant hepatic failure (FHF) with metabolic acidosis, INR >6, and renal dysfunction
may be apparent
Resolution of hepatic dysfunction in survivors. Oliguric renal failure can develop;
IV 4 d to 2 wk
death may occur in patients with FHF
Modified from Linden CH, Rumack BH: Acetaminophen overdose. Emerg Med Clin North Am 1984; 2:103.
During stage III, which occurs 3 to 4 days after ingestion, the full extent of hepatic injury and the prognosis
can be estimated. Hepatotoxicity can range from mild signs and symptoms accompanied by elevations in
serum hepatic transaminases (AST >1000 IU/L), to fulminant hepatic failure (FHF) with abdominal pain, right
upper quadrant tenderness, jaundice, hypoglycemia, dramatic serum hepatic transaminase elevations
(>10,000 IU/L), acidosis, coagulopathy, and encephalopathy.[6] As previously noted, patients with preexisting
liver disease, alcoholics,[32][62][74][76] fasting patients,[74] and patients taking certain medications that induce
cytochrome P-450 enzymes [7][13] ( Table 29–2 ) may be at higher risk for severe hepatotoxicity. Fatalities
occur during this stage from complications such as adult respiratory distress syndrome, cerebral edema,
uncontrollable hemorrhage, infection or multiorgan failure. Patients without preexisting liver disease who
survive this stage generally recover completely (stage IV).
Table 29-2 -- Agents Implicated in Induction of the Cytochrome P-450 MFOS Causing Increased APAP
Toxicity
Carbamazepine
Ethanol
Isoniazid
Phenobarbital (possibly other barbiturates)
Phenytoin
Sulfinpyrazone
Sulfonylureas
Rifampin
Primidone
Renal injury can develop, even in cases where hepatotoxicity is mild.[12][44][49] This is attributed to local injury
by in situ production of NAPQI in the renal tubular P-450 enzymes. Acute renal failure also occurs in severe
cases of acute hepatic failure as a consequence of liver injury (hepatorenal syndrome). Determining the
fractional excretion of sodium (FeNa) can aid in differentiating primary renal injury (FeNa >1) from
hepatorenal syndrome (FeNa <1).
Hepatotoxicity Related to Chronic Ingestion of Acetaminophen
Patients who develop hepatic injury following excessive dosing of acetaminophen, often for chronic pain, or
inadvertent overdosage of pediatric formulations, present most often to the emergency department with
manifestations of acute liver injury, rather than a history of acetaminophen overdosage. Two papers have
described a high frequency of chronic alcohol abuse in these patients who present with injury related to
chronic misuse of acetaminophen.[62][74] These studies are retrospective, and the question of whether the
chronic use of ethanol has led to increased susceptibility to liver injury or has simply resulted in a poor
history of the amounts ingested and poor judgment regarding the amounts ingested remains unanswered.
This association is suspected on the basis of theoretical grounds related to the stimulation of P4502E1 by
chronic ethanol consumption and the nutritional depletion, with presumed glutathione deficiency, of many
chronic ethanol users. However, two earlier studies of large populations of patients treated for acute
ingestions did not show an association between chronic ethanol use and liver injury.[38][60]


The differential diagnosis of acetaminophen poisoning includes many toxic, infectious, environmental, and
metabolic causes of hepatocellular injury (see Table 21–1 ). In the alcoholic patient, the distinction between
hepatotoxicity due to ethanol and that due to chronic ingestion of excessive amounts of acetaminophen has
been based on the following: (1) the demonstration of transaminase levels higher than those normally seen
in alcoholic hepatitis (>300 IU/L), and (2) a history of chronic ingestion of acetaminophen.[30][61] The
importance of a thorough evaluation for acetaminophen poisoning, including a careful history and
measurement of a serum acetaminophen concentration, cannot be overemphasized.


LABORATORY STUDIES
Initial Assessment
For the patient who presents within 8 hours of an acute acetaminophen ingestion, measurement of a
postingestion acetaminophen level at 4 hours or later is the only laboratory test initially needed. Because of
the over-the-counter availability of acetaminophen and the lack of early symptoms after overdose, a serum
acetaminophen concentration should be measured in all suicidal overdose patients.[4] Patients with delayed
presentations require, at a minimum, measurement of hepatic transaminase levels in addition to an
acetaminophen level. Other tests to be considered include prothrombin time (PT), INR (International
Normalized Ratio), electrolytes, and creatinine.
Use of the Acetaminophen Nomogram
The measured serum acetaminophen level at 4 hours or longer following an acute ingestion predicts the
possibility of hepatic injury when plotted on the standard acetaminophen nomogram ( Fig. 29–2 ). In the
United States, the generally accepted paradigm is to treat all patients who have serum acetaminophen
concentrations on or above the lower line (=150 µg/mL). The upper nomogram line, which begins at 200
µg/mL at 4 hours, depicts the risk of acetaminophen-induced hepatotoxicity determined by Rumack and
Matthew in their original study.[58] This line is used in Europe and Canada to determine the need to treat a
patient with acetaminophen overdose. The lower line that begins at 150 µg/mL at 4 hours was added later to
prevent treatment errors caused by inaccuracies in the history or in laboratory measurements.[60] A single
measurement of the serum acetaminophen concentration is sufficient to determine the need for treatment
following acute ingestions. The nomogram is not valid for chronic ingestions.
Figure 29-2 Nomogram: Serum acetaminophen concentration versus time of ingestion. The lower (modified) line, which is used by
most practitioners in the United States, is 25 per cent below the actual (original) hepatotoxicity risk line that is used in Europe and
Canada. (Courtesy of McNeil Pharmaceuticals.)
Attention must be paid to the units of measure used by the laboratory (µg/mL, mmol/L, or mg/dL) when one
interprets the level. Micrograms per milliliter and millimoles per liter are interchangeable and are the units
used most frequently in the reporting of acetaminophen levels. A level reported in milligrams per deciliter
must be multiplied by 10 in order to convert the units to micrograms per milliliter; for example, 25 mg/dL is
equivalent to 250 µg/mL. The failure to understand this difference can result in misinterpreting a toxic level
as nontoxic.
Extended-Release Products
In most cases, laboratory testing of extended-release products is similar to that for regular-release products;
that is, drawing a single level at least 4 hours after ingestion.[15] This strategy is supported by a human-
volunteer, crossover comparison trial of supratherapeutic (75 mg/kg) ingestion of regular-release APAP and
extended-release APAP. In this study, all peak acetaminophen levels occurred less than 4 hours after
ingestion, the area under the curve was less for extended-release APAP, and terminal elimination kinetics
were similar for both formulations.[15] When very large ingestions are suspected, more conservative
practitioners have advocated obtaining two levels 4 to 6 hours apart and treating with NAC if either level
goes above the toxic line.[9][70][71]
Assessment of Hepatic Injury
Laboratory indicators of hepatic injury should be measured initially and daily during therapy in any patient
with a serum acetaminophen concentration above the treatment nomogram line. With progressive hepatic
failure, testing should be done every 12 hours. Most patients who will develop liver toxicity have an elevated
AST level within 24 hours of ingestion, and, in one small series, all cases had reported AST elevation within
36 hours.[64] The demonstration of a normal AST at 36 hours after an acetaminophen ingestion is sufficient
to eliminate the possibility of liver toxicity.[2]
When liver injury occurs following acetaminophen ingestion, additional diagnostic testing is needed to guide
treatment and assess prognosis. Severe hepatic injury is associated with extensive disruption of
hepatocytes, decreased capacity to synthesize coagulation factors, decreased glycogen and altered glucose
homeostasis, and impairment of synthesis and excretion of bilirubin. In some cases, renal failure develops.
The extent of toxicity can be assessed by determination of prothrombin time, INR, arterial pH, and serum
creatinine ( Table 29–3 ). Patients with an INR greater than 2 at 24 hours, 4 at 48 hours, or 6 at 72 hours are
likely to develop FHF.[39] Persistent metabolic acidosis despite intravascular volume repletion also indicates
a poor prognosis. This should be differentiated from a lactic acidosis, occurring early in overdose and
without evidence of FHF, that is due to a direct effect of acetaminophen on hepatic lactic acid uptake and
oxidation.[17] Transaminase levels do not predict the clinical course. They may decline either during hepatic
recovery or with progressive FHF. During recovery, it is common for declining serum transaminases to
precede the decline of the serum bilirubin. Acute renal insufficiency also occurs and indicates a poorer
prognosis when the serum creatinine is greater than 300 mmol/L (3.4 mg/dL) in association with a
prothrombin time greater than 100 seconds and grade III or grade IV hepatic encephalopathy.[33][61]
Table 29-3 -- Prognostic Indicators of Most Severely Poisoned Patients: Liver Transplantation Criteria at
King’s College Hospital, London
Arterial pH <7.3 (at any time after FHF develops that fails to correct with colloid loading)
OR
In patients with a normal arterial pH, all three of the following:
Prothrombin time >100 sec *
Creatinine level >300 µmol/L (3.4 mg/dL)
Grade III or grade IV hepatic encephalopathy
Adapted from Makin AJ, Williams R: Acetaminophen-induced hepatotoxicity: Predisposing factors and
treatments. Adv Intern Med 1997; 42:453–483.
* Assumes no fresh-frozen plasma or vitamin K replacement therapies.


TREATMENT ( Table 29–4 )
Acute Overdose
Gastrointestinal decontamination with activated charcoal is useful after acetaminophen overdose, although
rapid drug absorption limits its effectiveness more than 2 hours after ingestion.[57] Acetaminophen is well
adsorbed by activated charcoal. In clinical settings where there is a high likelihood that acetaminophen
remains in the stomach, activated charcoal should be administered in order to reduce the amount of
acetaminophen absorbed. Although activated charcoal can adsorb NAC,[28] there is no evidence that this
adsorption is clinically significant.[52] The administration of NAC within 8 hours has been shown effective
regardless of the amount of acetaminophen ingested or the use of activated charcoal, suggesting that in all
cases the standard doses of NAC employed provide a wide margin of safety.[68] Administration of activated
charcoal is especially important when other agents are ingested in addition to acetaminophen. In these
cases, gastric decontamination measures appropriate to these agents should be undertaken without regard
for the need for subsequent NAC treatment.
Table 29-4 -- Treatment

ACUTE OVERDOSE
1. Activated charcoal, 1 g/kg within 4 hr of ingestion
2. N-Acetylcysteine: Treat if APAP level measured =4 hours post ingestion falls above lower nomogram line
(United States) or upper nomogram line (Europe and Canada)
Dose
Load: 140 mg/kg PO once
Maintenance: 70 mg/kg PO every 4 hours for 17 doses *
Other
Administer first dose within 8 hr of ingestion
Repeat dose if vomiting occurs within 1 hr of dose administration
Can be given IV. Contact regional poison center or medical toxicologist for indications and guidelines
Can be given in pregnancy
3. Delayed presentation >24 hr post ingestion with NAC if APAP level measurable or if hepatic transaminases
are elevated
Chronic Ingestion
1. If APAP measurable or hepatic transaminases elevated, treat with NAC for 24 to 36 hr, then reassess levels.
Evidence of progressive hepatotoxicity dictates continued NAC treatment as for hepatotoxicity
Hepatotoxicity
1. Administer NAC, in doses described above
If INR <2 at 72 hr post ingestion, can stop NAC
All other cases, continue NAC until INR <2
Consider intravenous NAC (United States)
Transfer to Liver Center
1. INR >5
Or any of these complications
2. Serum creatinine >200 µmol/L (2.3 mg/dL)
3. Metabolic acidosis (pH <7.35 or serum bicarbonate <18 mEq/L)
4. Hypotension
5. Hepatic encephalopathy
6. Hypoglycemia
Liver Transplant
See Table 29–3 for criteria
* Shorter protocols being studied or used by some toxicology experts.
Antidotal Therapy: N-Acetylcysteine (NAC)
Mechanism of the Effect of NAC
Timely administration of the antidote N-acetylcysteine (NAC) protects the liver from toxic levels of
acetaminophen via a number of proposed mechanisms (see Fig. 29–1 ). First, the administration of NAC
increases the synthesis and availability of glutathione.[31] The administration of NAC increases the amount
of acetaminophen bound initially by sulfate, increasing the fraction of the initial sulfation product of
acetaminophen and reducing the amount of NAPQI formed.[65] In addition, the reduced sulfur group of NAC
can also bind and detoxify NAPQI.[16] In animal models, NAC also reduces NAPQI back to
acetaminophen,[31] a mechanism that has not been demonstrated in humans. NAC has other less well-
characterized extrahepatic[8][25] and microcirculatory[20] effects. In patients with hepatic failure, NAC
decreases the development of cerebral edema, prevents the progression of hepatic encephalopathy, and
improves survival.[18][27][38] NAC scavenges free radicals and decreases the accumulation of neutrophils in
the injured liver.[25] NAC may also enhance the capacity of the cellular proteolytic enzymes to degrade the
toxic protein–acetaminophen adduct.[8] Treatment with NAC improves cardiac output, hepatic oxygen
delivery, and hepatic oxygen consumption in patients with hepatic failure, possibly by improving
microcirculation. This effect is postulated to be due to increases in the local production and stabilization of
nitrous oxide.[18][20]
Administration
Timely administration of the antidote N-acetylcysteine (NAC) protects the liver from toxic levels of
acetaminophen. With acute overdose, patients who have serum acetaminophen levels above the nomogram
line should receive the first dose of NAC within 8 hours of the ingestion. The first doses should be
administered empirically when diagnostic acetaminophen levels cannot be obtained within this 8-hour
window. NAC therapy can be discontinued if the awaited serum acetaminophen level falls below the
nomogram treatment line.
NAC is effective when administered by both the oral[59][68] and the intravenous (IV)[50][66] routes. A 20-hour
intravenous regimen is used routinely in England and Canada, while a 72-hour oral regimen is used in the
United States, where an approved intravenous formulation is not available. No deaths from hepatic injury
have been reported in patients treated within 8 hours of overdose by either of these regimens. No serious
complications have been reported following the use of oral NAC.[42] In contrast, intravenous NAC has been
shown to cause urticaria, anaphylactoid reactions, and, rarely, death.[40][66][75]
Dose
The standard oral regimen has consisted of a loading dose of 140 mg/kg followed by an additional 17
maintenance doses of 70 mg/kg given every 4 hours. NAC is available in 10 per cent and 20 per cent
formulations. It has a foul sulfurous odor and should be diluted 4:1 in juice or other palatable beverage. Any
dose vomited within 1 hour of administration should be repeated. Patients who continue to vomit during
attempted oral administration of NAC may tolerate slower administration through a nasogastric tube. In
some cases, retention of oral NAC requires the intravenous administration of antiemetics, such as
intravenous metoclopropamide, 10 mg per dose up to 1 to 2 mg/kg (pediatric, 0.1 mg/kg) or intravenous
ondansetron, 0.15 to 0.18 mg/kg every 2 to 4 hours, up to 3 doses (pediatric, 40 kg or less, 0.1 mg/kg; >40
kg, 4 mg). Intravenous administration of the oral solution (in the United States) is an option when other
attempts to administer the antidote have failed. This should be done under the guidance of a medical
toxicologist or regional poison center (see later).
Studies are currently being conducted in the United States to assess the safety of shorter courses of oral
NAC for patients with acute APAP overdose. Treatment continues until the acetaminophen level is
nondetectable and the absence of evidence of liver injury at 24 hours is documented. Patients with evidence
of liver injury are treated for the full 72-hour course. Strict specific clinical guidelines must be followed. A
regional poison center or medical toxicologist may be contacted for information on these shorter protocols.
Use of Intravenous NAC in the United States
Treatment of acetaminophen overdose with intravenous NAC has not been approved in the United States,
and a pyrogen-free formulation is not available. Nevertheless, very severely poisoned patients who cannot
tolerate oral NAC have benefited from intravenous administration of the oral formulation.[66][75] The most
common indication for intravenous use of the oral formulation has been management of the seriously
poisoned patient with intractable vomiting despite nasogastric instillation and adequate antiemetic therapy. It
has also been used in other high-risk cases such as pregnancy and hepatic failure.[66][75] When used for
such high-risk cases, the same dosing protocol as that outlined earlier for the oral preparation is suggested.
The oral NAC solution requires careful preparation to minimize serious complications during intravenous
administration. The intravenous administration of NAC should be undertaken only in consultation with a
medical toxicologist or regional poison center to ensure that the indications for its usage are correct and that
it is administered in the safest possible manner.
The High-Risk Patient

Studies of chronic acetaminophen ingestion that suggest increased risk of toxicity in alcoholics and in fasting
patients with regard to the treatment of the patient with acute acetaminophen are
controversial.[10][38][39][60][67][74] Analysis of two large populations of patients treated for acute ingestions did
not show an association between chronic ethanol use and liver injury. [38][60] A comparison of patients acutely
ingesting APAP with and without a history of ethanol use found that chronic ethanol use was associated with
increased hepatotoxicity when the APAP level was above the “200/probable risk” line or when NAC was
started more than 8 hours postingestion. However, there were no differences in outcome when the APAP
level was “low risk” (below the “200/probable risk” line) or when NAC was started within the first 8 hours.[69]
Based on the current state of knowledge and the lack of controlled studies, we do not recommend routine
deviations from the standard nomogram approach to the treatment of acute ingestions of acetaminophen in
this population.
Other patients who chronically use agents that induce cytochrome P-450 activity, such as sulfonylureas,
rifampin, isoniazid, phenobarbital, phenytoin, primidone, and carbamazepine (see Table 29–2 ), are also
theoretically at increased risk for developing hepatotoxicity following chronic, and possibly acute, ingestion
of acetaminophen.[7][43] Again, while there is no clear evidence to guide a deviation from the use of the
standard nomogram to make treatment decisions in this population of patients following acute ingestions, a
heightened awareness should attend the evaluation of patients who take these agents in combination with
chronic excessive doses of acetaminophen.
Late Presentations of Acetaminophen Poisoning
Patients who present more than 24 hours after an acute ingestion and who have either detectable serum
acetaminophen or transaminase elevation (AST is the first to rise) require treatment. The nomogram cannot
be used for levels drawn more than 24 hours postingestion. For patients in whom no acetaminophen is
detectable and no elevation in serum transaminases has developed 36 hours or more after ingestion, there
is little to no risk of hepatotoxicity, and these patients can be safely discharged.[2] The development of
hepatotoxicity mandates the standard course of treatment.
Acute Cases in Which the Time of Ingestion Is Uncertain
Patients with elevated acetaminophen levels following acute ingestions in whom the time of ingestion cannot
be determined may require empirical therapy. Oral NAC is relatively harmless, so that treatment in uncertain
cases is safe and reasonable. The most conservative (earliest) estimate of the time of ingestion should be
used to determine the likelihood of toxicity.
Chronic Ingestions
The assessment of toxicity and management decisions are not well defined in patients who present with a
history of chronic ingestion of large doses of acetaminophen, usually for the treatment of pain, or inadvertent
overdosage during the treatment of fever in children.[22][54] An acetaminophen level measured during a
period of chronic excessive ingestion has no predictive value. Ingestion of more than 7.5 g in a 24-hour
period (150 mg/kg in children) should be considered potentially toxic.[2] Chronic ingestion of 60 to 420
mg/kg/day, reported retrospectively, has been associated with hepatic injury in children. [22] Patients with no
underlying risk factors and with reliable histories who have ingested less than these amounts may be safely
discharged without laboratory evaluation. They should avoid the use of acetaminophen-containing products
for the next 24 hours. Certain patient populations, such as suicidal adults or adolescents, nutritionally
depleted or fasting patients, ethanol abusers, and patients receiving other inducers of P-450 cytochromes
who have ingested acetaminophen, require further evaluation regardless of the history. The absence of
transaminase elevation in patients with prolonged chronic ingestion suggests that liver injury has not
occurred. Laboratory evidence of hepatotoxicity requires treatment with NAC. An argument can be made for
the treatment of high-risk patients with measurable APAP levels even in the absence of elevation of the
AST. This represents a very conservative approach.
Pregnancy
There is substantial evidence that acetaminophen crosses the placenta and can cause fetal death following
maternal overdose.[53] NAC is effective in treating the pregnant woman and does not harm the fetus.[41] In
keeping with the basic tenet of treating the mother, all pregnant women with toxic overdoses of
acetaminophen should be treated. Studies of cord blood in infants born to women treated for acetaminophen
overdose near term have demonstrated evidence that NAC does cross the placenta. Whether it may prevent
fetal hepatotoxicity is unknown.[23]
Pediatrics
Pediatric patients with acetaminophen poisoning should be evaluated and treated in the same manner as
adults. Although it has been suggested that young children are less likely to develop hepatotoxicity following
acetaminophen ingestion, no studies have clearly proved that they are at lower risk than adults.[59] A number
of reports demonstrate significant hepatotoxicity in children following acute acetaminophen
overdose.[22][34][54] Significant, sometimes fatal, hepatotoxicity has been associated with inadvertent
overdose during chronic administration of acetaminophen to children with acute febrile illness.[21][22][46][54]
The Use of NAC in Fulminant Hepatic Failure
Several British studies have shown that treatment with intravenous NAC reduces mortality in patients with
FHF due to acetaminophen, even when treatment is delayed 48 to 72 hours or longer.[18][20][27][39] These
patients should receive treatment with NAC until their condition stabilizes and the INR is less than 2, which
requires that NAC therapy be extended beyond the conventional 72-hour-regimen duration. The intravenous
administration of NAC may be of greater benefit to patients with FHF than administration via the oral route.
The use of intravenous NAC avoids the hepatic first-pass clearance that occurs with orally administered
NAC and delivers higher serum concentrations to the rest of the body. The administration of prostaglandins,
such as misoprostol or prostacyclin, also appears to be useful in the treatment of FHF,[35] possibly by
improving microvascular circulation.[20]
Liver Transplantation for FHF
Orthotopic liver transplantation may be life-saving for patients with FHF that has resulted from
acetaminophen.[5][45] The criteria for transplantation are better defined for acetaminophen than for most
other causes of FHF ( Table 29–3 ).[45] The most important task of the treating physician is to identify which
patients are at high risk for mortality and arrange their transport to specialty transplant centers before clinical
deterioration precludes the procedure. In many cases, rapid deterioration often results in multiple-organ
failure and death before transplantation can be done.[5] Indications for referral to a transplant center include
an INR greater than 5 or any of the following complications: renal impairment (creatinine >200 µmol/L [2.3
mg/dL]); metabolic acidosis (pH <7.35 or serum bicarbonate <18 mEq/L); hypotension, encephalopathy, or
hypoglycemia.[39] A rising PT on the fourth day after overdose is the single best marker of a poor
prognosis.[19] Indicators of the need for transplantation are listed in Table 29–3 .
Other
Cerebral edema complicating fulminant hepatic failure should be managed with mannitol, but
hyperventilation should be avoided. A study of cerebral blood flow and metabolic rate for oxygen in 30
patients with FHF and grade 4 encephalopathy (20 cases due to acetaminophen hepatotoxicity)
demonstrated significant increases in these parameters in response to mannitol (100 mL of 20 per cent over
10 minutes) and NAC treatments. In contrast, hyperventilation produced significant decreases in both
measurements.[73] Patients with hepatotoxicity may have occult infections that can benefit from parenteral
and enteral antibiotics.[56] In patients with concomitant renal failure, continuous arteriovenous hemofiltration
(CAVHD) is preferable to conventional hemodialysis. In a series of patients, hemodialysis resulted in a
significant increase in mean intracranial pressure (ICP), rising to more than 25 mmHg in 55 per cent of the
treatments. In contrast, no significant increase in mean ICP developed during CAVHD. This difference may
be due to increased osmotic shifts during hemodialysis, with the resulting osmotic gradient causing passage
of water into the brain. [3][14]


DISPOSITION
The final disposition of the patient with acetaminophen ingestion is based on assessment of the risk for or
clinical evidence of hepatotoxicity. Otherwise healthy patients who acutely ingest APAP and have serum
acetaminophen concentrations below the lower nomogram line (see Fig. 29–2 ) require no further treatment
for acetaminophen poisoning. Disposition should be guided by the treatment needs of other medical or
psychiatric problems. Parents of children with acetaminophen exposures may benefit from poison prevention
counseling. Patients with elevated serum acetaminophen concentrations who display no evidence of
hepatotoxicity or who have mild hepatotoxicity can be managed in a nonmonitored setting for supervised
NAC treatment, with appropriate suicidal precautions. Patients with progressive hepatotoxicity or fulminant
hepatic failure require intensive care.


SEQUELAE
Previously healthy patients who survive liver injury and all of its inherent complications generally make a full
recovery without sequelae. [45] In cases of overdose in which treatment is delayed, hepatic damage can be
severe and can result in FHF and death.


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alcohol: Analysis of instances of therapeutic misadventure. Hepatology 1995; 22:767.


Uncited references
Kaplowitz N, Aw TY, Simon FR, et al: Drug-induced hepatotoxicity. Ann Intern Med 1986; 104:826.
Koff R: Viral hepatitis. In: Schiff L, Schiff ER, ed. Diseases of the Liver, 7th ed. Philadelphia: JB
Lippincott; 1993:492-577.
Periera LMMB, Langley PG, Hayllar KM, et al: Coagulation factor V and VIII:V ratio as predictors of
outcome in paracetamol-induced fulminant hepatic failure: Relation to other prognostic indicators.
Gut 1992; 33:89.
Selden BS, Curry SC, Clark RF, et al: Transplacental transport of N-acetylcysteine in an ovine model. Ann
Emerg Med 1991; 20:1069.


Chapter 30 – Salicylates
J. WARD DONOVAN JAWAID AKHTAR
Essentials
• Consider in any patient with an anion gap metabolic acidosis or altered mental status.
• Early signs and symptoms include tachypnea, diaphoresis, hyperpyrexia, vomiting, and tinnitus or
deafness.
• The usual acid-base disturbance is a mixed respiratory alkalosis and metabolic acidosis with alkalemia.
• Salicylate levels correspond poorly to severity of toxicity, and the Done nomogram may significantly
underestimate or overestimate severity of ingestions.
• Presence of altered mental status or agitation reflects severe salicylate toxicity or presence of co-
ingestants with central nervous system (CNS) effects.
• Salicylate toxicity should be considered with any analgesic overdose (acetaminophen [APAP] or
nonsteroidal anti-inflammatory drug [NSAID]).
INTRODUCTION
Since its introduction 100 years ago, aspirin (acetylsalicylic acid) has been widely prescribed and used as an
antipyretic, analgesic, and anti-inflammatory agent. Aspirin is still found in most homes in spite of its
replacement by other NSAIDs and acetaminophen. Aspirin has also found new uses, including prophylactic
therapy for migraine headaches and colon cancer, and as an antiplatelet agent for prevention of
cerebrovascular and coronary ischemia. As a result, acute and chronic poisoning by aspirin is a declining but
still common clinical problem. From 1987 to 1999, aspirin exposures decreased from 16.1 to 7.8 per cent of
all reported analgesic poisonings. Aspirin exposure still accounts for over 16,000 cases and approximately
35 deaths per year reported to U.S. poison centers.[29] Aspirin has a much higher fatality ratio than
acetaminophen or ibuprofen, with 2.1 deaths per 1000 cases versus 1.4 and 0.1 per 1000 for APAP and
ibuprofen, respectively.[29]
In addition to acetylsalicylic acid, other salicylate-containing products are commonly used. These include
liniments containing methyl salicylate and trolamine salicylate, keratolytics containing salicylic acid
(orthohydroxybenzoic acid), sunscreens with homomethyl salicylate, and antidiarrheals with bismuth
subsalicylate. Chinese proprietary medications also often contain salicylates.[9] Aspirin is also found in
combination with antihistamines, decongestants, acetaminophen, caffeine, barbiturates, and opioids. This
can result in a mixed intoxication complicating a salicylate overdose. Two of the serious complications of
aspirin use strike those at the extremes of age: Reye’s syndrome in infants and chronic salicylate toxicity in
the elderly.


Pharmacology
Salicylates produce analgesic, antipyretic, and anti-inflammatory effects. This occurs predominantly through
inhibition of cyclooxygenase, with subsequent decrease in the production of prostaglandins and related
autacoids. Therapeutic doses of acetylsalicylic acid are 10 to 20 mg/kg for children and 650 to 1000 mg
every 4 to 6 hours for adults. This will produce a serum salicylate level of 3 to 6 mg/dL. The potentially toxic
acute dose is greater than 150 mg/kg, with serious toxicity possible when 300 to 500 mg/kg is ingested, or
roughly one adult tablet/kg.[40] Chronic toxicity occurs when more than 100 mg/kg is taken daily, particularly
in infants and the elderly.
Toxic doses for other salicylate formulations can be calculated from aspirin equivalency. Oil of wintergreen
contains 98 per cent methyl salicylate, equivalent to 1400 mg of acetylsalicylic acid per milliliter. Other
methyl salicylate topical preparations may be less concentrated, and their aspirin equivalent dose can be
calculated by their percentage by weight or volume. Bismuth subsalicylate contains 8.77 mg/L of salicylic
acid, and trolamine salicylate cream for osteoarthritis contains 500 mg of salicylate per 10 g.
Absorption of salicylate occurs in the stomach and proximal intestine, and peak levels in therapeutic doses
occur at 1 to 2 hours with standard preparations and 4 to 6 hours for enteric-coated tablets. After overdose,
however, levels may not peak for 10 to 60 hours.[28][45][46] Reasons for delayed absorption include formation
of insoluble concretions, ingestion of coated tablets, contraction of the pylorus, and combination with drugs
that delay gastric emptying, such as opioids and anticholingergics.[26][28][45] Conversely, liquid preparations
of salicylates such as methyl salicylate, bismuth subsalicylate, and liniments are absorbed within 1 hour.
Acetylsalicylic acid is hydrolyzed to salicylate (salicylic acid, or 2-hydroxybenzoic acid) in the intestinal wall,
liver, and red blood cells.[34] Both forms are pharmacologically active, but salicylic acid is the predominant
form in plasma. It, in turn, is metabolized to the inactive forms of salicyluric acid and glycine or glucuronic
acid conjugates. With therapeutic doses, only a small amount is excreted in urine as salicylic acid, but this
greatly increases in toxic doses.
Acetylsalicylic acid is rapidly cleared from the blood, but salicylic acid binds strongly to plasma albumin and
has a low volume of distribution of 0.17 L/kg at therapeutic doses.[26] At high doses, protein binding
becomes saturated and the volume of distribution increases to 0.35 L/kg. [26][34] This higher volume of
distribution results from a higher proportion of free drug at toxic concentrations and greater distribution of
salicylate into tissues. While variable, 50 to 75 per cent of the drug is unbound when tissue concentrations
exceed about 75 mg/dL.[36] Salicylate distribution into tissues is also facilitated as plasma becomes
acidemic and the proportion of nonionized drug increases. The pK a of salicylate is 3.0, so salicylate is
almost all ionized and therefore relatively impermeable to membranes at physiologic pH. As the plasma pH
decreases, the proportion of nonionized salicylate increases and thereby shifts into tissues.[5]
The elimination kinetics of salicylate are dependent on dose, because of the combination of saturable
enzyme mechanisms and the more linear process of urinary excretion. As the drug concentration increases,
the enzymatic first-order elimination processes saturate and become zero-order, resulting in much longer
half-lives (Michaelis-Menton kinetics). There is a decrease in the proportion of salicylate metabolites
excreted, and a corresponding increase in salicylic acid renal excretion. The elimination half-life of salicylate
in therapeutic doses is 4 hours, but it increases to 15 to 29 hours with toxic plasma levels.[26][28]
Pathophysiology
Salicylate directly stimulates the CNS respiratory center in the medulla, resulting in hyperventilation
characterized by an increase in both the depth and rate of respiration. Salicylates also uncouple
mitochondrial oxidative phosphorylation, causing an increase in oxygen consumption and CO2 production.
This further enhances respiratory stimulation, leading to respiratory alkalosis.[46] In compensatory response,
the kidneys excrete bicarbonate as well as sodium and potassium, and this contributes to the metabolic
acidosis. The metabolic acidosis is aggravated by increased pyruvic and lactic acids from inhibition of
mitochondrial respiration. Also, disruption of Krebs cycle metabolism and glycolysis leads to
gluconeogenesis and lipolysis, with increased ketone formation. The salicylate ion itself makes a small
contribution to the resultant anion gap metabolic acidosis.
Dehydration also occurs from hyperpnea, vomiting, and diaphoresis and fever caused by increased skeletal
muscle metabolism. Increased sodium, potassium, and water elimination accompany renal bicarbonate
excretion, aggravating dehydration and hyperlacticemia. Potassium and bicarbonate are depleted, and
hydrogen ions shift to the extracellular space. Inhibition of liver lactate elimination also contributes to
metabolic acidosis.[5]
Salicylates increase permeability of the pulmonary vasculature to fluid and protein, and pulmonary lymph
flow and protein clearance increase.[46] Blockade of the cyclooxygenase metabolic pathway may also lead to
increased arachidonic acid breakdown, resulting in enhanced production of leukotrienes.[27] Leukotrienes
have proinflammatory effects and may also increase microvascular permeability. These mechanisms can
cause noncardiogenic pulmonary edema in the severely toxic patient.
Other physiologic effects include vasoconstriction of the auditory microvasculature, resulting in tinnitus.
Salicylates enhance insulin secretion from pancreatic islet cells and thus can cause hypoglycemia, but they
also decrease peripheral glucose utilization, which can cause hyperglycemia.[26] In addition to
gastrointestinal irritation, salicylates stimulate the medullary chemoreceptor trigger zone to cause nausea
and vomiting.
Hematologic effects include inhibition of platelet aggregation, decrease of factor VII, and
hypoprothrombinemia. In severe cases, hepatotoxicity can result in decreased production of factors II, VII,
IX, and X. Despite this, bleeding disorders and prolongation of the prothrombin time are mild and
uncommon.


Clinical effects of salicylate toxicity depend on the serum level, patient age, and acuity of ingestion. Children
and the elderly are more susceptible to toxicity than adolescents and adults and are likely to develop
metabolic acidosis as the predominant acid-base disturbance.[10][34] Chronic therapeutic misuse in infants
and the elderly is associated with the highest mortality, from both delays in diagnosis and a higher salicylate
concentration in the cerebrospinal fluid. [10][18][32]
The earliest manifestations of salicylate intoxication are usually nausea, vomiting, diaphoresis, tinnitus, and
deafness. Preexisting hearing deficits, common in the elderly, may confound evaluation of the otic
symptoms.[20] These early symptoms occur when serum salicylate levels reach 25 to 30 mg/dL and are
accompanied by hyperventilation. Hyperpyrexia may be seen in children but is rare in adults. As toxicity
worsens, hypotension, noncardiogenic pulmonary edema, oliguria, acidemia, cerebral edema, delirium,
seizures, and coma may supervene ( Table 30–1 ).
Table 30-1 -- Clinical Features ofSalicylate Toxicity

Nausea, vomiting, and epigastric discomfort
Tinnitus and deafness
Sweating, hyperpyrexia, and dehydration
Hyperpnea and tachypnea
Disorientation, hallucinations, lethargy, agitation, coma, and seizures
Renal failure
Acid-base disorders (e.g., respiratory alkalosis, mixed respiratory alkalosis, and anion gap metabolic acidosis)
Hypokalemia and hyponatremia or hypernatremia
Hypoglycemia/hyperglycemia
Hypoprothrombinemia
Serious effects of acetylsalicylic acid toxicity include acid-base disturbances and accompanying electrolyte
abnormalities. The acid-base hallmark of salicylate toxicity is an anion gap metabolic acidosis. A mixed
picture of respiratory alkalosis producing an alkalemic pH with concomitant anion gap metabolic acidosis is
present in most adults with moderate toxicity. In children younger than 4 years of age, metabolic acidosis
and acidemia may predominate.[1] At any age, worsening toxicity can result in acidemia and rapid
distribution of salicylic acid into the crucial tissues of the brain, lung, and heart. This results in
encephalopathy, seizures, noncardiogenic pulmonary edema, and cardiovascular collapse in severe
cases.[37] The development of respiratory acidosis due to CNS depression, pulmonary edema, or co-
ingestants is a particularly grave event.[10] Dehydration is almost always present in salicylate toxicity due to
decreased oral intake, vomiting, tachypnea, diaphoresis, and obligatory early diuresis.[18] Severe
hypokalemia can result from vomiting, intracellular shifts in exchange for hydrogen ions, and urinary losses.
Hypoglycemia often occurs, particularly in children.[41] Even in the normoglycemic state, the cerebrospinal
fluid glucose level has been shown to be reduced.[42]
In addition to tachypnea from direct CNS stimulation, respiratory distress and hypoxia can result from
aspiration or noncardiogenic pulmonary edema. The latter more often occurs in older patients, smokers, and
those with salicylate levels greater than 100 mg/dL, chronic toxicity, acidemia, or CNS involvement.[44]
Purpuric lesions and facial petechiae may be seen, particularly after gastric lavage or repetitive vomiting.
Gastrointestinal bleeding in acute overdose is uncommon despite the presence of mild coagulopathies and
gastritis in overdose.
Neurologic disorders are a manifestation of severe toxicity and are usually associated with acidemia and
cerebral edema. Agitation, confusion, irritability, and restlessness are early findings. This is followed by
lethargy and then coma. Seizures may also occur due to cerebral edema or reduced brain glucose. Co-
ingestion or administration of CNS-depressant drugs increase the risk of respiratory depression, acidemia,
and neurologic complications.[17] Neurologic involvement is more common in those at extremes of age and
in chronic toxicity with delayed diagnosis.[2][18][44]
A clear distinction should be made between the features and severity of acute versus chronic salicylate
toxicity ( Table 30–2 ). Unlike the acute overdose in which the history is usually readily available and
presentation is early, chronic overuse is often not recognized and presentation occurs after the onset of
severe effects.[40] In chronic cases, tissue salicylate levels are disproportionately greater due to systemic
acidosis, chronicity of exposure, and later presentation.[2][18][19] Salicylate levels cannot be reliably correlated
to severity, and levels as low as 30 to 40 mg/dL can be life threatening.[3]
Table 30-2 -- Differential Characteristics of Acute and Chronic Salicylism

Features Acute Chronic
Age Young adult Older adult/infants
Etiology Overdose Therapeutic misuse
Co-ingestants Frequent Rare
Past history Previous overdose or psychotherapy Concomitant medical
problems/chronic pain
Presentation Early Late
Dehydration Moderate Severe
Mental status Normal (unless co-ingestants or central nervous system Altered
(initial) toxicity has developed)
Serum
40 to =120 mg/dL 30 to =80 mg/dL
concentration
Mortality Low with appropriate therapy High
Aseptic meningitis, pseudosepsis, and a systemic inflammatory response syndrome have all been reported
as consequences of salicylate intoxication.[7][8][33] These are direct manifestations of salicylate toxicity and
can resolve with decline of tissue burden. Hepatotoxicity and Reye’s syndrome have been reported in both
acute and chronic salicylate use but resolve shortly after salicylates are withdrawn.[19][39]


Salicylate toxicity should be considered in all cases with a history of analgesic overdose, owing to patient
confusion about ingredients and combination products. Serum quantification should be obtained in these
cases for both acetaminophen and salicylate. NSAID toxicity can be established by the presence of renal
failure and/or metabolic acidosis, but assays are not usually available. In the absence of either a history of
analgesic ingestion or an anion gap metabolic acidosis, universal screening of all overdose patients for
salicylates has been shown to be unnecessary.[9][38]
Salicylate toxicity must also be considered in every patient presenting with an anion gap metabolic acidosis
and differentiated from other causes of this metabolic disorder ( Table 30–3 ). This includes poisonings from
acetaminophen, isoniazid, iron, NSAIDs, methanol, ethylene glycol, metformin, phenformin, and metabolic
toxins such as carbon monoxide, cyanide, and methemoglobin inducers. These toxic causes can usually be
determined by serum quantification. Cyanide diagnosis is by history and clinical condition. One common
interrelated group of conditions causing an anion gap metabolic acidosis are diabetic, alcoholic, and
starvation ketoacidosis. These can be diagnosed by the presence of serum acetone and/or urine ketones,
altered serum glucose, and history of alcohol abuse or dietary deficiency. Any condition causing an elevated
lactate level such as sepsis, shock, cellular toxins, and hepatic failure can cause an anion gap metabolic
acidosis, so a serum lactate level should be ordered. Finally, salicylate toxicity is often misdiagnosed in the
elderly on chronic salicylate therapy and instead mistaken for altered mental status from sepsis, meningitis,
or senile dementia.[2][3]
Table 30-3 -- Differential Diagnosis ofSalicylate Toxicity

Diabetic ketoacidosis, alcoholic ketoacidosis
Drug ingestion: acetaminophen, isoniazid, iron, ibuprofen, paraldehyde, metformin, phenformin, quinine
(cinchonism)
Toxic exposures: methanol, ethylene glycol, carbon monoxide, cyanide
Reye’s syndrome
Encephalopathy
Meningitis
Senile dementia
Acute or chronic renal failure
Systemic inflammatory response syndrome
Sepsis
Shock


LABORATORY STUDIES
Peak salicylate levels do not typically occur until at least 4 to 6 hours after ingestion and may be delayed
even longer due to salicylate-induced pyloric stenosis, gastric outlet obstruction, bezoar formation, or
pylorospasm.[21] Enteric-coated aspirin preparations or generic forms also can dissolve slowly and delay
peak levels.[45] Serial salicylate levels should be obtained immediately and then at least every 2 to 4 hours
until clearly decreasing. Levels can then be followed every 4 to 6 hours until less than 30 mg/dL. There is a
variability in the units used among different laboratories when reporting salicylate levels. One needs to
confirm the units (mg/dL vs. mg/L) before deciding on the presence of toxicity and need for further action.
The Done nomogram is no longer recommended to predict severity of salicylate toxicity. Its original use was
limited to acute ingestions of regular aspirin by children with normal mental status and normal serum pH.[14]
Recent studies question the accuracy and predictability of this nomogram. [15][31] Severity of toxicity should
be determined by the combination of serial plasma salicylate levels, acid-base status, acuteness of
ingestion, and mental status, rather than by the Done nomogram.
Bedside tests can be used to determine the presence of salicylates in urine, although they are of no
quantitative value, and false-positive results can occur. In the ferric chloride test, a few drops of 10 per cent
ferric chloride (Trinder’s reagent) are added to 1 mL of urine. A purple or brown color indicates the presence
of salicylic acid, acetoacetic acid, or phenylpyruvic acid. This qualitative test needs to be followed by serum
salicylate quantification. The Ames Phenistix can also be used to detect urine salicylates, but the positive
brown color can also indicate the presence of phenothiazines. The addition of 1 drop of concentrated sulfuric
acid differentiates the two by washing out the color if the cause is a phenothiazine.
Additional laboratory tests should include electrolyte and glucose determination, renal and liver function
tests, coagulation profile, and arterial blood gases in the presence of acidosis. Electrolytes should be
rechecked every 4 to 6 hours during therapy. An acetaminophen level is advisable if there is uncertainty
about which analgesic has been ingested. A chest radiograph is indicated to rule out the presence of
noncardiogenic pulmonary edema or aspiration pneumonitis. When the diagnosis is uncertain, other studies
should be considered, such as head CT, blood cultures, serum ketones, lumbar puncture, serum osmolality,
serum iron, and carboxyhemoglobin levels.


TREATMENT
Decontamination
Initial therapy for salicylate toxicity includes gastrointestinal decontamination and correction of fluid,
electrolyte, and acid-base disturbances ( Table 30–4 ). Decontamination is indicated in suicide attempts and
in ingestions of greater than 150 mg/kg in children, or for unknown amounts. [40] Activated charcoal has
become the mainstay of decontamination therapy.[12][46] Ipecac-induced emesis is still used for accidental
ingestions in children at home, but it is possible that activated charcoal available over-the-counter in
pharmacies may replace ipecac. Large-bore gastric lavage may be indicated in large acute overdoses
presenting within an hour after the dose. Whole-bowel irrigation effectively decreases absorption of enteric-
coated aspirin, but it is unknown whether it is superior to repeated doses of activated charcoal.[25][30]
Table 30-4 -- Treatment of Salicylate Toxicity

Gastric Lavage
Only for a large and potentially life-threatening ingestion (30–60 g) within an hour of ingestion. Do not use for
chronic ingestion.
Activated Charcoal
1 g/kg PO initially. Repeat doses at 2 to 4 hours of 25 g, or 0.5 g/kg.
Hydration and Electrolyte Imbalance
Initially 1 to 2 L normal saline (10–20 mL/kg in children).
Correct hypokalemia aggressively.
Urinary Alkalinization
1–2 mEq/kg of NaHCO3 bolus intravenously, then 850 mL of D5W with 150 mL of 8.4% NaHCO3 and infuse at
250 mL/hr (1.5 to 2 times maintenance fluid rate).
Add 20–40 mEq potassium to each liter of fluid. Adjust dose for renal dysfunction.
Exercise caution in chronic toxicity and in the elderly because of the risk of noncardiogenic pulmonary edema.
Monitor urine and serum pH.
Hemodialysis Indications
Serum levels greater than 100 mg/dL in acute ingestion
Serum levels higher than 60 mg/dL in chronic intoxication
Pulmonary edema
Renal failure
Nonresponse to standard therapy
Altered mental status and acidemia
Multiple doses of activated charcoal have been used to both decrease absorption and enhance elimination
of salicylates.[4][6][22][43] Because of delayed or prolonged absorption in some cases, or desorption of
salicylate from charcoal during intestinal passage, at least one additional dose of charcoal is warranted after
initial decontamination.[4][13][16] Multiple-dose activated charcoal does not significantly enhance elimination if
urinary alkalinization is also employed, but it is uncertain whether multiple-dose activated charcoal alone
increases elimination.[6][11][24][30] The initial charcoal dose should be 1 g/kg body weight, followed by 25 g
every 2 to 4 hours for subsequent doses (0.5 g/kg in children to maximum 25 g).
Fluids/Alkalinization
Fluid resuscitation should be aggressive, performed with initial boluses of 10 to 20 mL/kg of intravenous
normal saline. This should be given until a good urine output of 1 to 3 mL/kg/hr is maintained. This may
require 2 to 4 liters in adults and is well tolerated in healthy adolescents and adults. In the elderly and those
with cardiac or renal disease, invasive hemodynamic monitoring may be necessary in severe toxicity to
monitor volume status. Patients with altered mental status should receive a bolus of 50 per cent dextrose
even if normoglycemic, and arterial blood gas analysis should be performed in these patients.[42] Acidemia
must be vigorously corrected with 1 to 2 mL/kg of sodium bicarbonate initially to prevent shifts of non-ionized
salicylate into the brain and lungs.
Urinary alkalinization enhances salicylate elimination and should be used when salicylate levels are greater
than 40 mg/dL in acute ingestions and 30 mg/dL in chronic cases. In toxic states, renal elimination of
salicylic acid increases and assumes greater importance in drug elimination. Alkalemia is not a
contraindication to bicarbonate therapy, because most patients still have a significant base deficit, but the
serum pH should be monitored and kept below 7.55.[46] Increasing the urine pH to 7.5 or greater will
increase salicylate excretion severalfold by trapping ionized salicylate in the proximal tubule and preventing
reabsorption.[35] Urinary alkalinization can be achieved by adding 150 mL of NaHCO 3 (44 mEq/50 mL) to
850 mL of D5W and infusing at 250 mL/hr (one and one-half to two times maintenance fluid rate for
children). This method is as effective as using larger fluid amounts to initiate a forced diuresis, but it avoids
the likelihood of fluid overload and pulmonary or cerebral edema, even in the elderly with chronic toxicity.[36]
In patients with myocardial dysfunction the infusion rate may need to be decreased. Alkalinization and fluid
resuscitation may exacerbate pulmonary and cerebral edema. Hypovolemia and hypokalemia impede
urinary alkalinization by decreasing glomerular filtration rate and bicarbonate excretion, respectively.[46]
Hypokalemia also results in the exchange of potassium for hydrogen ions in the distal renal tubule, resulting
in decreased urinary pH in the collecting duct. In salicylate toxicity, salicylic acid is also reabsorbed in the
collecting duct by simple diffusion, a passive process that increases as the urinary pH decreases, thus
increasing the non-ionized form of salicylic acid. Thus, hypokalemia can result in decreased urinary
elimination of salicylic acid.[10a] Volume deficit should be corrected initially, and 40 mEq of potassium
chloride should be included in each liter of the intravenous fluid. The amount of potassium infused would
depend on the status of renal function. Difficulty may still occur in achieving an alkaline urine in some
patients even in the presence of normovolemia and normokalemia.[36]
Urine pH and output should be monitored hourly, and serum electrolytes and salicylate levels obtained every
4 hours until symptoms have resolved and levels are less than 30 mg/dL. Common pitfalls include failure to
administer adequate fluids and NaHCO 3 or to maintain a urine output of 1 to 2 mL/kg/hr with a urine pH of
7.5 to 8.0. If urine output is inadequate after fluid resuscitation and fluid overload is a concern, diuretics may
be needed, particularly in the elderly or those with cardiac or renal dysfunction. In this subset of patients,
fluid and bicarbonate therapy needs to be carefully monitored to prevent fluid overload. Hemodialysis should
be considered early in the management of such patients.
Airway
Patients who develop agitation, seizures, coma, or respiratory failure may require sedation, paralysis, and
intubation with mechanical ventilation. A common pitfall after intubation is failure to perform mechanical
hyperventilation to maintain a respiratory alkalosis. [46] This failure results in a predominant metabolic
acidosis and acidemia, which in turn causes an increase in the proportion of nonionized serum salicylate
and subsequent shifts of drug into the CNS. Rapid deterioration and death can be the consequence. Serial
arterial blood gases during this stage of therapy are essential, with a goal of maintaining a serum pH of 7.40
to 7.50 and a PCO2 of 25 to 30 mmHg.
Extracorporeal Elimination
This is indicated for high serum salicylate levels (greater than 100 mg/dL in acute ingestions and 60 mg/dL
in chronic toxicity), intractable acidosis, renal failure, pulmonary edema, or CNS disturbances such as
confusion, disorientation, stupor, coma, or seizures. Hemodialysis is the method of choice because it
corrects both the acid-base and electrolyte abnormalities as well as effectively clearing salicylate.[10][31]
Hemoperfusion also effectively clears salicylate but does not offer the other advantages and has greater
complications.[10][23] Peritoneal dialysis and hemofiltration are not as effective and should be used only if
hemodialysis is not available. The endpoints of dialysis include correction of any abnormalities and a
salicylate level of less than 30 mg/dL.


DISPOSITION
Patients with ingestions greater than 150 mg/kg or suicidal ingestions should be seen in an emergency
department and hydrated after initial decontamination. For the purposes of medically clearing a patient, at
least two serial salicylate levels should be obtained. The final level should be obtained a minimum of 3 to 4
hours after the preceding level. If the second, or final, level is declining and is less than 30 mg/dL with
minimal or no symptoms, the patient may be discharged or referred for psychiatric counseling. Symptomatic
patients or those with levels greater than 30 mg/dL should be admitted or have prolonged treatment in the
emergency department. Patients with salicylate levels persistently above 40 mg/dL, or with metabolic
acidosis or CNS, pulmonary, or renal effects, should be admitted and a regional poison center contacted.
Referral or transfer to a medical toxicologist is appropriate for patients who are severely toxic or at extremes
of age or in whom supportive measures have not been successful and extracorporal elimination is being
considered.[32][46]


SEQUELAE
There are no long-term sequelae from direct drug effects for survivors of acute or chronic salicylate toxicity.


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BMJ 1985; 291:1492.
23. Jacobsen D, Wiik-Larsen E, Bredesen JE: Haemodialysis or haemoperfusion in severe salicylate

poisoning. Hum Toxicol 1988; 7:161-163.
24. Johnson D, Eppler J, Giesbrecht E, et al: Effect of multiple-dose activated charcoal on the clearance of
high-dose intravenous aspirin in a porcine model. Ann Emerg Med 1995; 26:569-574.
25. Kirshenbaum LA, Mathews SC, Sitar DS, et al: Whole bowel irrigation versus activated charcoal in
sorbitol for the ingestion of modified release pharmaceuticals. Clin Pharmacol Ther 1989; 46:264-271.
26. Krause DS, Wolf BA, Shaw LM: Acute aspirin overdose: Mechanisms of toxicity. Ther Drug
Monit 1992; 14:441-451.
27. Lee TH: Mechanisms of aspirin sensitivity. Am Rev Respir Dis 1992; 145:534-536.
28. Levy RI: Overwhelming salicylate intoxication in an adult. Arch Intern Med 1967; 119:399-402.
Poison Control Centers. Am J Emerg Med 1999; 17:435-487.
30. Mayer AL, Sitar DS, Tenenbein M: Multiple-dose charcoal and whole-bowel irrigation do not increase
clearance of absorbed salicylate. Arch Intern Med 1992; 152:393-396.
31. McGuigan MA: Death due to salicylate poisoning in Ontario. Can Med Assoc J 1986; 135:891-894.
32. McGuigan MA: A two-year review of salicylate deaths in Ontario. Arch Intern Med 1987; 147:510-512.
33. Nair J, Stacy M: Aseptic meningitis associated with salicylate overdose [letter].
Psychosomatics 1993; 34:372.
34. Notarianni L: A reassessment of the treatment of salicylate poisoning. Drug Safety 1992; 7:292-303.
35. Prescott LF, Balali-Mood M, Critchley JAJH, et al: Diuresis or urinary alkalinization for salicylate
poisoning?. BMJ 1982; 285:1383-1386.
36. Prescott LF, Critchley JAJH, Proudfoot AT: Diuresis or urinary alkalinization for salicylate poisoning?.
BMJ 1983; 286:147.
37. Ralston M, Pearigen PD, Ponaman ML, et al: Transient myocardial dysfunction in a child with salicylate
toxicity. J Emerg Med 1995; 13:657-659.
38. Sporer KA, Khayam-Bashi H: Acetaminophen and salicylate serum levels in patients with suicidal
ingestion or altered mental status. Am J Emerg Med 1996; 14:443-447.
39. Starko KM, Mullick FG: Hepatic and cerebral pathology findings in children with fatal salicylate
intoxication: Further evidence for a causal relation between salicylate and Reye’s syndrome.
Lancet 1983; 1:326-329.
40. Temple AR: Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern
Med 1981; 141:364-369.
41. Thisted B, Krantz T, Strom J, et al: Acute salicylate self-poisoning in 177 consecutive patients treated in
ICU. Acta Anaesthesiol Scand 1987; 31:312-316.
42. Thurston JH, Pollock PG, Warren SK, et al: Reduced brain glucose with normal plasma glucose in
salicylate poisoning. J Clin Invest 1970; 49:2139-2145.
43. Vertrees JE, McWilliams BC, Kelly HW: Repeated oral administration of activated charcoal for treating
aspirin overdose in young children. Pediatrics 1990; 85:594-598.
44. Walters JS, Woodring JH, Stelling CB, Rosenbaum HD: Salicylate-induced pulmonary edema.
Radiology 1983; 146:289-293.
45. Wortzman DJ, Grunfeld A: Delayed absorption following enteric coated aspirin overdose. Ann Emerg
Med 1987; 16:434-436.
46. Yip L, Dart RC, Gabow PA: Concepts and controversies in salicylate toxicity. Emerg Med Clin North
Am 1994; 12:351-364.


Chapter 31 – Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
FRANK P. PALOUCEK KEVIN O. RYNN
Essentials
• Most NSAID exposures result in mild and nonspecific gastrointestinal-related symptoms such as
nausea, vomiting, abdominal tenderness, and abdominal pain.
• Rare NSAID-induced toxicities include acute renal failure, acute hepatitis, seizures, coma, or aseptic
meningitis.
• An anion gap metabolic acidosis predominantly occurs with massive ingestions of arylpropionic acid
NSAIDs and nabumetone.
In 1999, 72,403 poison exposures to NSAIDs were reported by the American Association of Poison Control
Centers Toxic Exposure Surveillance System.[32][35] Of these, 73 per cent were attributed to ibuprofen and 1
per cent to indomethacin. There were 1492 (2.1 per cent) exposures classified as resulting in moderate
toxicity and 203 (0.3 per cent) as severe toxicity. Nine deaths were attributed to these agents. Currently, 18
agents are marketed in the United States. Three of these, ibuprofen, naproxen, and ketoprofen, are
available over the counter.
Pharmacology
The NSAIDs are typically classified by chemical structure into five organic acid derivatives and the alkanone
nabumetone. The five organic acid families are (1) indole/indene acetic acids (etodolac, indomethacin, and
sulindac); (2) heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac); (3) arylpropionic acids (ibuprofen,
naproxen, flurbiprofen, ketoprofen, oxaprozin, and fenoprofen); (4) anthranilic acids (mefenamic acid and
meclofenamate); and (5) enolic acids: (a) oxicams (piroxicam) and (b) pyrazolidinediones (phenylbutazone).
This structural classification is not useful toxicologically because the groups are not mutually exclusive for
any specific adverse event.[12][21][23][31][33][39][40][41][43][44]
As a general rule, all NSAIDs undergo hepatic metabolism and exhibit extensive plasma protein binding. For
most agents the unchanged parent compounds and metabolites are predominantly eliminated by the
kidneys and have short elimination half-lives (< 6 hours). The short elimination half-life has significant
implications toxicologically, because competitive inhibition of prostaglandin synthesis and the resultant
effects last only as long as the drug itself. The benefit from a short elimination half-life depends on adequate
renal function; renal insufficiency enhances the probability for chronic toxicity by prolonging drug elimination.
From a treatment standpoint, the short elimination half-lives coupled with extensive protein binding result in
minimal benefits for elimination-enhancing therapies, such as hemodialysis, hemoperfusion, or multiple-
dose activated charcoal. This does not preclude potential benefits from these therapies should elimination
half-life be prolonged, saturation of protein binding occur, or supportive management of specific
manifestations (severe acidosis) be needed. A few NSAIDs, however, have long elimination half-lives:
nabumetone (24 hours), naproxen (9–20 hours), oxaprozin (42–50 hours), phenylbutazone (50–65 hours),
and piroxicam (30–90 hours). These agents undergo enterohepatic recirculation, which contributes to the
prolonged elimination half-life. This provides possible justification for multiple-dose activated charcoal
therapy, although the benefit of this therapy has not been studied. Additionally, the presence and extent of
enterohepatic recirculation correlates with chronic intestinal toxicity.
The extensive and competitive nature of plasma protein binding by NSAIDs results in several significant
drug interactions.[5][18][44] Clinically relevant toxicities of methotrexate, sulfonylureas, and warfarin occur after
these drugs are displaced by the NSAIDs from plasma protein binding sites. Also, NSAIDs
pharmacodynamically interfere with and blunt the antihypertensive effects of thiazide diuretics, beta-
adrenergic receptor antagonists, or angiotensin-converting enzyme inhibitors. [14]
Pathophysiology
NSAIDs, except nabumetone, are organic acids that inhibit the synthesis and release of prostaglandins by
reversible, competitive inhibition of cyclooxygenase activity. Among the older NSAIDs, NSAIDs, except
nabumetone, inhibit cyclooxygenase-1, the cyclooxygenase isoform that is the initial enzyme in the
prostaglandin synthetic pathway. Cyclooxygenase-1 is found in blood vessels, stomach, and kidney, hence
the occurrence of gastrointestinal or renal adverse effects seen in acute or chronic exposure settings.
Gastrointestinal adverse effects result from decreased production of the cytoprotective prostaglandins I 2 and
E2, with subsequent local tissue damage and bleeding. Severe adverse renal effects may partly be due to
inhibition of renal prostaglandin-mediated compensatory responses to diminished renal blood flow, resulting
in vasoconstriction, further decreased renal blood flow, and decreased glomerular filtration rate.[11] This
toxicity generally does not occur in adequately hydrated, healthy persons with normal renal function.
Nabumetone is an exception. It is not an organic acid, and it selectively inhibits cyclooxygenase-2 (normal
production induced by cytokines and inflammatory mediators). It is an alkanone that is converted to an acetic
acid derivative in vivo; thus, it can produce an anion gap metabolic acidosis in large ingestions, as do some
arylpropionic acid NSAIDs. However, nabumetone’s selective inhibition of cyclooxygenase-2 results in
decreased adverse gastrointestinal adverse effects. Some NSAIDs are nonselective inhibitors of both
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Newer COX-2 inhibitors are discussed below.
NSAIDs also interfere with prostaglandin-mediated platelet aggregation through inhibition of cyclooxygenase
and subsequent inhibition of thromboxane A2 (TXA2) synthesis. TXA2 causes vasoconstriction and
enhances platelet aggregration. Thus, inhibition of TXA2 production may lead to increased bleeding times as
well as bleeding complications. The hypersensitivity reactions seen and shared by NSAIDs may be related
to diversion of arachidonic acid metabolism from cyclooxygenase-mediated pathways to lipooxygenase-
mediated pathways, as suggested by research with zileuton. [24]


Most exposures result in mild and nonspecific symptoms primarily gastrointestinal in origin ( Table 31–1
). [4][7][12][21][24][33][39][40][41][43][44] Nausea, vomiting, abdominal tenderness, and abdominal pain are
associated with both acute and chronic exposure to NSAIDs.[41] Gastrointestinal ulceration and bleeding are
more commonly associated with chronic ingestion of NSAIDs.[4][6][9][10][12][13][19][21][23] NSAIDs can cause
esophageal ulceration, gastric petechiae, macroscopic erosions, intramucosal bleeding, and peptic
ulceration.[41][42] In the small intestine, NSAID therapy is associated with enteropathy, perforation, ulceration,
and strictures.[4][37] NSAIDs are also associated with colitis, appendicitis, colonic bleeding and perforation,
and diverticulitis and can exacerbate inflammatory bowel disease.[4] The more significant gastrointestinal
manifestations—ulceration and perforation—are predominantly due to chronic exposures, are idiosyncratic,
and are associated with a marked age-related mortality.[4]
Table 31-1 -- Clinical Presentation of NSAID Toxicity

Acute Chronic
Gastrointestinal Abdominal pain, nausea, bleeding, vomiting Enteropathies, gastritis
Central Nervous
Coma, confusion, dizziness, seizures, tinnitus Psychosis
System
Anion gap acidosis (arylpropionic acids,
Metabolic Neutropenia
nabumetone)
Interstitial nephritis, papillary
Renal Azotemia, acute renal insufficiency
necrosis
Elevation of transaminases,
Hepatic Elevation of transaminases
hepatic failure
Aseptic meningitis, asthma exacerbation,
Hypersensitivity Stevens-Johnson syndrome
necrotizing fasciitis, rash
Gynecologic Tocolysis
Dermal Facial scarring
Acute renal insufficiency, acute tubular necrosis, and acute interstitial nephritis have all been associated with
NSAID use. These effects are seen in either acute or chronic exposure.[1][16][23][27][28][39][40][43] Patients at
highest risk include the elderly, dehydrated patients, and patients with renal insufficiency, congestive heart
failure, or ascites secondary to cirrhosis. These effects can occur with normal therapeutic doses, although a
chronic manifestation, histologically characterized by renal papillary necrosis, is usually associated with
excessive analgesic use. Rarely, hepatotoxicity has occurred with chronic use or acute overdose of NSAIDs;
this is probably an idiosyncratic metabolic event. [2][29][36] Dizziness, drowsiness, lethargy, confusion, blurred
vision, nystagmus, diplopia, ataxia, coma, headache, muscle fasciculations, tinnitus, hallucinations, and
seizures have been reported with acute overdose.[5][21][23][43] Idiosyncratically, acute NSAID use can result in
symptoms and cerebrospinal fluid findings consistent with aseptic meningitis.[20][21][22][33] Symptoms usually
occur within hours of the first dose or early in a course of treatment and resolve within a few days of drug
discontinuation. The occurrence is more common in young adults with underlying collagen vascular disease
receiving either naproxen, sulindac, tolmetin, or ibuprofen.[33] Decreased platelet aggregation, aplastic
anemia, thrombocytopenia, and hemolytic anemia have been reported with the NSAIDs, primarily as
idiosyncratic events. Other manifestations include an anion gap metabolic acidosis, apnea, hypotension,
tachycardia, allergy, and anaphylaxis.[46] The anion gap acidosis is predominantly reported with the
arylpropionic acid NSAIDs and nabumetone. Whether this is due to acid metabolites or other factors has not
been determined. There are no significant variations or peculiarities to separate acute pediatric from adult
overdoses, but there are pediatric peculiarities to note. Therapeutic use of NSAIDs in pediatric patients can
be associated with development of necrotizing fasciitis,[3][6] and chronic use may predispose to facial
scarring.[45] NSAID use in pregnant women has been associated with neonatal renal failure.[27]


A critical factor in reviewing the differential diagnoses listed in Table 31–2 is to recognize the ubiquity of
prostaglandins throughout the body and the general nonspecificity of most symptoms of exposure. More
specifically, for acute overdoses, the clinician must recognize the similarity of acute NSAID overdosage to
salicylate ingestion, which can have a significantly poorer prognosis, and the potential for concomitant
acetaminophen exposure.[17] Severe acute idiosyncratic toxicity with therapeutic doses occurs, and any
recent exposure to NSAIDs warrants their inclusion in the differential diagnosis. Finally, serious
gastrointestinal pathology and/or renal insufficiency can occur with chronic use.
Table 31-2 -- Differential Diagnosis ofAcute NSAID Toxicity

Acute NSAID Overdose
Other ingestants
Abrin (rosary pea)
Acetaminophen
Alcohols
Carbon monoxide
Colchicine
Cyanide
Ethylene glycol/methanol (with acidosis)
Isoniazid
Lead
Opiates
Ricin (castor bean)
Salicylates
Ticlodipine
Gastrointestinal disease
Bleeding disorders
Gastric
Intestinal
Colonic strictures
Small bowel disease
Infections
Acute NSAID Overdose
Gastric
Pulmonary


LABORATORY STUDIES
Initial testing should include serum electrolytes, complete blood cell count, serum acetaminophen
concentration, and a pregnancy test, if appropriate ( Table 31–3 ).[23][40][43] In symptomatic patients check
acid-base status with either serum electrolytes or arterial blood gas analysis and measure a serum salicylate
level. Serum concentration for specific NSAIDs is generally not available nor useful.[25] A nomogram for
ibuprofen has been proposed, but its use is limited by limited test availability and unproven benefit.[34]
Table 31-3 -- Essentials of Treatment of NSAID Toxicity

General Treatment Guidelines
Stabilization, ABCs, supportive care
Gastrointestinal decontamination
Single-dose activated charcoal: 15–25 g in children; 50–100 g in adults
Multiple-dose activated charcoal for specific agents: piroxicam, nabumetone, naproxen, and sulindac
Laboratory Studies
Serum electrolytes, complete blood cell count, acetaminophen level
Pregnancy testing in female of child-bearing age
In symptomatic patients check acid-base status with either serum electrolytes or arterial blood gases and
measure a serum salicylate level.
Admission Criteria
Onset or continuation of significant symptoms; refractory metabolic acidosis, central nervous system
depression, acute renal failure, other target end-organ damage
Poor home environment and/or follow-up
Suspected child abuse
Continued suicidal ideation


TREATMENT
General supportive care, evaluation, and gastrointestinal decontamination with activated charcoal are
indicated (see Table 31–3 ). Multiple-dose activated charcoal may be indicated for enhanced elimination of
piroxicam and the enterohepatically recirculated drugs: nabumetone, naproxen, and sulindac.[15][30][33]
However, no evidence predicts or suggests any elimination benefit from multiple-dose activated charcoal,
nor from hemodialysis/hemoperfusion, especially given the general good prognosis associated with these
agents as sole ingestants.
Unusual complications such as seizures should be treated with standard therapies.


DISPOSITION
Patients with few or no symptoms should be observed in the emergency department for 4 to 6 hours for
progression of toxicity. They can be discharged if the toxicity resolves and they are not suicidal. Patients
should be admitted for any of the following reasons: (1) inadequate environment/observation for appropriate
follow-up, (2) suicidal ideation, or (3) onset or continuation of significant metabolic acidosis, central nervous
system depression, renal insufficiency, or other target end-organ damage. Additionally, pediatric patients
may also be admitted for suspected child abuse. Admission should otherwise be for management of
persistent severe signs or symptoms or for complications from co-ingestants.
Appropriate psychiatric evaluation or referral should be made for suicide attempts.


SEQUELAE
Generally, the magnitude of acute renal insufficiency from acute NSAID overdose has rarely required
hemodialysis or other extracorporeal modalities. It resolves spontaneously with or without specific treatment
measures, although follow-up has usually been limited to hospital stays and defined by normalization or
significant improvement in serum creatinine values.


SPECIAL SITUATIONS
COX-2 Inhibitors
Celecoxib and rofecoxib selectively inhibit COX-2, compared to COX-1. With selective inhibition of
cyclooxygenase activity (COX-2) at inflammatory sites, fewer adverse gastrointestinal and renal effects are
expected. This selectivity may be lost with large ingestions. No cases of poisoning from these drugs have
been reported; in overdose patients, clinical effects similar to those of the nonselective NSAIDs may occur.


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Med 1995; 155:211-212.
2. Banks AT, Zimmerman HJ, Ishak KG, et al: Diclofenac-associated hepatotoxicity: Analysis of 180 cases
reported to the Food and Drug Adminsitration as adeverse reactions. Hepatology 1995; 22:820-827.
3. Bigby M, Stern R: Cutaneous reactions to nonsteroidal anti-inflammatory drugs: A review. J Am Acad

Dermatol 1985; 12:866-876.
4. Bjarnason I, Macpherson AJS: Intestinal toxicity of non-steroidal anti-inflammatory drugs. Pharmacol

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5. Bright TP, McNulty CJ: Suspected central nervous system toxicity from inadvertent nonsteroidal
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6. Browne BA, Holder EP, Rupnick L: Nonsteroidal anti-inflammatory drugs and necrotizing fasciitis. Am J
Health-Syst Pharm 1996; 53:265-269.
7. Butt JH, Barthel JS, Moore RA: Clinical spectrum of the upper gastrointestinal effects of nonsteroidal
antiinflamatory drugs. Am J Med 1988; 84(Suppl 2A):5-14.
9. Chan TYK: Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs:
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10. Chan TYK, Critchley AJH: Usage and adverse effects of Chinese herbal medicines. Hum Exp
Toxicol 1996; 15:5-12.
11. Ciabattoni G, Boss AH, Patrignani P, et al: Effects of sulindac on renal and extrarenal eicosanoid
synthesis. Clin Pharmacol Ther 1987; 41:380-383.
12. Court H, Volans G: Poisoning after overdose with nonsteroidal anti-inflammatory drugs. Adverse Drug
React Acute Poison Rev 1984; 3:1-21.
13. Estes LL, Fuchs DW, Heaton AH, et al: Gastric ulcer perforation associated with use of injectable
ketorolac. Ann Pharmacother 1993; 27:42-43.
14. Feenstra J, Grobbee DE, Mosterd A, et al: Adverse cardiovascular effects of NSAIDs in patients with
congestive heart failure. Drug Safety 1997; 17:166-180.
15. Ferry DG, Gazeley LR, Busby WR, et al: Enhanced elimination of piroxicam by administration of
activated charcoal or cholestyramine. Eur J Clin Pharmacol 1990; 39:599-603.
16. Fong J, Gora ML: Reversible renal insufficiency following ketorolac therapy. Ann
17. Fowler PD: Aspirin, paracetamol, and non-steroidal anti-inflammatory drugs. Med Toxicol 1987; 2:338-
366.
18. Frazee LA, Reed MD: Warfarin and nonsteroidal antiinflammatory drugs: Why not?. Ann
Pharmacother 1995; 29:1289-1291.
19. Gertner E, Marshall PS, Filandrinos D, et al: Complications from the use of Chinese herbal medications
containing undeclared prescription drugs. Arthritis Rheum 1995; 5:614-617.
20. Greenberg GN: Recurrent sulindac-induced aseptic meningitis in a patient tolerant to other nonsteroidal
anti-inflammatory drugs. South Med J 1988; 81:1463-1464.
21. Hoppmann RA, Peden JG, Ober SK: Central nervous system side effects of non-steroidal anti-
inflammatory drugs. Arch Intern Med 1991; 151:1309-1313.
22. Horn AC, Jarrett SW: Ibuprofen-induced aseptic meningitis in rheumatoid arthritis. Ann
Pharmacother 1997; 31:1009-1011.
23. Insel PA: Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of
gout. In: Hardman JG, Limbird LE, Molinoff PB, et al ed. Goodman and Gilman’s The Pharmacologic Basis
of Therapeutics, 9th ed. New York: McGraw-Hill; 1996:617-657.
24. Israel E, Fischer AR, Rosenberg MA, et al: The pivotal role of 5-lipoxygenase by zileuton in the reaction
of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis 1993; 148:1447-1451.
25. Joseph R, Dickerson S, Willis R, et al: Interference by nonsteroidal anti-inflammatory drugs in EMITd
TDx assays for drugs of abuse. J Analyt Toxicol 1995; 19:13-17.
27. Kaplan BS, Restaino I, Raval DS, et al: Renal failure in the neonate associated with in utero exposure to
non-steroidal anti-inflammatory agents. Pediatr Nephrol 1994; 8:70-74.
28. Kulling PEJ, Beckman EA, Skagius ASM: Renal impairment after acute diclofenac, naproxen and
sulindac overdoses. J Toxicol Clin Toxicol 1995; 33:173-177.
29. Lewis JH: Hepatic toxicity of non-steroidal anti-inflammatory drugs. Clin Pharmacol 1984; 3:128-138.
30. Laufen H, Lietold M: The effect of activated charcoal on the bioavailability of piroxicam in man. Int J
Clin Pharmacol Ther Toxicol 1986; 24:48-52.
31. Linden CH, et al: Metabolic acidosis after acute ibuprofen overdosage. J Pediatr 1987; 111:922-925.
33. Marinac JS: Drug- and chemical-induced aseptic meningitis: A review of the literature. Ann
34. McElwee NE, Veltri JC, Bradford DC, et al: A prospective population-based study of acute ibuprofen
overdose: Complications are rare and routine levels are not warranted. Ann Emerg Med 1990; 19:657-662.
35. McGolddrick MD, Bailie GR: Nonnarcotic analgesics: Prevalence and estimated economic impact of
toxicities. Ann Pharmacother 1997; 31:221-227.
36. Minocha A, Greenbaum DS, Gardiner J: Impact of non-steroidal anti-inflammatory drugs on formation of
gallstones. Vet Hum Toxicol 1994; 36:514-516.
37. Oren R, Ligfumsky M: Indomethacin-induced colonic ulceration and bleeding. Ann

39. Singh G, Ramey DR, Morfeld D, et al: Comparative toxicity of non-steroidal anti-inflammatory agents.
Pharmacol Ther 1994; 62:175-191.
40. Smolinske SC, Hall AH, Vandenberg SA, et al: Toxic effects of nonsteroidal anti-inflammatory drugs in
overdose. Drug Safety 1990; 5:252-274.
41. Szabo S, Spill WF, Rainsford KD: Non-steroidal anti-inflammatory drug–induced gastropathy. Med
Toxicol 1989; 4:77-94.
42. Traversa G, Walker AM, Ippolito FM, et al: Gastrointestinal toxicity of different nonsteroidal
antiinflammatory drugs. Epidemiology 1995; 6:49-54.
43. Vale JA, Meredith TJ: Acute poisoning due to non-steroidal anti-inflammatory drugs. Med
Toxicol 1986; 1:12-31.
44. Verbeeck RK: Pharmacokinetic drug interactions with non-steroidal anti-inflammatory drugs. Clin
Pharmacokinet 1990; 19:44-66.
45. Wallace CA, Farrow D, Sherry DD: Increased risk of facial scars in children taking nonsteroidal
antiinflammatory drugs. J Pediatr 1994; 125:819-822.
46. Zuckerman GB, Uy CC: Shock, metabolic acidosis and coma following ibuprofen overdose in a child.
Ann Pharmacother 1995; 29:869-871.


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Chan NN, Fauvel NJ, Feher MD: Non-steroidal anti-inflammatory drugs and metformin: A cause for
concern?. Lancet 1998; 352:201.
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Ann Pharmacother 1997; 31:1034-1039.
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Toxicol 1995; 19:529-530.


Chapter 32 – Colchicine
LINDSAY M. MURRAY
Essentials
• The patient has a history of ingestion, or access to, gout medications or of ingestion of Autumn crocus or
glory lilies.
• The patient frequently presents during an initial asymptomatic phase.
• Onset of gastrointestinal symptoms within 12 to 24 hours after acute overdose heralds significant
toxicity.
• The diagnosis should be considered in patients presenting with gastrointestinal symptoms followed by
development of multiorgan failure.
INTRODUCTION
Colchicine is an alkaloid extracted from the plant Colchicum autumnale (Autumn crocus, meadow saffron). It
is also found in high concentrations in Gloriosa superba (glory lily). Historically, it was widely used in the
treatment of acute gout. A dose of 0.5 mg was taken every 2 to 3 hours until relief of symptoms or
gastrointestinal toxicity occurred, with a total dose of no greater than 3 mg given over a 24-hour period. Even
at these doses, therapy frequently had to be curtailed before symptomatic relief because of gastrointestinal
side effects.[6] In recent years, many physicians have switched to nonsteroidal anti-inflammatory agents to
treat gout because of colchicine’s narrow therapeutic-toxic index. Currently, low-dose, long-term oral
colchicine therapy in doses of 1 to 2 mg is used for prophylaxis of gout, Behçet’s syndrome, and familial
Mediterranean fever.
Serious colchicine intoxication is relatively rare, most commonly occurring in the context of suicide attempt
or therapeutic overdose. However, it is associated with high rates of morbidity and mortality and the potential
seriousness of the intoxication is often underestimated at initial presentation.[9]


PHARMACOKINETICS/PATHOPHYSIOLOGY
Pharmacokinetics
Colchicine is rapidly absorbed after oral administration, with peak levels occurring from 0.5 to 2 hours after
ingestion.[25] Absorption is not significantly delayed after overdose,[18] although absorption may be delayed
by coingested drugs.[4a] Bioavailability after oral administration ranges from 25 to 40 per cent because of
extensive first-pass hepatic metabolism.[11][24] After absorption, colchicine is rapidly redistributed from
plasma to all tissues, where it binds with high affinity to intracellular binding sites. The distribution half-life is
from 45 to 90 minutes, and the apparent volume of distribution is 21 L/kg in patients with toxicity.[18]
Terminal elimination half-lives in toxic patients range from 10.6 to 31.7 hours, with elimination being
primarily via hepatic metabolism.[18]
Pathophysiology
Colchicine binds to tubulin and prevents its polymerization into microtubules.[4] It is thus able to impair those
cellular functions that involve microtubules. This is the putative mechanism for its therapeutic action in acute
gouty arthritis; impairment of microtubular-dependent neutrophil migration and phagocytosis results in a
reduced inflammatory response to the presence of uric acid crystals in synovial fluid. In toxic doses,
colchicine arrests mitosis in metaphase because chromosome separation is dependent on microtubular
function. Tissues consisting of cells with a rapid rate of division are preferentially affected. The diarrhea,
bone marrow suppression, and alopecia associated with colchicine toxicity are attributable to blockade of
mitosis in gastrointestinal mucosa, hematopoietic cell lines, and hair follicles, respectively. The presence of
numerous metaphasic mitotic figures in small bowel epithelium has been confirmed at postmortem
examination after death by colchicine poisoning.[14] However, metaphase arrest alone cannot account for
the multiple organ failure that occurs with severe colchicine toxicity. These complications probably result
from inhibition of less well understood microtubular functions associated with intracellular transport
networks, maintenance of nuclear structure, extracellular secretion of hormones and neurotransmitters, and
cytoplasmic motility.[22]


The severity of toxicity after colchicine overdose is dose related. Severe cases of colchicine toxicity present
a relatively distinct clinical syndrome characterized by delayed onset of multiorgan toxicity and a high
incidence of mortality. In a series of 69 cases, ingestions estimated at less than 0.5 mg/kg were associated
with gastrointestinal symptoms and coagulation disturbances only and no mortality. Ingestions of 0.5 to 0.8
mg/kg were associated with bone marrow aplasia and a morbidity of 10 per cent, and ingestions greater than
0.8 mg/kg were associated with cardiovascular collapse and death within 72 hours.[3] It should be
emphasized, however, that significant toxicity has been reported after estimated doses less than 0.5 mg/kg.
Thus, any overdose of colchicine should be regarded as significant until proved otherwise.
It is convenient to divide the clinical presentation of colchicine toxicity into three sequential (and usually
overlapping) stages ( Table 32–1 ). Less severe cases may not progress beyond the first stage. Patients
with the most severe cases will die during the second stage.
Table 32-1 -- Clinical Stages of Significant Colchicine Toxicity

Stage Time of Onset Features
Stage 1: Gastrointestinal phase 2–24 hr post ingestion Nausea, vomiting, diarrhea, abdominal pain
Intravascular volume depletion
Peripheral leukocytosis
Bone marrow suppression
Adult respiratory distress syndrome
Cardiac dysrhythmias, failure, arrest
Consumptive coagulopathy
Fever
Hypomagnesemia
Hyponatremia, hypocalcemia
Hypophosphatemia
Stage 2: Multiorgan failure phase 24–72 hr post ingestion
Ileus
Metabolic acidosis
Mental status changes
Neuromuscular abnormalities
Oliguric renal failure
Pancytopenia
Stage Time of Onset Features
Secondary sepsis
Seizure
Resolution of organ system derangements
Stage 3: Recovery phase 6–8 days post ingestion Rebound leukocytosis
Alopecia
After a significant acute oral overdose, the patient may remain asymptomatic for 2 to 24 hours. The toxic
patient then develops severe nausea, vomiting, diarrhea, and abdominal pain. This symptomatology
corresponds to gastrointestinal mucosal damage.[23] During this stage fluid losses from vomiting and
diarrhea may be significant and result in hypovolemic shock.
Multisystem organ failure is characteristic of the second stage, with onset from 24 to 72 hours after
ingestion. Pulmonary, neurologic, renal, hematologic, and cardiovascular involvement are typical. Acute
adult respiratory distress syndrome (ARDS) may be a consequence of hypovolemic shock or sepsis or occur
as a result of direct damage to the pulmonary vasculature.[10] Bone marrow suppression is heralded by
lymphopenia, followed by granulocytopenia, reticulocytopenia, and thrombocytopenia, reaching a nadir at 4
to 8 days after ingestion.
Sepsis may complicate the leukopenia associated with this stage of toxicity.[3] Disseminated intravascular
coagulopathy was also noted to be a frequent complication in one large series of patients with colchicine
toxicity.[3] Fever occurs commonly and may be a direct drug effect or a sign of complicating infection.[1]
Shock is frequently observed during this phase, is of cardiogenic and/or hypovolemic origin, and is strongly
associated with mortality.[20] Cardiac rhythm disturbances including sinus bradycardia and sinus arrest,[21]
complete atrioventricular block,[23] and sudden cardiac arrest[22] have been reported. Renal failure in acute
colchicine toxicity is multifactorial and related to prolonged hypotension, hypoxemia, sepsis, and
rhabdomyolysis.[22] Metabolic derangements described in association with significant colchicine toxicity
include metabolic acidosis, hyperglycemia, hypokalemia, hypocalcemia, hypophosphatemia, and
hypomagnesemia.[17] Neurologic disturbances include delirium, coma, seizures, transverse myelitis, and
ascending paralysis.[16][22] Death is a frequent complication during this period and most commonly occurs
from profound cardiogenic shock, sudden cardiac arrest, or sepsis. Cardiac arrest has been observed as
early as 36 hours after acute colchicine ingestion.[21]
In those patients who survive the second stage, a rebound leukocytosis occurs 7 or more days after initial
symptoms and corresponds to the recovery of bone marrow function. Alopecia commonly occurs at about
this time. Complete recovery is the rule.


The diagnosis of colchicine toxicity is not difficult if a history of colchicine overdose is available. The chief
diagnostic error occurs when a patient presents in the asymptomatic phase, the ingestion is judged as
nontoxic, and the patient is discharged prematurely ( Table 32–2 ).
Table 32-2 -- Differential Diagnosis of Colchicine Toxicity

History of Ingestion Known History of Ingestion Unknown
Asymptomatic drug overdose Acute abdomen
Other toxic causes of gastroenteritis Cardiogenic shock
Iron Gastroenteritis
Salicylates Hypovolemic shock
Fluoride Septic shock
Caustics
Cardiac glycosides
Nicotine
Paraquat/diquat
Mushrooms
Metals/metalloids
Botanical toxins: Abrin, ricin
If the history of overdose is unavailable, the initial clinical presentation can be mistaken for gastroenteritis or
an acute abdomen. Late presentations may mimic hypovolemic, septic, or cardiogenic shock from other
causes.


LABORATORY STUDIES
Given the potential for severe multisystem organ failure as described earlier, extensive baseline laboratory
studies should be performed on presentation. These include electrolytes, complete blood cell count,
coagulation profile, renal function tests, liver function tests, electrocardiography, and chest radiography.
These studies need to repeated during a hospital admission at intervals dictated by the patient’s clinical
course.
Although colchicine concentrations in biologic fluids can be measured, they are not readily available and not
useful in the management of colchicine poisoning.


TREATMENT
The key points in management of acute colchicine toxicity are early recognition of the potential severity of
this intoxication, early gastrointestinal decontamination, and aggressive supportive care ( Table 32–3 ).
Table 32-3 -- Treatment Essentials of Colchicine Toxicity

Decontamination
Oral activated charcoal
Supportive care
Admit all patients for minimum of 24 hr observation.
Monitor:
Blood counts
Cardiac rhythm
Fluid and electrolyte status
Vital signs
Institute as dictated by subsequent course:
Antibiotic therapy
Artificial ventilation
Correction of electrolyte and acid-base abnormalities
Fresh-frozen plasma
Inotropes/vasopressors
Intravenous fluid therapy
Invasive hemodynamic monitoring
Plasma expanders
Enhanced elimination techniques
Not indicated
Colchicine antibodies
Not available at present
Decontamination of the gut by the administration of oral activated charcoal is the management priority for the
patient presenting in the first (asymptomatic) stage of colchicine intoxication; prevention of absorption of
even small amounts of colchicine may favorably affect the severity of the intoxication and ultimate prognosis.
In patients who present later (during the second stage of intoxication), resuscitative effects take precedence
over gastrointestinal decontamination.
Although colchicine is normally considered to be rapidly absorbed after ingestion, delayed decontamination
may be of particular value after ingestion of colchicine-containing plants. At a postmortem examination
performed more than 30 hours after Colchicum autumnale ingestion, more than two thirds of the ingested
colchicine was recovered from the gut.[7]
Careful monitoring of vital signs and cardiac rhythm should be instituted on arrival. An intravenous cannula
should be placed and intravenous fluid therapy begun in any symptomatic patient. In those patients who
present with substantial delay, immediate resuscitative measures may be required. Baseline laboratory
studies as outlined earlier should be performed.
Careful monitoring, not only of vital signs and cardiac rhythm but also of fluid and electrolyte status and
blood cell counts, is mandatory. Further supportive therapy is dictated by clinical status and may include
intravenous crystalloid rehydration, plasma expansion, inotropic and vasopressor drugs, artificial ventilation,
correction of electrolyte and acid-base disturbances, correction of coagulation disorders, and antibiotic
treatment of infectious complications.
Because of colchicine’s large volume of distribution and high affinity to intracellular binding sites, attempts at
enhancing elimination by repeat-dose activated charcoal, hemodialysis, or hemoperfusion are unlikely to be
effective.
The bone marrow suppression associated with colchicine toxicity has been reported to respond to the
administration of granulocyte colony-stimulating factor.[8][12] However, it is unclear whether these reports
represent a true therapeutic response or the natural course of recovery. In any case, it must be remembered
that deaths after colchicine poisoning seldom result from bone marrow aplasia, and this therapy should not
be regarded as routine.
An exciting new prospect in the management of severe colchicine toxicity is the use of colchicine-specific
Fab fragments. These have been produced in goats immunized with a conjugate of colchicine and serum
albumin, and they effectively reverse colchicine toxicity in mice.[19] When recently administered to a patient
with severe colchicine toxicity, a rapid improvement in hemodynamic parameters and ultimate survival were
observed.[2] Unfortunately, colchicine-specific Fab fragments are not yet commercially available.


DISPOSITION
All patients in whom colchicine toxicity is diagnosed or even suspected require hospital admission. The
asymptomatic patient should be admitted for a minimum of 24 hours observation. If no symptoms of
intoxication (diarrhea, vomiting, or abdominal pain) are evident at the end of that period, colchicine toxicity is
unlikely. The symptomatic patient should be admitted to an intensive care unit for careful monitoring and
supportive care.


SEQUELAE
Infectious or hemorrhagic complications during the second stage contribute to the morbidity and mortality of
colchicine toxicity. Complete recovery can be anticipated in those patients who survive the second stage.
The alopecia observed during the recovery phase is not permanent, with hair regrowth beginning after the
first month.


SPECIFIC SITUATIONS
Acute colchicine toxicity has been reported in a number of unusual circumstances, including intraurethral
administration for the treatment of condyloma acuminata,[16] ingestion of Gloriosa superba tubers,[15] and
when colchicine powder was mistaken for methamphetamine and insufflated.[1] The observed clinical course
in these cases was similar to that after oral overdose.
Intravenous colchicine is occasionally used to treat acute gout and is associated with toxicity when
administration guidelines are not strictly observed.[26]
Severe toxicity from chronic administration of therapeutic doses of oral colchicine is rare but can occur in the
elderly or patients with renal or hepatic disease.[5] The appearance of gastrointestinal symptoms usually acts
as a safety mechanism, resulting in discontinuation of the drug before the appearance of severe symptoms.
Myopathies and neuropathies have been reported as a reversible toxic reaction to long-term colchicine
therapy.[13]


REFERENCES
1. Baldwin LR, Talber TL, Sampler R: Accidental overdose of insufflated colchicine. Drug
Safety 1990; 5:305-312.
2. Baud FJ, Sabouraud A, Vicaut E, et al: Brief report: Treatment of severe colchicine overdose with
colchicine-specific Fab fragments. N Engl J Med 1995; 332:642-645.
3. Bismuth C, Gautier M, Conso F: Aplasie médullaire après intoxication aiguë á la colchicine. Nouv Press
Med 1977; 6:1625-1629.
4. Borizy GG, Taylor EW: The mechanism of action of colchicine: Binding of colchicine-H3 to cellular
protein. J Cell Biol 1967; 34:525-533.
4a. Borron SW, Scherrmann JM, Baud FJ: Markedly altered colchicine kinetics in a fatal intoxication:
Examination of contributing factors. Hum Exp Toxicol 1996; 15:885-890.
5. Carr AA: Colchicine toxicity. Arch Intern Med 1965; 115:29-33.
6. Conaghan PG, Day RO: Risks and benefits of drugs used in the management and prevention of gout.
Drug Safety 1994; 11:252-258.
7. Elwood MG, Robb GH: Self poisoning with colchicine. Postgrad Med J 1989; 65:752-755.
8. Folpini A, Furfori P: Colchicine toxicity—clinical features and treatment: Massive overdose case report.
Clin Toxicol 1995; 33:71-77.
9. Garden AL, Judson JA: Fatal colchicine overdose. NZ Med J 1990; 103:412.
10. Heaney D, Derghazarian CB, Pineo GF, et al: Massive colchicine overdose: Report on the toxicity. Am
J Med Sci 1976; 271:233-238.
11. Hunter AL, Klaassen CD: Biliary excretion of colchicine. J Pharmacol Exp Ther 1974; 192:605-607.
12. Katz R, Chuang LC, Sutton JD: Use of granulocyte colony-stimulating factor in the treatment of
pancytopenia secondary to colchicine overdose. Ann Pharmacother 1992; 26:1087-1088.
13. Kuncl RW, Duncan G, Watson D, et al: Colchicine myopathy and neuropathy. N Engl J
Med 1987; 316:1562-1568.
14. McIntyre IM, Ruszkiewicz AR, Crump K, Drummer OH: Death following colchicine poisoning. J Forens
Sci 1994; 39:280-286.
15. Mendis S: Colchicine cardiotoxicity following ingestion of Gloriosa superba tubers. Postgrad Med
J 1989; 65:752-755.
16. Naidus R, Rodvien R, Nielke CH: Colchicine toxicity: A multisystem disease. Arch Intern
Med 1977; 137:394-396.
17. Putterman C, Ben-Cherit E, Caraco Y, Levy M: Colchicine intoxication: Clinical pharmacology, risk
factors, features and management. Semin Arthritis Rheum 1991; 3:143-155.
18. Rochdi M, Sabouraud A, Baud FJ, et al: Toxicokinetics of colchicine in humans: Analysis of tissue,
plasma and urine data in ten cases. Hum Exp Toxicol 1992; 11:510-516.
19. Sabouraud A, Urtizberea M, Grandgeorge M, et al: Dose-dependent reversal of acute murine colchicine
poisoning by goat colchicine-specific Fab fragments. Toxicology 1991; 68:121-132.
20. Sauder P, Kopferschmitt J, Jaeger A, et al: Haemodynamic studies in eight cases of acute colchicine
poisoning. Hum Toxicol 1983; 2:169-179.
21. Stahl N, Weinberger A, Benjamin D, et al: Fatal colchicine poisoning in a boy with familial
Mediterranean fever. Am J Med Sci 1976; 278:77-81.
22. Stapczynski JS, Rothstein RJ, Gaye WA, et al: Colchicine overdose: Report of two cases and a review
of the literature. Ann Emerg Med 1981; 10:364-369.
23. Stemmermann GN, Hayashi T: Colchicine intoxication: A reappraisal of its pathology based on a study
of three fatal cases. Hum Pathol 1971; 2:321-332.
24. Thomas G, Girre C, Scherrmann JM, et al: Zero-order absorption and linear disposition of oral
colchicine in healthy volunteers. Eur J Clin Pharmacol 1989; 37:79-84.
25. Wallace SL, Ertel NH: Plasma levels of colchicine after administration of a single dose.
Metabolism 1973; 22:749-753.
26. Wallace SL, Singer JZ: Review: Systemic toxicity associated with the intravenous administration of
colchicine—guidelines for use. J Rheumatol 1988; 15:495-499.


Chapter 33 – Muscle Relaxants
JAY L. SCHAUBEN
Essentials
• Lethargy, euphoria, disorientation, confusion, coma
• Central nervous system/cardiac/respiratory depression
• Muscular incoordination, ataxia, myoclonic jerks, flapping tremors, seizures (rare)
• Mild hypotension and tachycardia
• Anticholinergic effects with certain agents
INTRODUCTION
Although we normally classify the therapeutic agents useful for acute, painful musculoskeletal problems
arising from muscle injury or spasm as “muscle relaxants,” this clinical grouping accommodates a
remarkably heterogeneous assembly of medications. They differ greatly in their chemical, pharmacologic,
pharmacokinetic, and toxicologic properties, exhibiting a wide array of both type and severity of effects after
overdose. In 1998, the American Association of Poison Control Centers Toxic Exposure Surveillance
System reported 12,688 cases involving the muscle relaxants covered in this chapter.[29] Forty-eight per cent
of these exposures resulted in symptoms related to the exposure. Thirteen deaths resulted from the
ingestion of carisoprodol, methocarbamol, cyclobenzaprine, baclofen, or meprobamate, alone or in
combination with other agents. Abuse potential has not escaped this group. Methocarbamol has been the
subject of various substance abuse studies and reports, as has carisoprodol, whose dependence and
potential for development of tolerance has been widely reported, purportedly linked to its metabolite
meprobamate.[25][43] Given the diversity of effects that can be produced by this group of agents, the vast
majority of patients will recover with prompt recognition of the toxic condition and rapid institution of
supportive care.


Pharmacology
The majority of the skeletal muscle relaxants act on the central nervous system (CNS) as simple
depressants, blocking action on interneurons and probably modifying perception of pain. Meprobamate
potentiates gamma-aminobutyric acid A (GABAA) receptor Cl- currents indirectly and directly and, at high
concentrations, blocks N-methyl-D-aspartate (NMDA) receptor-activated currents.[39] Carisoprodol exerts its
effects through its metabolite meprobamate. Baclofen, a derivative of gamma-aminobutyric acid, increases
GABAB-associated neurotransmission.[32][33] Orphenadrine directly causes dopamine release,
noncompetitively antagonizes the NMDA receptor, noncompetitively blocks norepinephrine uptake, and has
significant peripheral antimuscarinic actions and central effects that account for its ability to reduce skeletal
muscle spasm without direct skeletal muscle relaxant activity.[11][21] Likewise, cyclobenzaprine, structurally
related to amitriptyline and exhibiting very mild antidepressant effects, has anticholinergic, antihistaminic,
and sedative properties. It weakly inhibits presynaptic norepinephrine and serotonin reuptake while also
inhibiting gamma and alpha motor neurons within the brain stem. [27][34] Dantrolene directly acts on skeletal
muscle, blocking Ca2+ release from the sarcoplasmic reticulum, without affecting impulse transmission,
transmembrane potential, or the release of acetylcholine at the myoneuronal junction. Methocarbamol and
the structurally similar analogs chlorphenesin and mephenesin are centrally acting skeletal muscle relaxants
that block spinal polysynaptic reflexes without directly affecting skeletal muscle. Various other members of
this group also manifest weak to moderate anticholinergic effects. Pharmacokinetic parameters for this
group are found in Table 33–1 .
Table 33-1 -- Pharmacokinetic Parameters of Muscle Relaxants

Drug Absorption/Distribution Metabolism Elimination
Liver: metabolized to
<1% eliminated in urine
meprobamate and
Carisoprodol Peak 1–4 hr unchanged; 4.7% as
other metabolites
meprobamate
T½: 1.5–6 hr
85% eliminated
Rapid and complete absorption; prolonged 15% metabolized by unchanged in urine within
Baclofen
with overdose liver 72 hr; some metabolites
appear in feces
Liver metabolism
Up to 30% of dose
T½: 14 hr; may be
Orphenadrine Well absorbed; peak 2–4 hr eliminated unchanged in
prolonged in
acidic urine
overdose
Drug Absorption/Distribution Metabolism Elimination
Completely absorbed with significant first-
50% eliminated in urine as
pass metabolism; undergoes Extensively
metabolites; 14% feces;
Cyclobenzaprine enterohepatic circulation; peak 4–6 hr, metabolized by the
15% bile; <1% unchanged
prolonged in overdose. Highly protein liver
in urine
bound (93%)
Slow, incomplete; 20–35% of dose Liver with active 97% metabolites
Dantrolene absorbed; peak 3–6 hr; significant protein metabolites T½: eliminated in urine; 1–3%
binding 5–15 hr unchanged in urine
40–50% metabolites
eliminated in urine;
Rapid, almost complete absorption; peak
Methocarbamol Liver 10–15% eliminated
1–2 hr; widely distributed in body tissues
unchanged in urine; small
amount found in feces
Pathophysiology
The clinical responses to overdose of muscle relaxants in most cases are exaggerations of their main
therapeutic effects, which explain the CNS and respiratory depression, muscle flaccidity, and the
anticholinergic toxidrome with those agents manifesting antimuscarinic effects. The ability to decrease gut
motility, coupled with the physicochemical properties of selected agents promoting concretion formation
within the gastrointestinal tract, often leads to delayed onset, prolongation, and, in some cases, relapse of
serious symptomatology. Chlormezanone also has sedative as well as muscle relaxant properties.
Unfortunately, few reports are available outlining the experiences in poisoning with this agent.


CLINICAL PRESENTATION ( Table 33–2 )
Acute Toxicity
The majority of muscle relaxants taken in toxic quantities will primarily produce CNS depression, including
coma in severe cases (e.g., methocarbamol and related agents). Lethargy, drowsiness, confusion, ataxia,
dysmetria, euphoria, CNS stimulation, and muscular incoordination appear in less severe cases. Although
oral dantrolene overdose may also result in lethargy, it is more likely to remain uneventful. [35] Hallucinations
and dystonic reactions have been reported with chlorzoxazone. Mild tachycardia (carisoprodol,
chlormezanone), mild hypotension (chlormezanone), horizontal and vertical nystagmus, mydriasis, blurred
vision, and respiratory depression in patients with significant CNS depression can occur. Dry mouth, nausea,
vomiting, and abdominal pain may also be part of the clinical picture.
Table 33-2 -- Clinical Presentation of Muscle Relaxant Toxicity

Central Nervous System
Depression:
Confusion
Drowsiness
Lethargy
Ataxia
Coma
Death
Altered mental status:
Auditory/visual hallucinations
Euphoria
Agitation
Delirium
Seizures
Cerebral edema
Neuromuscular
Muscle weakness/flaccidity
Hyporeflexia
Myoclonus
Cardiovascular
Tachycardia/bradycardia
Conduction abnormalities
Hypotension/hypertension
Shock
Cardiac arrest
Anticholinergic Effects
Dry mucous membranes, flushed skin
Hyperthermia
Tachycardia
Mydriasis, blurred vision
Diminished/absent bowel sounds, paralytic ileus
Urinary retention
Other
Hypothermia
Rhabdomyolysis
Nausea, vomiting, abdominal pain
Baclofen
Baclofen overdose can present as marked cerebral, cardiac, and respiratory depression; hyporeflexia;
muscle flaccidity; myoclonic jerks; and hypothermia.[10][33] Toxicity has occurred after inadvertent intrathecal
overdose.[12][44] Initial agitation, behavioral disturbances, and delirium witnessed after following toxic
ingestions quickly led to flaccidity, absent limb reflexes, deep coma unresponsive to painful stimuli, and loss
of spontaneous respirations within 3 to 5 hours after ingestion. Seizures may develop within 6 hours of
ingestion, with muscle twitching and myoclonus noted throughout the course and recovery. Seizures have
occurred after oral ingestions ranging from 150 to 2000 mg.[44] Hypertension and hypotension, as well as
sinus bradycardia, supraventricular tachycardia, normal sinus rhythm, and tachycardia, have been reported,
although hypotension and bradycardia occur most commonly.[2][9][33][36] Cardiac conduction abnormalities,
such as prolonged QTc and PR intervals, first-degree heart block, blocked premature atrial contractions,
junctional escape beats, and rapid supraventricular tachydysrhythmias have been reported to occur within
the first 12 hours after ingestion.[33][41] Mydriasis with sluggish reaction to light is common, although normal
and miotic pupils with varying degrees of light response have also been seen. Deep tendon reflexes are
often absent in severe intoxications. [33]
In a review of 12 baclofen overdoses, 10 patients required mechanical ventilation, 5 had one or more
seizures, and 5 reported prolonged myoclonus requiring neuromuscular blockade. [33] In another analysis of
37 baclofen intoxications, the clinical presentation was noted to vary widely based on the character of the
exposure.[22] All of the acute overdose victims became encephalopathic, with most also displaying varying
degrees of respiratory and neuromuscular depression. Ten of 11 patients with acute-on-chronic cases
experienced respiratory and neuromuscular depression.
Carisoprodol
Carisoprodol is capable of producing prolonged CNS depression owing to its major metabolite
meprobamate.[1] Meprobamate, itself a very potent CNS depressant, produces effects similar to
barbiturates. As with the majority of skeletal muscle relaxants, carisoprodol overdose commonly results in
lethargy, stupor, slurred speech, nystagmus, headache, weakness, and hypoactive deep tendon
reflexes.[1][16] Likewise, tachycardia, hypotension, cardiac dysrhythmias, respiratory depression, pulmonary
edema, and paradoxical CNS stimulation may also be noted. Cerebral edema may be evident after severe
intoxications.[1]
Complications reported from meprobamate toxicity should also be anticipated in carisoprodol overdose. Fifty
per cent of meprobamate-overdosed patients (50 patients) in one series manifested deep (grade 3 or 4)
coma; 16 of the 50 patients required assisted ventilation.[3] Meprobamate can also induce severe and
persistent hypotension as a consequence of its ingestion in toxic quantities, with 46 per cent of patients in
the aforementioned review manifesting this effect.[3] Hypotension is not necessarily a consequence of the
CNS depression, but rather it may be the result of a direct effect on the vasomotor center, a depression of
myocardial contractility, or due to acute cardiac failure.[7] Auditory and visual hallucinations have also been
reported in a significant number of meprobamate-toxic patients.[5]
In contrast to the minor anticholinergic potential effects caused by the muscle relaxants previously
discussed, a few members of this group discussed below exhibit more pronounced anticholinergic effects
that can add complexity to the differential diagnosis and the clinician’s attempt to distinguish the offending
agent.
Orphenadrine
Orphenadrine intoxication may result in mydriasis, tachycardia, coma, and seizures within 2 hours of
ingestion. Athetoid movements, cardiac arrest, shock, and hypothermia have also been described.[45] Death,
more often than not, is due to cardiac and/or respiratory arrest after status epilepticus. It has been postulated
that orphenadrine exerts a direct depressant effect on myocardial contraction and cardiac conduction.[45] In
less severe cases, the traditional anticholinergic toxidrome prevails: delirium, hallucinations, tachycardia,
hypertension, mydriasis, dry skin and mucous membranes, hyperthermia, decreased gastric motility with
diminished bowel sounds, and urinary retention. Interestingly, rhabdomyolysis and paradoxical diaphoresis
have been reported.[19]
Cyclobenzaprine
Central cholinergic blockade resulting in agitation, confusion, and hallucinations is the most striking feature
of cyclobenzaprine overdose. These effects are often accompanied by peripheral anticholinergic findings.
Unlike orphenadrine ingestion, cyclobenzaprine ingestion rarely results in coma, seizures, hypotension,
dysrhythmias, and impaired cardiac conduction.[28] Respiratory insufficiency may develop in association with
severe CNS depression but is relatively uncommon. In one case series, 39 per cent of patients manifested
drowsiness, 27 per cent had dry mouth, and 11 per cent reported dizziness, representing the most common
effects noted. Confusion, nervousness, tachycardia, fatigue, dysgeusia, and blurred vision also appeared
frequently.[34] Similarly, a review of 402 cyclobenzaprine overdoses of 5 to 1000 mg found no seizures or
deaths, and dysrhythmias other than sinus tachycardia were infrequent and not life threatening.[47] The most
common effects of cyclobenzaprine overdose included lethargy, sinus tachycardia, agitation, and
hypertension or hypotension. All patients developed symptoms within 4 hours after ingestion that persisted
for up to 24 hours. The authors concluded that ingestion of less than 1 g of cyclobenzaprine would not
produce life-threatening cardiovascular or neurologic effects but was more likely to result in lethargy and
anticholinergic manifestations. [47]
Chronic Toxicity
Bilateral sensorineural hearing loss, pericarditis associated with pleural effusion, and pleural fibrosis have all
been reported with chronic dantrolene use.[30] Idiosyncratic hepatotoxic effects (centrilobular necrosis and
hepatitis) have been reported with long-term chlorzoxazone, chlormezanone, and dantrolene use.[8]
Acneiform rashes and fixed drug eruptions have also been described with the oral use of dantrolene,
chlormezanone, and chlorphenesin,[37] whereas chronic baclofen administration has been associated with
fatigue, lassitude, giddiness, mental confusion, depression, headaches, euphoria, muscle weakness,
nausea, vomiting, and diarrhea.[46][52] In one study, most patients with chronic overexposure manifested
psychiatric signs only, including hallucinosis, impaired memory, catatonia, and acute mania when compared
with acute and acute-on-chronic exposures.[22]
Withdrawal
Abrupt cessation of baclofen administration after several months of use has led to seizures within 12 to 96
hours. This abrupt withdrawal may be due to intrathecal catheter dysfunction.[31] Seizures may be preceded
by auditory and/or visual hallucinations, paranoid ideations, insomnia, dyskinesias, confusion, and agitation.
Withdrawal reactions can last up to 8 days and mimic benzodiazepine, chlormezanone, and other sedative
hypnotic withdrawal states.[4][15][23][40][48][51][52] Baclofen withdrawal symptoms appear to respond to
reinstitution of baclofen. Benzodiazepines purportedly provide limited benefit.[18] Meprobamate dependence
has been reported after carisoprodol use.[26] Chronic meprobamate use can cause addiction and the usual
constellation of sedative-hypnotic withdrawal reactions after abrupt removal of this drug, particularly if the
daily ingestion reaches or exceeds 1200 to 2400 mg for a period of 8 months or longer.[6][42] Death has been
reported after the sudden withdrawal of meprobamate.[49] When attempting to manage the withdrawal
reaction, meprobamate can be reinstituted or phenobarbital can be substituted to control the symptoms.


As a collective group, muscle relaxants in overdose result in CNS depression, with or without anticholinergic
signs and symptoms. The differential list of potential toxins is therefore extensive ( Table 33–3 ) and can be
divided based on the presence or absence of anticholinergic manifestations. Although organophosphates
commonly produce discernible cholinergic effects that could easily distinguish this exposure from that of
other agents on this list, it should be remembered that in some patients (especially children), nicotinic and/or
CNS effects can occur in the absence of muscarinic effects.
Table 33-3 -- Differential Diagnosis of Muscle Relaxant Overdose

Central Nervous System Depression Without Anticholinergic Syndrome
Barbiturates
Benzodiazepines
Sedative-hypnotics (e.g., chloral hydrate, glutethimide, methaqualone)
Carbon monoxide
Ethanol
Isopropanol, ethylene glycol
Opioids
Clonidine, other central a2 agonists
Lithium
Organophosphates
Central Nervous System Depression with Anticholinergic Syndrome
Antihistamines
Cyclic antidepressants *
Antiparkinsonian agents *
Antispasmodics
Belladonna alkaloids and synthetic agents
Anticholinergic plants
* Anticholinergic manifestations are variable, with some patients exhibiting few signs or symptoms consistent with this toxidrome.
In patients presenting with anticholinergic symptoms, one should consider cyclic antidepressants, because
serious effects of this overdose can require a different therapeutic approach to maintain patient stability.
Although the anticholinergic toxidrome is shared by all agents listed under “CNS Depression with
Anticholinergic Syndrome” in Table 33–3 , these agents can have variable effects on the CNS. As a general
rule, the clinician should always consider the possibility of multiple substance ingestions when attempting to
correlate presenting symptomatology with known toxidromes.


LABORATORY STUDIES
In general, patient condition, clinical situation, and specific toxic effects dictate the laboratory testing of the
overdosed patient. Electrolyte and serum glucose determination, a complete blood cell count, urinalysis, and
an electrocardiogram (EKG) may be checked and repeated based on clinical course and potential for
change in condition. In addition, baclofen and other muscle relaxants with significant anticholinergic effects
require monitoring of creatine phosphokinase and renal function, especially in patients with prolonged
seizures or coma. The management of orphenadrine ingestions should include assessment of hepatic
aminotransferases, glucose, electrolytes, and prothrombin time, because alteration in these values has been
reported.[44] In the case of prolonged deep coma (carisoprodol, meprobamate), electroencephalographic
assessment may be indicated.
Unfortunately, most muscle relaxants are not usually assayed by hospital laboratories. In some instances,
blood concentrations do not correlate with toxic effects ( Table 33–4 ). If the diagnosis is in doubt, toxicology
qualitative screens or quantitative assessments could be useful in ruling out other toxins on the differential
diagnostic list, such as cyclic antidepressants or barbiturates. Measurement of carboxyhemoglobin
concentration is mandatory if carbon monoxide exposure is considered. Obviously, screens and blood levels
not readily available for initial diagnostic purposes do little more than confirm the diagnosis, because they
are usually reported too late to be of use in the management of the patient.
Table 33-4 -- Laboratory Assessment of Muscle Relaxant Toxicity

Drug Comments
Blood levels confirmatory but do not dictate management. Therapeutic doses have produced
blood concentrations of 0.08–0.4 mg/L. A serum concentration in a fatal overdose was
Baclofen *
reported at 17 mg/L. Occasional transient elevations in lactate dehydrogenase and aspartate
aminotransferase have been observed.
Single 350-mg doses have produced plasma concentrations of 2.1 and 0.24 mg/L at 1 and 6
hours post ingestion, respectively. Blood concentrations do not seem to correlate well with
Carisoprodol * clinical effects. Death has been reported at levels as low as 6.5 mg/L and as high as 39.3
mg/L; stupor and coma have been seen at levels of 13.4 and 31 mg/L, and drowsiness has
been seen with plasma concentrations of 37 and 38 mg/L.
Chlormezanone
Blood levels in fatal cases have ranged from 9 to 53 µg/mL.
*
Chlorzoxazone * Oral ingestion of 600 mg can produce peak concentrations between 9 and 20 mg/L.
Assessment of plasma concentration is not routinely available nor extensively studied.
Therapeutic levels of 10–40 ng/mL are obtained following a 40-mg oral dose. A fatality has
been reported with a serum level of 260 ng/mL. Gas chromatography, high-pressure liquid
Cyclobenzaprine
chromatography, and thin layer chromatographic methods of qualitative analysis can confuse
cyclobenzaprine with other cyclic antidepressants. Gas chromatography/mass
spectrophotometry apparently can readily identify cyclobenzaprine.
Drug Comments
Oral dose of 2000 mg and 4000 mg produced peak concentrations of 25.8 and 41 mg/L,
Methocarbamol
respectively. Fatal plasma concentrations in mixed overdoses have ranged from 257 to 525
*
mg/L.
Orphenadrine Toxicity has been noted at blood levels of 2 µg/mL, with fatalities occurring at 4–8 µg/mL.
* Note: Without accessibility of gas chromatograph–mass spectrophotometric analysis, qualitative or quantitative toxicologic analysis is
generally not available.


General Management
Airway management procedures are instituted for respiratory instability. If opioids are suspected, naloxone
should be administered. If benzodiazepines are known or suspected and severe respiratory depression
occurs, a trial of flumazenil may be considered if no contraindications exist. However, the potential for
inducing sedative-hypnotic withdrawal, including seizures, exists, and flumazenil should be used judiciously.
Once administered, further benzodiazepine treatment for agitation and seizures will probably be ineffective
until the flumazenil effect clears. Hypotension should be managed initially with intravenous crystalloids,
followed by vasopressors (dopamine, norepinephrine) if needed. Care should be exercised with fluid
loading, owing to the possibility of certain agents producing pulmonary edema (e.g., carisoprodol). Agitation
can be treated with benzodiazepines. Seizures require prompt treatment with standard anticonvulsant
protocols: benzodiazepines, phenobarbital, phenytoin. With these regimens, the clinician should be prepared
for further respiratory depression and blood pressure instability. Core body temperature should be monitored
in patients with severe agitation or repetitive seizures.
Table 33-5 -- Treatment Essentials for Muscle Relaxant Overdose

Stabilization
Airway and respiratory support as required
Correction of hypotension:
Crystalloid fluid bolus
Trendelenburg position
Dopamine/norepinephrine
Epinephrine considered for refractory bradycardia/hypotension
Seizures:
Diazepam
Pediatric: 0.1 mg/kg IV
Adult: 5 to 10 mg IV
Repeat as necessary
Lorazepam
Pediatric: 0.05 mg/kg IV
Adult: 2–4 mg/dose IV
Repeat as necessary
Phenobarbital
Pediatric: 10 mg/kg IV, repeat as necessary *
Adult: 10 to 20 mg/kg IV
General Management
Lavage may be indicated in early presentations or late presentations with symptoms or evidence of decreased
gut motility and/or concretion formation.
Single-dose activated charcoal, 50–75 g (1 g/kg pediatric)
Multiple-dose activated charcoal as indicated by specific toxin (25 g adults, 0.5 mg/kg children)
Benzodiazepines for agitation
Supportive care
Specific Toxins
Baclofen
Bradycardia/hypotension responsive to atropine
Adult: 0.5 mg IV every 5 minutes to maximum of 0.04 mg/kg
Pediatric: 0.02 mg/kg pediatric, maximum 1.0 mg in children, 2.0 mg in adolescents
Anticholinergic manifestations: physostigmine not recommended except in the most severe patients
unresponsive to supportive care after cyclic antidepressants have been ruled out; 1–2 mg IV over 5 minutes;
can repeat up to 5 mg (0.02 mg/kg up to 0.5 mg pediatric)
Single-dose activated charcoal
Carisoprodol
Consider pulmonary artery catheterization to guide fluid administration.
Hemodialysis/hemoperfusion may be effective for ongoing severe toxicity due to high meprobamate levels.
Orphenadrine
unresponsive to supportive care after cyclic antidepressants have been ruled out; 1–2 mg IV over 5 minutes,
can repeat up to 5 mg (0.02 mg/kg up to 0.5 mg pediatric)
Cyclobenzaprine
unresponsive to supportive care after cyclic antidepressants have been ruled out; 1–2 mg IV over 5 minutes,
can repeat up to 5 mg (0.02 mg/kg up to 0.5 mg/kg pediatric)
* Be prepared to intubate and support respirations.
After stabilization of cardiac and respiratory functions, fluids and electrolytes should be monitored very
closely. Dysrhythmias are managed with standard antidysrhythmic medications except when noted in the
following discussion. Those patients manifesting cardiovascular instability require continuous EKG and
blood pressure monitoring. As with ingestions of cyclic antidepressants, cyclobenzaprine, baclofen, and
orphenadrine ingestions require frequent assessments of vital signs and EKG monitoring.
Gastric lavage may be indicated if the patient presents within 1 hour after the ingestion, and later if there is
evidence of anticholinergic-induced decrease in gut motility, manifested by decreased or absent bowel
sounds. Induced emesis with syrup of ipecac is not recommended, owing to the high risk and rapid onset of
central nervous system and respiratory depression. Patients should receive a minimum of one dose of
activated charcoal, 1 g/kg, or 50 to 75 g in an adult, with or without a cathartic. Although the efficacy of
multiple-dose activated charcoal regimens (0.5 g/kg, or 25 to 30 g in an adult, every 4 to 6 hours) has not
been established for these drugs, no studies exist to refute this regimen’s ability to enhance systemic
clearance or provide beneficial gastrointestinal adsorptive effects for large ingestions of other agents in this
group, or for those exhibiting enterohepatic circulation such as cyclobenzaprine. The risk of enhanced
aspiration associated with multiple-dose regimens must be considered in the decision to use this therapy.
Toxin-Specific Management
Baclofen
Atropine has been reported to be effective in managing bradycardia and hypotension associated with
baclofen overdose.[9][14] Although physostigmine has also been reported useful in intrathecal iatrogenic
baclofen overdose, it has been implicated in causing cardiac arrest in larger baclofen intoxications.[12][38]
Therefore, it is not recommended except for the most severe patients who are refractory to general
supportive care. Currently, there are no data to substantiate the use of any elimination enhancement
procedure for baclofen, including extracorporeal removal. In cases of intrathecal overdose, rapid removal of
30 to 50 mL of cerebrospinal fluid has been advocated.[12][38] Supportive care remains the mainstay of
therapy.
Carisoprodol
Hypotension due to the meprobamate metabolite should be treated very cautiously with intravenous
crystalloids, because pulmonary edema can be exacerbated as a consequence of such protocols.[3][7][24]
Pulmonary artery catheterization may be helpful in guiding fluid administration to correct hypotension.[13]
Close assessment of fluid administration and urine output should be continued until 48 to 72 hours after
significant recovery is noted. Hemodialysis and hemoperfusion enhance removal,[17] having been reported to
reduce the elimination half-life of meprobamate more than threefold.[20] Institution of extracorporeal removal
modalities should be considered in patients when clinical deterioration is occurring despite conventional
therapy. Continuous arteriovenous charcoal hemoperfusion has also been found to be effective in enhancing
the elimination of meprobamate.[27]
Orphenadrine
This drug purportedly undergoes enterohepatic cycling, with at least eight metabolites currently identified.
Theoretically, multiple-dose activated charcoal regimens should decrease the recirculation of active
metabolites, although no data are currently available documenting its utility in enhancing elimination.
Nevertheless, orphenadrine may have prolonged and delayed absorption from the gastrointestinal tract,
owing to its potent antimuscarinic actions on gut motility. Orphenadrine-induced hypotension should be
treated with intravenous dopamine, norepinephrine, or epinephrine if refractory. Agitation and seizures can
be treated with benzodiazepines. Physostigmine can be used cautiously to manage severe central
anticholinergic effects[45] but may precipitate seizures if administered rapidly and is contraindicated if cyclic
antidepressant toxicity is also suspected.
Cyclobenzaprine
In a review of 402 ingestions, therapeutic management consisted mainly of gastrointestinal decontamination

and general supportive care. Ingestions of less than 100 mg required gastrointestinal decontamination
only. [47] Although some authors have recommended managing cyclobenzaprine overdose with the standard
alkalinization protocol used for cyclic antidepressants,[34] the effectiveness of such therapy has not been
proved, and it is not routinely recommended. Agitation and seizures can be treated with benzodiazepines.
Physostigmine should be reserved for severe and uncontrollable anticholinergic manifestations,[28][34] with
the same concerns for its use as expressed earlier. No data exist on the therapeutic efficacy of multiple-
dose activated charcoal with cyclobenzaprine.


DISPOSITION
Symptomatic carisoprodol ingestions should be observed for a minimum of 24 hours. Patients with
carisoprodol ingestions who remain asymptomatic 8 hours after an ingestion may be discharged. Because of
the delayed onset and prolonged duration of toxicity associated with cyclobenzaprine, patients should be
observed for toxic effects at least 8 hours after ingestion.[28] Baclofen ingestions in elderly patients and in
any patient manifesting symptoms, regardless of amount ingested, should prompt admission. Although
specific recommendations concerning other muscle relaxants are lacking, prudence dictates monitoring
patients for 6 to 8 hours after ingestion to observe for onset of toxic effects and longer if decreased gut
motility due to anticholinergic effects exists. All patients who have attempted suicide require assessment for
further suicidal risk and possible psychiatric evaluation before discharge.


SEQUELAE
Sequelae resulting from skeletal muscle relaxant intoxication result from cardiorespiratory depression,
seizures, or rhabdomyolysis. Residual effects are minimal unless tissue and organ system damage due to
hypoxia/anoxia, or myoglobin-induced renal injury occurs. Tissue damage secondary to these factors could
potentially result in nonresolving residual effects commensurate with the damage received.


REFERENCES
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4. Arnold ES, Rudd SM, Kirshner H: Manic psychosis following rapid withdrawal from baclofen. Am J
Psychiatry 1980; 137:1466-1467.
5. Bailey DV, Shaw RF: Interpretation of blood glutethimide, meprobamate, and methyprylon concentrations
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8. Chan CH: Dantrolene sodium and hepatic injury. Neurology 1990; 40:1427-1432.
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Med 1986; 4:552-553.
10. Cooke DEM, Glasstone MA: Baclofen poisoning in children. Vet Hum Toxicol 1994; 36:448-450.
11. Curry SC, Agnone FA, Mills KC: Neurotransmitter principles.

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12. Delhaas EM, Brouwers JRBJ: Intrathecal baclofen overdose: Report of 7 events in 5 patients and review
of literature. Int J Clin Pharmacol Ther Toxicol 1991; 29:274-280.
13. Eeckhout E, Huyghens L, Loef B, et al: Meprobamate poisoning, hypotension and the Swan-Ganz
catheter. Intensive Care Med 1988; 14:437-438.
14. Ferner RE: Atropine treatment for baclofen overdose. Postgrad Med J 1981; 57:580-581.
15. Garabedian-Ruffalo SM, Ruffalo RL: Adverse effects secondary to baclofen withdrawal. Drug Intell Clin
Pharm 1985; 19:304-306.
16. Goldberg D: Carisoprodol toxicity. Milit Med 1969; 134:597-601.
17. Haapanen EJ: Hemoperfusion in acute intoxication: Clinical experience with 48 cases. Acta Med
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18. Harrison SA, Wood Jr CA: Hallucinations after preoperative baclofen discontinuation in spinal injury
patients. Drug Intell Clin Pharmacol 1985; 19:747-749.
19. Heckerling PS, Bartow TJ: Paradoxical diaphoresis in cyclobenzaprine poisoning. [Letter]. Ann Intern
Med 1984; 101:881.
20. Jacobsen D, Wiik-Larsen E, Saltvedt E, et al: Meprobamate kinetics during and after terminated
hemoperfusion in acute intoxications. J Toxicol Clin Toxicol 1987; 25:317-331.
21. Kornhuber J, Parsons CG, Hartmann S, et al: Orphenadrine is an uncompetitive N-methyl-D-aspartate

(NMDA) receptor antagonist: Binding and patch clamp studies. J Neural Transm Gen Sect 1995; 102:237-
246.
22. Lee TH, Chen SS, Su SL, et al: Baclofen intoxication: Report of four cases and review of literature. Clin
Neuropharmacol 1992; 15:56-62.
23. Lees AJ, Clarke CRA, Harrison MJ: Hallucinations after withdrawal of baclofen. Lancet 1977; 1:858.
24. Lhoste F, Lemaire F, Rapin M: Treatment of hypotension in meprobamate poisoning. N Engl J

Med 1977; 296:1004.
25. Littrell RA, Hayes LR, Stillner V: Carisoprodol (Soma): A new and cautious perspective on an old agent.
South Med J 1993; 86:754-756.
26. Littrell RA, Sage T, Miller W: Meprobamate dependence secondary to carisoprodol (Soma) use. Am J
Drug Alcohol Abuse 1993; 19:133-134.
27. Lin JL, Lim PS: Continuous arteriovenous hemoperfusion in meprobamate poisoning. J Toxicol Clin
Toxicol 1993; 31:645-652.
28. Linden CH, Mitchiner JC, Lindzon RD, et al: Cyclobenzaprine overdosage. [Abstract]. J Toxicol Clin
Toxicol 1983; 20:281-288.
29. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 annual report of the American Association of
Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1999; 17:435.
30. Mahoney JM, Bachtel MD: Pleural effusion associated with chronic dantrolene administration. Ann
31. Meythaler JM, Steers WD, Tuel SM, et al: Continuous intrathecal baclofen in spinal cord spasticity: A
prospective study. Am J Phys Med Rehabil 1992; 71:321-327.
32. Nakagawa Y, Ishima T, Ishibashi Y, et al: Involvement of GABA(B) receptor systems in action of
antidepressants: Baclofen but not bicuculline attenuates the effects of antidepressants on the forced swim
test in rats. Brain Res 1996; 709:215-220.
33. Nugent S, Katz MD, Little TE: Baclofen overdose with cardiac conduction abnormalities: Case report
and review of the literature. Clin Toxicol 1986; 2:321-328.
34. O’Riordan W, Gillette P, Caideron J, et al: Overdose of cyclobenzaprine, the tricyclic muscle relaxant.
Ann Emerg Med 1986; 15:592-593.
35. Paloucek FP, Erickson TE, Lundquist S, et al: Oral dantrolene ingestion: A case series. [Abstract]. Vet
36. Patterson V, Watts M, Burnes D, et al: Management of severe spasticity with intrathecal baclofen
delivered by manually operated pump. J Neurol Neurosurg Psychiatry 1994; 57:582-585.
37. Pembroke AC, Saxena SR, Kataria M, et al: Acne induced by dantrolene. Br J
Dermatol 1981; 104:465-468.
38. Penn RD, Kroin JS: Failure of physostigmine in treatment of acute severe intrathecal baclofen
intoxication. [Letter]. N Engl J Med 1990; 322:1533-1534.
39. Rho JM, Donevan SD, Rogawski MA: Barbiturate-like actions of the propanediol dicarbamates
felbamate and meprobamate. J Pharmacol Exp Ther 1997; 280:1383-1391.
40. Rivas D, Chancellor MB, Hill K, et al: Neurological manifestations of baclofen withdrawal. J
Urol 1993; 150:1903-1905.
41. Roberge RJ, Martin TG, Hodgman W, et al: Supraventricular tachyarrhythmia associated with baclofen
42. Rumack BH (ed): POISINDEX management monograph: Meprobamate. Denver, Micromedex. Edition
expired 2/29/96.
43. Rust GS, Hatch R, Gums JG: Carisoprodol as a drug of abuse. Arch Fam Med 1993; 2:429-432.
44. Saltuari L, Marosi MJ, Kofler M, et al: Status epilepticus complicating intrathecal baclofen overdose.
[Letter]. Lancet 1992; 339:373-374.
45. Sanster B, Van Heijst ANP, Zimmerman ANE: Treatment of orphenadrine overdose. N Engl J
Med 1977; 296:1006.
46. Smith CR, LaRocca NG, Giesser BS, et al: High dose oral baclofen: Experience in patients with multiple
sclerosis. Neurology 1991; 41:1829-1831.
47. Spiller HA, Winter ML, Mann KV, et al: Five-year multicenter retrospective review of cyclobenzaprine
toxicity. J Emerg Med 1995; 13:781-785.
48. Stein R: Hallucinations after sudden withdrawal of baclofen. [Letter]. Lancet 1977; 2:44-45.
49. Swanson LA, Okada T: Death after withdrawal of meprobamate. JAMA 1963; 184:780-781.
51. Terrence CF, Fromm GH: Complications of baclofen withdrawal. Arch Neurol 1981; 38:588-589.
52. Yassa RY, Iskander HL: Baclofen-induced psychosis: Two cases and a review. J Clin
Psychiatry 1988; 49:318-320.


Uncited reference
Swiger ME, Bowers BM: Baclofen withdrawal and neuropsychiatric symptoms: A case report and review of
other case literature. Comp Psychiatry 1986; 27:396-400.


Chapter 34 – Vitamins
EDWARD W. CETARUK
Vitamins, taken in the proper amounts, are essential for health maintenance the prevention of certain
diseases such as scurvy, rickets, pellagra. They are generally considered healthy harmless, even in doses
far exceeding the recommended daily allowance (RDA) are touted to enhance athletic performance prevent
the common cold, facilitate weight loss, treat a multitude of medical ailments.[21] However, taken in excess
either chronically or acutely, many vitamins can cause significant toxicity. The fat-soluble vitamins A and D
accumulate in the body’s fat stores when taken in excessive doses over time. Chronic vitamin A and D
toxicity has been widely reported in the literature. Additionally, these vitamins can cause acute toxicity. The
water-soluble vitamins (the vitamin B complex and ascorbic acid) are commonly thought to be safe because
they are readily excreted in the urine. However, these vitamins also produce toxicity when taken in excessive
amounts.
VITAMIN A
The RDA is 5000 IU for adults and 2000 to 3000 IU for children.
Essentials: Hypervitaminosis A
• History of excessive intake of preformed vitamin A
• Chronic hypervitaminosis A: brittle nails, dry scaling skin, alopecia, arthralgias, hepatosplenomegaly,
ascites, headache, bone pain, hypercalcemia
• Acute hypervitaminosis A: headache, lethargy and/or irritability, nausea, vomiting, delayed generalized
desquamating rash
• Evidence of elevated intracranial pressure (pseudotumor cerebri) including headache, papilledema,
bulging fontanelles in children, nausea, vomiting, blurred vision, and/or diplopia
Pharmacology/Pathophysiology
Pharmacology
Vitamin A is found in food as retinyl esters and is absorbed from the small intestine by a carrier-mediated
process after being converted to retinol by pancreatic esterase. It is stored primarily (80–90%) in the
perisinusoidal stellate (Ito) cells of the liver as retinyl esters.[8] Vitamin A 1 (retinol) undergoes enterohepatic
circulation; other water-soluble metabolites are excreted in the urine and feces. In the retina, vitamin A,
converted to 11-cis-retinal, integrates into the photosensitive protein rhodopsin. It also regulates the
synthesis of proteins, bone metabolism, and the processes of cell differentiation and keratinization in
epithelial tissues such as the skin, hair, and nails.[33]
Pathophysiology
Retinol mobilized from the liver is transported bound to retinol-binding protein (RBP) in a 1:1 molar ratio.[36]
Toxicity results when the carrying capacity of the RBPs is overwhelmed and free retinol is available to bind
with cellular lipoproteins.[36] Vitamin A lyses cell membranes and inhibits membrane-associated processes
in animal models.[22] The toxic effects of retinol at these target tissues produce the characteristic
dermatologic abnormalities of hypervitaminosis A, as well as bone and cartilage resorption, cortical
hyperostosis, and periosteal calcifications.[17][22][36][40] In the liver, storage of excess vitamin A causes
hyperplasia and hypertrophy of the perisinusoidal stellate cells, perisinusoidal fibrosis, and cirrhosis that
presents clinically as hepatosplenomegaly, portal hypertension, mild to moderate transaminase elevations,
and, rarely, death.[18][29][47] The mechanism by which hypervitaminosis A produces pseudotumor cerebri is
not known.
The clinical presentation of hypervitaminosis A varies with the time course of the exposure and with age (
Table 34–1 ). The diagnosis of vitamin A toxicity, especially in the chronic form, is often delayed because of
the relatively nonspecific nature of the symptoms and effects on multiple organ systems.
Table 34-1 -- Clinical Presentation of Hypervitaminosis A

Acute and Chronic Manifestations
Adult Pediatric
System Acute Chronic Acute Chronic
Central and peripheral nervous Drowsiness Headache Irritability Headache
systems
Headache Lethargy Bulging
fontanelles
Pheripheral Bulging
neuritis fontanelles
Blurred vision Blurred vision Papilledema
Diplopia Photophobia
Papilledema Dry mucosa
Head, eye, ear, nose, & throat
Conjunctivitis
Dry mucosa
Epistaxis
Gastrointestinal Anorexia Anorexia Anorexia Anorexia
Nausea Nausea Nausea Nausea
Vomiting Vomiting Vomiting Vomiting
Abdominal pain Abdominal pain Abdominal pain
Diarrhea
Hepatomegaly Hepatomegaly
Hepatic
Ascites
Desquamation Desquamation Erythema
Alopecia Desquamation
Brittle nails Alopecia
Skin
Pruritus Cheilosis
Xeroderma Pruritus
Xeroderma
Muscle weakness Myalgias Myalgias
Musculoskeletal Arthralgias Arthralgias
Bone pain Bone pain
Weight loss
Malaise/fatigue
Other
Petechiae
Fever
Based on data from references 17 , 18 , 22 , and 36 .
Chronic Toxicity
Adults with chronic hypervitaminosis A complain of the gradual and progressive onset of anorexia, malaise,
weight loss, myalgias, arthralgias, fatigue, and bruising. They usually have a history of taking in excess of
25,000 IU per day. Toxicity can occur with the use of retinoids for dermatologic diseases. Patients who
develop elevated intracranial pressure (pseudotumor cerebri) complain of headache and nausea. They may
have papilledema, with markedly elevated opening pressures on lumbar puncture. Infants are more sensitive
to vitamin A toxicity, which can develop with consumption of 7.5 to 15 mg of retinol daily for 30 days.[33] They
may present with persistent irritability and bulging fontanelles, as well as other symptoms seen in adults.
Gastrointestinal effects range from nausea and abdominal pain to hepatotoxicity with hepatosplenomegaly,
cirrhosis, ascites, esophageal varices, and jaundice. Patients with vitamin A toxicity may have significant
hypercalcemia, with secondary bone pain, ectopic calcifications, polyuria, and polydipsia. Integumentary
signs include brittle hair and nails, alopecia, stomatitis, rash, and dry, scaling skin. Patients may often have
one or more ophthalmologic findings such as blurred or double vision, eye pain, xerophthalmia,
conjunctivitis, corneal ulcerations or calcifications, and papilledema. Patients may also be ingesting large
amounts of beta-carotene, which has negligible toxicity but which can produce a generalized orange skin
color (betacarotenemia) that may be mistaken for jaundice.[17][18][22][36]
Acute Toxicity
Acute toxicity usually follows the acute ingestion of several hundred thousand units of vitamin A. Patients
present with abdominal pain, headache, irritability, weakness, nausea, and vomiting a few hours to 1 day
after ingestion. These symptoms are followed shortly by a generalized erythematous desquamating rash,
alopecia, cheilitis, petechiae, and hepatosplenomegaly.[17][18][22][36]
The diagnosis of hypervitaminosis A is often missed because of its diffuse organ system involvement.
Patients typically are in good health except for complaints localized to the musculoskeletal, integumentary,
and nervous systems. The differential diagnosis of the hypercalcemia seen in hypervitaminosis A is similar
to that of vitamin D ( Table 34–2 ). Pseudotumor cerebri is associated with a number of medications and
medical conditions that are listed in Table 34–3 . Other causes of increased intracranial pressure such as
space-occupying mass lesions should also be excluded.
Table 34-2 -- Differential Diagnosis of Hypercalcemia

Aluminum toxicity
Hyperthyroidism
Hypervitaminosis A
Idiopathic hypercalcemia of infancy
Lithium therapy
Malignancies
Milk alkali syndrome
Primary hyperparathyroidism
Renal failure
Sarcoidosis
Secondary hyperparathyroidism
Thiazide use
Table 34-3 -- Causes of Pseudotumor Cerebri

Adapted from Goldfrank LR: Vitamins. In Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank’s
Toxicological Emergencies, 5th ed. Norwalk, CT, Appleton & Lange, 1994, pp 535–544.
The hepatotoxicity seen in chronic hypervitaminosis A is characterized by hyperplasia and hypertrophy of the
perisinusoidal stellate (Ito) cells of the liver causing perisinusoidal fibrosis, sinusoidal congestion, and
cirrhosis. Other xenobiotics known to cause a similar pattern of liver injury include chronic arsenic, ethanol,
and pyrrolizidine alkaloid ingestion.[38] All of these agents can produce a Budd-Chiari syndrome with ascites,
hepatosplenomegaly, and peripheral edema. It is notable that pyrrolizidine alkaloids are found in a number
of plant species (Crotalaria, Senecio, Symphytum officinale) used in herbal teas, and patients using
megadose vitamin therapy may also be using herbal medicine products.[3][54]
Laboratory Studies
Blood chemistry studies may reveal hypercalcemia, normal to elevated serum phosphate levels, and an
elevated alkaline phosphatase level. Liver function tests may show mild to moderate transaminase
elevations and hyperbilirubinemia, with hypoprothrombinemia noted on coagulation studies. Anemia and/or
leukopenia have been reported. Hyperlipidemia and hypertriglyceridemia are also seen. Lumbar puncture
may demonstrate high opening pressures due to pseudotumor cerebri, but cerebrospinal fluid cell counts
and chemistries remain normal. An electrocardiogram may reveal a prolonged Q-Tc. Bone radiographs can
demonstrate subperiosteal and ectopic calcifications.
Treatment
Most signs and symptoms resolve spontaneously after the withdrawal of all sources of vitamin A. Brittle
nails, coarse hair, and alopecia may persist for weeks after discontinuation of vitamin A supplementation but
should resolve. Treatment of hypercalcemia includes intravenous fluid hydration and monitoring of renal
function. Furosemide may increase renal calcium excretion. Prednisone in an adult in a dose of 20 mg/d
orally has also been used to treat vitamin A–induced hypercalcemia. [6][16] Pseudotumor cerebri can be
treated with lumbar punctures to remove cerebrospinal fluid and with diuretics and prednisone (see Table
34–8 ).
Table 34-8 -- Treatment of Vitamin Toxicity *

Vitamin Therapy
Vitamin withdrawal
A (retinol) Hypercalcemia; fluids, furosemide, prednisone, monitor renal function
Pseudotumor cerebri: lumbar puncture, diuretics, prednisone
B6 (pyridoxine) Vitamin withdrawal
Vitamin withdrawal
Antiemetics (e.g., promethazine)
C (ascorbic acid)
Hemolysis: intravenous fluids, packed red blood cells as needed for anemia, monitor renal
function
Vitamin withdrawal
D Diet: low calcium, low vitamin D
(cholecalciferol)
Hypercalcemia: fluids, furosemide, prednisone, biphosphonate inhibitors, monitor renal
function
Vitamin withdrawal
Niacin Acute: Aspirin or ibuprofen for vasodilation

Chronic: Hepatotoxicity: supportive care; rhabdomyolysis: intravenous fluids to maintain
urinary output 1–2 mL/kg/hr, urinary alkalinization for urinary aciduria, monitor renal function
* Gastrointestinal decontamination with oral activated charcoal (1 g/kg) is indicated in cases of acute overdose. However, most cases of
vitamin toxicity are secondary to chronic overuse and will not require gastrointestinal decontamination.
Disposition
Patients with significant hypercalcemia, renal or hepatic failure, or cardiac dysrhythmias require hospital
admission. Patients with mild to moderate hypercalcemia can be treated as outpatients with monitoring of
renal function and serum calcium levels.
Sequelae
Ectopic calcifications may persist. Renal failure due to nephrocalcinosis may require short- or long-term
hemodialysis. Although early liver injury may resolve, the structural abnormalities associated with the
development of cirrhosis persist despite withdrawal of vitamin A therapy.
Specific Situations
Excessive vitamin A intake has been found to be teratogenic, producing birth defects primarily associated
with cranial neural crest development.[46][58] Children, patients with pre-existing liver disease and/or protein
malnutrition, and those taking tetracycline-like antibiotics may be at higher risk for developing toxicity with
excessive vitamin A intake.[22][37]


VITAMIN B6
The term vitamin B 6 refers to three structural forms of the vitamin: pyridoxine, pyridoxal, and pyridoxamine.
All these pyridine derivatives have the same biologic activity in preventing pellagra, the syndrome of vitamin
B6 deficiency. By convention, the terms pyridoxine and vitamin B 6 are synonymous. The RDA is 2.0 mg for
adults and 0.5 to 1.0 mg for children.
Essentials
• History of excessive intake of vitamin B6
• “Stocking-glove” peripheral sensory neuropathy, preserved motor strength, depressed deep tendon
reflexes
Pharmacology
Pyridoxal phosphate functions as a coenzyme in decarboxylation, transamination, and racemization

reactions in amino acid metabolism. Pyridoxine is required for the conversion of tryptophan to 5-
hydroxytryptamine (serotonin), as well as dopa to dopamine.[34] Pyridoxine is also essential for the synthesis
of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by the enzyme glutamate
decarboxylase. It is well absorbed from the gastrointestinal tract, and pyridoxal phosphate is the primary
circulating form. It undergoes hepatic metabolism to 4-pyridoxic acid.
Pathophysiology
Pyridoxine deficiency causes decreased brain GABA levels, thought to be the cause of seizures seen in
patients with pyridoxine deficiency. [34] Isoniazid (INH) antagonizes the action of pyridoxine at several sites,
causing a clinical picture similar to that of pyridoxine deficiency.[61] INH is metabolized to a hydrazone
derivative that directly inhibits pyridoxine phosphokinase. INH hydrazides also inactivate pyridoxal 5'
phosphate, an essential coenzyme for glutamate decarboxylase.[25] Pyridoxine is depleted by the formation
of isonicotinylhydrazine-pyridoxine complexes that are excreted in the urine.[7][48] The sum of these effects
causes decreased levels of GABA, an effect that is reversed by the antidotal administration of pyridoxine for
INH-induced seizures.[57] N-methylhydrazine, a metabolite of gyromitrin found in Gyromitra esculenta
mushrooms, also binds to pyridoxine and interferes with enzymes requiring pyridoxine as a cofactor.
In excess amounts, taken either acutely or chronically, pyridoxine produces a pure sensory neuropathy;
weakness is not a feature. In seven adults, chronic doses of 5 to 6 g/day for 2 to 3 months or lesser amounts
for longer time periods produced a distal neuronopathy predominantly affecting position, vibration, and deep
tendon reflexes.[49] In another case series of female patients, lower doses of 200 to 500 mg/day were
associated with paresthesias, numbness, ataxia, and pain. Signs included sensory deficits, sensory ataxia,
Romberg’s sign, and loss of Achilles reflexes.[42] Histologic studies in both humans and animals have shown
the underlying pathology of this sensory neuropathy to be a primary neuronopathy of dorsal root neurons
and a secondary axonopathy. Motor neurons remain intact.[4][30][49][59]
The predominant feature seen in both acute and chronic pyridoxine toxicity is a sensory neuropathy ( Table
34–4 ). The patient may complain of difficulty walking, loss of balance, and loss of manual dexterity. Physical
examination demonstrates decreased touch, proprioception, temperature, and vibration. Reflexes are
absent, and motor strength is preserved. Patients may be ataxic or have a wide-based gait. The Romberg
test, which demonstrates an increase in ataxia when visual imput is interrupted, is positive. The sensory
deficits follow a “stocking-glove” distribution and in severe cases may include perioral numbness. Symptoms
may persist or progress for 2 to 3 weeks after pyridoxine is discontinued. Although most patients recover
completely, permanent deficits may result. Paresthesias and Lhermitte’s sign, painful shock-like sensations
elicited by neck flexion that radiate down the spine and occasionally into the lower extremities, may also
occur.[1][5][49]
Table 34-4 -- Clinical Presentation of Pyridoxine Toxicity

Absent Babinski signs
Ataxia
Clumsiness
Decreased/absent deep tendon reflexes
Dyspepsia
Stocking-glove sensory losses:
Light touch
Proprioception
Temperature
Vibration
Nausea
Paresthesias/Lhermitte’s sign
Perioral numbness (late)
Preserved muscle strength
Wide-based gait
Based on data from references 1 , 4 , 5 , and 49 .
INH and ethambutol both cause a sensory neuropathy and may confound the diagnosis of pyridoxine-
induced sensory neuropathy in patients taking pyridoxine-INH combinations as part of tuberculosis treatment
regimens or in those treated with high dose pyridoxine for acute INH overdose.[61] Toxic causes of sensory
neuropathy are numerous ( Table 34–5 ). However, many compounds that cause sensory neuropathies may
not do so in the pattern caused by pyridoxine, and many also cause concomitant motor neuropathies. A
careful exposure and medication history is essential in determining the likely cause of a toxin-induced
neuropathy. Medical conditions, including diabetes mellitus, hypothyroidism, and certain neoplasms, are
associated with sensory neuropathies and must be considered in the clinical evaluation.
Table 34-5 -- Differential Diagnosis of Pyridoxine Neuronopathy

Acrylamide
Allyl chloride
Arsenic
Carcinoma
Carbon disulfide
Chloramphenicol
Cisplatin
Colchicine
Diabetic neuropathy
Disulfiram
Doxorubicin
Ethambutol
Ethionamide
Glutethimide
Gold
Hexane
Hydralazine
Hypothyroidism
Isoniazid
Metronidazole
Nitrous oxide
Phenytoin
Platinum
Taxol
Thallium
Vincristine
Vitamin B12 deficiency
Laboratory Studies
Increased serum pyridoxal phosphate levels have been measured in patients taking high dose (1 to 3 g/day)
vitamin B 6 supplements. These levels returned to normal after pyridoxine was discontinued, although
sensory deficits persisted longer. Quantitative neurologic measurements showed elevation of thermal and
vibratory sensory thresholds, reduction of sural sensory potential amplitudes, and unchanged sural nerve
conduction velocity.[5]
Treatment
All sources of supplemental pyridoxine should be withdrawn (see Table 34–8 ).
Disposition
Patients with severe sensory neuropathies require long-term follow-up and may need physical therapy and
ambulation aids.
Sequelae
A husband and wife treated with 132 g and 183 g, respectively, of intravenous pyridoxine over 3 days for
Gyromitra mushroom poisoning developed permanent sensory neuropathies. Both patients had profoundly
impaired limb proprioception and appendicular ataxia that did not resolve. One year after onset, neither had
recovered joint position sense, resulting in their permanent inability to walk. [1]
Specific Situations
Pyridoxine antagonizes the effects of L-dopa in the treatment of Parkinson disease, by promoting its
peripheral decarboxylation to dopamine and reducing the amount available to cross the blood-brain barrier.
Pyridoxine-induced peripheral neuropathy may be seen in patients with concurrent or pre-existing INH-
induced peripheral neuropathy.[41]


VITAMIN C
Vitamin C is an essential dietary nutrient because it cannot be synthesized by humans. The RDA for vitamin
C is 60 mg for adults and 40 mg for children.
Essentials
• History of excessive vitamin C intake
• Unexplained hemolytic syndromes
• Uricosuria and/or oxalic aciduria, with or without renal stones
Pharmacology
Vitamin C (ascorbic acid) is a required cofactor for the function of a number of enzymes involved in
hydroxylation and amidation reactions, such as collagen and proteoglycan synthesis, and microsomal drug
metabolism. It is readily absorbed from the gastrointestinal tract by a saturable, energy-dependent process.
At lower concentrations, metabolism in the liver produces a number of metabolites, including oxalate. At
higher concentrations, unchanged vitamin C is also excreted in the urine.[34]
Pathophysiology
Insufficient dietary intake of vitamin C causes scurvy.[34] Excessive vitamin C intake has been found to
increase the urinary excretion of oxalate.[53][56] Whether this increased oxalate excretion causes calcium
oxalate renal stones is controversial. However, no sound scientific data thus far can support a direct causal
relationship between increased vitamin C intake and increased incidence of calcium oxalate renal
stones.[12][15][23][53][56] Several cases of severe hemolysis have been reported after high doses of oral and
intravenous vitamin C.[20][27][44] The mechanism by which vitamin C induces hemolysis is unknown.
However, patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or paroxysmal nocturnal
hemoglobinuria may be at higher risk.[9][27][44]
Patients with significant vitamin C toxicity are uncommon and are usually receiving doses as high as 40 to
80 g/day (orally and/or intravenously) as part of megadose vitamin therapies. Indications range from cancer
and schizophrenia to acquired immunodeficiency syndrome (AIDS). Excessive vitamin C intake most
commonly causes gastrointestinal symptoms, including nausea, abdominal cramping, and diarrhea.[23]
Large acute oral ingestions or large intravenous doses of vitamin C have caused hemolysis, with resultant
anemia and hemoglobinuria.[27][44] Patients with pre-existing hemoglobinopathies or enzymopathies may be
at higher risk for hemolysis.[2]
The differential diagnosis includes other hematologic causes of hemolysis, including enzymopathies such as
G6PD deficiency, sickle cell anemia, and paroxysmal nocturnal hemoglobinuria; other exogenous sources of
oxidative stress (fava beans, nitrates); or other oxidant medications (e.g., dapsone, primaquine,
phenazopyridine).
Laboratory Studies
The complete blood cell count may show evidence of hemolysis and resultant anemia. Significant hemolysis
will cause elevated serum lactate dehydrogenase and decreased haptoglobin levels. Urinalysis may show
hemoglobinuria, uricosuria, and oxaluria. Reports that vitamin C destroys dietary vitamin B12 have been
shown to be based on an analytical laboratory error, and this is not a true interaction.[52]
Treatment
All sources of vitamin C should be withdrawn, and supportive therapies including antiemetics should be
administered as needed. Significant vitamin C–induced hemolysis requires intravenous hydration to maintain
adequate urine output, monitoring of renal function, and transfusions as needed for anemia (see Table 34–8
).
Disposition
Patients with significant hemolysis necessitating intravenous fluids or transfusion, or who have
hemoglobinuria-induced renal failure, require hospital admission.
Sequelae
No sequelae have been reported.


VITAMIN D
The RDA of vitamin D for adults and children is 400 IU.
Essentials: Hypervitaminosis D
• History of excessive intake of vitamin D 2 (calciferol) or D3 (cholecalciferol)
• Signs and symptoms of hypercalcemia, including weakness, headache, polyuria, polydipsia, anorexia,
nausea, vomiting, altered mental status, weight loss or failure to thrive, bone and/or abdominal pain, and
cardiac dysrhythmias
• Other findings of hypercalcemia, normal or elevated phosphorus levels, albuminuria, hypercalciuria,
ectopic soft tissue calcifications, and pancreatitis
Pharmacology
Vitamin D is well absorbed from the gut and stored in fat deposits. It is also synthesized in the skin. It
functions as a hormone to regulate calcium homeostasis by increasing gut absorption of calcium, increasing
calcium mobilization from bone, and decreasing calcium excretion by the kidneys. It is transported on
vitamin D–binding protein and undergoes hydroxylation by hepatic P-450 microsomal enzymes to calcifediol
(25-OHD3), which is then transported to the kidney where it undergoes 1-hydroxylation to its final active form
calcitriol (1,25-[OH]2D3). [32] The 25-OHD3 derivative is the predominant form associated with hypercalcemia
due to the clinical syndrome of hypervitaminosis D.[28][39][51]
Pathophysiology
Hypervitaminosis D can result from excessive vitamin D dietary supplementation,[24] inaccurately and
excessively fortified dairy products,[28] prolonged use of vitamin D–fortified infant formulas,[39] or ingestion of
vitamin D rodenticides. Iatrogenic hypervitaminosis D is seen in poorly monitored vitamin D therapy for
disorders such as rickets and hypoparathyroidism.[26][51] The toxic manifestations are due to hypercalcemia.
Although hypervitaminosis D may present acutely, it usually presents with the insidious onset of symptoms
of hypercalcemia ( Table 34–6 ). The diagnosis requires a high index of suspicion of excessive vitamin D
intake as the cause of unexplained hypercalcemia. Patients’ complaints may seem somewhat diffuse due to
the many organ systems affected. Signs and symptoms may involve any combination of the gastrointestinal,
musculoskeletal, cardiovascular, renal, and central nervous systems. Patients with vitamin D toxicity and
significant hypercalcemia may have bone pain, polyuria, polydipsia, and ectopic soft tissue calcifications,
including nephrocalcinosis and corneal calcifications. Children, especially infants, may present primarily with
irritability, failure to thrive, nausea, and vomiting. Patients may also have pancreatitis, progressive renal
failure, and, rarely, hypercalcemia-induced cardiac dysrhythmias.[24][26][28][45][51]
Table 34-6 -- Clinical Presentation of Hypervitaminosis D

System Adult Pediatric
Headache Headache
Neurologic
Confusion Irritability
Anorexia Anorexia
Nausea Nausea
Gastrointestinal Vomiting Vomiting
Abdominal pain Abdominal pain
Pancreatitis (rare)
Musculoskeletal Bone pain Bone pain
Cardiovascular Dysrhythmias (rare) Hypertension
Polyuria
Renal
Renal failure (rare)
Weakness/fatigue Weakness/fatigue
Other Weight loss Weight loss
Polydipsia Failure to thrive
Based on data from references 24 , 26 , 28 , 45 , and 51 .
The differential diagnosis of hypervitaminosis D is essentially that of hypercalcemia and includes

hypervitaminosis A, lithium therapy, hyperparathyroidism, malignancies, sarcoidosis, and renal failure (see
Table 34–2 ).
Laboratory Studies
Blood chemistry studies show hypercalcemia, hyperphosphatemia, and azotemia. Urinalysis may show
proteinuria. Serum cholecalciferol (25-OHD3), calcitriol (1,25-[OH]2D3), and/or parathyroid hormone (PTH)
levels may help to make the diagnosis of hypervitaminosis D. Elevated serum cholecalciferol (25-OHD3)
levels, normal or elevated serum calcitriol (1,25-[OH]2D3) levels, and normal or low parathyroid hormone
(PTH) levels are seen. An electrocardiogram should also be obtained, especially in patients taking digoxin.
Treatment
Initial management is the withdrawal of all exogenous sources of vitamin D and a low-calcium, low-vitamin D
diet. Treatment of hypercalcemia includes intravenous fluid hydration and monitoring of renal function.
Furosemide may increase renal calcium excretion. Glucocorticoids have been effective in reducing serum
calcium levels, although the primary mechanism is unclear.[27][55] Bisphosphonate inhibitors of bone
resorption have also been used to treat hypercalcemia due to hypervitaminosis D[45][51](see Table 34–8 ).
Disposition
Patients with significant hypercalcemia, renal or hepatic failure, or cardiac dysrhythmias require hospital
admission. Patients with mild to moderate hypercalcemia can be treated as outpatients with monitoring of
renal function and serum calcium levels.
Special Situations
Digoxin toxicity, especially in the setting of renal failure, could be worsened by hypervitaminosis D–induced
hypercalcemia.


NIACIN
The RDA for niacin is 20 mg for adults and 9.0 mg for children.
Essentials
• Ingestion of immediate-release (IR), or crystalline, niacin produces flushing, nausea, headache,
vasodilation, and pruritus.
• Sustained-release (SR) preparations of niacin have a lower incidence of these symptoms but a higher
incidence of gastrointestinal complaints [35] and hepatotoxicity.
• Signs and symptoms of niacin toxicity should resolve after its use is discontinued.
Pharmacology
Niacin (vitamin B3) is readily absorbed from the gut and converted into either nicotine adenine dinucleotide
(NAD) or nicotine adenine dinucleotide phosphate (NADP). Both function as important coenzymes in
multiple cellular oxidation-reduction reactions. At doses of 500 mg to 3000 mg/day, niacin is an effective
hypolipidemic agent, reducing serum concentrations of total cholesterol, very low density lipoprotein, low
density lipoprotein cholesterol, and triglyceride levels while increasing high density lipoprotein cholesterol
levels. Niacin affects lipoprotein metabolism at many sites, including lipolysis, triglyceride synthesis,
lipoprotein transport, and lipoprotein lipase activity.[20][35][60] Niacin’s hypolipidemic effect is unrelated to its
role as a vitamin.
Pathophysiology
Niacin toxicity may present as an acute vasodilatory syndrome or as a subacute hepatotoxic syndrome.
Niacin-induced vasodilatory symptoms are thought to be prostaglandin-mediated and are lessened by taking
an aspirin daily while on niacin therapy. [35][60] The mechanism of niacin-induced hepatotoxicity is unknown.
Noninvasive radiologic studies and liver biopsies show fatty liver infiltration that resolves with the cessation
of niacin use.[11][31] Liver biopsies also demonstrate hepatocellular death, cholestasis and canalicular
plugging, portal fibrosis, and inflammatory changes.[43] Dietary deficiency causes pellagra.[34]
Clinical Presentation ( Table34–7 )
Acute Toxicity
The vasodilatory syndrome is more commonly seen with the IR, or crystalline, form of niacin. It can occur
acutely after ingestion of as little as 100 mg of IR niacin. Patients usually complain of a severe flushed
sensation, nausea, pruritus, dizziness, lightheadedness, and headache. These symptoms are usually self
limited and tend to occur less frequently as patients develop tolerance. They are lessened by premedication
with aspirin or ibuprofen.
Table 34-7 -- Clinical Presentation of Niacin Toxicity

Abdominal pain
Acanthosis nigricans
Anorexia
Diarrhea
Edema
Encephalopathy
Fatigue
Flushing
Headache
Jaundice
Myalgias
Myoglobinuria
Nausea
Pruritus
Vasodilation
Vomiting
Weakness
Weight loss
Based on data from references 11 , 13 , 19 , 35 , and 43 .
Chronic Toxicity
Subacute or chronic toxicity occurs more commonly with use of SR niacin preparations. These patients have
a higher frequency of gastrointestinal complaints as well as signs and symptoms of hepatic dysfunction,
including jaundice, abdominal pain, ascites, edema, elevated serum ammonia levels, hepatic
encephalopathy, and, rarely, fulminant hepatic failure.[10][11][13][20][31][35][43] Myopathy has been reported with
muscle weakness, fatigue, and myalgias.[19]
Niacin may cause exacerbation of pre-existing peptic ulcer disease.[35] Information regarding niacin toxicity
in the pediatric population is extremely limited.
The acute vasodilatory syndrome seen with IR niacin may easily be confused with an allergic response. A
history of symptoms temporally related to the ingestion of niacin should suggest the diagnosis. The
hepatotoxicity seen with prolonged use of niacin, usually in the SR form, includes signs of portal fibrosis,
inflammation, and cirrhosis, as well as parenchymal injury and hepatocyte death. Other toxic and medical
causes of cirrhosis must also be considered. A careful exposure and medication history is essential.
Laboratory Studies
Patients with niacin-induced hepatotoxicity may have elevated serum hepatic transaminase and alkaline
phosphatase levels, hyperbilirubinemia, acidemia, and hypoprothrombinemia.[11][13][14][20][31][35][43]
Hyperglycemia, sometimes severe,[50] and hyperuricemia are also seen. Rhabdomyolysis, with elevated
serum creatinine phosphokinase levels, has been reported with niacin-induced myopathy.[19]
Treatment
Symptoms of acute niacin toxicity can be managed with aspirin or ibuprofen ( Table 34–8 ). For chronic
toxicity, niacin should be stopped. Patients with significant hepatic dysfunction, such as encephalopathy,
may require intensive care monitoring and supportive care until liver function recovers. Treatment of
rhabdomyolysis includes maintenance of urinary output (1–2 mL urine/kg/hr), urinary alkalinization for
urinary aciduria, and monitoring of renal function.
Disposition
With the exception of patients with significant hepatic dysfunction, most patients can be managed as
outpatients after cessation of niacin use.
Sequelae
No sequelae have been reported.


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Chapter 35 – Iron
MILTON TENENBEIN
Essentials
• A history of ingestion of iron is noted.
• Gastrointestinal symptoms predominate early (abdominal pain, vomiting, hematemesis,
hematochezia).
• Abdominal radiograph may show radiopaque tablets.
• Shock, acidosis, and decreased level of consciousness occur in severe cases.
• Serum iron concentration is in the toxic range.
INTRODUCTION
Although iron poisoning is the most common cause of death due to poisoning in young children,[18] it is also
a significant problem in adolescents and adults.[24] Iron poisoning is unique within the realm of overdose
toxicology because, unlike other toxins, iron is not a xenobiotic. Because it is naturally occurring and highly
reactive, complex systems have evolved for the absorption, transport, storage, and utilization of this
essential metal. Because the capacities of these systems are not completely understood, many aspects of
the management of iron poisoning are controversial, making iron poisoning one of the most difficult acute
overdoses to treat.


Pharmacology
Under normal conditions the oral bioavailability of inorganic iron is less than 10 per cent. Non–heme-bound
iron is absorbed predominantly in the ferrous state in the duodenum and proximal jejunum, a process that
depends on mucosal cell binding. This iron is bound to ferritin within the intestinal mucosal cell.
Subsequently, if needed by the body, the iron is bound in the ferric state to transferrin, a carrier protein.
Transferrin then transports the iron through the plasma to cells for storage until needed for the manufacture
of iron-containing proteins and enzymes.[21][28]
In overdose, it is unknown whether the oral bioavailability of iron is more, less, or equal to the bioavailability
after therapeutic dosing.
Pathophysiology
Iron is a potent catalyst of free radical formation and is capable of oxidizing a wide range of substrates,
including lipid, protein, DNA, and various biomolecules. [11] Biologic damage does not occur in individuals
with physiologic amounts of iron because of the presence of transport and storage proteins such as
transferrin and ferritin. In the acute overdose situation, these protective mechanisms can be overwhelmed,
resulting in tissue damage and dysfunction. This is most likely to occur in tissues with high metabolic activity
that are exposed to increased iron concentrations because free radicals produce damage at their sites of
generation.
Typical iron poisoning targets include the gastrointestinal tract,[35] the cardiovascular system,[33][38] and the
liver. [10][19] Gastrointestinal epithelial cells have high metabolic activity and after an overdose are exposed to
very high concentrations of iron. Despite pathologic similarities to an alkali or acid injury, iron-induced
damage to the gastrointestinal lining is not caustic or corrosive. This damage accounts for the abdominal
pain, vomiting, gastrointestinal bleeding, and intestinal infarcts seen early in iron poisoning and the
gastrointestinal strictures seen several weeks later. Gastrointestinal signs and symptoms should be thought
of as local rather than systemic toxicity and are produced by much lower doses, 10 to 20 mg/kg, versus
more than 40 mg/kg usually associated with systemic toxicity. Other areas of high metabolic activity such as
the cardiovascular system and liver are also sensitive to the deleterious effects of increased iron
concentrations. This results in distributive and cardiogenic shock and acute hepatic necrosis. Shock or liver
failure is the usual cause of death in iron poisoning.
The metabolic acidosis of iron poisoning can be very severe. Although partly secondary to lactate resulting
from hypoperfusion, it is largely a direct effect of excess iron. After the capacity for plasma iron binding has
been exceeded, ferric ions are then hydrated as follows:
Therefore, each nonbound ferric ion generates three protons,

accounting for the marked acidosis.
Coma is seen in severe iron poisoning and is secondary to iron-induced metabolic disruptions such as
acidosis, hypoperfusion, and hepatic failure.
Coagulopathy can occur in iron poisoning. There are two distinct types: early and late onset.[32] The early
coagulopathy occurring within hours of ingestion is a functional, reversible, serum iron
concentration–dependent impairment of coagulation. Very high iron concentrations inhibit the function of
protease enzymes of the coagulation cascade. The late coagulopathy develops at least 24 hours after iron
ingestion and is a consequence of iron-induced hepatotoxicity.


There are five stages of iron poisoning[2] ( Table 35–1 ). Stage I consists of gastrointestinal symptoms
including abdominal pain, vomiting, hematemesis, and hematochezia. Onset is typically within 2 hours of
ingestion; and if gastrointestinal symptoms do not occur within 6 hours, then the patient has not ingested a
dangerous amount of iron. Ingestion of enteric-coated iron tablets is an exception to this 6-hour rule.
Gastrointestinal hemorrhage during stage I can be life-threatening.
Table 35-1 -- Clinical Presentation *

Stage I—Gastrointestinal (0.5–6.0 hr) †
Abdominal pain
Vomiting
Diarrhea
Hematemesis
Hematochezia
Stage II—Relative Stability (4–12 hr) ‡
Gastrointestinal symptoms improve
Subclinical hypoperfusion and metabolic acidosis
Stage III—Shock and Acidosis (6–72 hr)
Hypoperfusion
Metabolic acidosis
Coma
Coagulopathy
Potential multisystem failure
Stage IV—Hepatic Necrosis (12–96 hr)
Coma
Coagulopathy
Jaundice
Stage V—Bowel Obstruction (2–4 wk)
Abdominal pain
Vomiting
Dehydration
* Stages may overlap in severe poisonings.
† The absence of gastrointestinal symptoms by 6 hours after ingestion indicates an insignificant ingestion (exception: ingestion of enteric-
coated iron tablets).
‡ Patients are not normal during stage II. Assess closely for early hypoperfusion and monitor blood gases.
There is considerable confusion regarding stage II, which is a period of relative stability. It is best thought of
as a “lull before the storm,” a gap between the lessening of gastrointestinal symptoms and the appearance
of shock. The patient’s condition is not normal during stage II, however, and careful assessment will show
evidence of hypoperfusion and acidosis. Therefore, vigilance is required after gastrointestinal symptoms
have ameliorated to determine whether the patient has truly recovered or is destined for deterioration.
Stage III, shock and acidosis, accounts for most iron poisoning deaths. The etiology of the shock can be
multifactorial and includes hypovolemia due to vomiting and gastrointestinal hemorrhage, which occur early;
distributive shock with an onset within the first 24 to 48 hours of ingestion; and cardiogenic shock, which
occurs several days later and is due to the direct effect of iron on the myocardium. These causes can
overlap, and severely iron-poisoned patients require invasive physiologic monitoring to guide management.
Metabolic acidosis occurs during this stage.
Stage IV, hepatotoxicity, occurs within 48 hours of iron ingestion. It does not develop in all iron-poisoned
patients and is independent of the occurrence of shock. It is the second most common cause of death in iron
poisoning.
Stage V, bowel obstruction, may develop 2 to 4 weeks after the ingestion. The primary presenting symptom
is vomiting. The obstruction is due to a subacute inflammatory reaction occurring within the mucosal aspect
of a segment of the gastrointestinal tract with subsequent stricture formation. The most common site is the
gastric outlet, but any portion of the gut can be involved. Abdominal pain persisting for several days after the
iron ingestion is a prognosticator.[35]


The differential diagnosis is usually not difficult because the diagnosis is usually the chief complaint: iron
ingestion ( Table 35–2 ).
Table 35-2 -- Differential Diagnosis

1. Only an issue if the history of iron ingestion is not known.
2. Consider metabolic, structural, and infectious causes for the gastrointestinal signs and symptoms.
3. Other poisonings with similar gastrointestinal symptoms include aspirin, theophylline, organophosphates,
carbamates, other metals and metalloids, paraquat, colchicine, and mushrooms.
In the rare situation of the iron ingestion being concealed, the diagnosis is challenging and could be
confused with metabolic, structural, and infectious causes for the gastrointestinal signs and symptoms.
Other poisonings that present with similar gastrointestinal symptoms include aspirin, theophylline,
organophosphates, carbamates, other metals and metalloids, paraquat, colchicine, and mushrooms.


LABORATORY STUDIES
Key investigations include an abdominal radiograph ( Fig. 35–1 ) and serum iron concentration
determination.
Figure 35-1 Abdominal radiograph of a 21-year-old woman 2 hours after ingestion of a potentially lethal amount of ferrous sulfate
tablets.
Radiographs
There are four potential explanations for a negative abdominal radiograph. These are (1) the patient did not
ingest iron, (2) the patient ingested a solution of iron, (3) the patient ingested a pediatric multivitamin plus
iron product,[7] and (4) the iron tablets have already dissolved. Because iron is irritative to gastrointestinal
mucosa, abdominal pain, vomiting, or diarrhea is produced when there is a significant amount of dissolved
iron within the gut lumen. Therefore, asymptomatic patients with no opacities on their abdominal radiographs
will not develop significant iron toxicity. Patients with normal abdominal radiographs are unlikely to benefit
from any gastrointestinal decontamination procedure. Children’s chewable vitamins are rarely visible on
radiographs.
Serum Iron Concentration
The serum iron concentration verifies the ingestion, and the peak concentration (2–4 hours after ingestion)
guides the management and indicates the prognosis. The risk for significant toxicity occurs when the peak
serum iron concentration exceeds 500 µg/dL, and the prognosis worsens with values greater than 1000
µg/dL. Serum iron concentrations obtained more than 4 to 6 hours after ingestion contribute little to
management because iron rapidly migrates intracellularly. However, if enteric-coated tablets have been
ingested, serial serum iron concentrations are required, with the duration dependent on the results of the
tests.
Other
Arterial blood gas analysis is important because the presence of acidosis is a direct indicator of iron-induced
tissue dysfunction. Iron poisoning is one of the conditions that can produce an anion gap metabolic acidosis.
Other important investigations include electrolytes, liver, renal, and coagulation profiles.[2]
Profiles combining abdominal radiographs, blood glucose, white blood cell count, and the presence of
abdominal symptoms have been shown to be of no value in predicting serum iron concentration.[4][12][15][24]
The total iron-binding capacity is not useful in the assessment or management of these patients. [4][37]


TREATMENT
Treatment of iron overdose is difficult, with several aspects being controversial, particularly gastrointestinal
decontamination and deferoxamine therapy ( Table 35–3 ).
Table 35-3 -- Treatment Essentials

1. Stabilize patient as needed.
2. Estimate risk for systemic toxicity by amount of elemental iron ingested and abdominal radiograph. If risk
exists then continue with following management.
3. Establish intravenous (IV) access.
4. Administer IV crystalloids to replace gastrointestinal losses or if hypotension develops.
5. Measure serum iron concentration (hourly specimens may be required during early phase to identify trend,
especially for the ingestion of enteric-coated iron tablets).
6. Obtain blood gas analysis and liver, renal, and coagulation profiles.
7. Gastrointestinal decontamination: whole bowel irrigation if tablets are seen on radiograph (0.5 L/hr in children
< 6 and 1.5–2.0 L/hr in older children and adults; if not tolerating this rate, decrease rate by 50% and increase
as tolerated).
8. Deferoxamine infusion for any of the following:
a. Serum iron > 400–500 µg/dL
b. Signs and symptoms of systemic toxicity
c. Metabolic acidosis
Dose: 15 mg/kg/hr for no longer than 24 hours. If you believe that the clinical situation warrants longer infusion,
consider alternating a 12-hour hiatus with a 12-hour infusion.
9. Correct hypovolemia before deferoxamine therapy.
10. Provide care in intensive care unit with invasive physiologic monitoring if serum iron level > 1000 µg/dL or
for coma, shock, or metabolic acidosis.
If the patient’s condition is stable or has stabilized, the need for treatment begins with estimation of the risk
for clinically important systemic toxicity by calculating the amount of ingested elemental iron ( Table 35–4 ).
This requires at least 40 mg/kg; however, gastrointestinal signs and symptoms are regularly seen with
ingestions of one half of that amount. An abdominal radiograph is very important because it corroborates the
ingestion and can even be useful for estimating the ingested dose[13][23] (see Fig. 35–1 ). If the patient is
asymptomatic and no iron is seen in the radiograph, then a significant ingestion likely has not occurred.
Table 35-4 -- Amount of Elemental Iron in Common Tablets

Ferrous Salt Elemental Iron Content (%) Tablet Size (mg) Elemental Iron Content/Tablet (mg)
Sulfate 20 300 60
325 65
Fumarate 33 200 66
Gluconate 12 300 36
Multivitamins with iron:
Children’s chewable 4–18
Adult 6–50
Prenatal 36–65
Decontamination
If the possibility exists of there being enough iron within the gastrointestinal tract to produce systemic
toxicity, then gastrointestinal decontamination should be performed. Whole bowel irrigation with polyethylene
glycol electrolyte lavage solution is the procedure of choice.[6][14][31] A nasogastric tube is required, and the
dose is 500 mL/hr * for children younger than 6 years old and 1.5 to 2.0 L/hr for older children and adults. If
vomiting occurs, reduce the rate of administration by 50 per cent with the goal to gradually increase to the
desired rate. The endpoint is a clear rectal effluent and the absence of visible iron on repeat abdominal
radiograph.[14] If an extraordinary amount (greater than 240 mg/kg elemental iron) is present in the stomach,
a gastrotomy for its direct removal should be considered, particularly if gastrointestinal decontamination has
failed.[25][36] This failure may be due to iron bezoar formation or adherence of the tablets to the gastric
wall.[8]
Other decontamination modalities are ineffective. Iron is poorly adsorbed to activated charcoal,[5] and
evidence is particularly strong for the inefficacy of ipecac and gastric lavage for iron poisoning,[30][31] making
the use of any of these three treatment modalities problematic. Because iron absorption is a saturable
process with only a relatively small proportion of the dose being absorbed, an infinite sink-like effect occurs
in the gut after overdose. This confounds strategies directed at complexation of iron within the
gastrointestinal tract. Intragastric complexation of iron by the administration of solutions of either phosphate
or bicarbonate is ineffective and dangerous and therefore not advised. Intragastric deferoxamine
administration to complex iron within the gut is not recommended. Ferrioxamine, the resultant chelant, is
absorbed from the gut,[32][39][40] is toxic, and has been shown to be lethal in dogs[39] and in mice.[1]
* Editors’ note: Currently no consensus exists regarding the appropriate rate of administration for polyethylene glycol electrolyte lavage solution
in pediatric poisoning cases. Some authorities recommend an initial rate based on the patient’s body weight (e.g., 10–15 mL/kg/hr), whereas
others suggest an absolute volume per hour (e.g., 500 mL/hr). Regardless of the initial rate chosen, the rate should be decreased if vomiting
occurs and increased as tolerated until the desired hourly rates are achieved.
Chelation
Deferoxamine, the antidote of choice for iron poisoning, is synthesized from ferrioxamine B, a growth factor
found in the microorganism Streptomyces pilosus. Deferoxamine is negligibly absorbed after oral dosing and
is the most potent and specific iron chelator available. The chelation of iron by deferoxamine produces
ferrioxamine, which is excreted in the urine and feces.
Indications
The need for chelation therapy is guided by the serum iron concentration, the presence of severe
gastrointestinal symptoms, hypoperfusion, altered mental status, or the development of metabolic acidosis.
Serum iron measurement should be an estimate of peak concentration that for conventional tablets occurs
between 2 and 4 hours after ingestion. Because excess iron quickly migrates intracellularly, later estimations
are of little use. The serum specimen should be obtained before initiation of chelation therapy because the
presence of deferoxamine can falsely lower the serum iron levels when measured by the usual laboratory
methods.[9][12]
Clinically important toxicity is associated with serum iron levels greater than 500 µg/dL, making 400 to 500
µg/dL a reasonable indication for deferoxamine therapy. The other indication for deferoxamine therapy is
systemic toxicity, which is marked by the presence of signs and symptoms or metabolic acidosis. The latter
indicates that non–protein-bound iron is present and is producing disruption of homeostasis.
Route and Dose
Deferoxamine should be given intravenously because this route is more effective,[26] although the
manufacturer recommends intramuscular administration. Because there is a risk of acute renal failure in
deferoxamine-treated patients with intravascular volume deficits,[16] hypovolemia should be corrected with
intravenous crystalloid infusions before initiation of chelation.
Recommendations for dose and duration of intravenous therapy are empirical. The usual dose is 15
mg/kg/hr. Rapid infusion at many times this rate risks hypotension. The endpoint for therapy is especially
problematic. Neither serum iron concentration nor the presence of normal colored urine is useful. The
resolution of acidosis can be used as a guide for stopping therapy. Prolonged deferoxamine infusion, greater
than 24 to 48 hours, may precipitate acute respiratory distress syndrome.[34] If a prolonged infusion is
deemed necessary for severe, ongoing problems such as persistent metabolic acidosis or hypoperfusion,
consider administering the initial 24 hours of continuous deferoxamine infusion, followed by alternating 12
hours of deferoxamine infusion with a 12-hour hiatus to allow for excretion of ferrioxamine.[3]
For all but mildly iron-poisoned patients, meticulous supportive care is paramount and a critical care setting
is recommended. Intravascular volume and bicarbonate requirements are high. There is a need for
monitoring multiple parameters, including cardiovascular (the early insertion of a Swan-Ganz catheter is
desirable), acid-base, hematologic, coagulation, renal, and hepatic, and the timely correction of clinically
significant abnormalities. Extracorporeal removal is ineffective. However, if acute renal failure occurs,
hemodialysis should be considered early to prevent accumulation of the toxic compound ferrioxamine. Acute
hepatic necrosis is treated with hepatic failure protocols, and the need for immediate liver transplant should
be evaluated.[17]


DISPOSITION
Any patient without symptoms and signs and with no iron seen in the abdominal radiograph can be
discharged from the emergency department. All patients with evidence of, or significant risk for, systemic
iron toxicity should be admitted to the hospital. Patients with coma, shock, metabolic acidosis, or serum iron
concentrations greater than 1000 µg/dL should be admitted to an intensive care unit. Admitted patients
should be re-evaluated 2 weeks after discharge for determination of serum iron concentration and
assessment of the gastrointestinal tract.


SEQUELAE
Acute complications of iron poisoning include coma, shock, hepatic necrosis, acute renal failure (in
deferoxamine-treated hypovolemic patients), and lung injury (in patients treated with prolonged
deferoxamine courses). Yersinia infection may occur in deferoxamine-treated patients.[20][22] A long-term
complication of iron poisoning is gastrointestinal stricture and obstruction.[35]


SPECIFIC SITUATIONS
Iron overdose during pregnancy has a higher relative incidence[27] and is unique among overdoses because
the fetus enjoys protection from the direct effects of iron.[29] Significant fetal hyperferremia does not occur,
despite its presence in the mother, because transplacental iron absorption is an active saturable process.
Risk to the fetus occurs when the mother decompensates. Therefore, the presence of a fetus should not
change the management of iron poisoning. The indications for deferoxamine therapy are the same, and the
teratogenic risk of this agent is overstated.[20]


REFERENCES
1. Adamson IYR, Sienko A, Tenenbein M: Pulmonary toxicity of deferoxamine in iron-poisoned mice.
2. Banner Jr W, Tong TG: Iron poisoning. Pediatr Clin North Am 1986; 33:393-409.
3. Cheney K, Gumbiner C, Benson B, Tenenbein M: Survival after a severe iron poisoning treated with
intermittent infusions of deferoxamine. J Toxicol Clin Toxicol 1995; 33:61-66.
4. Chyka PA, Butler AY: Assessment of acute iron poisoning by laboratory and clinical observations. Am J
Emerg Med 1993; 11:99-103.
5. Decker WJ, Combs HF, Corby DG: Adsorption of drugs and poisons by activated charcoal. Toxicol Appl
Pharmacol 1968; 13:454-460.
6. Everson GW, Bertaccini EJ, O’Leary J: Use of whole bowel irrigation in an infant following iron overdose.
Am J Emerg Med 1991; 9:366-369.
7. Everson GW, Oudjhane K, Young LW, Krenzelok EP: Effectiveness of abdominal radiographs in
visualizing chewable iron supplements following overdose. Am J Emerg Med 1989; 7:459-463.
8. Foxford R, Goldfrank L: Gastrotomy: A surgical approach to iron overdose. Ann Emerg

Med 1985; 14:1223-1226.
9. Gevirtz NR, Wasserman LR: The measurement of iron and iron-binding capacity in plasma containing
deferoxamine. J Pediatr 1966; 68:802-804.
10. Gleason Jr WA, deMello DE, deCAstro FJ, Connors JJ: Acute hepatic failure in severe iron poisoning.
J Pediatr 1979; 95:138-140.
11. Halliwell B, Gutteridge JMC: Oxygen free radicals and iron in relation to biology and medicine: Some
problems and concepts. Arch Biochem Biophys 1986; 246:501-514.
12. Helfer RE, Rodgerson DO: The effect of deferoxamine on the determination of serum iron and iron-
binding capacity. J Pediatr 1986; 68:804-806.
13. Hosking CS: Radiology in the management of acute iron poisoning. Med J Austral 1969; 1:576-581.
14. Kaczorowski JM, Wax PM: Five days of whole-bowel irrigation in a case of pediatric iron ingestion. Ann
Emerg Med 1996; 27:258-263.
15. Knasel AL, Colllins-Barrow MD: Applicability of early indicators of iron toxicity. J Natl Med
Assoc 1986; 78:1037-1040.
16. Koren G, Bentur Y, Strong D, et al: Acute changes in renal function associated with deferoxamine
therapy. Am J Dis Child 1989; 143:1077-1080.
17. Kozaki K, Egawa H, Garcia-Kennedy R, et al: Hepatic failure due to massive iron ingestion successfully
treated with liver transplanation. Clin Transplant 1995; 9:85-87.
18. Litovitz T, Manoguerra A: Comparison of pediatric poisoning hazards: An analysis of 38 million exposure
incidents. Pediatrics 1992; 89:999-1006.
19. Luongo MA, Bjornson SS: The liver in ferrous sulfate poisoning. N Engl J Med 1954; 251:995-999.
20. Melby K, Slordahl S, Gutteberg TJ, Nordbo SA: Septicemia due to Yersinia enterocolitica after oral
overdoses of iron. BMJ 1982; 285:467-468.
21. Mills KC, Curry SC: Acute iron poisoning. In: Ford MD, Olshaker JS, ed. Concepts and Controversies
in Toxicology, Philadephia: WB Saunders; 1994:397-413.
22. Mofenson HC, Caraccio TR, Shariff N: Iron sepsis. Yersinia enterocolitica septicemia possibly caused
by an overdose of iron. N Engl J Med 1987; 316:1092-1093.
23. Ng RCW, Perry K, Martin DJ: Iron poisoning: Assessment of radiography in diagnosis and
management. Clin Pediatr 1979; 18:614-616.
24. Palatnick W, Tenenbein M: Leukocytosis, hyperglycemia, vomiting and positive x-rays are not indicators
of severity of iron overdose in adults. Am J Emerg Med 1996; 14:454-455.
25. Peterson CD, Fifield GC: Emergency gastrotomy for acute iron poisoning. Ann Emerg
Med 1980; 9:262-264.
26. Propper RD, Shurin SB, Nathan DG: Reassessment of the use of desferrioxamine B in iron overload.
N Engl J Med 1976; 294:1421-1423.
27. Rayburn W, Aronow R, Delancey B, Hogan MJ: Drug overdose during pregnancy: An overview from a
metropolitan poison control centre. Obstet Gynecol 1984; 64:611-614.
28. Skikne B, Baynes RD: Iron absorption. In: Brock JH, Halliday JW, Pippard MJ, et al ed. Iron
Metabolism in Health and Disease, London: WB Saunders; 1994:151-187.
29. Tenenbein M: Poisoning in pregnancy. In: Koren G, ed. Maternal fetal Toxicology: A Clinician’s Guide,
New York: Marcel Dekker; 1994:223-252.
30. Tenenbein M: Inefficacy of gastric emptying procedures. J Emerg Med 1985; 3:133-136.
31. Tenenbein M: Whole bowel irrigation in iron poisoning. J Pediatr 1987; 111:142-145.
32. Tenenbein M, Israels SJ: Early coagulopathy during severe iron poisoning. J Pediatr 1988; 113:695-
697.
33. Tenenbein M, Kopelow ML, deSa DJ: Myocardial failure and shock in iron poisoning. Human
Toxicol 1988; 7:281-284.
34. Tenenbein M, Kowalski S, Sienko A, et al: Pulmonary toxic effects of continuous desferrioxamine
administration in acute iron poisoning. Lancet 1992; 339:699-701.
35. Tenenbein M, Littman C, Stimpson RE: Gastrointestinal pathology in adult iron overdose. J Toxicol Clin
Toxicol 1990; 28:311-320.
36. Tenenbein M, Wiseman N, Yatscoff RW: Gastrotomy and whole bowel irrigation in iron poisoning.
Pediatr Emerg Care 1991; 7:286-289.
37. Tenenbein M, Yatscoff RW: The TIBC of iron poisoning: Is it useful?. Am J Dis Child 1991; 145:437-
439.
38. Vernon DD, Banner W, Dean JM: Hemodynamic effects of experimental iron poisoning. Ann Emerg
Med 1989; 18:863-866.
39. Whitten CF, Chen Y, Gibson GW: Studies in acute iron poisoning: II. Further observations on
desferrioxamine in the treatment of acute experimental iron poisoning. Pediatrics 1966; 38:102-110.
40. Whitten CF, Gibson GW, Good MA, et al: Studies in acute iron poisoning: Deferoxamine in the
treatment of acute iron poisoning: Clin Observations, experimental studies and theoretical considerations.
Pediatrics 1965; 36:322-335.


Chapter 36 – Caffeine and Related Nonprescription Sympathomimetics
KRISTIN M. ENGEBRETSEN CARSON R. HARRIS
Essentials
• Toxicity may occur with acute overdoses or chronic administration.
• Hyperadrenergic symptoms such as hypertension, tachycardia, and agitation, along with gastrointestinal
effects prevail in most acute overdoses.
• Larger overdoses may result in hypertensive crisis, dysrhythmias, myocardial infarction, rhabdomyolysis,
and seizures.
• Serum levels do not influence on the clinical management of the patient.
INTRODUCTION
Many people depend on stimulants to keep them alert and improve their productivity. Coffee alone is
consumed in an estimated 80–98 per cent of U.S. homes with one out of every three persons consuming an
average of 200 mg of caffeine per day.[50] Caffeine is commonly accepted and is not usually perceived as a
drug by most people. It is found in chocolate, carbonated sodas, and coffee as well as in over-the-counter
oral analgesics, migraine treatments, and products promoting alertness ( Table 36–1 ). Nonprescription
sympathomimetics such as ephedrine, phenylpropanolamine, and phenylephrine have been abused for their
stimulant effects and are commonly found in cold preparations and dieting agents. Phenylpropanolamine is
found in approximately 33 over-the-counter preparations and 29 prescription medications.[62][63] Twelve
different preparations containing either caffeine or phenylephrine are available without a prescription.[63] Due
to ephedrine’s widespread abuse potential and serious adverse effects, the Food and Drug Administration
(FDA) has proposed regulation for some dietary supplement products to limit dose amount, duration of use,
and marketing strategies. In addition to the FDA proposal, 21 states have passed more stringent regulations
on products containing ephedrine, including prescription requirements, changes in dose scheduling, and
limitations on advertising claims of ephedrine-containing products.[56] Ephedrine is also used in the illicit
manufacturing of amphetamines.
Table 36-1 -- Common Consumer Products Containing Caffeine

Category Product Amount of Caffeine
Coffee Brewed coffee 40–180 mg/5 oz
Instant coffee 30–190 mg/5 oz
Decaffeinated brewed coffee 2–5 mg/5 oz
Decaffeinated instant coffee 1–5 mg/5 oz
Tea Brewed commercial tea 20–90 mg/5 oz
Brewed imported tea 25–110 mg/5 oz
Instant tea 2–20 mg/5 oz
Iced tea 67–76 mg/12 oz
Soft drinks Diet Coke 46 mg/12 oz
Coca Cola 46 mg/12 oz
Diet Pepsi 36 mg/12 oz
Pepsi Cola 38.4 mg/12 oz
Mountain Dew 54 mg/12 oz
Ginger ale 0 mg/12 oz
Root beer 0 mg/12 oz
Tab 46 mg/12 oz
Tonic water 0 mg/12 oz
Fresca 0 mg/12 oz
Dr. Pepper 39.6 mg/12 oz
Jolt Cola 70.8 mg/12 oz
Food Chocolate milk 1–15 mg/8 oz
Milk chocolate 2–7 mg/8 oz
Dark semi-sweet chocolate 5–35 mg/1 oz
Baker’s chocolate 26 mg/1 oz
Chocolate candy 7.7 mg/1 oz bar
Chocolate-covered candy 2.8 mg/1 oz bar
Chocolate pudding, instant 5.5 mg/½ cup
Medications No Doz 100 mg/tablet
Vivarin 200 mg/tablet
Cafergot 100 mg/tablet
Fiorinal 40 mg/tablet
Midol 32.4 mg/tablet
Dexatrim 200 mg/tablet
Dexatrim Extra Strength 200 mg/tablet
Excedrin 65 mg/tablet
Anacin 32 mg/tablet
From Snyder SH, Skylar P: Psychiatric progress. Behavioral and molecular actions of caffeine: Focus on
adenosine. J Psychiatr Res 1984; 18:91.
Anacin Extra Strength 32 mg/tablet
From Snyder SH, Skylar P: Psychiatric progress. Behavioral and molecular actions of caffeine: Focus on
adenosine. J Psychiatr Res 1984; 18:91.


PHARMACOKINETICS
Caffeine is rapidly absorbed and in adults undergoes both oxidation and N-demethylation, with
approximately 1 per cent excreted unchanged in the urine.[2][39] Caffeine is metabolized to theophylline by
the cytochrome P-450 enzyme system. However, in neonates approximately 85 per cent of a dose is
excreted unchanged in the urine.[2] Decreased elimination and a prolonged half-life may increase caffeine
toxicity in neonates and premature infants ( Table 36–2 ). The metabolism of a child approaches that of an
adult at the approximate age of 8 months.[2]
Table 36-2 -- Elimination Half-Life of Caffeine in Different Age Groups

Premature Infants Neonates Children Adults
65–102 hr 82 hr 14.4 hr 3–7.5 hr
From Kanfer I, Dowse R, Vusumuzi V: Pharmacokinetics of oral decongestants. Pharmacotherapy 1993;
13:116s.
Phenylpropanolamine is a weak base that is readily absorbed in the small intestine.[38][48] Maximum
concentrations occur approximately 1.5 hours after ingestion.[14][69][71][76] The volume of distribution is 3.4
L/kg.[60] Approximately 90 to 97 per cent of a given dose of phenylpropanolamine will be excreted
unchanged in the urine within 24 hours.[2][38] Four per cent is metabolized by parahydroxylation or oxidative
deamination resulting in the formation of hippuric acid.[70][74] The half-life of phenylpropanolamine ranges
from 3.7 to 5.8 hours.[14][29][49][60][69][71][76] Approximately 8–20 per cent of a dose of ephedrine undergoes N-
demethylation to phenylpropanolamine.[70]
Phenylephrine has a bioavailability of 38 per cent.[2][30][38] Approximately 86 per cent of a given dose is
excreted unchanged in the urine.[2][19][30] The remaining phenylephrine undergoes conjugation, sulfation,
glucuronidation or conjugated deamination by monoamine oxidase. [30][35][38] The half-life of phenylephrine
ranges from 2.1–3.4 hours.[30]


PATHOPHYSIOLOGY
Caffeine has many effects in the body. The three most commonly documented effects are (1) adenosine
receptor antagonism, (2) phosphodiesterase inhibition, and (3) enhanced intracellular calcium levels.[13]
Adenosine receptor antagonism leads to vasoconstriction, hypertension, tremor, and agitation. These effects
are frequently seen in caffeine overdose.[72] These effects are the reverse of those seen with adenosine
agonist activity, such as arterial vasodilation, inhibition of catecholamine release, and slowing of cardiac
pacemaker cells.[13][50]
Caffeine inhibits phosphodiesterases, causing increased levels of cyclic AMP, which results in increased
levels of catecholamines. Muscle contractility is enhanced through increased intracellular calcium levels and
increased permeability of the sarcoplasmic reticulum to calcium.[50][75] Stimulation of gastric acid and
intestinal secretions and lowering of lower esophageal sphincter tone by caffeine commonly result in
diarrhea and abdominal cramping.[50]
Beneficial effects of caffeine include bronchodilation and vasodilation in the treatment of apnea in premature
infants. Although caffeine-induced vasodilation may lower blood pressure, caffeine-induced medullary
stimulation and increased catecholamine release offset this effect.
Phenylpropanolamine and ephedrine act primarily via increased ß1- and ß2-adrenergic receptor agonist
activity and enhanced release of catecholamines.[36] Phenylpropanolamine is as potent as ephedrine but
causes less central nervous system (CNS) stimulation. Phenylephrine is a selective a 1-adrenergic receptor
agonist.[36] It is a derivative of epinephrine and produces similar therapeutic and adverse effects. Peripheral
vasoconstriction and tachycardia are the most common adverse effects. Table 36–3 compares the a- and ß-
adrenergic receptor activity and CNS stimulation of caffeine and other nonprescription sympathomimetics.
Chronic misuse of these agents may lead to cardiovascular abnormalities, such as vasculitis, stroke
syndrome, cardiomyopathy, hypertension, and dysrhythmias.
Table 36-3 -- Actions of Selected Sympathomimetic Agents at Peripheral Adrenergic Receptors in the
Substance Alpha-Adrenergic Response Beta-Adrenergic Response CNS Stimulation
Amphetamine ++ ++ +++
Caffeine ++ + +
Ephedrine ++ +++ ++
Phenylephrine ++++ 0 +
Phenylpropanolamine +++ + +++
+, week activity.
++++, strongest activity.
Oral preparations of these drugs are the most common forms available, but each of these agents may also
be used intravenously. Phenylephrine is also available as a nonprescription inhaler. Phenylpropanolamine
and caffeine may be sold on the street falsely as cocaine or amphetamines. In these cases, the agents may
be snorted, ingested, or taken intravenously.


All the nonprescription sympathomimetics (i.e., caffeine, ephedrine, phenylpropanolamine, and

phenylephrine) share some similar clinical features when taken in excessive amounts. Common symptoms
include nausea, vomiting, diarrhea, abdominal pain, tremors, anxiety, agitation, and headaches.[1] Less
common but more severe symptoms include delirium, seizures, hypertensive crisis, intracerebral
hemorrhage, and myocardial infarction. Debate still exists as to whether or not a single dose of caffeine or
phenylpropanolamine can result in clinically significant hypertension.[44][57][59] However, hypertensive crisis
is documented in significant acute overdoses.[29] Phenylpropanolamine differs from caffeine in that
phenylpropanolamine-induced hypertension is associated with a reflex bradycardia.[36] Caffeine overdose is
most commonly associated with tachycardia. Although severe toxicity and death may be caused by any of
these agents in an overdose situation, ephedrine, phenylpropanolamine, and phenylephrine appear to have
more reported cardiovascular complications than caffeine.[10][25][50][51][58]
Although hyperthermia is frequently seen with severe overdose of the psychostimulants (amphetamines,
methamphetamines, and cocaine), it is rarely seen in caffeine overdoses. Sympathomimetic overdoses,
however, can cause severe hyperthermia that may be lethal if untreated.[7][11] The hyperthermia is thought to
be due to activation of specific dopamine receptors.[11] Increased motor activity and stimulant-induced
seizures are also possible causes of hyperthermia after sympathomimetic overdose.
Acute Toxicity
In adults, ingestion of 500–1000 mg of caffeine may result in nausea, vomiting, diarrhea, tremors, and
agitation.[1][50] Most patients have sinus tachycardia and a mild hypertension. Increases in cardiac output
and glomerular filtration rate (GFR) can increase urine production. Dehydration and hypokalemia are
common. Death due to caffeine overdose is rare but can result from the spontaneous vomiting that occurs
with ingestion of large amounts. Caffeine-related deaths from dysrhythmias, seizures, and neurologic effects
have been reported.[17][20][43] The estimated lethal dose of caffeine in an untreated adult is 5–10 g,[12][50] and
in children 78 mg/kg has caused serious symptoms.[47][50][66] This may be due to the slower elimination of
caffeine by children. Table 36–4 summarizes the clinical effects of over-the-counter sympathomimetics.
Table 36-4 -- Clinical Effects of Caffeine Toxicity

Mild and Common Severe and Uncommon
Sinus tachycardia Seizure
Reflex bradycardia with phenylpropanolamine Hypertensive crisis
Hypertension Hyperthermia
Nausea, vomiting, diarrhea, cramps Myocardial infarction/chest pain
CNS agitation, anxiety Delirium
Palpitations Intracerebral hemorrhage
Chronic Toxicity
Chronic excessive ingestions of over-the-counter sympathomimetic and caffeine frequently result in

tachycardia, hypertension, and palpitations. Myocardial infarction, vasculitis, cardiomyopathy, and
dysrhythmias (paroxysmal atrial tachycardia, premature ventricular contractions, bigeminy, ventricular
tachycardia, and ventricular fibrillation) have been reported in large and chronic overdoses. [3][17][37][47][50][81]
A cerebral vasculitis from chronic use and misuse of ephedrine may cause an acute intracerebral
hemorrhage.[80] Chronic use and misuse may also lead to sustained hypertension and subsequent
hemorrhage.[5] With chronic use, certain individuals may tolerate extremely large ingestions with minimal
side effects, although others may experience severe symptoms at a fraction of the dose.[10][23][45][46][57][64]


Multiple medical and psychological conditions may mimic sympathomimetic toxicity ( Table 36–5 ). Serious
medical conditions, including sepsis, intracranial hemorrhage, metabolic disorders, myocardial infarction,
and primary dysrhythmias, must be excluded when patients present with signs of stimulant overdose.
Psychiatric complications such as mania, anxiety, and panic attacks must also be considered in the
differential diagnosis. Sympathomimetic abuse and overdoses may exacerbate pre-existing psychiatric,
neurologic, and cardiac conditions. [25][40][52]
Table 36-5 -- Differential Diagnosis of Caffeine Toxicity

Other drugs
MAO inhibitors
Cocaine
Amphetamines
Theophylline
PCP
LSD
Anticholinergics
Cardiac abnormalities
Cardiomyopathy
Hypertensive crisis
Myocardial infarction
Primary dysrhythmia
Metabolic dysfunction
Hyperthyroidism
Pheochromocytoma
Hypoxia
Hypoglycemia
Hyperthermia/sepsis
Anxiety
Mania
Panic disorder
Sleep disorder
CNS disturbances
Intracranial hemorrhage
Headache: migraine or tension


LABORATORY STUDIES
Laboratory values will not influence the medical management for an individual with either an acute or chronic
toxicity. Drug levels can confirm the diagnosis or the agent ingested, but do not routinely correlate with
symptoms and are not readily available.
Electrocardiogram (EKG) and chest radiograph may be indicated if cardiac dysrhythmias or cardiomyopathy
are suspected. Electrolytes should be monitored because vomiting and diarrhea can lead to fluid and
electrolyte imbalances. Rhabdomyolysis, hypokalemia, and lactic acidosis have been reported.[67][83] A
creatine kinase level greater than five times the normal range indicates significant rhabdomyolysis.[82] Other
laboratory tests required to evaluate conditions listed in the differential diagnosis can be performed as
needed. A computed tomographic (CT) scan of the head is indicated if intracranial hemorrhage is suspected.
Subclinical increases in white blood cell count and serum glucose level are common but clinically
insignificant.


TREATMENT ( Table36–6 )
Acute Overdose
Treatment in all cases is supportive with attention to airway, breathing, and circulation. Oral activated
charcoal, 1–2 g/kg of body weight is the primary mode of gastrointestinal decontamination. Gastric lavage
may be considered if the patient presents to the emergency department within 1 hour after ingestion, has
ingested a potentially life-threatening amount of drug, and does not have nausea and vomiting.
Table 36-6 -- Treatment Essentials in Caffeine Toxicity

Effect Therapy Dose (Adult)
Decontamination Activated charcoal 50–100 g PO
Dysrhythmia Benzodiazepines Diazepam: 5–10 mg IV q 5–10 min
Lorazepam: 1–2 mg IV q 5 min
Esmolol: LD 500 µg/kg IV over 1 min; follow with 50 µg/kg/min
Esmolol
IV infusion; titrate up q 5 min to a max of 200 µg/kg/min prn
Lidocaine: 1–1.5 mg/kg IV bolus over 2–3 min; may repeat dose
Lidocaine
of 0.5 mg/kg in 5–10 min up to a total of 3 mg/kg
Procainamide: LD 15–18 mg/kg given as slow infusion over
Procainamide 25–30 min; maintenance dose 1–6 mg/min by continuous IV
infusion
Hypertension Benzodiazepines Diazepam: 5–10 mg IV q 5–10 min
Sodium nitroprusside: 0.5 µg/kg/min, increase by 0.5 µg q 5 min
Sodium nitroprusside
until desired effect; maximum dose of 10 µg/kg/min
Seizures Benzodiazepines Diazepam: 5–10 mg IV q 5–10 min
Phenobarbital Phenobarbital: 10–20 mg/kg IV given at a rate of 25–50 mg/min
Nausea/vomiting Rehydration if necessary Titrate crystalloids to maintain urine output of 1–2 mL/kg/hr
Potassium/electrolyte
Replace electrolytes as needed.
replacement
Antiemetics
Metoclopromide: Adult= 5–10 mg IV, PO, or IM up to a
Metoclopromide
maximum dose of 1 mg/kg
Pediatric: 0.1 mg/kg to maximum 10 mg dose
Effect Therapy Dose (Adult)
Ondansetron Ondansetron
Adult: 0.15 mg/kg IV (maximum 8 mg dose)
Pediatric: =40 kg 0.15 mg/kg/IV
>40 kg 4 mg IV
Intravenous crystalloids are indicated for significant vomiting or diarrhea, and electrolyte losses should be
replaced. Urine output should be maintained at 1–2 mL/kg/hour.
Rhabdomyolysis may result in acute intrinsic renal failure, which may be avoided with intravenous (IV)
crystalloids and IV mannitol, 0.5–1 g/kg over 5–10 minutes to maintain urine output of 1–2 mL/kg/hour. With
significant aciduria the addition of sodium bicarbonate to maintain a urine pH value greater than 6.0 may
protect the renal tubules and improve the prognosis of acute renal failure associated with
rhabdomyolyisis.[34][65] If these treatments fail to produce diuresis or if electrolyte abnormalities persist,
hemodialysis may be required.
Caffeine may produce hypokalemia directly by activation of the Na+/K+-ATPase pump or secondarily by
induction of emesis and diuresis.[61][67] Metabolic acidosis and catecholamine-induced intracellular shifts of
potassium may also potentiate electrolyte abnormalities.[67] Potassium and other electrolytes should be
monitored and replaced as needed.
An antiemetic such as metoclopromide or ondansetron may be considered if protracted vomiting occurs.

Temperature should be monitored closely. Stimulant-induced hyperthermia should be treated aggressively
utilizing fans, ice water lavage, and ice water baths when necessary. Benzodiazepines such as diazepam
and lorazepam should be given to patients who are agitated, hypertensive, or tachycardic. Benzodiazepines
are frequently underutilized and often will decrease blood pressure and heart rate without further
complications. Benzodiazepines may decrease or stop agitation, which can contribute to the development of
rhabdomyolysis. The dose should be titrated intravenously to effect. The patient should be monitored for
respiratory depression.
The over-the-counter sympathomimetics may precipitate seizures in overdose.[43] Intravenous diazepam or

lorazepam should be administered until seizures subside. If seizures persist, phenobarbital should be
administered.
With hypertensive crisis unresponsive to benzodiazepines, sodium nitroprusside is the drug of choice
because of its short duration of action. The dose can be titrated to maintain a normal blood pressure.
Phentolamine, an a-adrenergic receptor antagonist, has a longer duration of action and cannot be titrated as
easily to effect. Nitroglycerine should be considered in cases with myocardial ischemia and infarction. Beta-
adrenergic receptor antagonists should be avoided in a hypertensive crisis because unopposed a-
adrenergic receptor agonist effects may result in further increases in blood pressure and adverse cardiac
effects. Although labetolol blocks both a1- and ß2-adrenergic receptors, its a 1-adrenergic antagonist effect is
one-fifth to one-tenth that of its ß-adrenergic receptor antagonism. Use of labetolol may still result in
unopposed a-adrenergic receptor agonism and further increases in blood pressure, and is not
recommended. Reflex bradycardia should resolve with treatment of hypertension.
Chronic Toxicity
Treatment of chronic stimulant overdoses is more complicated because of the lack of well-controlled, long-
term studies on chronic abuse of stimulants other than caffeine. Most data is extrapolated from acute toxicity
or individual case reports. Chronic ingestion of caffeine is usually benign, but a withdrawal syndrome may be
encountered if caffeine is stopped abruptly.[26][73] Headaches, lethargy, and agitation are the most commonly
encountered effects. Reintroduction of caffeine followed by a gradual taper should relieve symptoms and
prevent any further withdrawal symptoms.
Diet aids containing phenylpropanolamine are frequently abused by women.[10][14][17][46] Increasing doses
over months to years may be used to maintain diet and weight. Tolerance to these products develops
readily, and large amounts may be ingested daily.[64] Prolonged and excessive misuse or abuse of these
products has led to cardiomyopathy.[10] Hemorrhagic stroke and intracerebral hemorrhage may be
encountered with both acute or chronic misuse or abuse of phenylpropanolamine and
ephedrine.[15][25][35][42][51][77] Phenylpropanolamine-induced psychosis or relapsing of underlying psychiatric
conditions has been documented.[52][68] Standard medical therapies are recommended for these
complications.


DISPOSITION
If the patient has ingested an immediate release preparation and remains asymptomatic for 4 to 6 hours, he
or she may be discharged after appropriate psychiatric care. If a sustained release preparation has been
ingested, a minimum of 12 hours is recommended for observation.
Patients with ischemic chest pain, dysrhythmias, seizures, or findings of cerebrovascular hemorrhage should
also be admitted for further management.


SEQUELAE
Cardiomyopathy[10] and neurologic complications from intracerebral hemorrhage or infarction[15][25][42][51][77]

can persist.


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Chapter 37 – Herbals and Other Dietary Supplements
MARY E. PALMER MARY ANN HOWLAND
Essentials
• History of herbal and supplement use preceded the illness.
• Groups at risk for toxicity include patients with chronic illnesses, body-builders, dieters, users of
aphrodisiacs, women seeking herbal abortion, recreational drug users, patients self-medicating for
infection, persons at extremes of age, and patients of various ethnic backgrounds.
• Unexplained hematologic, neurologic, hepatic, renal, or gastrointestinal toxicity occurs, particularly in
patients of certain ethnic origins and cultures.
INTRODUCTION
Herbals Under the Law
An herbal is a medicinal or food substance usually made from a flowering plant, rarely from gymnosperms,
fungi, or algae. “Botanicals” may be used interchangeably for any type of plant part (e.g., root, bark) from
any type of plant. Twenty-five to 32 per cent of drugs are derived from plants; therefore, some herbals
should be considered drugs, but all are regulated as foods.[49][61] Legally, a product is a drug, food, or
dietary supplement, depending on its intended use. For this reason, the term herbals is broadened here to
include dietary supplements and other products purchased through herbal, health food, and other stores, as
well as by mail order or Internet. These agents share similar usage and the same degree of regulation under
U.S. federal law.
The regulation of herbals has been loosened as a result of the 1994 Dietary Supplement Health and
Education Act (DSHEA) after a massive grass-roots lobbying effort.[13][34][95] This reflects the widespread
and growing trend toward use of alternative medicine in general and dietary supplements in particular.[46] In
1994, the herbal industry alone was estimated to be a $1.5 billion market in U.S. (compared with $7 billion in
Germany), and the entire supplement market is growing by approximately 20 per cent per year.[34][95]
According to a survey of 1653 adults conducted by the Food and Drug Administration (FDA), approximately
53 per cent use a dietary supplement.[53]
Under DSHEA, the burden of proof to establish safety is no longer with the manufacturer. Instead, the FDA
must prove toxicity before restricting sales of supplements. As a result, it can no longer be assumed by
consumers and health care providers that all pills bought off a shelf are closely regulated by the federal
government. Labels cannot specify a disease (e.g., arthritis) but may less specifically describe rationale for
use (e.g., “eases joint stiffness”) and can be suggestively named (e.g., “Arthri-Sore No More”). Disclaimers
that the FDA neither approved nor reviewed the product must be printed on the label but in any size font
desired by the manufacturer. Currently, the Center for Food Safety and Applied Nutrition (CFSAN) of the
FDA plans to establish, by 2010, a scientifically based program that will regulate the safety, composition,
and labeling of dietary supplement products. Without regulations, the potency and freedom from
contaminants/adulterants may differ widely brand to brand and batch to batch of any given supplement.
In contrast to the United States, Germany requires all plant herbals to be approved by the Federal Health
Agency’s Commission E. Over 400 monographs cover various aspects of safety and efficacy of the
economically most important herbals ( Table 37–1; courtesy of The American Botanical Council). These
monographs are generally respected as the best available accumulation of scientific knowledge existing on
various phytochemicals[131]; however, German products are not equivalent to U.S. products. In addition, the
monographs are not regularly updated, nor are reference sources cited.
Table 37-1 -- Top-Selling Herbals *

Rank
#,
Common Name CHI,
(Species Name) OTC Selected Uses Potential Toxicity Commission E/Other
Aloe (Aloe vera) #7 Wound healing, cure-all Abdominal pain, A
catharsis
Diuretic, anticancer,
Astragalus (Astragalus immune stimulation,
CHI Unknown N/A
membranaceus) uterine relaxation or
hemorrhage, infection
Cayenne (Capsicum Digestive aid, topical
Irritation N/A
spp.) analgesia
Digestive aid,
Camomile (German)
antispasmodic, anti- Rare hypersensitivity A
(Matricaria recutita)
inflammatory
Cascara (Rhamnus
OTC Anthraquinone laxative Fluid/electrolyte shifts A
purshiana)
Cranberry (Vaccinium
#10 Urinary tract infection N/A; safe[130]
macrocarpon)
Hypersensitivity,
Menstrual cramps,
Dong Quai (Angelica photosensitivity, N/A; not
CHI menstrual problems,
sinensis) coumarins recommended[130]
hypertension, laxative
(anticoagulation?)
Immune stimulation,
Echinacea/coneflower A? E. pallida root;
#1 colds, flu, human Hypersensitivity
(Echinacea augustifolia) safe[130]
immunodeficiency virus
Ephedra or Ma Huang Asthma, abuse, weight Central nervous system
#8 A; equivocable[130]
(Ephedra sinica) loss and body-builders stimulation (see test)
Rank
#,
Common Name CHI,
N/A; recommended
Fo-Ti, Ho Shou Wu Anthraquinone laxative, except
CHI Report of hepatitis[17]
(Polygonum multiflorum) cancer, longevity longevity/cancer[130];
see reference 17
Feverfew (Tanacetum N/A; safe,[130] skin
Migraine prophylaxis
parthenium) reactions
Atherosclerosis,
antithrombotic,
Garlic (Allium sativum) #2 A
hypertension,
gastrointestinal, cure-all
Ginger (Zingiber
CHI Antiemetic digestive aid A
officinale)
Antiplatelet activity;
Intracerebral blood flow bleeding; intraocular
Ginkgo (Ginkgo biloba) #5 A; safe[130]
and memory aid in elderly hemorrhage, subdural
hematoma
Ginseng abuse
Adaptogen, aphrodisiac, syndrome[115]
Ginseng (Panax
#4 atherosclerosis, anemia, (controversial); A
ginseng)
hypertension, diabetes germanium
contamination[8]
Oral sores, digestive aid, Most say none;
genitourinary, human neutropenia,
N/A; not recommended,
Goldenseal (Hydrastis immunodeficiency virus; paresthesias,
#3 probably safe[130] but
canadensis) false reputation for respiratory failure,
see reference 59
interfering with drug vomiting, diarrhea in
screens large doses[59]
Gotu Kola (Centella Longevity, aphrodisiac, N/A; not efficacious;
asiatica) hypertension, anxiety probably safe[130]
?Calming, anticancer,
Jujube (Ziziphus jujuba) CHI ?Unknown N/A
hypoglycemic, infection
Sleep aid, abuse ? A; doubt abuse effect
Hops (Humulus lupulus)
hallucinogen and safety
Licorice rhizome Cough, peptic ulcer,
CHI Hypokalemia A; equivocable[130]
(Glycyrrhiza glabra) cancer
Milk Thistle (Silybum
Hepatoprotection A; seed only
marianum)
Rank
#,
Common Name CHI,
Pau D’arco (Tabebuia N/A; not
Anticancer Increased bleeding
impetiginosa) recommended[130]
Peony (Paeonia ?CNS depression,
CHI Diuretic? unknown U
obovata) hypotension
Peppermint (Mentha
Digestive aid Not infants/children A
piperita)
Fluid/electrolyte shifts;
Psyllium (Plantago spp.) OTC Bulk laxative substitution with A
Digitalis lanata [118a]
Venereal disease, human
Red Clover (Trifolium
immunodeficiency virus, Increased bleeding N/A; not effective[130]
pratense)
cancer
?Tonic, longevity, lower
Rehmannia (Rehmannia ?Hypoglycemia;
CHI blood pressure, liver and N/A
glutinosa) unknown
kidney support
Benign prostatic
Saw Palmetto (Serenoa hypertrophy; enlarged A berry; ineffective
Antiandrogenic?
repens) breasts, aphrodisiac, breast effects[130]
diuretic
Schisandra (S. CHI Sedative, aphrodisiac, N/A; equivocable[130]
chinensis) hepatoprotection,
longevity, adaptogen ?CNS depression
Senna (Cassia senna) OTC Anthraquinone laxative Fluid/electrolyte shifts A
Siberian Ginseng,
Eleuthero
#9 Adaptogen, aphrodisiac A
(Eleutherococcus
senticosus)
Slippery Elm (Ulmus Demulcent, emollient,
OTC N/A; demulcent safe[130]
fulva) abortifacient
Valerian (Valeriana
Sleep aid A root; approved [130]
officinalis)
White Willow Bark (Salix Massive overdose or
Pain, inflammation A
alba) pediatrics: salicylism
Witch Hazel (Hamamelis
OTC Astringent A
virginiana)
* The top selling herbals in the United States based on survey data with permission from the author and publisher.[13] Rank # is order of
sales, CHI denotes that it is a top-selling Chinese herbal, and OTC signifies an ingredient in over-the-counter preparations. Herbal use is
based on several references[40][99][130] unless otherwise referenced. Commission E status is provided courtesy of the American Botanical
Council. A, Approved; U, unapproved; N/A, not available. If no status is available or it is controversial, another opinion is expressed.[130]
Surveillance and Research
Data on use and toxicity of dietary supplements is almost nonexistent beyond scattered surveys and case
reports. There are no comprehensive tracking systems or centralized databases to follow adverse effects.
The FDA has a surveillance system MEDWatch that is currently underutilized.[76][120] The World Health
Organization (WHO) also has begun a database of adverse effects.[45] Only one of four trade associations
contacted tracks adverse effects, but on only one of its products.
Adverse effects are often rare events, and research on rare events is difficult to perform. Given the current
regulatory climate and the inability to patent foods, there is little industry incentive to do so. If a dietary
supplement produces one adverse event in 1000 patients, at least 3000 patients would be needed in a study
to have a 95 per cent chance of detecting that adverse event.[101] Furthermore, many product formulations
are combinations, making it impossible to discern the offending agent. In one survey, no information of any
kind could be found on 60 per cent of ingredients in products marketed.[103]
Quality Assurance
Lack of quality assurance on dietary supplements has already presented serious consequences for patients.
Contamination with or intended use of heavy metals has been reported for lead,[4][44][75][100][106][119]
arsenic,[70][78][126] mercury,[7][78] thallium,[113] cadmium, [4][139] and dichromate,[138] especially in traditional
ethnic medicines. Adulterations with prescription medicines include nonsteroidals (resulting in renal failure
and agranulocytosis), corticosteroids (resulting in Cushing’s syndrome and myopathy), and
benzodiazepines.[19][58][105][132] Plant misidentifications and substitutions have also resulted in disastrous
effects, ranging from hepatic vaso-occlusive syndrome to renal failure.[22][48][58][133][134] Well-intended
foragers have made lethal substitutions (e.g., foxglove for comfrey).[22] Some products falsely advertise and
do not contain any of the claimed substance at all. [36][41] There are also problems with the route of
administration. For instance, comfrey has probable efficacy when used topically but if taken internally it can
cause hepatic veno-occlusive disease. Nonetheless, it is still marketed for oral use.
The Role of Health Care Practitioners
Inquiring about the use of dietary supplements is a new key component in taking the history of present
illness. One survey assessed usage among patients in an urban emergency department and found that 21
per cent of patients used botanical supplements.[71] Review of over 5000 cases involving dietary
supplements through the National Poisons Unit in London revealed that 12 per cent of these exposures were
symptomatic, and a probable causal link between exposure and symptoms was established in at least 6 per
cent of symptomatic patients.[101]
The regional poison center should be consulted in the management of patients and to contribute information
to the TESS database. The FDA MEDWatch Surveillance Program ([800] FDA-1088 for health care
providers; [800] FDA-4010 for consumers) is designed to track adverse effects and is the primary vehicle for
restricting supplements that may present public health risks. The Centers for Disease Control and
Prevention (CDC) should also be notified ([404] 639–2530). Health care providers can and should play a key
role in enhancing our otherwise poor national surveillance by contacting these agencies to report adverse
effects possibly associated with supplement use. When the herbal is suspected to be culpable, then it
should be obtained for later laboratory analysis through a poison center, department of health, or other
specialty laboratory.


Given the massive number of products available, the discussion here focuses on those products with the
greatest potential for toxicity. The pharmacology and pathophysiology of the various products is discussed
under an organ system stratification highlighting central and peripheral nervous systems (CNS and PNS)
and cardiovascular, hepatic, gastrointestinal, hematologic, endocrine, and multiorgan systems. A discussion
of drug interactions is also provided.
CNS stimulants produce a sympathomimetic toxidrome: hypertension, tachycardia, mydriasis, diaphoresis,

hyperthermia, agitation, and hallucination. Cerebrovascular accidents, seizures, cardiovascular collapse,
coma, and death occur in extreme cases. Ephedra or Ma Huang has been used to treat bronchoconstriction
for centuries, because of its activity at ß2-adrenergic receptors. It contains pseudoephedrine, ephedrine and
other similar alkaloids. These are sympathomimetics that cause either direct or indirect stimulation of a- and
ß-adrenergic receptors. Caffeine, found in coffee, tea, guarana, kola, or bisseynut, is a methylxanthine that
behaves like a ß-adrenergic agonist and produces CNS hyperstimulation in high doses.
Khat (Catha edulis) is widely used in the Arabian pennisula and east Africa for its amphetamine-like effects.
Its use has spread to the United States. Khat contains over 30 compounds, including cathine
(norpseudoephedrine), cathinone, and tannins. Cathinone is the main psychoactive ingredient and is
contained in higher concentrations in red khat (which is more potent than white khat), which will stain the
mouth red. Centrally, cathinone works to release dopamine at the presynapse. In the periphery, cathinone
and cathine promote norepinephrine release. Chronic use is associated with oral cancers, constipation
(tannins), hypertension, and psychological dependence.
Nicotinic, anticholinergic, and cholinergic toxidromes result from stimulation of nicotinic receptors and from
blockade and stimulation of muscarinic receptors, respectively. These also have a presentation similar to
that of other stimulants ( Table 37–3 ) except that nicotinic agents also produce fasciculations and muscle
weakness to the point of respiratory depression, and anticholinergics produce dry, flushed skin, urinary
retention, and diminished bowel sounds. Although betel nut (Areca catechu) is chewed worldwide for mild
CNS stimulant effects and as a digestive aid, the pyridine alkaloid arecoline produces central and peripheral
cholinergic effects similar to pilocarpine, with diarrhea, vomiting, salivation, and seizures as well as
bronchospasm. Chronic use is associated with oral cancer. Arnica (Arnica montana) contains choline and
other unidentified toxic extracts. It is used topically to heal wounds, but oral ingestion can be lethal.[99]
Table 37-3 -- Selected Herbals and Supplements with Potential Toxicity

Cardiovascular Disease
Stimulants: ephedra (ma huang, Ephedra sinica), caffeine (coffee, tea, guarana [Paullinia cupana]), khat (Catha
edulis), betel (Areca catechu), Kola nut (Cola spp.)
Anticholinergic toxidrome: bittersweet (Celastrus scandens), mandrake (Mandragon officinarum), deadly
nightshade (Atropa belladonna), jimsonweed (Datura stramonium); contamination/adulteration
Nicotinic toxidrome: lobelia (Lobelia inflata), blue cohosh (Caulophyllum thalictroides), broom (Cytisus
scoparius), horse chestnut (Aesculus spp.), tobacco (Nicotiana spp.)
Cholinergic toxidrome: khat (Catha edulis), betel (Areca catechu), arnica (Arnica montana)
a2-Adrenergic receptor antagonist/potential monoamine oxidase inhibitor: yohimbe (Pausinystalia yohimbe)
Cardiac glycosides: oleander (Nerium oleanderi), foxglove (Digitalis purpurea, D. lanata), dogbane (Apocynum
cannabimum), wallflower (Cheiranthus cheiri), lily-of-the-valley (Convallaria majalis), red squill (Urginea
maritima), Bufo species venom (products from Bufo bufo gargarizans in China, B. alvarius or B. marinus in the
United States; Asian names: “ch’an su”, “Kyushin”; U.S. street names include “Love Stone,” “Rock Hard”)
Sodium channel activation/blockade: aconite from monkshood (Aconitum spp.; “chuanwu,” “caowu”) and
larkspur (Delphinium spp.); blockade by quinine (Cinchona spp.)
Uncertain direct toxicity?: arnica (Arnica montana), Chinese cucumber (compound Q or Trichosanthes kirilowii),
Tripterygium wilfordii[32]
Hypotension: hawthorn (high-dose Craetaegus laevigata), false hellebore (Veratrum spp.), black cohosh
(Cimicifuga racemosa), white cohosh (Actea spp.)
Dysrhythmias: arsenic
Gastrointestinal Disease
Vomiting diarrhea: pokeweed (Phytolacca americana), cohoshes (see earlier), nutmeg (Myristica fragrans); pau
d’ arco (Tabeluia spp.), pennyroyal (Hedeoma pulegioides); Salmonella infection from rattlesnake (Crotalis
spp.); anthraquinones (see Table 37–1 ); metals/metalloids including selenium; caustic effects: Spanish fly
Hepatic Disease
Hepatic veno-occlusive disease (pyrrolizidine alkaloids): coltsfoot (Tussilago farfara), comfrey (Symphytum
officinale, S. x uplandicum), gordolobo (Senecio spp.), life root (Senecio aureus), over 350 species especially in
genera Senecio, Heliotropium, Crotalaria.
Noninfectious hepatitis: blue-green algae (microcystins), chaparral (Larrea tridentata), germander (Teucrium
chamaedrys), jin bu huan (Stephania sinica), kombucha,[102] lobelia (Lobelia inflata), mistletoe (Phoradendron
flavescens, Viscum album), pennyroyal (Hedeoma pulegioides), fo-ti, ho shou wu (Polygonum multiflorum)
Renal Disease
Adulteration/contamination with metals/metalloids including dichromate and nonsteroidal anti-inflammatory
drugs (NSAIDs); colloidal silver, germanium (also ingredient in some ginseng preparations), jin bu huan
(Stephania sinica), licorice rhizome (Glycyrrhiza glabra); misidentifications (e.g., Aristolochia fangchi [“guang
fangji”] substituted for slimming agent Stephania tetrandra [“fangji”]); pennyroyal (Mentha pulegium [European],
Hedeoma pulegioides [American]); spanish fly (cantharidin from beetles); wormwood (Artemesia
absinthium)[136]
Neurologic Disease
Seizure: anticholinergic toxidrome (see earlier list), Chinese cucumber (compound Q or Trichosanthes kirilowii),
gamma hydroxybutyrate, Ma Huang or other central nervous system stimulants; wormwood (Artemesia
absinthium)
Sedation and/or obtundation: Adulteration with benzodiazepines, kava-kava (Piper methysticum), wormwood
(Artemesia absinthium), valerian (Valeriana officinalis), hops (Humulus lupulus), passion flower (Passiflora
incarnata); gamma hydroxybutyrate, gamma-butyrolactone, late hepatotoxicity
Hallucinations: anticholinergics (see earlier), catnip? (Nepeta cataria), hops? (Humulus lupulus), khat (Catha
edulis), nutmeg (Myristica fragrans), wormwood (Artemesia absinthium)
Peripheral neuropathy: buckthorn,[18] germanium heavy metal contamination, podophyllum (Podophyllum
peltatum), selenium, vitamin B6 excess
Muscle weakness: corticosteroid adulteration, hypokalemia from licorice or anthraquinones, cathartics,
diuretics; germanium, kava-kava (Piper methysticum)
Other: coenzyme Q10 paresthesias, colloidal silver (irreversible), blue-green algae saxitoxins, pseudotumor
cerebri from vitamin A excess
Hematologic Disease
Anticoagulation from decrease in vitamin K–dependent coagulation factors: coenzyme Q10?, beta-carotene,
herbals that cause hepatotoxicity (e.g., pennyroyal)
Anticoagulation from coumarin constituents: alfalfa (Medicago sativa), Angelica species (e.g., dong quai or
Angelica sinensis), horse chestnut (Aesculus spp.), Melilot (Melilotus officinalis), red clover (Trifolium pratense),
tonga bean (Cassia oppositifolia), woodruff (Galium odoratum), yarrow (Achillea millefolium)
Anticoagulation from platelet binding: white willow (Salix alba) in large doses or in children, methyl salicylate;
arnica (Arnica montana) contains helenalin, which interferes with platelet sulfhydryl groups and platelet
aggregation; Ginkgo biloba (inhibits platelet activation factor)
Anticoagulation from unknown mechanism: pau d’arco (Tabebuia spp.)
Reversal of anticoagulation: broccoli, vitamin K
Anemia: Germanium, vanadium, and other heavy metals; zinc excess
Methemoglobinemia: asafoetida (Ferula assafoetida) in presence of fetal hemoglobin
Agranulocytosis: Zhong gan ling (contains nonsteroidal anti-inflammatory agents: aminopyrine, dipyrone) and
adulteration with other NSAID agents, particularly phenylbutazone
Leukocytosis: Podophyllum (Podophyllin peltatum), pokeweed (Phytolacca americana)
Metabolic Disorders
Cyanide toxicity (Fruit pits of Prunus species; Hydrangea spp.)
Thyrotoxicosis from Kelp[2]
Hypoglycemia: rehmennia, ginseng, vanadium, ubiquinone. Over 400 plants have been identified as
hypoglycemics, and hypoglycin in the young Jamaican akee fruit can cause profound hypoglycemia
Lactic acidosis: kombucha tea[27]
Steroid effects to watch: yams (Dioscorea spp.), dehydroepiandrosterone (DHEA), melatonin (estrogen
blockade?), saw palmetto (Serenoa repens antiandrogenic?), many body-building products
Wilson’s disease: copper excess[101]
Pulmonary Disease and Anaphylaxis
Bronchiolitis obliterans: Sauropus androgymus
Pulmonary hypertension: monocrotaline (pyrrolizidine alkaloid)
Anaphylaxis: bee pollen, royal jelly; any plant that potentially can trigger type I hypersensitivity, particularly
members of Asteraceae (e.g., daisy and goldenrods) such as Chamomilla, Echinacea, Senecio, and many
more
Selected Herbals Associated with Cancer in Laboratory Animals
Calamus (Acorus calamus), croton oil (Croton tiglium), rue (Ruta graveolens), sassafras (Sassafras albidum),
betel (Areca catechu; oral cancer in humans), khat (Catha edulis; oral cancer in humans). Plants containing
pyrrolizidine alkaloids (see earlier listing on hepatic veno-occlusive disease). Aristolochia fangchi associated
with urothelial carcinoma.
CNS depression can be produced by herbal products. Wormwood (Artemisia absinthium) has been
restricted since the recognition of absinthism, the psychosis and cognitive impairment suspected in such
famous absinthe drinkers as Vincent Van Gogh and Edgar Degas at the turn of the 20th century. Alpha- and
ß-isomers of the terpene thujone, the active agents of wormwood, are believed to act much like camphor to
produce CNS sedation and seizures, whereas its hallucinatory effects are probably due to its affinity for the
same receptor as tetrahydrocannabinol (THC) found in marijuana.[39] Renal toxicity has also been
reported.[136] Thujone produces a pica, may be addictive, and seems to be making a comeback as a drug of
abuse.[10]
Another CNS depressant that can cause seizures is -hydroxybutyrate (GHB), and more recently its
precursor -butyrolactone (GBL). Although its structure is similar to -aminobutyric acid (GABA) and it was
used briefly as an anesthetic agent in the 1960s, it produces seizures as well as coma. Theories about
seizure genesis include stimulation of presynaptic GABAB receptors and release of excitatory amino acids
such as glutamate, but the mechanism remains unclear.[6]
The mild sedative actions of hops (Humulus lupulus), valerian (Valeriana officinalis), and passion flower
(Passiflora incarnata) are poorly understood, but their efficacy is lent credibility by German Commission E
approval. The activity of hops is probably related to a volatile alcohol, methylbutinol, rather than the phenol
constituents humulone and lupulone. Hops has a close taxonomic relationship with marijuana and is
occasionally smoked.[40] Kava-kava (Piper methysticum) is used as a sedative and has many active
lactones, whose proposed mechanisms include GABA and local anesthetic effects. Its effects are additive to
ethanol.[99]
Peripheral Nervous System
Metals/metalloids and podophyllum both produce peripheral neuropathy along with other multisystem effects
and are discussed later. Selenium and germanium are sold as supplements and produce peripheral
neuropathy. Vitamin B6 in high, chronic doses (>500 mg/d) produces an axonal neuropathy and progressive
sensory ataxia.[9][117]
Cardiovascular System
Yohimbine is a selective, competitive a2-adrenergic receptor antagonist that can cause a sympathomimetic
toxidrome. It also has a number of dose-dependent actions, including a1 and serotonin receptor antagonism
at lower concentrations followed by local anesthetic, anticholinesterase, and monoamine oxidase inhibitor
activity[130] and by dopamine antagonism at much higher doses. Alpha2-adrenergic receptors in the CNS are
inhibitory, and their blockade enhances sympathetic outflow, whereas blockade of peripheral presynaptic a2-
adrenergic receptors also potentiates the release of norepinephrine. Blockade of a2-adrenergic receptors on
vascular smooth muscle can produce vasoconstriction or vasodilation depending on the vascular
bed.[11][41][54][58][62][64][89][108] Allegedly, yohimbine improves erectile function by venodilation, but its efficacy
for sexual impotence is controversial. Unlike other sympathomimetics, bronchospasm has been reported
from enhanced acetylcholine release through an a2-adrenergic receptor blockade.[86]
Aconitine is contained in monkshood or wolfsbane and larkspur (Aconitum and Delphinium) species. It has
been used in herbal cardiac medications and abused for its nervous system effects.[30][31][50][123][124][128][129]
Aconitine activates sodium channels and has widespread effects on the excitable membranes of cardiac,
neural, and muscle tissue. Afterdepolarizations with triggered automaticity result from enhanced inward
sodium current during the action potential. This can produce life-threatening tachydysrhythmias or
bradycardia and respiratory depression. Paresthesias, hypersalivation, dizziness, ataxia, nausea, vomiting,
diarrhea, and respiratory muscle weakness may begin as soon as a few minutes to several hours after
ingestion.
Cardiotoxic agents that block Na +-K+-ATPase are contained in oleander (Nerium oleanderi), foxglove
(Digitalis purpurea, D. lanata),[118a] dogbane (Apocynum cannabimum), wallflower (Cheiranthus cheiri), lily-
of-the-valley (Convallaria majalis), red squill (Urginea maritima), and toad venom products (Bufo bufo
gargarizans in China, B. alvarius or B. marinus in the United States; Asian names: “Ch’an Su”, “Kyushin”;
U.S. street names include “Love Stone”, “Rock Hard”[26][96]). Blockade of the Na+-K+-ATPase pump
increases intracellular calcium. Therapeutic doses increase inotropy, whereas toxic doses produce abnormal
automaticity and atrial and ventricular dysrhythmias. By an independent mechanism, these agents are also
vagotonic, producing bradycardia and atrial nodal block. In addition, toad venom derivatives also contain
hallucinogenic bufotenins.
Hepatic System
Pyrrolizidine alkaloids are metabolized by the cytochrome P-450 system in the liver and produce toxic
pyrrole derivatives that act as alkylating agents. Hepatic veno-occlusive disease results in hepatic
congestion, ascites, and edema. Patients may die, develop chronic cirrhosis and/or hepatic carcinoma, or
recover completely.[59]
Other hepatotoxic agents cause hepatitis directly or through toxic metabolites. For instance, pennyroyal oil
(Hedeoma pulegiodes or Mentha pulegium) contains 3 per cent terpenes, primarily pulegone. Pulegone is
metabolized by the cytochrome P-450 system to produce menthofuran. Both agents bind to macromolecules
in the hepatocytes, but only pulegone and its enol intermediates deplete glutathione.[1]
Some theorize that hepatotoxicity of some botanicals may be mediated through an immune response.[92] For
instance, hepatotoxicity from germander and Jin Bu Huan tends to be produced on second exposures and in
some cases is associated with eosinophilia. Others maintain that direct toxicity is the mechanism [from
germander’s metabolite, furano neoclerodane, and from the almost 100 per cent levo-tetrahydropalmatine
contained in Jin Bu Huan, as compared with only 3 per cent in its parent plant Stephania sinica (other
reported botanical sources have included Lycopodium serrata and Polygala chinensis)].
Gastrointestinal System
Anthraquinone laxatives (senna [Cassia spp.], buckthorn or cascara [Rhamnus purshiana], rhubarb [Rheum
spp.]) contain glycosides activated in the bowel to produce derivatives that stimulate colonic motility,
probably by inhibiting Na+-K+-ATPase in the intestine. They also act as bulk-forming agents, promoting
accumulation of water and electrolytes in the gut lumen and producing fluid and electrolyte shifts that can be
life threatening.[59][64] They are sold in some over-the-counter laxative preparations as well as in botanical
dietary supplements. Chronic use may result in laxative dependency and fluid and electrolyte depletion,
resulting in cardiovascular compromise. Melanosis coli, a black pigmentation pattern of the colonic mucosa,
is pathognomonic for chronic anthraquinone use and has an epidemiologic association with carcinoma. [118]
Anthraquinone derivatives may be detected by a red discoloration when urine is alkalinized and then by a
yellow-brown discoloration when acidified, in what is called Borntrager’s reaction.[85]
Pokeweed (Phytolacca americana) contains phytolaccine, which is a potent gastrointestinal irritant capable
of producing hemorrhagic gastritis, hypotension, and death. It also contains pokeweed mitogen, which
produces lymphocytosis 2 to 4 days after ingestion. In addition to catharsis, intended herbal usages beyond
catharsis are wide ranging and include use as an anticancer agent.[110][130]
Podophyllin, pennyroyal, and metals/metalloids are examples of substances that produce transient vomiting
and diarrhea before more serious toxicities.
Hematologic System
Coumarins anticoagulate by inhibiting vitamin K 2,3-epoxide reductase, the enzyme required for the
regeneration of vitamin K1. This inhibition depletes vitamin K1, whose reduced form is required to activate
clotting factors II, VII, IX, and X. Abuse of coumarin-containing herbals can produce a bleeding diathesis.[68]
Excessive ingestion of vitamin K supplements and broccoli pills has been associated with antagonism of
therapeutic anticoagulation. [38] Ingestion of kelp has been associated with immune-mediated
thrombocytopenia and severe depression of erythropoiesis.[107] Vanadium has been noted to cause
hemolytic anemia in animals[141] and zinc excess, a sideroblastic anemia, in humans.[63] Ginkgo may also
cause bleeding through its antiplatelet effects.
Endocrine System
Licorice rhizome (Glycyrrhiza glabra) contains inhibitors of 11 ß-hydroxysteroid dehydrogenase, which

converts cortisol to cortisone. This enzyme inhibition results in high levels of cortisol, which activates
mineralocorticoid receptors in the kidney with the same binding affinity as aldosterone.[47] Chronic use
results in hypokalemia, with muscle weakness, sodium and water retention, and hypertension that can result
in bradycardia, heart failure, or cardiac arrest.[37]
Many supplements contain steroids and other hormones. Body-builders use plant-derived and even insect-
derived steroids with unknown effects. [103] Diosgenin found in yams (Dioscorea spp.) is used in the
manufacturing of progesterone and cortisone.[97] Ecdysterone is derived from insects and has been shown
to produce coronary vasoconstriction in rats.[103] Dehydroepiandrosterone (DHEA, as a dieting or body-
building aid) and melatonin (as a sleep aid) are two endogenous hormones on sale as popular supplements.
No one knows how to dose these safely or if they even are safe. DHEA in large doses may cause
masculinization and increased risk of ovarian cancer in women and increased risk of prostatic enlargement
and prostate cancer in men. Melatonin may cause vasoconstriction and antiestrogen effects.[84] Ingestion of
kelp has caused thyrotoxicosis by iodine loading.[101]
Renal Effects
Use of Aristolochia fangchi has been associated with renal failure rapidly progressing to interstitial fibrosis
and end-stage renal disease and with urothelial carcinoma.[98a][133][134] This Chinese-herb nephropathy
developed when Aristolochia fangchi was substituted for Stephania tetrandra in Chinese herbal pills used for
weight loss. Aristolochic acids are nitrophenanthrene derivatives that have demonstrated carcinogenic
effects in rats.[96a]
Multisystem Effects
Podophyllum is the resin of the mayapple plant Podophyllum peltatum. Podophyllum contains many
compounds including podophyllotoxin and podophyllic acid. Its many actions include inhibition of tubulin
binding, resulting in metaphase arrest, and direct mitochondrial effects. Podophyllum is available for external
treatment of venereal warts, and its derivatives are used commercially for a range of carcinomas. Catharsis
is prominent after ingestion. Acute severe sensorimotor neuropathy and bone marrow suppression after
leukocytosis can occur even after one-time acute exposures[98] and may be directly related to the inhibition
of microtubules. Lethargy, confusion, and autonomic instability have also been described in large
exposures.[59][131] Podophyllum is teratogenic by both the oral and dermal routes of exposure and should
never be used in pregnant women.
Metals/metalloids have been an important ingredient or contaminant of herbal remedies, especially those
associated with ethnic groups. [7][44][70][75][78][100][106][113][119][126][139] Metals/metalloids bind to sulfhydryl
groups, inhibit or uncouple oxidative phosphorylation, and affect various enzyme systems throughout the
body, resulting in effects on multiple organ systems. Initial symptoms are predominantly gastrointestinal after
acute ingestions and neurologic with chronic intake. Exposure is usually oral but can be dermal, as in the
case of “surma” or “kohl,” lead-based eye makeups used in Middle Eastern, Indian, and African cultures.[3]
Although there is much overlap among the clinical presentations of various metals, some present with
distinctive or predominant features. Arsenic is associated with prolonged QTc and dysrhythmias, lead with
abdominal cramping and wristdrop, and thallium with a severe sensory neuropathy. Mercury is known to
produce erethism (also known as “mad hatter’s disease”: emotional lability, forgetfulness, delirium) and
acrodynia or “pink disease” (erythematous hyperkeratotic edema of the palms, soles, and face with a pink
rash). Mees lines and discoloration of nail beds may infrequently be a hint to past or present toxicity with all
of these agents, including selenium. [33][59]
Drug Interactions
Toxicity of herbals can be produced through drug interactions.[38][41] Prescription drugs may increase levels
of herbal ingredients (quinidine and haloperidol can reduce metabolism of sparteine in broom (Cytisus
scoparius), a slimming agent, resulting in circulatory collapse) or vice versa (piperine in Piper species may
increase theophylline or phenytoin levels). Classic monoamine oxidase inhibitor food interactions are
suspected to occur with yohimbine. St. John’s wort decreases plasma concentrations of the protease
inhibitor indinavir, probably by induction of cytochrome P450–mediated metabolism. Finally, interactions of
various herbals could be problematic; for instance, chronic use of anthraquinones and licorice could produce
profound hypokalemia.[37]


With over 20,000 dietary supplement products on the market, clinical presentations will vary depending on
the product involved. Every organ system and toxidrome is represented among potential toxicities, and
relevant clinical information is presented in Tables 37–1 , 37–3 , and 37–4 .
Table 37-4 -- Physical Examination Findings Useful in Differential Diagnosis *

Hypotension, wheezing: anaphylaxis from plant substances or cardiogenic shock
Hypertension, tachycardia: stimulants, anticholinergics, nicotinics, yohimbe, thyrotoxicosis
Bradycardia and/or dysrhythmias: magnesium overdose, cardiac glycosides, aconitine, gamma
hydroxybutyrate, jin bu huan (Stephania sinica), quinine, arsenic
Mental status change: hallucinogens, stimulants, sedatives, drug interactions, agents causing metabolic
changes: thyrotoxicosis, hypoglycemia, cyanide toxicity
Mydriasis: stimulants, anticholinergics, nicotinic agents
Oral mass: oral cancer from khat or betel nut use
Gum bleeding, bruising: coumarin-containing agents
Flushing: anticholinergics, niacin, chromium picolinate and spirulina (niacin-like reactions)
Blue skin, good oxygenation: methemoglobinemia, argyria (colloidal silver)
Dry skin, urinary retention, decreased bowel sounds: anticholinergics
Diaphoretic skin: cholinergics, stimulants
Vomiting or Diarrhea: metals/metalloids, cardiac glycosides, hepatotoxic drugs, salmonella from rattlesnake,
blue-green algae, cathartics; kombucha tea (symbiotic yeast and bacteria); hemorrhagic vomiting or diarrhea
may occur with iron overdose, pokeweed, or any agent that causes anticoagulation.
Right upper quadrant tenderness: hepatotoxic supplements; also test for acetaminophen
Fasciculations: nicotinics
Peripheral neuropathy: see Table 37–3
Muscle weakness: germanium, hypokalemia from diuretics, cathartics, licorice rhizome, magnesium excess,
nicotinic agents: lobelia (Lobelia inflata), blue cohosh (Caulophyllum thalictroides), broom (Cytisus scoparius),
horse chestnut (Aesculus spp.), tobacco (Nicotiana spp.)
Discolorations: jaundice from hepatotoxic drugs, purple mouth from pokeweed berries, red mouth from khat,
blue eye shadow kohl or surma contains lead, yellow skin and flaking from chronic kava-kava use; blue skin
from silver (argyria), photosensitization from numerous plant substances, orange skin from vitamin A excess,
red urine after alkalinization indicates anthraquinone cathartic use, Mees’ lines on fingernails from
metals/metalloids
Alopecia: selenium, thallium, and other metals/metalloids
Cushing’s syndrome: adulteration with corticosteroids, unclear role of other plant/animal steroids
Odors: mint: pennyroyal, methylsalicylate, menthol. Garlic: garlic, arsenic, selenium, thallium, organophosphate
contamination. Almond: cyanogenic fruit pits.
* See Tables 37–1 and 37–3 for more information on the classes and individual substances.
The prospect of learning this new pharmacopeia is daunting, especially since so little is known about most of
these substances. For instance, less than a 5 per cent knowledge of herbals and other dietary supplements
was claimed by physicians surveyed in Great Britain.[101] Health care practitioners should focus this
educational process in three ways. The first goal is to learn what are the most frequently sold products and
their efficacy and safety profiles, because these products are the ones that patients are most likely to use
(see Tables 37–1 and 37–2 ). Such sales information is difficult to obtain (especially for nonbotanical
supplements) and is based largely on survey results.
Table 37-2 -- Selected Top-Selling Dietary Supplements

Top Three Sellers Overall
Melatonin
Coenzyme Q
Chromium picolinate
Categories of Nonbotanical Supplements
Minerals
Vitamins
Oils/lipid-like substances
Proteins/amino acids
Glandulars, foods, synthetics, unknowns
Selected Nonherbal Dietary Supplements with Documented or Uncertain Potential for Toxicity
Coenzyme Q10 (Ubiquinone)
Colloidal silver
Copper
Dehydroepiandrosterone (DHEA)
Gamma-Hydroxybutyrate (GHB)
Germanium
Selenium
Vanadium
Vitamin excess: Vitamin A, B6, D
Zinc
The second area of focus is on products that may be used rarely but have known or strong potential for
toxicity. This is organized by organ system ( Table 37–3 ) and is based on literature review, including
German Commission E status (courtesy of the American Botanical Council), discussions with government
and trade associations, as well as poison center experience. The final goal is to identify the substances
where immediate intervention may mean the difference between life and death. A few examples of such
clinical presentations are given here. Ultimately, health care practitioners should view themselves as
researchers contributing to a fund of knowledge about dietary supplements and report adverse effects
associated with such products to their regional poison center and to the FDA MEDWatch program.
Selected Acute Life-Threatening Toxicities from Herbals
A 42-year-old Hispanic male presented to a New York City hospital with nausea and vomiting. After telling
the triage nurse that he had taken a “sex pill” bought in an herbal store, he was put into a room. Thirty
minutes later, he was found unconscious and asystolic. The treating physician had heard of the association
between aphrodisiacs and cardiac glycosides,[26] but by the time the patient received 10 vials of digoxin-
specific antibody fragments (Digibind) he could not be revived. His digoxin level was 5.6 ng/dL. This
represented the sixth reported death in New York City of this type and occurred after restriction of sales. Two
previous cases had responded to timely Digibind.[14]
The aphrodisiac contained dried toad venom intended to be applied topically, but the product is also sold in
tea form.[79] It is included in Asian medicines called “Ch’an Su” and “Kyushin.” The aphrodisiacs bear many
other names, such as “Love Stone” or “Rock Hard,” and are derived from the venom of species Bufo bufo
gargarizans in China or B. alvarius (Colorado River Toad) or B. marinus (cane or marine toad) found in the
southwestern and western United States. The cardiotoxic steroid is bufadienolide, although the venom also
contains hallucinogenic bufotenin, the reason for the dangerous practice of “toad licking.”[91] Plant-derived
cardiac glycosides (see Table 37–3 ) also respond to Digibind and present like classic digoxin poisoning
(see Chapter 44 ): nausea, vomiting, bradycardia and any tachydysrhythmia except supraventricular
tachycardia without block.
Cardiac toxicity in the setting of chronic licorice (Glycyrrhiza glabra) or anthraquinone use should prompt a
search for hypokalemia. In a critically ill patient, fluid and electrolyte replacement should be instituted with
electrocardiographic analysis and/or rapid laboratory confirmation.
Agitated delirium is another situation that requires early recognition and intervention. Patients are typically
agitated, and, in extremis, they may be hallucinating and/or have seizures. They also present with mydriasis,
tachycardia, hypertension, and diaphoresis (but see section on anticholinergic toxicity later). Such a
toxidrome has become associated with use of the Chinese herbal ephedra or Ma Huang (Ephedra spp.).
Asian species contain alkaloid mixtures composed of ephedrine and pseudoephedrine. Despite long
traditional use in the treatment of asthma, ephedra alone or in combination with other drugs has been
associated with over 800 adverse events and at least 17 deaths (FDA, personal communication, 1997).
Many of these patients intended to achieve a “legal high” (one of the names of the many formulations is
“Herbal Ecstasy”) to enhance performance in the gym (one gym-goer suffered a stroke[34]) or to lose
weight.[12] Faced with epidemics of abuse, five states (Florida, Louisiana, New York, Ohio, and Nebraska)
passed various forms of restrictive legislation on Ma Huang and other forms of ephedrine and
pseudoephedrine. More states are in the process of joining them. In 1997, the FDA proposed regulations
governing dietary supplements containing ephedrine. In June 2000, the FDA withdrew certain provisions of
the proposed regulations, and thus far there is no additional regulation of these products.
Agitated delirium from an anticholinergic toxidrome is best differentiated from that of a sympathomimetic
toxidrome by the presence of dry (vs. diaphoretic) skin, diminished (vs. active) bowel sounds, and urinary
retention deserving of the mnemonic: blind as a bat, red as a beet, dry as a bone, hot as a hare, mad as a
hatter. Plants that produce anticholinergic toxicity include mandrake (Mandragora officinarum), jimsonweed
(Datura stramonium), bittersweet (Celastrus scandens), and deadly nightshade (Atropa belladonna). These
are usually taken for their hallucinogenic or genitourinary tract effects. In addition, contaminations of other
herbal substances with anticholinergic agents have been reported and occasionally lead to
misunderstanding of the herbal itself. For instance, anticholinergic properties are still falsely attributed to
burdock root (Arctium lappa) after an article published in 1978 reported such poisoning in a 26-year-old
woman who drank burdock tea, even though the amounts of atropine found in the tea were unrealistically
high for any plant.[15][16] Although physostigmine is the specific antidote, anticholinergic toxicity can benefit
from CNS sedation and aggressive cooling when necessary or if physostigmine is contraindicated (QRS
widening).
Gamma-hydroxybutyrate (GHB) was introduced in the health food market as a food supplement for body-
builders in the late 1980s with claims that it released growth hormone and could “turn fat into muscle.”
Intoxicated patients present with sedation, apnea, seizures, or coma (typically transient in single
ingestions).[24][28][43] There have been at least four fatalities from its abuse. Under federal law, its sale is now
restricted but its possession is not illegal; it has investigational drug status and is under review by the Drug
Enforcement Agency (DEA), although several states such as California have independently ruled that
possession is illegal. There is also a growing home industry that involves use of sodium hydroxide in the
manufacture of GHB, and this has resulted in cases of severe caustic injury. GHB has also gained popularity
as a recreational drug, promising to be like ethanol but without hangover or like Ecstasy (MDMA) with
euphoria. It has been used as a “date rape” drug in some parts of the United States. On New Year’s Day
1997, approximately 40 concert-goers in Los Angeles drank an orange substance that they were told was
kava-kava. They developed diffuse complaints, including nausea, vomiting, and sedation. Analysis of the
substance revealed 1,4-butanediol, which is metabolized to GHB (FDA, personal communication, March
1997). More recently, GBL, which is converted in the body to GHB, has been implicated in poisonings.[97a]
Pennyroyal oil and tea (Hedeoma pulegioides, Mentha pulegium) are used as abortifacients (to induce
abortion) and emmenagogues (to induce menses) as well as in traditional remedies for upper respiratory
tract infections given to children.[5] Toxic components include the terpene pulegone and its metabolites.
Doses as little as 10 mL can produce hepatotoxicity and glutathione depletion, renal failure, and spongiform
encephalopathy. Patients present with vomiting or diarrhea, which serve as a prodrome to the more serious
sequelae or which may be the only signs in low-dose ingestions. Patients may have a minty breath odor.
Use as an abortifacient stems from its action as a uterine irritant, which occurs in the toxic dose range. As
discussed in the section on pharmacology, the depletion of glutathione by pulegone and its enol
intermediates suggests potential benefit from use of N-acetylcysteine (NAC), which helps regenerate this
natural antioxidant. Although there is no research to support the practice, the safety of the antidote and the
potential benefits warrant its early use.


Considering the extensive use of herbals, the low incidence of serious toxicity is comforting. The differential
diagnosis of herbal toxicity should be approached like other cases of drug-related toxicity. Cause and effect
is often difficult to establish. It is sometimes difficult to know which came first, the illness or use of the herbal,
especially because herbal toxicity is poorly understood. Physical examination can help establish toxidromes
and narrow the differential diagnosis ( Table 37–4 ).


LABORATORY STUDIES
In symptomatic patients, an electrocardiogram and complete blood cell count should be obtained; tests to
determine levels of electrolytes, blood urea nitrogen, creatinine, and glucose done; an international
normalized ratio (INR) determined; a partial thromboplastin time measured; and liver function tests ordered.
Blood and urine specimens and the herbal should be held for later analysis if a causal effect is suspected
and an analysis is indicated. In asymptomatic patients, tests should be targeted to the organ system affected
by chronic ingestion of the implicated product to detect occult toxicity.
Electrocardiographic findings are useful in detection of cardiac abnormalities and electrolyte disturbances.
Quinine abuse, arsenic, and hypokalemia (e.g., licorice, cathartics) may be detected by prolongation of the
QTc interval. Hypokalemia is associated with flattening of T waves and presence of U waves, whereas
hyperkalemia can result in elevation and peaking of T waves on diffuse leads. Arsenic, cardiac glycosides,
and aconitine use are associated with dysrhythmias.
If cardiac glycoside toxicity is suspected, a stat digoxin level is requested. Cross-reactivity is incomplete, and
only low levels may be detected. However, this may represent exposure or toxicity. Polyvalent assays are
necessary to detect bufodienolides, oleandrin, and other plant-derived cardiac glycosides. If the laboratory
uses monovalent assays, serum digoxin levels may be negative.[14]
Diagnosis of supplement-induced illness often relies on laboratory findings. Liver function test abnormalities
may be the first sign of hepatotoxicity in a clinical course of liver failure. Complete blood cell count and
elevations of prothrombin time or INR and partial thromboplastin time are important to determine the effect
of potential anticoagulants or agents that cause agranulocytosis or leukopenia. Arterial blood gas analysis
may be useful in suspected toxicity from cyanide, salicylates, and other nonsteroidals (anion gap metabolic
acidosis) as well as in any patient with respiratory distress or signs of shock. Methemoglobin level should be
sent if cyanosis exists in the presence of good oxygenation.
Glucose should be checked given the hypoglycemic effects of some herbals and minerals such as
vanadium. Urinalysis and electrolytes can be useful in detecting cathartic and diuretic abuse. Proteinuria
may be an early sign of metal/metalloid ingestion. Benzodiazepine adulteration of an “herbal” sedative may
be detected on drug screens in sedated patients. Thyroid function tests should be sent if thyrotoxicosis is
suspected from kelp. Acetaminophen can be a co-ingestant in any intoxication, and blood levels should be
compared with the toxicity nomogram as appropriate. Pregnancy status should be obtained in all females of
reproductive age because of teratogenicity and other maternal-fetal issues.
Metals and metalloids are radiopaque; and if ingestion is suspected, the substance and the patient’s
abdomen should be radiographed. A 24-hour urine collection in a metal-free container should be sent for
arsenic, mercury, selenium, and thallium. In acute symptomatic ingestions, whole blood for lead, cadmium,
arsenic, mercury, and selenium should also be sent to a specialty laboratory. Interpretation of arsenic levels
is complicated by dietary arsenicals. Therefore, a history of seafood/shellfish/kelp ingestion should be
obtained.
Head computed tomography should be obtained in hypertensive patients with focal neurologic signs or
headache in the setting of a stimulant ingestion (stroke has been reported with a compound containing
ephedra). If the scan is negative, lumbar puncture (LP) should follow to exclude the 5 to 10 per cent of
patients with cerebral hemorrhages and negative imaging. High opening pressures on lumbar puncture can
confirm the diagnosis of pseudotumor cerebri from vitamin A hypervitaminosis and be therapeutic as well.
The regional poison center and/or department of health can assist in analyzing substances or determining
any necessary public health actions. Notification of cases to the FDA’s MEDWatch ([800] FDA-1088)
program can also lead to help in analysis of substances. The CDC ([404] 639–2530) can also be helpful in
making connection about epidemiology among symptomatic cases. The California FDA has a section
devoted to substance analysis and/or database information on medicines from various cultures. It also
screens for arsenic, lead, and mercury and may be contacted at (916) 445–2263.


THERAPY
Supportive care is the mainstay of therapy in most cases of herbal toxicity. Specific management follows
from known toxin-induced disease states. For instance, a patient may need neurosurgical consultation for a
CNS hemorrhage from stimulant abuse, liver transplant consultation for severe hepatotoxicity, or dialysis if
renal failure ensues from nephrotoxic agents.
Gastrointestinal Decontamination.
Activated charcoal should be administered to patients suspected of ingesting a potentially toxic substance
that, after consideration of absorption factors, is believed to be still accessible in the alimentary canal.
Gastric lavage is reserved for recently ingested highly toxic substances such as pennyroyal oil, cardiac
glycosides, or aconitine. Radiopacities on abdominal films attributed to metal/metalloid ingestion should
prompt whole-bowel irrigation and consideration should be given to use of a chelator.
Antidotes.
N-acetylcysteine should be considered in all cases of established hepatotoxicity because its use can
improve outcome in patients with fulminant hepatic failure from diverse etiologies.[65] Its role in preventing
hepatotoxicity due to pennyroyal oil is suggested by analogy with acetaminophen (both have production of
toxic metabolites via cytochrome P-450 with subsequent depletion of glutathione).
Other case-specific antidotes are listed in Table 37–5 . Some are theoretical or based on limited scientific
rigor. For instance, glutamic acid is used safely to prevent vincristine-induced peripheral neuropathy[73] and
may be used in podophyllin ingestions for the same reason, although their actions on microtubules differ.
Table 37-5 -- Specific Antidotes by Agentsor Class of Agents

Cardiac Glycoside Toxicity
Digibind 10 vials or more (to effect); Atropine for bradycardia
Wide-Complex Tachycardia from Quinine
Push ampules of sodium bicarbonate until complex narrows (blood pH not to exceed 7.5)
Aconitine Dysrhythmias
Bradycardia responds to atropine (2 mg). Treatment of tachydysrhythmia is unknown: precedent for
amiodarone and flecanide; cardiac bypass or balloon pump.[52][122][137] Avoid internal pacemaker and sodium
bicarbonate (see text).
Metals/Metalloids
In consultation with poison center, use chelation therapy for arsenic, lead, and mercury. No chelation for
cadmium, colloidal silver, selenium, and vanadium. Prussian blue (ferric ferrocyanide) has been used to
enhance fecal elimination of thallium (250 mg/kg/d PO in four divided doses) but is not commercially available
or approved by the U.S. Food and Drug Administration.
Hepatoxic Herbals (see Table 37–3 ).
N-Acetylcysteine, 140 mg/kg PO load with maintenance at 70 mg/kg every 4 hours for 17 doses or until hepatic
failure resolves. Efficacy is unknown.
Cyanide Toxicity
Cyanide antidote kit
Seizure/Agitated Delirium
Diazepam, 5–10 mg IV, in adults to start for agitation, or lorazepam, 2 mg IV, in adults for seizures; increase as
needed and observe respirations; intubate if necessary. Consider pyridoxine (vitamin B6) and barbiturates for
repetitive seizures.
Anticholinergic Toxidrome/Agitated Delirium
In consultation with poison center: physostigmine, 0.5 mg every 3 minutes IV up to 2 mg. Check every 3
minutes for bronchorrhea/other cholinergic signs. Give only if QRS complex is narrow.
Patient on a monitor with atropine at the bedside.
Contraindicated.
A note of caution regarding the treatment of aconitine: whereas sodium bicarbonate should be used to treat
wide-complex tachydysrhythmias from quinine toxicity, it poses a theoretical risk in the setting of aconitine
(Aconitium spp. or Delphinium spp.) poisoning in which the mechanism is excessive influx at the sodium
channel rather than sodium channel blockade.


DISPOSITION
Most ingestions/overdoses of plant herbals and other dietary supplements are nontoxic. If there are no
symptoms, the patient can be discharged after 6 hours of observation unless the toxin is known to have a
delayed onset or psychiatric intervention is indicated for a suicidal patient. The presence of symptoms
requires observation or admission. Gastrointestinal symptoms often precede more serious toxicity and
should not be minimized.


SEQUELAE
Some toxicities are delayed. This is particularly true of agents potentially capable of producing cancer
(partial list in Table 37–3 ). Some agents may induce cell-mediated immunity and need a second exposure
for toxicity.[105] Peripheral neuropathy and multiorgan system effects on the liver and bone marrow often
occur days to weeks after the acute insult with metals/metalloids. Teratogenicity is of concern and, with the
exception of a few substances, information is lacking.


SPECIAL SITUATIONS
Ethnicity
We live in a transcultural world. Although anyone can use Asian, African, Hispanic or other cultural
formulations, the index of suspicion for metals/metalloids and prescription medicine adulteration should be
raised in patients in whose cultures commonly use traditional
remedies.[7][19][26][31][42][44][59][60][67][70][75][78][94][100][106][113][116][119][126][132][133][134][138][139]
Pregnancy, Lactation, and Pediatrics
Numerous plant chemicals cross the placenta, are known teratogens, or are secreted in breast
milk.[41][48][72][101] For instance, pyrrolizidine alkaloids in teas consumed by pregnant or lactating mothers
have resulted in deaths of a neonate and infants.[112] Herbal medicine has been used in midwifery. Two
articles in midwife journals featured raspberry leaf (Rubus idaeus), although little research has been done in
pregnancy and it is not approved by Commission E. Red clover (Trifolium pratense) and blue cohosh
(Caulophyllum thalictroides) were also mentioned.[35][121] Red clover contains coumarins, which could
induce bleeding if taken excessively. Blue cohosh contains anagyrine, an animal teratogen. In addition,
traditional colic medicines, such as “azarcon” and “greta,” have been found to contain lead.[23] Newborns
with their higher levels of fetal hemoglobin may be more susceptible to certain herbals, such as asafoetida
(Ferula assa-foetida), which produced methemoglobinemia in a newborn.[77] Vitamins are usually viewed as
important to pregnant women and children; however, teratogenicity and toxicity in children have resulted
from vitamin A excess.[90][111]
Bradycardia and respiratory and CNS depression developed in children given Jin Bu Huan for pain relief.[25]
Other medicines commonly used in Chinese communities are potentially harmful to fetuses, infants, and
children.[29] Herbal medicines and supplements are not required to be packaged with child-proof caps, and
children are more likely to ingest excessive doses for their weight, regardless of the source.[69] Adolescents
are vulnerable to claims of body-building products and the seduction of a “legal high.”[103][105][57]
The Elderly
Elderly patients may have different pharmacokinetics compared with younger adults and are often taking
multiple medications, putting them at higher risk for toxic drug interactions.[38][72] Higher rates of impotence,
constipation, and sleep disturbances may make them more vulnerable to drugs such as yohimbine,
anthraquinone cathartics, and melatonin. Although melatonin is one of the top-selling sleep aids, evaluation
of large doses for prolonged periods of time, and potential interactions with estrogen replacement in
postmenopausal women (estrogen modifies melatonin) is lacking. Purity of these commonly available
products is uncertain.[20]
Red Flags: Reasons for Herbal Use That May Be Associated with Toxicity or Undertreatment
Specific reasons for use of herbals should serve as “red flags” to heighten concern about underlying disease
states.High-risk uses include treatments for cancer, human immunodeficiency virus (HIV) disease, and
arthritis, as well as for performance enhancement by body-builders or as aphrodisiacs and abortifacients (
Table 37–6 ). Use of aphrodisiacs should prompt inquiries about sexual impotence because the underlying
cause may be untreated diabetes, hypertension, substance abuse, or anxiety. Estimates of herbal use for
cancer and HIV disease range as high as 60 per cent and 73 per cent, respectively.[21][104]
Table 37-6 -- Rationales for Use of Dietary Supplements * That Are Associatedwith High Risk for Toxicity
or Undertreatment
Cancer/Human Immunodeficiency Virus/Arthritis
believed to prevent mutations. Certain species contain hepatotoxic
Blue-green algae: microcystins and neurotoxic saxitoxins.[82][127] Grown in open tanks
susceptible to filth. Little human toxicity data.
possible association with paresthesias, hypoglycemia, increased bleeding
Coenzyme Q10:
tendencies.[46][78][104] Little human toxicity data.
produces irreversible neurologic deficits, renal failure, and argyria with bluish
Colloidal silver:
discoloration of the skin. Historically used in over 650 other diseases.[55]
multiple system organ failure and death occurred in 5 cases with over 20
cases of nephrotoxicity, muscle neuropathy, paresthesias, and
Germanium:
anemia.[51][80][125][140] It has caused nephrotoxicity as an adjuvant to ginseng
preparations.[8]
popularized by false notion that sharks do not get cancer and belief that it
Shark cartilage:
blocks blood supply to tumors. Risk of undertreatment: efficacy doubtful.[130]
known to produce pulmonary edema, cerebral edema, cerebral hemorrhage,
Trichosanthes kirilowii
myocardial toxicity, and seizures and fever, especially with parenteral use.[59]
(Chinese cucumber,
Used with belief that it blocks replication of human immunodeficiency in T4
“compound Q10”):
cells.
Chinese herbal used externally for arthritis and now internally for immune
suppression. Implicated in cardiovascular collapse, vomiting, diarrhea, renal
Triptergium wilfordii:
failure, hypocalcemia, and death of a 36-year-old. No analysis of substance or
vehicle provided. To be watched.[32]
severe nausea, vomiting, anemia, bleeding tendencies.[130] No proven
Pau d’arco (Tabebuia spp.):
efficacy.
pits contain cyanogenic amygdalin and used under false belief that toxicity is
relatively selective for tumor growth. This was the rationale for laetril (also
Prunus seeds:
amygdalin), which is now banned. Seeds are still available for sale, and
toxicity was recently reported.[130][135]
Body-Builders/Athletes
Spirulina is used for its amino acid content but can have niacin-like side
Blue-green algae:
effects. Some species contain hepatotoxins and neurotoxins.
Used for presumed anabolic effects. Three companies recently settled in a suit
prosecuted by the Federal Trade Commission for making false claims.
Chromium picolinate:
Formulations contain niacin, which can cause flushing and weakness. Long-
term toxicity, if any, is unclear.
Dehydroepiandrosterone represents one of innumerable steroids and glandular agents that are sold as
(DHEA): supplements with uncertain toxicity if any.
Gamma hydroxybutyrate: see text: vomiting, sedation, apnea, seizure, coma, death.
Banned in 1989 by U.S. Food and Drug Administration (FDA) for association
with eosinophilia myalgia syndrome and deaths[66]; however, tryptophan still
L-Tryptophan: listed among ingredients in body-building products.[74] There is growing
concern that other amino acids especially phenylalanine may be associated
with connective tissue disorders (FDA, personal communication)
believed to have insulin-like effects associated with buildup of glycogen stores
Vanadium:
and weight loss.[57][93][114] Associated with hemolysis in animal models.[141]
alkaloid yohimbine produces hypertension, tachycardia, palpitations, tremors,
Yohimbe (Pausinystalia anxiety, paresthesias. Sales restricted in state of Georgia. Not approved by
yohimbe): German Commission E. Growing use among athletes. Also used as an
aphrodisiac and drug of abuse.
Abortifacients/Emmenagogues
Pennyroyal oil (Hedeoma
Hepatotoxicity, renal failure, spongioform encephalopathy. See text.
pulegioides, Mentha pulegium):
Contains glycoside caulosaponin that induces uterine contractions, constricts
Blue cohosh (Caulophyllum coronary blood vessels, and causes cardiac muscle toxicity. Alkaloid
thalictroides): methylcysticine can produce a nicotinic toxidrome (1/40 toxicity of
nicotine).[99][130] Also contains anagyrine, an animal teratogen.
Black cohosh (Cimicifuga Suspected to have estrogenic activity by indirect evidence. Can produce
racemosa): nausea, vomiting, and peripheral vasodilation.[99][130]
White cohosh (Actea spp.): Can produce stomach cramping, vomiting, circulatory collapse.[99][130]
Contains sparteine, which shares properties with quinidine and nicotine and
Broom (Cystisus scoparius):
was once used to induce labor (150 mg IM).
Tinnitus, deafness, visual disturbances, ataxia, seizures, hypotension, type IA
Quinine (Cinchona spp.):
dysrhythmias including torsades.
Contains alkaloids/coumarins that are toxic to the fetus or prevent
Rue (Ruta spp.):
implantation.
Trichosanthes kirilowii
(Chinese cucumber or discussed underCancer/Human Immunodeficiency Virus/Arthritis
“compound Q10”):
Aphrodisiacs/Sexual Impotency
Bufo bufo gargarizans, B. alvarius, B. marinus. See text: cardiac
Bufo venom: glycoside.[14][26] Nausea, vomiting, bradycardia, all tachydysrhythmias except
supraventricular tachycardia.
Cantharidin found in more than 2000 species of beetles is caustic to
Spanish fly: gastrointestinal and genitourital tract. Death produced with doses over 10
mg.[99]
Yohimbine: See Body-Builders/Athletes.
* Innumerable other supplements are used as well.
Some patients will present who have been in search of a “legal high.” They may use GHB (in states where
possession is still legal), Ma Huang, kava-kava, and hallucinogens including broom, hops, catnip (with
putative effect), nutmeg, mace, cinnamon, and even aconite-containing herbals (which results in an “out of
body” sensation that can be life threatening).[128]
Infections
Patients may take herbals to medicate infections. Recognition of such products may lead to diagnosis of an
undertreated infection such as pyelonephritis and, in the case of urinary tract infection, prevent
pyelonephritis or, in the case of venereal disease, to prevent sterility or, in general, prevent the progression
of a local infection to sepsis. Herbals used for fever include calamus (Acorus calamus), calendula
(Calendula officinali), and quinine. Propolis (bee glue) is a traditional treatment for tuberculosis. Upper
respiratory tract infections or pneumonia may be treated with antitussives/expectorants such as coltsfoot
(Tussilago farfara contains pyrrolizidine alkaloids), licorice (Glycyrrhiza glabra), and hyssop (Hyssopus
officinalis).[130] A partial list of agents used for urinary tract infections includes buchu (Barosma spp.),
cranberry (Vaccinium macrocarpon), life root (Senecio aureus contains pyrrolizidine alkaloids), goldenseal
(Hydrastis canadensis), horsetail (Equisetum arvense), and uva ursi (Arctostaphylos uva-ursi). Any herbal
diuretics may be used for this purpose as well. Botanical treatments for venereal disease include buchu
(Barosma spp.), chaparral (Larrea tridentata contains nordihydroguaiaretic acid), echinacea, Mormon tea
(Ephedra nevadensis), red clover (Trifolium pratense), and yellow Dock (Rumex crispus). Herbals noted to
be used as “alternatives” or “blood purifiers” also imply use in venereal disease[130] and should prompt
further workup of syphilis, gonorrhea, or chlamydia. Rarely, the herbal itself may be associated with
infection. Rattlesnake powder has been used as a traditional medicine in Mexican-American populations as
a cure for cancer and for blood and skin disorders. This powder has been linked to Salmonella arizona
infections.[109]
Dieters
A number of herbal slimming agents have been implicated in toxic conditions; and although many of the
original formulations are now off the market, reports of further toxicity have ensued.[56] Health care
practitioners should be aware that these herbal preparations may have been previously purchased outside
the United States, especially in Europe. Wall germander (Teucrium chamaedrys) was used in the treatment
of obesity until 26 cases of hepatotoxicity were reported to French pharmacovigilance centers. The
mechanism is probably immune mediated.[87] A second agent, broom (Cytisus scoparius), contains
sparteine and is included in herbal dieting aids. Sparteine has nicotinic effects and has been used to induce
labor through an injection dosed similarly to the diet product. High doses, especially in slow metabolizers or
in those taking competitive drugs, may produce circulatory collapse, respiratory arrest, cramps, vision
changes, headache, nausea, and obstetric emergencies.[11] Slimming products containing Stephania
tetrandra and Magnolia officinalis produced end-stage renal failure in at least 70 women in Belgium. These
Chinese products contained aristolochic acid from a plant that bears a common name (“Guang fangji”),
similar to that of the Stephania (“Fangji”). The inclusion of the toxic material was due to name
confusion.[133][134] An outbreak of bronchiolitis obliterans was reported in at least 200 cases, including four
deaths in Taiwan in 1995 when use of Sauropus androgynus as a “weight reduction vegetable” became
popular. This was marketed as a dietary supplement in the United States as “Defat Tablet,” and potential for
pulmonary toxicity from its use still exists from unused pills.[83][88] Dieters also use many of the body-building
products, including Ma Huang.


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Chapter 38 – Laxatives
SUSAN C. SMOLINSKE SUZANNE R. WHITE
Essentials
Acute Laxative Overdose
• Acute onset of diarrhea/abdominal cramping
• Absence of blood or leukocytes in stool
• Absence of fever, chills
Chronic Laxative Abuse

• History of chronic intermittent diarrhea and
vomiting
• Hypokalemia, usually with metabolic alkalosis
• Positive Clinitest or sodium hydroxide stool test
INTRODUCTION
The incidence of laxative exposures reported in 1997 to poison control centers was 15,099.[31] Most were
unintentional acute overdoses in children that resulted in minor, self-limiting symptoms, although eight had
life-threatening outcomes and 14 per cent were treated in a hospital setting. There was one fatality in 1995,
an elderly patient who received 10 phosphate enemas,[30] and two fatalities in 1997 in adults ingesting
sodium phosphate.[31] Laxative-induced chronic diarrhea is often unrecognized by both patients and
physicians. In a study of 359 patients with chronic diarrhea, 4.2 per cent of the cases were related to
excessive nondietary intake of magnesium in antacids, laxatives, or food supplements.[19] Diabetics and
patients with enteral feeding tubes are at risk for sorbitol-induced diarrhea from foods or medication.[16]
In addition to unintentional exposures, chronic deliberate abuse of laxatives is not uncommon. The
motivation for the majority percentage of these cases is psychological, with only 10 per cent citing chronic
constipation.[35] Patients often undergo extensive clinical investigation and may deny intake even after
confrontation with direct evidence of abuse. Four identifiable subgroups of patients abuse laxatives: (1)
women with eating disorders who are trying to control their weight; (2) young to middle-aged individuals,
usually women, often in health care–related professions, who surreptitiously use laxatives; (3) children given
laxatives as a form of child abuse; and (4) elderly patients with chronic constipation, in whom chronic toxicity
can occur.


Laxatives increase stool frequency by three major mechanisms: (1) an osmotic effect causing retention of
fluid in colonic contents; (2) a decrease in net water and electrolyte absorption through actions on the
colonic mucosa; and (3) increase in intestinal motility, shortening transit time and limiting absorption of water
and electrolytes. Grouping of laxatives by general mechanism is often used for classification, but individual
laxatives may have more than one effect.
Bulk-Forming
Bran, psyllium, and methylcellulose bind water and ions in the intestinal lumen, thereby softening feces.
Onset of laxative effects is generally delayed for 1 to 3 days. Bulk is increased through water absorption,
possibly by providing a growth medium for colonic bacteria, which increases fecal mass. Metabolites
generated from colonic bacteria may also increase luminal fluid osmotic activity. Psyllium contains allergenic
proteins derived from the endosperm and embryo of Plantago ovata, a Mediterranean plant. Therefore, IgE
reactions to psyllium can occur.
Saline/Osmotic
Magnesium salts, phosphates, sulfates, lactulose, glycerin, and sorbitol increase osmotic activity of luminal
fluid. Effects occur within 1 to 3 hours with high doses and in 6 to 8 hours in lower doses. Lactulose is
metabolized initially to fructose and galactose, then to lactate, acetate, and formate. The decreased pH may
enhance gut motility.
Magnesium salts increase duodenal secretion of cholecystokinin and stimulate gut prostaglandin excretion.
The contribution prostaglandin makes to the laxative effect has not been established, but increased levels
are a common effect of laxatives such as castor oil, phenolphthalein, bisacodyl, magnesium salts, and
anthraquinones. Stimulation of the cyclooxygenase pathway to produce prostaglandins is also one
postulated mechanism for the actions of cholera toxin.[13] Regardless of mechanism, the result is stimulation
of fluid secretion and increased motility.[34]
Stimulants
Anthraquinones (senna, cascara), bisacodyl, phenolphthalein, and docusate primarily stimulate colonic
motility. Mechanisms include (1) inhibition of intestinal sodium-potassium adenosine triphosphatase, which
decreases colonic sodium absorption; (2) increased prostaglandins; (3) increased cyclic adenosine
monophosphate synthesis that stimulates secretion of chloride and potassium and inhibits neural sodium
chloride uptake, causing net fluid secretion; (4) direct stimulation of Auerbach’s plexus; and (5) increased
nitric oxide synthase, which stimulates colonic fluid secretion. Laxative effects are delayed for 6 to 8 hours.
Anthraquinones, bisacodyl, and phenolphthalein damage the surface epithelium of colonocytes. The
damaged cells migrate to the intercryptal space and are taken up by macrophages, which form a dark brown
pigment known as “melanosis coli.”[4] Sodium depletion due to diarrhea increases serum aldosterone levels,
which stimulates sodium and water absorption in the colon. While conserving sodium, potassium is
secreted, resulting in increased fecal potassium loss. Renal potassium secretion also occurs secondary to
excessive circulating aldosterone. Hepatotoxicity from one case of chronic senna overuse was speculated to
be due to metabolism of sennosides to rhein danthron. This metabolite is structurally related to danthron, a
known hepatotoxin, and is found in rhubarb leaves, which have been associated with hepatotoxicity after
acute ingestion.[26]
Surfactants
Castor oil is hydrolyzed by pancreatic lipase in the small intestine to glycerol and ricinoleic acid, an anionic
surfactant that stimulates peristalsis and alters permeability, causing mucosal damage. Docusate is an
anionic compound that emulsifies feces, water, and fat, thereby hydrating and softening stool. It also has a
stimulant effect and alters net absorption of water and electrolytes. Onset with castor oil is rapid, within 1 to 3
hours, since ricinoleic acid acts in the small intestine. Docusate has an onset of 1 to 3 days.


CLINICAL PRESENTATION (Table38–1)
Stimulant Laxatives
Most acute overdoses of stimulant laxatives are accidental ingestions by children or malicious pranks, such
as baking chocolate-flavored laxatives into brownies. Nausea, vomiting, abdominal cramping, and diarrhea
are often the only effects from this type of laxative exposure. [8] Dehydration and electrolyte abnormalities
occur rarely in severe cases and are more common in children. Fever and chills are typically absent. Higher
morbidity may occur with massive doses. Older literature documents severe or fatal accidental pediatric
exposures to phenolphthalein, in doses of 650 mg to 2 g, manifesting as shock, pulmonary edema,
metabolic acidosis, cerebral edema, and multiorgan failure.[6][8][26] A more recent massive overdose in an
adult, who was also a chronic laxative
Table 38-1 -- Clinical Presentation of Laxative Toxicity

Nausea
Vomiting
Diarrhea
Abdominal cramping
Pink/red stool or urine discoloration (phenolphthalein, aloes, other anthraquinones)
Hypernatremia/hypocalcemia/hyperphosphatemia (phosphates)
Hypermagnesemia
Constipation
Abdominal bloating/pain
Gastrointestinal bleeding/anemia
Hypokalemia/muscle weakness/renal damage/rhabdomyolysis
Hypocalcemia/hypomagnesemia
Steatorrhea
Osteomalacia due to hypocalcemia
Pseudo–Bartter’s syndrome
Hepatotoxicity (senna)
Ammonium urate renal calculi
Lipoid Pneumonia
Often asymptomatic
Chronic cough
Dyspnea
Hypoxia
abuser, resulted in fatal hepatic failure and disseminated intravascular coagulation.[36] Saline/Osmotic Laxatives
Acute exposures to saline or osmotic laxatives are often iatrogenic, such as administration of multiple doses
of sorbitol or magnesium salts in patients receiving multiple-dose activated charcoal or excessive use of
phosphate enemas during colonic preparation.[17][22][32][38] These exposures carry a higher morbidity.
Patients with acute phosphate laxative overdose commonly present with carpopedal spasm and lethargy
due to hypocalcemia, and in severe cases hyperventilation, coma, seizures, tachycardia, heart block,
prolonged Q-Tc interval, diuresis, and cardiac arrest.[22][32][38] Hypermagnesemia may occur, especially in
patients with renal dysfunction, after magnesium sulfate or citrate ingestion.[22][32][33][38] Symptoms include
central nervous system depression, respiratory depression, hypotonia, hypotension, and cardiac rhythm
disturbances. Therapeutic use of psyllium has been associated with asthma, rashes, and anaphylaxis in
sensitized individuals.[20]
Chronic Laxative Use/Abuse
Stimulant Laxatives
Laxative abuse occurs most frequently in women and often presents as watery diarrhea, muscle weakness,
and hypokalemia. Chronic constipation, bloating, and abdominal pain alternating with diarrhea is typical.
Complications may include gastrointestinal bleeding, anemia, steatorrhea, pancreatic dysfunction,
hypokalemia, hypocalcemia, hypomagnesemia, rhabdomyolysis, renal failure, osteomalacia,
pseudo–Bartters’s syndrome with metabolic alkalosis, hyperaldosteronism secondary to volume
depletion–induced aldosterone secretion, and hepatotoxicity.[7][9][36] Phenolphthalein is one of the most
common causes of fixed drug eruption, characterized by well-defined, erythematous skin lesions that recur
in the same location within a few hours after each exposure.[41] After clear evidence of carcinogenicity was
found in 2-year rodent studies done by the National Toxicology Program, phenolphthalein was removed from
the market.[15] It is unclear whether other stimulant laxatives carry the same risk. Senna contains some
mutagenic components. The U.S. Food and Drug Administration (FDA) has requested that manufacturers
conduct additional research to assess risk before publication of the final monograph on a laxative.
Chronic use of herbal products labeled as “dieter’s teas” or “natural bowel cleansers” containing potent
stimulant laxatives, such as senna, aloe, buckthorn, and rhubarb, have been associated with severe
dehydration and hypokalemia. Nine deaths have been reported to the FDA in patients with eating disorders
or patients who were attempting rigorous weight-loss regimens using these products.[27]
Bulk Laxatives
Esophageal bezoars have been reported in patients with chronic bulk laxative ingestion.[1]
Lipoid Pneumonia
Mineral oil–based laxatives are the most common source of lipoid pneumonia, which occurs when the oil is
aspirated into the lung. These nonirritating oils do not provoke protective airway responses, such as cough
and glottic closure, and may impair mucociliary transport. Lipoid pneumonia most often occurs in debilitated
patients. Patients are often asymptomatic, with pneumonia discovered by routine chest radiography.
Productive cough, recurrent respiratory infections, chest pain, hemoptysis, dyspnea, rales, and wheezing
may be present.[3][18][29][39]


Infectious agents are the most common cause of acute diarrhea and must be considered in the absence of
history of acute laxative ingestion. Adverse effects of drugs and chemicals other than laxatives may present
primarily as diarrhea and should be considered in the unknown overdose (see Table 38–2 ).
Table 38-2 -- Differential Diagnosis: Acute Laxative Overdose

Infectious Agents
Food poisoning
Viral gastroenteritis
Medications
Antibiotics (ampicillin, clindamycin, erythromycin, amoxicillin/clavulinic acid)
Antineoplastic agents
Cisapride
Clofibrate
Colchicine
Digitalis glycosides
Gemfibrozil
Iodine
Iron
Levodopa
Lithium
Lovastatin
Misoprostol
Nicotine
Nonsteroidal anti-inflammatory drugs
Olsalazine
Opioid withdrawal
Podophyllum
Probucol
Procainamide
Propranolol
Quinidine
Serotonin reuptake inhibitors
Sorbitol or glycerin vehicle
Theophylline/xanthines
Thyroid hormone
Valproic acid
Toxins
Abrin/ricin
Boric acid
Glycol ethers
Insecticides (organophosphates, carbamates)
Marine toxins (ciguatera, domoic acid, scombroid, DSP)
Metals/metalloids (arsenic, mercury, thallium, chromium)
Mushrooms (group VII—gastrointestinal irritants)
Pokeweed
Chronic diarrhea can be due to inflammatory causes (ulcerative colitis, Crohn’s disease, acquired
immunodeficiency syndrome), malabsorption (celiac disease, lactase deficiency, short bowel syndrome),
secretory disorders (carcinoid syndrome), or altered motility due to fecal impaction or neurologic diseases (
Table 38–3 ). Inflammatory causes are associated with fever and fecal leukocytes. Malabsorption improves
with fasting and is accompanied by greasy, foul-smelling stools. Secretory disorders persist with fasting and
have other systemic effects of hormonal secretion, such as flushing, skin lesions, and bronchospasm with
carcinoid tumors and recurrent peptic ulcers with Zollinger-Ellison syndrome. Laxative abuse should be
suspected in patients with a history of extensive evaluation for idiopathic diarrhea who desire inpatient
evaluation.[19][25] Night-time diarrhea suggests organic disease, such as diabetic visceral neuropathy,
inflammatory bowel disease, or hyperthyroidism.
Table 38-3 -- Differential Diagnosis: Chronic Laxative Abuse

Inflammatory Diseases
AIDS-related infections (pathogens, opportunistic infections, AIDS enteropathy)
Other infection (amebiasis, giardiasis, campylobacteriosis)
Crohn’s disease
Eosinophilic gastroenteritis
Radiation enterocolitis
Ulcerative colitis
Malabsorption
Celiac disease
Lactase deficiency
Regional enteritis
Short bowel syndrome
Whipple’s disease
Secretory Disorders
Bile salt catharsis
Carcinoid syndrome
Mastocytosis
Microscopic colitis/collagenous colitis
Pancreatic adenoma
Rectal villous adenoma
Thyroid carcinoma, medullary
Zollinger-Ellison syndrome
Altered Intestinal Motility
Fecal impaction
Irritable bowel syndrome
Neurologic diseases
Dietary Factors
Cola beverages
Coffee
Fructose
Diverticular Disease of the Colon
Metabolic
Diabetes
Hyperthyroidism
Hypoadrenalism
Laxatives
Saline laxatives
Stimulant laxatives
Lipoid Pneumonia
Medications (see Table 38–2 )
Lipoid Pneumonia
Radiographic findings can include a nodular appearance, mimicking bronchogenic carcinoma and
sarcoidosis. Chronic aspiration pneumonia can also mimic lipoid pneumonia ( Table 38–4 ). Demonstration
of lipid substances in sputum macrophages is diagnostic of lipoid pneumonia but is not always apparent.
Radiographic findings with acute hydrocarbon pneumonitis are usually distinct, with diffuse bibasilar
infiltrates that progress over several days, rather than nodules. Lipoid pneumonia can present with ground-
glass radiographic characteristics, which may be confused with pulmonary edema. Bronchoscopy or
transbronchial biopsy is not usually necessary to make the diagnosis.
Table 38-4 -- Differential Diagnosis of Lipoid Pneumonia

Chronic mineral oil ingestion
Chronic aspiration pneumonia
Hydrocarbon aspiration


LABORATORY STUDIES
Stimulant Laxatives
Monitor serial electrolytes in patients with a history of acute overdose and severe vomiting or diarrhea.
Asymptomatic patients usually can be managed without laboratory studies.
Phosphate Laxatives
Serum sodium, potassium, calcium, and phosphorus levels should be monitored in symptomatic patients
after phosphate laxative overdose. The patient should also be monitored by electrocardiography.
Magnesium Laxatives
Serum magnesium and calcium levels are monitored after magnesium citrate or sulfate overdose.
Electrocardiography is used to monitor the patient’s status, and renal function must be established.
Bulk Laxatives
Plantain-containing products may be contaminated with Digitalis lanata. Digoxin levels should be obtained in
patients with signs and symptoms suggestive of cardiac glycoside toxicity (hyperkalemia, bradycardia,
hypotension, heart block). This Digitalis species contains at least 60 cardiac glycosides with variable cross-
reactivity to the polyclonal digoxin assay, with some having a prolonged half-life compared with digoxin.
Serum levels do not correlate well with toxicity and may remain elevated for a longer time. [37]
Phenolphthalein
To detect occult use, stools may be tested with a Clinitest tablet, used in home test kits for urine glucose
testing. In the presence of phenolphthalein the stool will change to a deep purple color. Addition of
potassium hydroxide will result in a magenta color, which will turn clear after acidification with hydrochloric
acid. [10] A similar test for urine involves addition of 2 mL of 0.1 N sodium hydroxide to 10 mL of ether extract.
A pink color indicates free phenolphthalein. Other anthraquinone laxatives may react in a similar way,
although it is only described with aloe and aloin. This test may remain positive for up to 4 days after
ingestion.[11] Urinalysis may reveal ammonium urate calculi crystals.[12] Proctosigmoidoscopy may show
dark or black mucosal pigmentation (melanosis coli) in patients who have been abusing anthraquinone
laxatives (aloe, cascara, phenolphthalein, senna) for several months or longer.
Osmotic Cathartics
To detect occult use, the stool osmotic gap can be calculated:
If the gap exceeds 100 mmol/L, osmotic diarrhea is present. A quantitative stool-soluble magnesium level of
greater than 45 mmol/L or 15 mmol/day indicates magnesium-induced catharsis.[19]
Other Laboratory Studies
Tests that may be useful in evaluating chronic laxative abuse include serum levels of calcium, magnesium,
phosphorus, electrolytes, blood urea nitrogen, creatinine, and protein. A barium enema examination will
show pathologic changes suggestive of laxative abuse, including dilated lumen and terminal ileum, loss of
haustration, pseudostrictures, or sandglass-formed spasms.[34] The presence of many stimulant laxatives
can be confirmed by qualitative thin-layer chromatography of urine.[14] In select situations, stools may be
studied for bacterial culture, ova and parasites, blood, leukocytes, mucus, fat, pH, and reducing substances.
Lipoid Pneumonia
Chest radiography may show nodules and masses or a diffuse ground-glass appearance, which can be
mistaken for pulmonary edema. Changes are usually in the lower and middle lobes, with the right lung more
commonly or heavily involved. Arterial blood gases should be measured in patients with dyspnea. In severe
cases, right-sided heart catheterization and monitoring of pulmonary capillary wedge pressure should be
considered. Sputum cytology can be useful in staining for lipid-containing macrophages. Bronchoscopy or
transbronchial biopsy is often done in the investigation of presumed lung carcinoma but is seldom helpful in
the diagnosis of lipid pneumonia.[5]


TREATMENT ( Tables 38–5 and 38–6 )
Acute Laxative Ingestion
Bulk Laxatives
Patients with a history of acute accidental ingestion can usually be treated at home with increased fluid
intake to prevent esophageal or gastrointestinal obstruction. Diarrhea is seldom severe enough to require
treatment.

Activated charcoal (for stimulants)
Cardiac monitoring
Fluid/electrolyte monitoring and replacement as required
Hemodialysis (hypermagnesemia in renal failure)
Phosphate binders (aluminum hydroxide, 30–45 mL) for phosphates immediately after ingestion
Increase dietary fiber to 14–28 g/d
Encourage fluid intake
Maintain adequate exercise
Bulk laxatives for 1-month trial:
Methylcellulose, 4–6 g/d
Polycarbophil, 4–6 g/d
Psyllium, 3–10 g/d
Psychiatric evaluation
Lipoid Pneumonia
Oxygen and ventilation as required
Discontinue exposure
Treat complicating infection
Table 38-6 -- Laxative Categories

Bulk Laxatives
Agar
Carboxymethylcellulose sodium
Glucomannan (Amorphophallus konjac)
Guar gum (Cyamopsis tetragonolobus)
Isphagala
Karaya
Malt soup extract
Methylcellulose
Plantain
Psyllium seeds (plantago)
Lubricant Laxatives
Dioctyl sodium sulfosuccinate
Mineral oil
Osmotic Laxatives
Glycerin
Lactulose
Sorbitol
Saline Laxatives
Magnesium citrate
Magnesium hydroxide (milk of magnesia)
Magnesium sulfate (Epsom salts)
Sodium sulfate (Glauber’s salts)
Sodium phosphate
Sodium potassium tartrate (Rochelle salt)
Stimulant Laxatives
Aloe (Aloe barbadensis)
Bisacodyl
Bitternut root bark (Juglans cinera)
Buckthorn (Rhamnus frangula)
Cascara sagrada (Rhamnus purshiana)
Castor oil
Colocynth (Cirullus colocynthis)
Dandelion root (Taraxacum officinale)
Danthron (discontinued)
Dehydrocholic acid
Jalap (Ipomoea purga)
Oxyphenisatin (discontinued)
Phenolphthalein (discontinued)
Podophyllum peltatum (mayapple)
Polygonum multiflorum (Fo-ti)
Rhubarb (Rheum officinale or R. palmatum)
Senna (Cassia alexandrina)
Yellow dock (Rumex crispus, sheep sorrel)
Stimulant Laxatives
Phenolphthalein reportedly adsorbs to activated charcoal, and administration of a single dose of charcoal
(without cathartic) soon after ingestion of any stimulant laxative may prevent delayed onset of diarrhea and
avoid discomfort and dehydration.
Phosphate Laxatives
Treatment of hypernatremia, hypocalcemia, and hyperphosphatemia may be required after phosphate

laxative overdose. Hypernatremia may be treated with isotonic saline if the patient is hypotensive. Once
tissue perfusion is restored, dextrose in 5 per cent water or 0.3 or 0.45 normal saline may be given, in doses
calculated to lower serum sodium levels by no more than 3 mEq/L/hr for the first few hours, then not to
exceed 1.5 mEq/L/hr thereafter until normalized. The free water deficit may be computed (water deficit =
total-body water × [PNa/140] – 1) to determine the total fluid requirements, given over 48 hours. Overly rapid
correction can lead to cerebral overhydration, potentially causing seizures and neurologic damage.
Hypocalcemia should be corrected parenterally if the patient has dysrhythmias, carpopedal spasm, seizures,
or mental status changes. Calcium gluconate or calcium chloride may be given, depending on severity of
hypocalcemia. Calcium correction should be carried out cautiously in the setting of hyperphosphatemia, and
consultation with a nephrologist may be warranted. Hyperphosphatemia will usually normalize without
treatment but may cause life-threatening hypocalcemia. In patients with hyperphosphatemia, most
symptoms are a result of hypocalcemia.
Magnesium Citrate/Sulfate/Hydroxide
Hypermagnesemia may require treatment, especially in patients with renal failure who present after an acute
magnesium overdose.[5][23] The patient is monitored for respiratory failure, muscle weakness, and cardiac
dysrhythmias. In patients with adequate renal function and urine output, treatment includes intravenous
saline and furosemide to promote diuresis and intravenous calcium for cardiac arrhythmias. In patients with
renal failure, severe symptoms, or serum magnesium level greater than 8 mEq/L, hemodialysis may be
required.
Chronic Laxative Ingestion
Potassium and other electrolyte deficiencies are corrected. Patients with severe symptomatic hypokalemia
may require intravenous potassium chloride, 10 to 15 mEq/hr. Typically, it will take 40 mEq to raise the
serum potassium level by 1 mEq/L. In asymptomatic patients, discontinuation of the laxative and oral
potassium supplementation may be sufficient.
Lipoid Pneumonia
Patients with mild symptoms do not require treatment unless hypoxic. Removal of exposure is sufficient to
allow resolution in most cases. In patients presenting with acute pneumonitis and mild hypoxia (PaO2 > 60
mmHg), oxygen supplementation and chest physiotherapy should be provided. Mechanical ventilation is
indicated, in conjunction with pulmonary end-expiratory pressure (PEEP), in patients with a PaO 2 less than
60 mmHg. Secondary infection is treated with antibiotics, as indicated by culture and sensitivity reports.
There is no clear-cut role for corticosteroids.


DISPOSITION
Acute Laxative Ingestion
Phosphate/Magnesium Laxatives
These types of laxatives may cause severe fluid and electrolyte imbalance and necessitate monitoring, with
admission to a telemetry unit if the imbalance is severe or persistent. Patients with hypermagnesemia
severe enough to require mechanical ventilation will need admission to the intensive care unit.
Stimulant Laxatives
Patients with stimulant laxative ingestion can be discharged from the emergency department after
administration of charcoal, with instructions to return if diarrhea is severe or persistent.
Chronic Laxative Ingestion
Patients with severe hypokalemia should be admitted to a telemetry unit floor until the potassium level is
within the normal range. Oral outpatient potassium supplementation may be sufficient for patients with mild
hypokalemia. Outpatient referral to a gastroenterologist to confirm the diagnosis and evaluate other
complications of abuse is appropriate. Psychiatric counseling should be arranged.
Lipoid Pneumonia
The patient should be admitted to the hospital if respiratory compromise is present or supplemental oxygen
is required.


SEQUELAE
Chronic abuse may result in “cathartic colon,” with atrophic mucosa and atony of the muscle layers in
nonfunctioning segments of intestine, often the ascending colon. It is presumed that local potassium
deficiency causes cathartic colon. A study of 47 patients with a history of chronic laxative use, defined as
more than three times per week for 1 year or longer, found loss of colonic musculature in 40 per cent.
Laxatives included bisacodyl, phenolphthalein, senna, and casanthranol.[24]
Anthraquinones are associated with pseudomelanosis coli, a harmless pigment deposition in the intestinal
wall, often discovered on routine sigmoidoscopy when evaluating a patient with chronic diarrhea.
Pigmentation can also occur with nonanthraquinone stimulants, such as bisacodyl and phenolphthalein. This
process requires at least 4 months of continuous laxative use. It occurs in 52 per cent of anthraquinone
users and 8 per cent of those taking other laxatives.[2]


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7. Chin RL: Laxative-induced hypokalemia. Ann Emerg Med 1998; 32:517-518.
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10. Devore AD, Ulshen MH, Cross RE: Phenolphthalein laxatives and factitious diarrhea. Clin
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11. DeWolff FA, De Haas EJM, Verweij M: A screening method for establishing laxative abuse. Clin
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12. Dick WH, Lingeman JE, Preminger GM, et al: Laxative abuse as a cause for ammonium urate renal
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13. Donowitz M: Magnesium-induced diarrhea and new insights into the pathobiology of diarrhea. N Engl J
Med 1991; 324:1059-1060.
14. Duncan A, Morris AJ, Camerson A, et al: Laxative induced diarrhoea—a neglected diagnosis. J R Soc
Med 1992; 85:203-205.
15. Dunnick JK, Hailey JR: Phenolphthalein exposure causes multiple carcinogenic effects in experimental
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16. Edes TE, Walk BE: Nosocomial diarrhea: Beware the medicinal elixir. South Med J 1989; 82:1497-
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17. Farley TA: Severe hypernatremic dehydration after use of an activated charcoal-sorbitol suspension. J
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18. Ferguson GT, Miller YE: Occult mineral oil pneumonitis in anorexia nervosa. West J
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19. Fine KD, Santa Ana CA, Fordtran JS: Diagnosis of magnesium-induced diarrhea. N Engl J
Med 1991; 324:1012-1017.
20. Freeman GL: Psyllium hypersensitivity. Ann Allergy 1994; 73:490-492.
22. Gerard SK, Hernandez C, Khayam-Bashi H: Extreme hypermagnesemia caused by an overdose of

magnesium-containing cathartics. Ann Emerg Med 1988; 17:728-731.
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26. Kendall AC: Fatal case of encephalitis after phenolphthalein ingestion. BMJ 1954; 2:1461.
27. Kurtzweil P: Dieter’s brews make tea time a dangerous affair. FDA Consumer 1997;7-11.July–August
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30. Litovitz TL, Felberg L, White S, et al: 1995 Annual report of the American Association of Poison Control
Centers Toxic Exposure Surveillance System. Am J Emerg Med 1996; 14:487-537.
31. Litovitz TL, Klein-Schwartz W, Dyer KS, et al: 1997 Annual report of the American Assocition of Poison
32. Martin RR, Lisehora GR, Braxton Jr M, et al: Fatal poisoning from sodium phosphate enema.
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33. Mofenson HC, Caraccio TR: Magnesium intoxication in a neonate from oral magnesium hydroxide
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old child following the administration of an adult Fleet enema. Ann Emerg Med 1989; 18:696-700.


Chapter 39 – Camphor and Mothballs
DEBORAH L. ANDERSON ANDREW R. TOPLIFF
CAMPHOR
Essentials
• Odor of camphor on breath or in urine
• Sudden onset of seizures
Introduction
Camphor has been used medicinally for centuries, most commonly as a rubefacient. [18] Accidental ingestion
of 20 per cent camphorated oil, mistaken for castor oil, has caused numerous cases of toxicity in the
past.[3][6][10][14][22] Although camphorated oil is no longer available and the efficacy of camphor itself is not
widely accepted, camphor remains a common ingredient in many over-the-counter preparations.
In liquid form, the human lethal dose of camphor is reported to range from 50 to 500 mg/kg.[28] In adults, 10
mL of 20 per cent camphorated oil (2 g) has been reported to cause symptoms, whereas 5 mL (1 g) resulted
in the death of a 19-month-old child.[27] Twenty grams of Vicks VapoRub, 10 mL of Campho-Phenique, and
16 mL of Vicks VapoSteam each contain about 1 g of camphor. Clinically significant camphor toxicity has
not been reported with ingestions of less than 30 mg/kg and is uncommon when less than 50 mg/kg of
camphor is ingested.[8] Acute camphor poisoning secondary to tasting or accidental ingestion of quantities
less than 1 teaspoonful is unlikely.[1]
Toxicokinetics/Pathophysiology
Camphor is a cyclic terpene with a characteristic, penetrating odor and a pungent, aromatic taste. Camphor
is rapidly absorbed from the mucous membranes and the gastrointestinal tract. Its lipophilic nature is
responsible for central nervous system (CNS) toxicity, which is believed to involve excitatory mechanisms
common to the cyclic terpenes. It is also absorbed through inhalation, through dermal application, and by
nasal instillation. It has been abused as an abortifacient orally and by intrauterine injection and readily
crosses the placenta.[10][25][30] It undergoes hepatic metabolism, with inactive metabolites excreted in the
urine often accompanied by an odor of camphor. Pulmonary elimination of camphor causes a distinctive
odor on the breath that is helpful in diagnosis.[3][28]
Symptoms of camphor toxicity usually begin 5 to 90 minutes after ingestion and are often abrupt in onset (
Table 39–1 ). Spontaneous emesis, with the odor of camphor readily apparent, typically occurs first. CNS
stimulation ensues with restlessness, confusion, delirium, and increased muscular activity. Severe toxicity
may include seizures, apnea, and coma. [20] Death results from respiratory depression or status
epilepticus.[10][25][28]
Table 39-1 -- Clinical Presentation of Camphor Toxicity

Adapted from Goldfrank LR, Bania TC: Camphor and mothballs. In Goldfrank LR, et al (eds): Goldfrank’s
Toxicologic Emergencies, 5th ed. Norwalk, CT, Appleton & Lange, 1994, p 1100.
Chronic ingestion of camphor can cause a variety of symptoms clinically similar to Reye’s syndrome.[14] In
chronic ingestion, CNS findings may or may not be present, depending on the dosage. Gastrointestinal
symptoms may include nausea, vomiting, epigastric pain, and hepatic enzymes elevation. Pathologic
hepatic changes often include such findings as granulomatous hepatitis and fatty metamorphosis.
With chronic dermal exposure, systemic effects and contact dermatitis can occur as well as significant
allergic responses. Ocular exposure results primarily in irritation only, although oral intake has been
associated with visual problems.
A variety of drugs that may acutely cause seizures should be considered and are listed in Table 39–2 .
Table 39-2 -- Drugs/Toxins Causing Early Onset of Seizures

Amphetamines
Antihistamines
Caffeine
Camphor
Carbamates
Carbon monoxide
Chloroquine
Cocaine
Cyanide
Diethyltoluamide
Hydrogen sulfide
Isoniazid
Lidocaine
Lindane
Nicotine
Organophosphates
Pennyroyal
Phencyclidine
Phenylpropanolamine
Propoxyphene
Propranolol
Sodium monofluoroacetate
Strychnine
Theophylline
Water hemlock
Withdrawal from sedative hypnotics, alcohol, barbiturates
Laboratory Studies
An electrolyte screen may be useful to rule out electrolyte abnormalities and hypoglycemia. Serum camphor
concentrations are generally not available. Increases in hepatic transaminase levels, lactic dehydrogenase
value, and albuminuria have occurred but are usually transient. Other laboratory studies should be dictated
by the history of exposure and the clinical scenario.[3][27][30]
Treatment
Treatment of camphor intoxication is primarily supportive with a focus on airway management and seizure
control ( Table 39–3 ). No antidotes are available.
Table 39-3 -- Treatment of Camphor Intoxication

Airway management
Activated charcoal, if alert
Seizure control
Benzodiazepines: diazepam, lorazepam
Phenobarbital
Skin decontamination
Flush with copious amounts of water
Ocular decontamination
Flush with copious amounts of water or normal saline
Ocular examination if eye remains irritated
Activated charcoal should be administered for gastrointestinal decontamination, although its efficacy is
doubtful.[10][20] Due to prominent CNS effects, the induction of emesis is contraindicated. If liquid camphor is
ingested, a nasogastric tube can be used to aspirate gastric contents before instillation of activated charcoal.
Alcohols and oil solutions should be avoided because they have been reported to enhance absorption of
camphor.[28] Although not readily available, lipid hemodialysis[3][9] and resin hemoperfusion[15] have been
reported to lower blood camphor concentrations in severely poisoned patients. Benzodiazepines such as
lorazepam or diazepam are indicated for symptoms of CNS hyperactivity, such as agitation, tremors, and
seizures. Phenobarbital can be used for recurrent or prolonged seizures.
Thorough flushing of exposed eyes and skin is usually sufficient treatment to relieve transient irritation
produced by camphor.
Disposition
Medical observation is indicated for all significant camphor exposures. Patients who remain asymptomatic
after 6 to 8 hours of observation can be released. Symptomatic patients will need admission for appropriate
monitoring and treatment. Recovery is usually complete within 24 to 48 hours after ingestion.
Sequelae
Prolonged seizure activity may result in hypoxic CNS damage and death.


MOTHBALLS
Essentials
Naphthalene
• Hemolysis
• Methemoglobinemia
• Gastrointestinal irritation, fever
Paradichlorobenzene
• Gastrointestinal irritation, if
anything
Introduction
Naphthalene and paradichlorobenzene are sole ingredients in moth repellents in the form of balls, flakes, or
crystals. Camphor is no longer an ingredient in these products. Paradichlorobenzene, being less toxic, is
more frequently used in mothballs as well as in toilet bowl and diaper pail deodorizers. Moth repellents are
also used in gardens and on lawns to deter pets and other animals.
Differentiating between these two white, crystalline solid compounds is important. Naphthalene can produce
serious hematologic and CNS effects, necessitating treatment, whereas paradichlorobenzene exposures are
generally inconsequential. Differentiation is possible through a variety of methods. Naphthalene feels dry to
the touch, whereas paradichlorobenzene feels moist and oily. A naphthalene mothball will float, whereas the
paradichlorobenzene-containing mothball will sink in a saturated salt solution (3 heaping tablespoonfuls of
salt and 4 ounces of tepid water stirred vigorously until the salt will not dissolve further[16]). On an abdominal
radiograph, paradichlorobenzene is densely radiopaque whereas naphthalene-containing mothballs are
radiolucent or faintly radiopaque.[32] This identification technique may be helpful when a large ingestion is
suspected and no mothballs are available for testing. Odors are characteristic and can be compared with
known samples. Other methods of differentiation have been described.[2][21][31]
Naphthalene
Pathophysiology
Naphthalene is well absorbed after oral,[11][17][19][33] dermal, [7][23] and inhalational[29] exposure. It is soluble
in fats and oils, and the administration of milk or food after ingestion may aid absorption. Hepatic
metabolism generates a-naphthol, ß-naphthol, a-naphtholquinone, and ß-naphtholquinone metabolites.[17] f
The a-naphthol oxidative metabolite is responsible for the severe hemolytic activity,[17][33] acute tubular
necrosis, and methemoglobinemia.
Less than one mothball containing 200 to 500 mg of naphthalene can cause hemolysis in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency.[11][33][34] These patients tend to be of African,
Mediterranean, and Far Eastern descent.[19][24] In the absence of G6PD deficiency these small quantities
are well tolerated. Infants are also much more susceptible to toxicity due to inadequate conjugation of toxic
metabolites.[7][23][29][33]
Clinical Presentation ( Table 39–4 )
Nausea, vomiting, abdominal pain, diarrhea, and fever may develop as early as 1 day after exposure.[11][34]
Development of clinically recognized hemolysis may be delayed 1 to 5 days and is typically preceded by
gastrointestinal symptoms. Signs of hemolysis, including pallor, tachypnea, weakness, jaundice, and dark
urine, may also be present or evolve over the next several days.[11][17][33][34] Cyanosis may indicate
methemoglobinemia.[29] Lethargy and seizures are other possible effects.
Table 39-4 -- Clinical Presentation of Naphthalene and Paradichlorobenzene Toxicities

Naphthalene Toxicity Paradichlorobenzene Toxicity
Acute
Nausea, vomiting Gastrointestinal irritation
Abdominal pain, diarrhea One case of questionable jaundice, methemoglobinemia, hemolysis reported[14]
Fever
Pallor, cyanosis
Jaundice, dark urine
Lethargy, seizures
Chronic
Nausea, vomiting Anemia
Fever, jaundice Hepatitis
Aplastic anemia Pulmonary granulomatosis
Hepatic centrilobular necrosis
Hemoglobin frequently is decreased with an increase in red cell fragmentation. Anisocytosis and
poikilocytosis with Heinz body formation may occur in severe cases.[7][11][17][19][23][24][29][34]
Chronic exposure has resulted in nausea, vomiting, fever, jaundice, lethargy, aplastic anemia, and hepatic
centrilobular necrosis.[13][33]
Other causes of hemolysis and methemoglobinemia that should be considered are listed in Table 39–5 .
Table 39-5 -- Differential Diagnosis of Naphthalene Toxicity

Causes of Hemolysis
Inherited hemoglobinopathy
Acquired hemolysis
Autoimmune
Disseminated intravascular coagulation
Vasculitis
Thrombotic thrombocytopenic purpura (TTP)
Drug-induced hemolysis
Causes of Methemoglobinemia
Hereditary
Oxidants
Nitrites
Nitrates
Aniline dye
Benzocaine, lidocaine
Sulfonamides
Dapsone
Pyridium
Chlorates
Laboratory Studies
Initial laboratory studies in a symptomatic patient or in a patient with suspected or known G6PD deficiency
should include a complete blood cell count with a peripheral smear, hepatic studies (especially bilirubin), and
renal function studies. Free hemoglobin in urine should be measured. In high-risk patients, blood smears
and hematocrit should be followed for at least 1 week after exposure.[25] An arterial blood gas analysis
including co-oximetry measurement of methemoglobin should be obtained in any cyanotic patient.
Treatment
Treatment of naphthalene toxicity is primarily supportive ( Table 39–6 ). Treatment should be initiated for
ingestions of one half or more of a naphthalene-containing mothball.[11][34] In early therapy, ipecac
syrup–induced emesis, in the first 2 hours after ingestion, is preferred to lavage, owing to the size of the
mothballs.[11] Activated charcoal should also be administered. Milk or fatty meals that increase absorption
should be avoided for several hours.[10][26]
Table 39-6 -- Treatment of Naphthalene and Paradichlorobenzene Toxicities

Naphthalene Toxicity
Gastric decontamination: emesis, activated charcoal for ingestion of = ½ mothball
Hemolysis: intravenous fluids, red blood cell transfusions
Methemoglobinemia: methylene blue, 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) IV over 5 minutes. May repeat
as needed to maximal dose of 7 mg/kg
Paradichlorobenzene Toxicity
Usually none
Emesis, activated charcoal for large ingestions
Transfusion may be indicated in cases of severe hemolysis.[11][26][34] Intravenous fluids to maintain urinary
flow may prevent renal deposition of cell breakdown products.[28] Administer oxygen and methylene blue to
patients symptomatic from methemoglobinemia or if levels exceed 30 per cent.
Exposed skin should be thoroughly washed with soap and water. Naphthalene is not easily removed from
clothing, and contaminated clothing should be discarded to prevent further exposure.[10]
Disposition
Admission should be considered for individuals with G6PD deficiency, with large ingestions or with
symptoms.[10]
Patients known or at risk for G6PD deficiency for whom gastrointestinal decontamination and baseline
laboratory studies have been completed and who remain asymptomatic after 4 to 6 hours of observation
may be discharged home. These patients should return for follow-up complete blood cell counts and
urinalysis for up to 5 days after ingestion.[26] Patients should be instructed to return if they develop
gastrointestinal symptoms, pallor, or dark urine.
Paradichlorobenzene
The toxicity of mothballs containing paradichlorobenzene is low,[26] with ingestion causing possible nausea
and vomiting only. Acutely, one case of hemolytic anemia[12] has been described, although causation was
not definitely shown. After chronic exposure, hepatotoxicity,[5] anemia,[4] and pulmonary granulomatosis[26]
have been reported.
Emesis is indicated when large amounts have been ingested. Activated charcoal can also be administered.
Milk and fatty foods should be withheld for several hours after ingestion to minimize absorption.[10] If the
composition of a mothball is unknown, gastric decontamination and treatment should proceed as outlined for
naphthalene.


REFERENCES
1. Alsop JA: Camphor toxicity from accidental ingestions [abstract]. Vet Hum Toxicol 1993; 35:346.
2. Ambre J, Ruo TI, Smith-Coggins R: Mothball composition: Three simple tests for distinguishing
paradichlorobenzene from naphthalene. Ann Emerg Med 1986; 15:724-726.
3. Antman E, Jacob G, Volpe B, et al: Camphor overdosage: Therapeutic considerations. NY State J

Med 1978; 78:896-897.
4. Campbell DM, Davidson RJ: Toxic haemolytic anaemia in pregnancy due to a pica for
paradichlorobenzene. J Obstet Gynecol Br Common 1970; 77:657-659.
5. Cotter LH: Paradichlorobenzene poisoning from insecticides. NY State J Med 1953; 53:1690-1692.
6. Craig JO: Poisoning by the volatile oils in childhood. Arch Dis Child 1953; 28:475-483.
7. Dawson JP, Thayer WW, Desforges JF: Acute hemolytic anemia in the newborn infant due to
naphthalene poisoning: Report of two cases, with investigations into the mechanism of the disease.
Blood 1958; 13:1113-1125.
8. Geller RJ, Spyker DA, Garrettson LK, et al: Camphor toxicity: Development of a triage strategy. Vet Hum
Toxicol 1984; 26:8-10.
9. Ginn HE, Anderson KE, Mercier RK, et al: Camphor intoxication treated by lipid dialysis.
JAMA 1968; 203:164-165.
10. Goldfrank LR, Bania TC: Camphor and mothballs. In: Goldfrank LR, et al ed. Goldfrank's Toxicologic
Emergencies, 5th ed. Norwalk, CT: Appleton & Lange; 1994:1095-1102.
11. Haggerty RJ: Toxic hazards. Naphthalene poisoning. N Engl J Med 1956; 255:919-920.
12. Hallowell M: Acute haemolytic anaemia following the ingestion of para-dichlorobenzene. Arch Dis
Child 1959; 34:74-75.
13. Harden RA, Baetjer AM: Aplastic anemia following exposure to paradichlorobenzene and naphthalene.
J Occup Med 1978; 20:820-822.
14. Jimenez JF, Brown AL, Arnold WC, et al: Chronic camphor ingestion mimicking Reye’s syndrome.
15. Kopelman R, Miller S, Kelly R, et al: Camphor intoxication treated by resin hemoperfusion.
JAMA 1979; 241:727-728.
16. Koyama K, Yamashita M: A simple test for mothball component differentiation using water and a
saturated solution of table salt: Its utilization for poison information service. Vet Hum Toxicol 1991; 33:425-
427.
17. Mackell JV, Rieders F, Brieger H, et al: Acute hemolytic anemia due to ingestion of naphthalene moth
balls. Pediatrics 1951; 7:722-728.
18. Mayer SE, Melmon KL: Surface-acting drugs. In: Gilman AG, Goodman LS, Gilman A, ed. Goodman
and Gilman's The Pharmacological Basis of Therapeutics, 6th ed. New York: Macmillan; 1980:955-956.
19. Melzer-Lange M, Walsh-Kelly C: Naphthalene-induced hemolysis in a black female toddler deficient in

glucose-6-phosphate dehydrogenase. Pediatr Emerg Care 1989; 5:24-26.
20. Phelen III WJ: Camphor poisoning: Over-the-counter dangers. Pediatrics 1976; 57:428-431.
21. Reeves RR, Pendarvis RO: A new method for the differentiation of naphthalene and
paradichlorobenzene mothballs. J AOA 1985; 85:806-808.
22. Reid FM: Accidental camphor ingestion [letter]. JACEP 1979; 8:339-340.
23. Schafer WB: Acute hemolytic anemia related to naphthalene: Report of a case in a newborn infant.
Pediatrics 1951; 7:172-174.
24. Shannon K, Buchanan R: Severe hemolytic anemia in black children with glucose-6-phosphate
dehydrogenase deficiency. Pediatrics 1982; 70:364-369.
25. Siegel E, Wason S: Camphor toxicity. Pediatr Clin North Am 1986; 33:375-379.
26. Siegel E, Wason S: Mothball toxicity. Pediatr Clin North Am 1986; 33:369-375.
27. Smith AG, Margolis G: Camphor poisoning: Anatomical and pharmacologic study: report of a fatal case;
experimental investigation of protective action of barbiturate. Am J Pathol 1954; 30:857-868.
28. Tracy TM: Ingredients index. In: Gosselin RE, Smith RP, Hodge HC, ed. Clinical Toxicology of
Commercial Products, 5th ed. Baltimore: Williams & Wilkins; 1984:II-259.
29. Valaes T, Doxiadis SA, Fessas P: Acute hemolysis due to naphthalene inhalation. J
Pediatr 1963; 63:904-915.
30. Weiss J, Catalano P: Camphorated oil intoxication during pregnancy. Pediatrics 1973; 52:713-714.
31. Winkler JV, Kulig K, Rumack BH: Mothball differentiation: Naphthalene from paradichlorobenzene.
Ann Emerg Med 1985; 14:30-32.
32. Woolf AD, Saperstein A, Zawin J, et al: Radiopacity of household deodorizers, air fresheners, and moth
repellents. Clin Toxicol 1993; 31:415-428.
33. Zinkham WH, Childs B: Defect of glutathione metabolism in erythrocytes from patients with a
naphthalene-induced hemolytic anemia. Pediatrics 1958; 22:461-471.
34. Zuelzer WW, Apt L: Acute hemolytic anemia due to naphthalene poisoning. JAMA 1949; 141:185-190.


Chapter 40 – Essential Oils
Susi Vassallo
Essentials oils are organic compounds distilled from plants. They are also known as aromatic or volatile oils
because they evaporate easily, leaving a pleasant aroma. Essential oils lend fragrance and flavor to foods
and perfumes and have been used throughout history for medicinal purposes, religious ceremonies,
massage, bathing, and perfumery. Aromatherapy with essential oils has emerged in homeopathic practice
by naturalists and herbalists, and over-the-counter sales of these products are flourishing.
Numerous essential oils exist. This chapter focuses on those known for their toxicity in overdose ( Table
40–1 ). Most essential oils are not intended for internal use; nevertheless, intentional and accidental
ingestions do occur. The oils are also absorbed after topical application, and concentrated preparations
have produced toxicity by dermal exposure.
Table 40-1 -- Toxic Characteristics and Treatment of Essential Oils

Essential Onset of
Oil Toxin Toxic Amount Toxicity Clinical Symptoms Treatment
Absinthe Thujone Chronic Unknown; Altered mental status Decontamination
consumption long-term use
associated Seizures, coma Supportive care
with toxicity
CNS excitation Decontamination
1–2 tsp or
Camphor Camphor <30 min Seizures
50–500 mg/kg Supportive care
Hepatotoxicity (transient)
Cinnamic Mucosal irritation Decontamination

Cinnamon Drops <60 min
acid Facial flushing of skin, eyes
Geraniol Immediate Mucosal irritation

mucous
Citronella 10–15 mL Supportive care
membrane
Citronellol Pulmonary aspiration
irritation
Inhalation: Pulmonary irritation,
Decontamination
edema, aspiration
May be
Ingestion: CNS
minutes to
Clove Eugenol 1–2 tsp depression/seizures, metabolic Supportive care
hours after
acidosis, hepatotoxicity
smoking
Essential Onset of
Oil Toxin Toxic Amount Toxicity Clinical Symptoms Treatment
smoking
Dermal: Cutaneous damage,
N-Acetylcysteine
allergic reaction
Vomiting, diarrhea
Euphoria, headache, seizures,
Eucalyptus Eucalyptol <5 mL <3 hr Supportive care
coma, respiratory depression
Painful micturition
Mucosal irritation Decontamination
2 g in adult,
<6 hr, may be
Peppermint Menthol drops in CNS depression
rapid Supportive care
neonate
Dyspnea; apnea in newborns
CNS stimulation followed by
15–30 mL 3–6 hr Decontamination
CNS depression
Abdominal pain
Nutmeg Myristicin
1–2 whole Shock, metabolic acidosis
May be sooner Supportive care
nutmegs Allergic symptoms
Clinical course can be protracted
Early: Nausea/vomiting,
Death within 2 hyperventilation, respiratory
Decontamination
hr reported alkalosis, tinnitus, decreased
5 mL (1 tsp) or hearing, diaphoresis
Oil of
Salicylates less in small
wintergreen Alkalinization
child Toxicity may Late: Metabolic acidosis,
be delayed hypotension, hyperthermia, Hemodialysis
from 6–12 hr hepatotoxicity, coagulopathy
Supportive care
Within 10 min, Nausea, vomiting Decontamination
more
Pennyroyal Pulegone 5 mL Seizures, coma Supportive care
commonly
1–24 hr Hepatic/renal/pulmonary toxicity N-Acetylcysteine
Nausea, vomiting Decontamination
Vertigo, hallucinations, stupor,
Sassafras Safrole 5 mL 10–90 min Supportive care
aphasia
Shock, respiratory depression N-Acetylcysteine
CNS, central nervous system.
ABSINTHE OIL
Absinthe oil is derived primarily from wormwood, Artemisia absinthium, a member of the daisy family.
Wormwood has been used for the treatment of intestinal helminthic infestations. Wormwood extract was the
main ingredient of the toxic green-colored liqueur absinthe,[114] whose color came from the chlorophyll of the
wormwood plant.[5] The toxic component of oil of absinthe is the terpene known as thujone. Thujone is
present in other plants, including the tansy (Tanacetum vulgare), sage (Salvia officinalis), and thuja (Thuja
occidentalis), known as white cedar.[114]
Historical Aspects.
It has been hypothesized that overindulgence in absinthe led to the mental deterioration of the artist Vincent
van Gogh.[6][63] In fact, it has been written that van Gogh developed an affinity for terpenes in general,
drinking terpentines used for his painting and putting camphor on his pillow and mattress to fight insomnia. [6]
A diagnosis that has been proposed to unify van Gogh’s absinthe drinking habits, profession, family history,
and mental illness is acute intermittent porphyria.[63] Both camphor and thujone induce hepatic
aminolevulinic acid synthase in the presence of a block in heme synthesis, a biochemical abnormality
characteristic of porphyria.[13]
Paintings by Henri de Toulouse-Lautrec, such as “Monsieur Boileau at the Cafe”; Edouard Manet’s “The
Absinthe Drinker”; and Edgar Degas’ “L’Absinthe” attest to the popularity of the drink in France in the late
19th century. Pablo Picasso painted “Absinthe Drinker” in 1901 and later created an abstract representation
of absinthe glasses in response to a French threat to ban the substance.[5][118]
Absinthe was banned in France in 1915 because of its suspected habit-forming and mind-altering properties.
It is still occasionally found in the antique shops of Paris. Today, thujone-free derivatives of wormwood are
used in foods. The anise-flavored drink Pernod has replaced absinthe in French culture.
Clinical Presentation.
The manifestations of acute ingestion with absinthe are those resulting from acute ethanol intoxication
because absinthe is the flavoring agent of alcoholic beverages. Long-term ingestion of absinthe oil may lead
to neurologic symptoms including paresthesias, mental status alteration, seizures, coma, and death.
Injection of animals with thujone produces seizures and death.[5] It is postulated that thujone and delta-9-
tetrahydrocannabinol, the active ingredient in marijuana, interact with common receptor sites in the central
nervous system and have similar behavioral effects.[24][118] Although thujone and delta-9-
tetrahydrocannabinol have similar molecular structures, there is no experimental evidence in support of this
theory.
Treatment.
Treatment is supportive. Acute toxicity other than ethanol intoxication has not been reported.


CAMPHOR
Camphor oil, a cyclic terpene with a ketone structure, is derived from the Cinnamomum camphora tree, of
the laurel family.[89] Although camphor may be obtained from all parts of the tree, the leaves are the major
source. Synthetic camphor has replaced most of the natural product and is produced from the alpha-pinene
found in the turpentine of Pinus pinaster and Pinus palustris.[114]
Camphor is used primarily today as an antipruritic, a rubifacient, and a nasal decongestant. Camphorated
mothballs continue to cause problems, although they are no longer widely commercially available. A large
number of camphor intoxications have occurred when camphor was mistakenly administered orally instead
of castor oil.[4][11][56][88][95][123] Similarity in packaging appearance, proximity in pharmacy displays, and price
stickers that obscured product labels resulted in the confusion of one product for the other.[115] Camphor
toxicity has occurred after use as an abortifacient.[48]
The toxic dose of camphor is between 50 and 500 mg/kg. Camphorated oil is pure camphor (20%) in
vegetable oil. Spirits of camphor contain 10 per cent camphor. Two commonly available camphor-containing
compounds are Vicks VapoRub and Campho-Phenique, containing 4.7 per cent and 10.8 per cent camphor,
respectively.[20][96] Therefore, ingestion of small amounts of these products may result in toxicity. In the
earlier literature, 20 deaths from camphor were reported.[99] One gram of camphor proved fatal in a 19-
month-old child.[84] In 1919, 1 to 1.5 tablespoons of camphorated oil were administered to 20 children
instead of castor oil. All became rapidly ill and most had seizures, but none died.[11] In addition to the oral
route, camphor toxicity has occurred by ingestion of nasally instilled nose drops and inhalational,[97]
dermal,[97][106] and transplacental exposure.[88][123]
Clinical symptoms develop rapidly, within 5 to 90 minutes after ingestion. * The patient often smells of
camphor, a common clinical clue to its presence. The major toxicity of camphor is central nervous system
stimulation producing sudden seizures. In one patient series, 9 of 19 children experienced a seizure within 4
to 120 minutes after ingesting 0.7 to 6.0 g of camphor.[20] In one child, seizures occurred within 2 hours of
ingestion of 1 tablespoon of Vicks VapoRub, about 0.7 g of camphor. This child had also received intranasal
camphor twice daily for 5 months. [84] Increased muscular excitability may precede or follow seizures. Jerking
of the hands and twitching of the lower extremities is described.[4][20] Vomiting may be the only symptom or
may precede or follow other symptoms.[20] Acute camphor poisoning has occurred after frequent use of
camphorated nose drops for nasal congestion.[92] Ingestion of camphor in place of castor oil in an attempt to
induce labor resulted in seizures and transient elevations of hepatic transaminase levels in a woman 40
weeks pregnant. The fetus died within 30 minutes of delivery. The exact cause of death was unclear, but
camphor was detected in the amniotic fluid and cord and fetal blood 36 hours after ingestion.[88] However,
also reported is a normal delivery after maternal ingestion in which the baby and the amniotic fluid smelled
strongly of camphor.[123]
In addition to central nervous system toxicity, hepatotoxicity as manifested by transient elevation in hepatic
transaminases is reported.[4][84][88] Long-term administration of a home remedy containing camphor and
ethanol to a 6-month-old boy resulted in a Reye’s-like syndrome and death. Although the clinical course was
consistent with Reye’s syndrome, the authors argued that a toxin may have caused the child’s demise on
the basis of the histologic examination of the liver and brain and attributed the illness to chronic camphor
ingestion.[51]
* References 10 , 19 , 20 , 48 , 84 , 88 , 92 , 120 and 123 .

Treatment.
Airway management, good supportive care, and treatment of seizures if needed are the mainstays of
management. Attempts to remove camphor by induction of emesis are contraindicated because of the rapid
onset of altered mental status and seizures. Seizures are best treated with a benzodiazepine, such as
diazepam and lorazepam, or phenobarbital.[99] Frequently, a single seizure occurs, after which the patient
recovers and remains well, but status epilepticus has been reported. [56] Extracorporeal removal of camphor
is of no clinical benefit and is not indicated. Of historical interest are several case reports of the use of
Amberlite hemoperfusion resin followed by lipid hemodialysis in camphor-intoxicated patients.[4][33][56] In one
instance, plasma camphor levels suggested some removal of camphor by the Amberlite cartridge. [56] In
another case, little benefit was derived from charcoal hemoperfusion.[72]


CINNAMON OIL
Cinnamon oil is distilled from the tree Cinnamomum verum (syn. C. zeylanicum blume) of the Lauraceae
family. The main constituents of cinnamon oil are geraniol and citronellol. Other names for cinnamon oil
include cassia oil, Saigon cinnamon, and oil of Chinese cinnamon. It is used as a flavoring agent and as a
scent in perfumes. Children soak toothpicks in cinnamon oil, then suck or chew the toothpick for flavor.
Cinnamon oil contains primarily 80 per cent cinnamaldehyde, an irritant. Cinnamaldehyde is excreted in the
urine as benzoic and hippuric acids. [114]
Because cinnamic aldehyde is an irritant, reactions to cinnamon-flavored mouthwashes include mild

swelling of the lips and tongue. Long-term use of cinnamon-containing oral products, including toothpaste,
has caused leukoderma, stomatitis, contact urticaria, and cheilitis.[73][74] Ocular exposures occur most
commonly from touching the eyes with fingers contaminated with the oil. Ingestion of the oil has resulted in
mild facial erythema, a sensation of warmth, nausea, and mild abdominal pain.[83] One case report
describes a second-degree burn on the posterior thigh from cinnamon oil spilled from a broken vial in the
pants pocket.[101] Cinnamon from Cinnamomum cassia may be smoked for its mild stimulant effects.
Treatment.
Treatment for cinnamon oil exposure consists primarily of decontamination of the exposed area with soap
and water, local burn therapy, or irrigation of the eyes with normal saline. The eyes should be examined for
corneal abrasions if the patient has eye irritation.


CITRONELLA OIL
Citronella oil is distilled from dried leaves of members of the family Labiatae.[114] The oil has several
constituents, primarily geraniol and citronellol. It is used as a perfume and as an insect repellent and was
formerly applied to female dogs while in heat to deter interested males.[69]
Ingestion of oil of citronella is usually benign, although there is some risk of aspiration.[109] Citronella is a
mucous membrane irritant. In a reported series of five cases, two patients showed signs of mild aspiration
pneumonia, and three children were completely well.[109] In another report, one child died after ingesting
about 3 teaspoons of a citronella preparation. However, the fatal outcome was probably due to the therapy
administered, including salt water–induced emesis, nikethamide, and adrenaline. Cerebral hemorrhages at
postmortem examination were indicative of sodium chloride intoxication.[69]
Treatment.
Treatment is supportive. Gastric emptying, which may lead to complications, including aspiration, should be
avoided. A single dose of oral activated charcoal may be given but is probably not critical to the
management. Most patients do well with observation and treatment for aspiration, should it occur.


OIL OF CLOVE
Oil of clove is derived from parts of the plant known as Syzygium aromaticum, also called Eugenia
caryophyllata or Eugenia aromatica. Cloves are the dried, unopened flower buds of the tropical evergreen E.
aromatica. Oil of clove is 82 to 85 per cent eugenol. Clove oil is used as a flavoring agent in foods,
mouthwashes, and other pharmaceuticals. The accepted daily oral intake of eugenol is 2.5 mg/kg.[117] A
dermal irritant, it has been used since ancient times as a local anesthetic applied to the gums for toothache.
It continues to be used as a disinfectant in root canal procedures in commercially available preparations
containing as much as 90 to 100 per cent eugenol.[57][114] Clove cigarettes contain 30 to 40 per cent
shredded clove buds, and the rest is tobacco. Dry clove buds contain 15 per cent wt/vol oil of clove, or 120
to 130 mg of eugenol in 1 g of dry clove buds.[18]
Eugenol causes pulmonary, hepatic, and dermal toxicity, as well as allergic manifestations. Eugenol inhibits
sensory nerve activity, and smoking of clove cigarettes has led to aspiration pneumonitis through blunting of
the laryngeal reflex.[37] Cases of pulmonary edema, hemoptysis, bronchospasm, dyspnea, chronic cough,
epistaxis, epiglottitis, and pulmonary infection have also been temporally related to smoking of clove
cigarettes.[18][39][45][46] Studies on the lungs of rats exposed directly to eugenol revealed the development of
abnormal breathing patterns, alveolar edema, congestion, pneumonia, and atelectasis. The mechanism of
injury is unknown.[17][59]
A 7-month-old child who ingested 1 teaspoon of oil of clove experienced metabolic acidosis and central
nervous system depression.[58] Ingestion of 1 to 2 teaspoons of oil of clove in a 2-year-old boy resulted in
metabolic acidosis, coma, seizures, hypoglycemia, and liver failure.[43] In studies on the effects of eugenol
on the liver, incubation of hepatocytes with eugenol resulted in conjugates with sulfate, glucuronic acid, and
glutathione. Covalent binding of these conjugates to cellular proteins was observed. Loss of intracellular
glutathione and covalent binding of eugenol metabolites to cellular proteins, resulting in cell death, was
completely prevented by the addition of N-acetylcysteine (NAC).[112]
Eugenol inhibits peripheral sensory nerve activity in low doses and at higher doses can produce
neurotoxicity.[57] Permanent local anesthesia and anhidrosis was reported in a woman who spilled oil of
clove on her face while attempting to apply it directly to her gums.[47]
A dental patient experienced shortness of breath, hypotension, rash, edema, and pruritus immediately on
exposure to zinc oxide–eugenol tooth cement.[75]
Acute allergic reaction manifesting as sloughing of the oral mucosa, loss of papillae on the tongue,
ulceration at the vermilion border, and mild facial swelling followed the application of zinc oxide–eugenol
temporary tooth restoration.[8]
Treatment.
Supportive care and decontamination, either gastrointestinal or dermal, are the mainstays of therapy.
Respiratory support for pulmonary toxicity from inhalation injury, or treatment of allergic manifestations with
antihistamines, corticosteroids, or epinephrine may be specifically indicated. The oral dose of eugenol
expected to cause hepatotoxicity in humans is unknown. In animal models given oral eugenol, the mean
lethal dose was 2000 to 3000 mg/kg.[50] Although there are no data supporting the use of NAC for the
treatment of eugenol toxicity in humans, there is extensive clinical experience with N-acetylcysteine as an
antidote for acetaminophen-induced hepatotoxicity, establishing both the safety and the efficacy of this
therapy. Based on this and the evidence for NAC in preventing hepatotoxicity in eugenol-poisoned rats,[11]
NAC may be administered orally in the patient who ingests eugenol and shows signs of hepatotoxicity.


EUCALYPTUS OIL
Eucalyptus oil was first described in 1790 by John White, an Australian surgeon.[65] It is a pale distillate of
fresh leaves of various species of the eucalyptus tree. The oil contains 1,8 cineole, an organic oxide known
as eucalyptol when obtained from the eucalyptus tree, in concentrations up to 70 per cent. Additional
constituents of the oil include alpha pinene, phellandrene, eudesmol, and other terpenes.[23]
Eucalyptus oil is available in many over-the-counter products for the treatment of upper respiratory infections
and muscle aches and pains. Recommendations for usage include oral, intranasal, and dermal applications
and steam vaporization for inhalation therapy. Toxicity has occurred by all these exposure routes, as well as
by subcutaneous injection.[68][102] Death in adults has occurred after 4 to 5 mL.[66] The safe dosage is
quoted as 0.06 to 0.2 mL.[70]
Severe toxicity has occurred after ingestion of less than 5 mL (1 teaspoon) of eucalyptus
oil.[2][7][30][32][55][80][93] Toxicity begins rapidly, with the onset of dizziness or giddiness within minutes,
although a delay in symptom onset for 2 to 3 hours is reported.[113] Rapid depression of consciousness is
most common, followed by coma. Seizures may occur but are infrequent. Gastrointestinal complaints occur
early with vomiting, diarrhea, marked abdominal pain, and a burning sensation in the mouth. Respiratory
depression, aspiration, stertorous breathing, cyanosis, and apnea are seen in serious toxicity and have
necessitated endotracheal intubation and mechanical ventilation. Miosis is frequently recorded; however,
dilated pupils are observed in some case reports.[38] Subnormal body temperature, intense headache, and
painful micturition are described. [66] The characteristic smell of eucalyptus on the breath and in the
secretions may continue for several days, providing a diagnostic clue. *
* References 2 , 7 , 30 , 32 , 55 , 80 , 81 , 93 and 113 .

Treatment.
Treatment is supportive, and mechanical ventilation and intensive care admission are necessary in severe
cases. Hemodialysis and peritoneal dialysis were performed in a single patient.[38] Peritoneal dialysis yielded
no objective evidence of benefit. After 4 hours of hemodialysis, an estimated 7.4 mL of eucalyptol had been
recovered, and the dialysate smelled of eucalyptus. There was no apparent clinical benefit.


NUTMEG
Nutmeg is the seed of the tall evergreen tree Myristica fragrans. It is commonly use as a flavoring agent. The
volatile oil is composed of hydrocarbons, alcohols, terpenes, and the compound myristicin, which gives
nutmeg its fragrance. Although myristicin makes up only 4 per cent of nutmeg oil, it is considered the chief
toxic component. However, other volatiles, such as eugenol, isoeugenol, linalool, geraniol, and borneol,
probably contribute significantly to the toxic effects.[85][86] The presence of an indole group makes the
structural formula of myristicin similar to that of reserpine.[116]
Poisoning with this spice was first reported in the 16th century.[25][35] Many cases of toxicity were reported
from Britain in the early 1900s where it was used as an abortifacient.[9][40][87][124] More recently, a woman in
her 30th week of gestation became toxic after eating cookies made with 1 tablespoon of nutmeg, the
equivalent of one whole nutmeg. She delivered a healthy infant at term.[59]
Symptoms appear from 3 to 6 hours after the ingestion of one to three whole nutmegs weighing a total of
approximately 5 to 15 g, or 1 to 2 tablespoons of ground nutmeg. Nutmeg primarily affects the central
nervous system, causing stimulation initially and then depression with increasing doses. Feelings of
detachment, restlessness, uneasiness, depersonalization, and impending doom are described, and inability
to concentrate, emotional lability, and dreamlike states have been reported.[35][59][76][122] Drowsiness, stupor,
and coma accompanied by respiratory depression may occur. Periorbital edema, flushing, and itching can
mimic an allergic reaction.[9][77][82][94] A combination of symptoms, including cutaneous flushing, tachycardia,
dry mouth, and hallucinations, may lead to the incorrect diagnosis of anticholinergic toxicity. The pupils may
be constricted early on, and this may differentiate the condition from anticholinergic poisoning; with time, the
pupils sometimes dilate.[38] Chorea-like movements have been reported in children.[124] Vomiting and
diarrhea are infrequently described, but abdominal pain is common. Symptoms may last from 1 to 8 days.[35]
There has been one reported fatality. [21]
Intravenous injections of myristicin in monkeys and dogs and intraperitoneal injections in rats and cats
produced central nervous system effects similar to those observed after oral poisoning.[116] Feline studies of
nutmeg poisoning demonstrated fatty degeneration and congestion of the liver, presumably the cause of
death.[22][52][121]“Nutmeg liver,” so named because the reticulated appearance of the liver resembles the
longitudinal section of a nutmeg, is also found in cats poisoned by nutmeg.[22][82]
Treatment.
Adequate sedation for central nervous system excitation and increased muscle activity, hydration, and
respiratory support are the fundamentals of therapy for symptomatic nutmeg intoxication. Gastric
contamination using a single dose of activated charcoal may be helpful.


PENNYROYAL OIL
Pennyroyal oil is derived from plants of the Labiatae family, particularly Mentha pulegium (Europe) and
Hedeoma pulegioides (North America). [114] The essential oil is obtained by steam distillation from fresh or
dried leaves. Forms available include tablets, teas made from leaves, and an alcohol-based essence.[61]
Since ancient times, it has been used to induce menstruation and as an abortifacient. Other purported uses
include as an antiseptic, as an antispasmodic, and for cutaneous eruptions or the common cold. Pennyroyal
has been advocated for use on pets in order to deter fleas, and death has been reported in a dog treated
with pennyroyal oil.[104]
Pharmacology/Pathophysiology.
The primary constituent of pennyroyal oil is R-(+)-pulegone, a monoterpene which is further metabolized
through the cytochrome P-450 system to menthofuran ( Fig. 40–1 ). R-(+)-Pulegone and menthofuran, as
well as their metabolites, produce direct hepatotoxicity. The elimination half-life of pulegone and
menthofuran is approximately 2.2 hours.[111] The administration of 300 to 500 mg/kg of pennyroyal oil to
mice resulted in centrilobular eosinophilic necrosis of hepatocytes and necrosis of pulmonary bronchiolar
cells in a dose-response manner.[34] The histologic pattern of liver damage was similar to the hepatic
changes seen on autopsy of a young female who ingested 500 mg/kg of the oil.[34] This patient also had
diffuse pulmonary damage, but conclusions regarding the contribution of pennyroyal to the pulmonary
toxicity could not be made because of the complex clinical course.[34]
Figure 40-1 Postulated mechanism for hepatotoxicity from pulegone. (From Sullivan JB, Rumack BH, Thomas H, et al: Pennyroyal
oil poisoning and hepatotoxicity. JAMA 1979; 242:2873–2874. Copyright 1979, American Medical Association.)
In a murine study, the degree of liver damage was proportional to the extent of hepatocyte binding by
pulegone and menthofuran.[34][76] The hepatotoxicity of pulegone was further exacerbated by glutathione
depletion. Glutathione levels decreased by 75 per cent in mice treated with hepatotoxic doses of pennyroyal
oil or pulegone, and this decrease in glutathione was followed by a rise in hepatic transaminase levels. Also,
mice with experimentally decreased levels of glutathione showed a significantly increased hepatotoxic
response to pennyroyal oil and pulegone.[34] Depletion of intrinsic glutathione by R-(+)-pulegone results in
the formation of reactive hepatotoxic metabolites. Menthofuran bound to hepatocytes (protein adducts) was
demonstrated by Western blot analysis in a patient who ingested pennyroyal oil, resulting in death. [3] In
contradistinction to pulegone, menthofuran causes minimal glutathione depletion when administered to
mice, and mice with experimentally depleted levels of glutathione showed no significant increase in
hepatoxicity when given menthofuran.[34]
Ingestion of 5 to 10 mL of pennyroyal oil has been reported to cause coma and seizures, and in one patient,
15 mL was fatal.[105] Gastrointestinal and central nervous system toxicity developed within 1 to 2 hours but
may develop within 10 minutes.[14] Hepatic and renal injury were noted within 24 hours.[105][119] At low
doses, patients report feeling dizzy, weak, and lightheaded. Nausea, vomiting, hematemesis, abdominal
pain, and cramping may persist for several days. Generalized urticarial rash has been reported.[105] More
severe effects, such as agitation, confusion, seizures, and coma, have occurred. Both mydriasis and miosis
may occur. In severe cases, disseminated intravascular coagulation, hepatic failure, pulmonary infiltrates,
and renal insufficiency may develop over 24 to 48 hours.[3][105] Autopsy shows centrilobular hepatic necrosis
and other multiple organ involvement, including enlarged pale kidneys, renal tubular degeneration, and
congestion of the lung and brain.[105] Laboratory abnormalities include elevation of hepatic transaminases,
anion gap metabolic acidosis, elevated lactate levels, renal insufficiency, and evidence of bleeding and
disseminated intravascular coagulation. Gas chromatography with electron-impact mass spectrometry can
identify and quantify pulegone and menthofuran from plasma samples. [3]
Treatment.
Basic supportive management and gastric decontamination, including gastric emptying with a nasogastric
tube and administration of activated charcoal, are the fundamental therapies for pennyroyal oil intoxication. If
the patient has already been vomiting, administration of activated charcoal without furthur attempts at gastric
emptying is reasonable. A patient who remains asymptomatic for 3 to 5 hours after ingestion may be
considered unlikely to develop toxicity. Should the patient show symptoms of toxicity, such as
gastrointestinal upset and central nervous system changes, subsequent hepatic, renal, or pulmonary toxicity
may develop.
Extrapolation from the acetaminophen toxicity model suggests a potential benefit of NAC
therapy.[3][15][34][110] NAC therapy is relatively nontoxic when administered orally and should be used in
symptomatic patients with known or suspected pennyroyal oil ingestion. The exact dosing regimen and
length of administration for pennyroyal intoxication are unknown; therefore, following the dosing
recommendations for NAC in the setting of acetaminophen toxicity is a reasonable starting point.[3][98] If
signs of hepatic or renal toxicity are present, NAC should be continued until the patient’s condition has
improved and hepatotoxicity has largely resolved. [41][42][54] Should no signs of hepatotoxicity develop within
the first 24 to 36 hours of NAC therapy, it may be stopped. The patient may then be observed for 12 hours
without NAC therapy for the development of laboratory abnormalities or clinical symptoms. Because the half-
lives of pennyroyal and its metabolites are relatively short, the 24-hour period of NAC therapy should be
adequate in preventing hepatotoxicity. However, because of the paucity of data in this area, a cautious
approach is prudent.


PEPPERMINT OIL
Oil from the Mentha plant is called peppermint oil, after the plant named Mentha piperita. Peppermint oil
from the M. piperita plant contains 50 per cent menthol. Menthol, a naturally occurring cyclic terpene alcohol,
gives the Mentha plant its characteristic smell. Menthol can also be extracted from other oils, such as
eucalyptus and citronella.[28]
Pharmacology/Pathophysiology.
Menthol is rapidly absorbed when ingested.[100] It is highly lipid soluble and undergoes hepatic metabolism,
with more water-soluble glucuronide conjugates excreted by the kidney. [28] Menthol’s cooling effect on the
skin occurs via inhibition of calcium exchange in thermoreceptors. The irritant and local anesthetic effects
are due to the stimulation of dermal nociceptors.[28] In patients with nasal congestion and cough, menthol-
containing cough lozenges, liniments, and inhalers produce subjective feelings of cooling and clearing of the
nasal passages. However, studies show that increased nasal congestion rapidly follows exposure to menthol
vapors.[16][31] The sensation of cooling and subjective feeling of improvement results from the stimulation of
cold receptors innervated by the trigeminal nerve supply to the nose.[28] Importantly, the stimulation of these
upper airway cold receptors causes a reflex impairment of respiration by inhibition of upper airway accessory
respiratory muscle activity.[71] This may explain apnea in neonates after exposure to menthol vapors.[49]
Indeed, the antitussive effect of menthol may be due to its inhibition of respiration via stimulation of upper
airway cold receptors.[28] Finally, menthol is thought to be a smooth muscle relaxant, perhaps explaining the
use of peppermint oil as an herbal treatment for irritable bowel. Although experiments suggest that
peppermint oil exerts an inhibitory effect on gastrointestinal smooth muscle, perhaps by interference with
mobilization of calcium ions,[27][62][107][108] administration of peppermint oil into the colon resulted in
increased colonic motility, abdominal cramping, and increased colonic pressure activity in another study.[90]
The primary toxic effects of menthol are mucous membrane irritation and central nervous system
depression. The toxic dose of menthol can be as little as 2 g in an adult.[70] Confusion, psychosis, and visual
disturbances have occurred. Long-term inhalation of menthol cigarettes can cause ataxia. A 2-month-old
experienced acute dyspnea and coma on instillation of 1 mL of menthol solution into the nose.[78] The
concentration of menthol in the solution was not given. The patient smelled strongly of menthol and had a
metabolic acidosis, pupillary deviation, hyperextension of the extremities, inspiratory stridor, and irregular
respirations. Recovery and normalization of vital signs occurred at 4 hours. Because of reports of adverse
reactions in neonates, the German medical authorities warned the public in 1964 against the use of menthol
in infants.[12]
A 13-year-old boy excessively inhaled 5 mL of olbas oil, containing approximately 200 mg of menthol,
instead of a few drops, on the day of admission. Olbas oil is a preparation containing 4 per cent menthol,
35.5 per cent peppermint oil, 35.5 per cent eucalyptus, 18.5 per cent oil of cajuput, 2.7 per cent juniper berry,
3.7 per cent wintergreen oil, and 0.1 per cent oil of clove. Symptoms included altered mental status,
described as “barely rousable and talking gibberish.” Nystagmus was noted, and the patient complained of
diplopia. Symptoms resolved over 12 hours, and the authors attributed the patient’s symptoms to
menthol.[79]
Treatment.
Treatment is supportive, based on the symptoms manifested by the patient. In most cases, these symptoms
are mild and self-limited. Rarely, severe toxicity may occur in a newborn. Education of parents is critical to
prevention of neonatal poisoning.


SASSAFRAS
Oil of sassafras is obtained from the root bark of the sassafras tree (Sassafras albidum), of the family
Lauraceae.[91] The oil has been used throughout history to destroy head lice, as well as to treat a variety of
problems, including hypertension, arthritis, gout, ocular inflammation, and menstrual irregularities.[61] Safrole
is the major constituent of oil of sassafras and has been shown to be a hepatocarcinogen in rats.[91] In 1960,
the United States Food and Drug Administration banned the use of safrole in foods. Before this, safrole was
used as a flavoring agent, imparting the flavor in root beer.
There are few case reports of oil of sassafras poisoning in the literature. One man, as reported in the
Cincinnati Lancet-Clinic in December 1888, died after ingesting 1 teaspoonful of the oil. He developed
vomiting and collapsed with dilated pupils, became stuporous, and died. Five other cases, all children
younger than 2.5 years, have been reported.[20] Symptoms occurred 10 to 90 minutes after ingestion of 3 to
30 mL and included vomiting, shock, stupor, vertigo, and aphasia. Experimental work indicates that
sassafras kills by respiratory paralysis and circulatory collapse.[49]
Safrole is a hepatocarcinogen in rats. Safrole carcinogenicity testing in animals found that a small dose of 66
mg/kg of safrole given to mice over a 3-week period produced hepatomas, pulmonary adenomas, and
adenocarcinomas in animals surviving 1 year.[29] Extrapolation to humans suggests a dose of 0.66 mg/kg
might lead to toxicity, depending on the chronicity of the exposure.[117] Despite the 1960 ban on safrole in
foods, sassafras tea is freely available in many health food stores. One tea bag may contain up to 2.5 g of
sassafras bark, or 200 mg of safrole.[91] There have been no reported cases of hepatotoxicity in humans
after a one-time ingestion of sassafras, nor are there clear cases of cancer in humans that may be attributed
to the use of sassafras.
Treatment.
Treatment for acute oil of sassafras ingestion is supportive and includes administration of oral activated
charcoal, support of respiration and circulation, and adequate fluid and electrolyte replacement.


OIL OF WINTERGREEN
Oil of wintergreen is obtained from the leaves of the Gaultheria procumbens plant, of the family Ericaceae. It
is also known as oil of sweet birch, oil of Gaultheria, or oil of Betula. Oil of wintergreen contains 98 percent
methyl salicylate.[114] Because of its rubifacient properties, it is used in many liniments and sprays to treat
myalgias and arthralgias. Koong Yick Hung Far Oil, a Chinese herbal product, contains 67 percent
wintergreen oil. The label indicates it should be taken orally, but “not in excessive amounts.” Because of its
pleasant odor and taste, children associate products containing oil of wintergreen with wintergreen candy.
One teaspoon (5 mL) of oil of wintergreen (98 per cent) is equivalent to 7 g of aspirin, a potentially lethal
dose in a small child. Several cases of fatal poisoning have been reported with ingestion of as little as 4 to 7
mL.[36] Numerous cases of accidental methyl salicylate poisoning have been reported in children, with
mortality rates ranging from 40 to 60 per cent.[26][36][64][103] The potentially fatal toxicity of oil of wintergreen is
frequently unappreciated by the parents and the treating physician. Dermal absorption also occurs and can
lead to life-threatening toxicity.
Poisoning by oil of wintergreen results in acute salicylate toxicity (see Chapter 30 ). The rapid absorption
and clinical course may result in death in as little as 2 hours,[53] although peak serum salicylate levels may
also be delayed, mandating frequent repetitive monitoring of these levels. Vomiting; diaphoresis; tinnitus;
severe acid-base disturbances, including anion gap metabolic acidosis and respiratory alkalosis; mental
status changes; seizures; cerebral edema; respiratory arrest; and death may occur rapidly.
Treatment.
Treatment should be instituted early and aggressively. The oil of wintergreen may be removed with a small
nasogastric tube in the patient who has not yet vomited. When the history of poisoning by oil of wintergreen
is obtained and the diagnosis is suspected, oral dosing of activated charcoal without a cathartic,
alkalinization of the urine, and fluid repletion with potassium supplementation should be instituted even
before the serum salicylate level is available—delaying therapy while awaiting serum salicylate levels may
result in death. Extracorporeal removal of salicylate by hemodialysis is indicated in the patient with an
altered level of consciousness or confusion, renal failure, pulmonary edema, worsening acid-base status,
rising salicylate levels in spite of therapy, and a serum level approaching or greater than 100 mg/dL.
Because victims of oil of wintergreen poisoning are often infants or small children, hemodialysis may be
extremely difficult or even technically impossible on an emergent basis. Exchange transfusion, which is
familiar to pediatricians, results in rapid salicylate removal.[1][26][67]


SUMMARY
The volatile oils are a large and diverse group of substances. Although many are relatively harmless in small
doses, some are highly toxic. Knowledge of the potential dangers of these agents is important in preventing
illness in unsuspecting users and in treating poisoning, should it occur.


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Chapter 41 – Antidysrhythmics
KARL A. SPORER
The action potential of a ventricular or Purkinje fiber ( Fig. 41–1 ) is generated by the flux of ions through
specific channels in the cell membrane. Membrane depolarization results from the net influx of positive
charges (sodium [Na+] and calcium [Ca2+ ]), and repolarization occurs secondary to the net efflux of positive
charges (potassium [K+]) ( Table 41–1 ).
Figure 41-1 EKG recording of ventricular muscle cell action potential. (Redrawn from Tan HL, Hou JY, et al: Electrophysiologic
mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995; 122:701–714.)
Table 41-1 -- Major Ion Currents Underlying the Cardiac Action Potential *
Action Potential Phase Current Direction Effect of Current on Action Potential
Phase 0 (upstroke; inward > outward INa Inward Rapid upstroke or action potential in atrial,
currents) ventricular, and Purkinje fibers
Phase 1 (initial repolarization; outward > Rapid early repolarization after overshoot of
ITO Outward
inward currents) action potential
ICa Inward Slow inactivation maintains early plateau phase
Phase 2 (plateau; inward ~ outward INaCa Inward May assist in maintenance of plateau phase
currents)
Residual slowly inactivating outward current
ITO Outward
during plateau phase
Phase 3 (rapid repolarization; outward > Delayed rectifier repolarizes membrane to near
IK Outward
inward currents) resting potential
Phase 4 (Diastole; Inward ~ or > Maintains high negative resting potential near -90
IK1 Outward
outward currents) mV
From Tan AHL, Hou CJY, Lauer MR, Sung RJ: Electrophysiologic mechanisms of the long QT interval
syndromes and torsades de pointes. Ann Intern Med 1995; 122:701–714.
* INa, Fast inward sodium current; ITO, transient outward potassium current; Ica, slow inward L type calcium channel; INaCA, electrogenic
sodium-calcium exchange current; I K, outward delayed rectifier potassium; IK1, outward potassium current that exhibits anomalous (inward-
going) rectification.
Phase 0 depolarization is mainly caused by the opening of the fast Na+ channels, allowing the influx of Na +
from a high concentration gradient toward a low concentration gradient. Phase 1 is a small depolarization
mediated by the transient outward current of K+.
The plateau phase, or phase 2, is maintained by the relatively slow influx of Ca2+ through the L-type
Ca2+ channel. The rapid repolarization of phase 3 is generated by the efflux of K+ through the delayed
rectifier K+ channel. The Na+/K+ adenosine triphosphatase (ATP) pump and the Na+
concentration–dependent electrogenic Na+/Ca2+ exchange pump function between action potentials to
maintain electrolyte balance.
Na+ channel blockers will slow the phase 0 rapid upstroke and prolong the length of the entire action
potential. For a given resting membrane potential, depolarization is associated with a reduced rate of voltage
change and reduced maximum voltage. In addition, the higher threshold requires a greater stimulus to
initiate the action potential. Clinically, this is manifested as Q-Tc prolongation in therapeutic concentrations
and QRS widening in toxic concentrations. In higher doses, the Na+ channel blockade diminishes cardiac
output; and in even higher concentrations it will also slow the heart rate.
Ca2+ channel blockers in toxic doses will develop bradycardia from the slowing of atrial and ventricular
action potentials. In addition, the slow and diminished action potential along with the low intracellular Ca2+
concentration will manifest as a diminished cardiac output, relative bradycardia, and peripheral vasodilation.
K+ channel blockers prolong the action potential by slowing the efflux of K+. In addition to prolonging the
action potential, this will also increase the resting membrane potential. There are currently no pure K+
channel blockers, and thus their clinical effects in isolation have not been determined.
The treatment of toxicity due to Ca2+ channel blockers and ß-adrenergic receptor antagonists is covered in
Chapters 43 and 42 , respectively.
CLASS IA: QUINIDINE, PROCAINAMIDE, DISOPYRAMIDE
Essentials
• Lethargy, confusion, coma
• Widened QRS and Q-Tc intervals
• Hypotension without tachycardia
• Anticholinergic symptoms (primarily from disopyramide)
The action potential of a ventricular or Purkinje fiber results from the rapid flux of Na+, Ca2+ , and K+ through
various transmembrane channels (see Fig. 41–1 and Table 41–1 ).[63] Antidysrhythmics work by partially
blocking the function of specific ion channels and thus slowing various phases of the action potential. In the
exaggerated response of toxicity, the surface electrocardiographic (EKG) abnormalities can be predicted.
Quinidine, procainamide, and disopyramide are antidysrhythmic drugs in the class IA category and function
as antidysrhythmics by blocking both the Na+ and K+ cardiac channels.
Pharmacology
See Tables 41–2 and 41–3 .
Table 41-2 -- Modified Vaughan-Williams Classification of Antidysrhythmic Drugs

Class Pharmacologic Effect Antidysrhythmic Drug
Depresses rapid action potential upstroke and decreases
IA conduction velocity (Na+ channel blockade) and significantly Quinidine, procainamide, disopyramide
prolongs repolarization (K + channel blockade)
Depresses rapid action potential upstroke in abnormal tissue Mexiletine, lidocaine, tocainide,
IB
(little effect in normal tissue) and enhances repolarization moricizine *
Markedly depresses rapid action potential upstroke and
decreases conduction velocity (Na+ channel blockade) but Propafenone, encainide, † flecainide,
IC
exerts little effect on repolarization (little or no K+ channel moricizine *
blockade)
Class Pharmacologic Effect Antidysrhythmic Drug
Propranolol, metoprolol, atenolol,
II Blocks ß-adrenergic receptors esmolol, labetalol, nadolol, pindolol,
sotalol, timolol and others
Primarily blocks K+ channels and slows repolarization (little or
III Sotalol, amiodarone, bretylium
no Na+ channel blockade)
Verapamil, diltiazem, nifedipine, and
IV Blocks L-type Ca2+ channels
others
From Tan AHL, Hou CJY, Lauer MR, Sung RJ: Electrophysiologic mechanisms of the long QT interval
syndromes and torsades de pointes. Ann Intern Med 1995; 122:701–714.
* Moricizine has been variously classified as a class IB and class IC agent.
† Encainide was removed from US market in 1991.
Table 41-3 -- Antidysrhythmics: Therapeutic Levels and Elimination Characteristics

Therapeutic Levels Half-Life Elimination Pathway Active Metabolites
Class IA
Quinidine 2–7 µg/mL 6–8 hr Hepatic Yes
Procainamide 4–10 µg/mL 3 hr Hepatic/renal Yes
Disopyramide 2–5 µg/mL 4–10 hr Renal/some hepatic No
Class IB
Lidocaine 3–5 µg/mL 1.5–2 hr Hepatic Yes
Tocainide 3–9 µg/mL 10 hr Hepatic/renal No
Mexiletine 1–2 µg/mL 10 hr Hepatic No
Class IC
Encainide 15–100 ng/mL 1–3 hr Hepatic Yes
Propafenone 0.2–0.4 µg/mL 6–7 hr Hepatic No
Moricizine 0.25–3 µg/mL 2–4 hr Hepatic Unknown
Class III
Amiodarone 1–2 µg/mL 20–30 d Hepatic No
Bretylium Not available 5–10 hr Renal No
Sotalol 1.4–1.7 mg/L 9–11 hr Renal No
Pathophysiology
Type IA agents depress the rapid action potential upstroke (phase 0) and decrease conduction velocity by
Na+ channel blockade. They also significantly prolong repolarization and depress the slope of phase 4
depolarization by K+ channel blockade.[38][63] At therapeutic doses, patients will commonly manifest a
prolonged Q-Tc interval and an increased risk of torsades de pointes (polymorphic ventricular dysrhythmia).
At toxic doses, patients will demonstrate increased Q-T c and QRS intervals. Hypotension in type IA
intoxication is caused by depressed myocardial contractility from the Na+ channel blockade and peripheral
vasodilation from the K+ channel blockade.
Procainamide is hepatically metabolized to the pharmacologically active N-acetyl procainamide (NAPA),

which is renally excreted. Toxicity of NAPA commonly occurs in patients on therapeutic doses of
procainamide in the setting of decreasing renal function.[14] Hypotension occurs mainly with intravenous
infusions that exceed 20 mg/min.
The Na+ channel blockade of quinidine and probably the other type IA agents has been demonstrated to
increase in acidotic environments and worsen its toxicity.[30]
The most serious manifestations of a type IA intoxication are primarily cardiovascular ( Table 41–4 ).[38] Mild
intoxications may only manifest sinus tachycardia with Q-T c prolongation and a normal blood pressure.
Almost any dysrhythmia can occur in more serious cases, but the most common ones are QRS and Q-Tc
interval prolongation, bundle branch blocks, ventricular tachycardia (often polymorphic), and ventricular
fibrillation.[3][4][9][16][17][31][35][37][48][50][54][55][56][57][59][60][66][68][70]
Table 41-4 -- Clinical Presentation of Antidysrhythmic Intoxication

Type IA
Mild or early intoxication—tachycardia, normal blood pressure, and Q-Tc prolongation
Moderate to severe intoxication—QRS widening, hypotension with relative bradycardia, lethargy, confusion,
coma (anticholinergic symptoms, mostly disopyramide)
Type IB
Confusion, coma, seizures
Hypotension, widened QRS, ventricular dysrhythmias, and asystole in massive intoxication
Type IC
Q-Tc prolongation
Hypotension
Bradycardia
Coma, respiratory depression, seizures
Type III
Amiodarone—increased PR interval, rare sinus bradycardia
Sotalol—rapid-onset hypotension, bradycardia, Q-Tc prolongation, ventricular dysrhythmias
Bretylium—profound coma, occasional transient hypertension followed by hypotension
Hypotension commonly develops in severe intoxications and may be accompanied by a relative bradycardia.
Central nervous system (CNS) symptoms are also commonly noted in type IA intoxication and can range
from lethargy, confusion, coma, and respiratory depression to seizures. Quinidine has been noted to cause
cinchonism, a syndrome characterized by tinnitus, vertigo, blurred vision, headache, and confusion.
Disopyramide can produce significant anticholinergic effects in overdose and rarely has produced
hypoglycemia during therapeutic use.[16][45] The anticholinergic effects of disopyramide are mostly mediated
through its main metabolite, mono-N-dealkyldisopyramide.
The differential diagnosis of patients who present with a prolonged QRS interval, hypotension, relative
bradycardia, and CNS symptoms includes a consideration of other drugs that possess type IA toxicity, other
cardiotoxic agents, as well as severe electrolyte abnormalities ( Table 41–5 ).
Table 41-5 -- Differential Diagnosis of Antidysrhythmic Intoxication

Types IA, IC
Other Agents That Can Prolong Q-Tc and Cause Torsades
Phenothiazines
Chloroquine, quinine
Cocaine
Amantadine
Arsenic
Choral hydrate
Organophosphates
Diphenhydramine
Terfenadine
Astemizole
Other Agents with Cardiac Toxicity
ß-Blockers
Calcium channel blockers
Electrolyte Abnormality
Hypokalemia
Hypomagnesemia
Hypocalcemia
Type IB
Other causes of seizures (see Chapter 18 )
Severe intoxications
Type IA drugs
ß-Blockers
Type III
Amiodarone, sotalol
Other ß-blockers
Flecainide, encainide
Bretylium
Any sedative/hypnotic
Clonidine
Tetrahydrozoline
Laboratory Studies
The EKG is critical in predicting and following toxicity. An increase in the QRS complex width of more than
25 per cent over baseline has been used as a reliable indication of quinidine toxicity and has been
commonly seen in both disopyramide and procainamide toxicity.[11]
Drug levels of quinidine, procainamide, and NAPA are available, but rarely on a timely basis. Serum K+,
Ca2+ , and magnesium (Mg2+ ) levels can help to rule out significant electrolyte abnormalities.
Treatment
Early cardiac monitoring with intravenous access is important in these patients with a potential for lethal
dysrhythmias ( Table 41–6 ). Aggressive gastrointestinal decontamination will be most useful early after
ingestions. Attention to airway management in patients with lethargy or coma is important because type IA
toxicity can be worsened by acute respiratory acidosis.
Table 41-6 -- Treatment of Antidysrhythmic Intoxication

All Classes
Airway management, supportive care
Gastrointestinal decontamination—activated charcoal
Electrocardiographic monitoring
Type IA, IC[38][40]
Cardiac Conduction Delays
NaHCO3 1–2 mEq/kg IV boluses. Maintain arterial pH at 7.4 to 7.5.
Hypotension
0.9% NaCl 200–500 mL bolus infusions to correct hypovolemia
NaHCO3 1–2 mEq/kg IV boluses. If still hypotensive, consider a pressor agent.
Dopamine, norepinephrine, or epinephrine. Central hemodynamic monitoring may be helpful in guiding this
therapy.
Consider the use of an intra-arterial balloon pump or temporary cardiopulmonary bypass for intractable
hypotension.
Dysrhythmias
Bradydysrhythmias—isoproterenol or epinephrine infusion. Consider a pacemaker.
Polymorphic ventricular tachycardia (torsades de pointes)
Magnesium, 2 g IV bolus. May repeat in 5–15 minutes.
Isoproterenol or overdrive cardiac pacing
Other
Consider hemodialysis or hemoperfusion in patients with procainamide intoxication and large ingestions, high
plasma concentrations, presence of circulatory collapse, or renal insufficiency.
Type IB
Seizures
Lorazepam IV
Phenobarbital IV load for persistent seizures
Hypotension
0.9% NaCl 200–500 mL bolus infusions to correct hypovolemia
Dopamine, norepinephrine or epinephrine. Central hemodynamic monitoring may be helpful in guiding this
therapy.
Consider the use of an intra-arterial balloon pump or temporary cardiopulmonary bypass for intractable
hypotension.
Type III
Treat as for types IA and IC.
Amiodarone—cholestyramine may be useful for gastrointestinal decontamination.
Sotalol—glucagon may reverse ß-adrenergic receptor antagonist effects (see Chapter 42 ).
Sodium bicarbonate (NaHCO3) has been shown to be an effective therapy in reversing the EKG and cardiac
contractility changes caused by quinidine in both animal models and in case reports.[4][15][38] It has also been
reported effective in procainamide toxicity and logically should be helpful in disopyramide toxicity.[23]
Several mechanisms may account for the efficacy of NaHCO 3 in quinidine toxicity. Increasing the
extracellular Na+ concentration may overcome the inhibition of conductance through Na+ channels.
Alkalinization has been demonstrated to diminish the relative potency of quinidine at the Na+ channel.[30]
There may also be some beneficial effect of lowering the serum K+. It is generally recommended that the
serum pH be kept between 7.45 and 7.5.
Patients who develop torsades de pointes should be treated with the usual pharmacologic interventions.
Magnesium sulfate, overdrive pacing, and isoproterenol infusions have been very effective in suppressing
this dysrhythmia.[67] Logically, NaHCO3 should lessen the QTc prolongation and also be helpful in
suppressing torsades de pointes, but this has not been demonstrated clinically.
Ventricular ectopy and ventricular dysrhythmias related to class IA toxicity can be more difficult to treat. The
use of either class IA or IC (flecainide, encainide or propafenone) antidysrhythmics would be expected to be
ineffective or to worsen the dysrhythmia. There is modest evidence that bretylium may be helpful in this
scenario. NaHCO3 and lidocaine would be logical therapies. Hypotension should initially be treated by fluid
resuscitation and administration of NaHCO3. Hypotensive patients unresponsive to fluids have been treated
successfully with norepinephrine, isoproterenol, and dopamine. The only animal studies evaluating this
question concluded that isoproterenol was superior to dopamine and glucagon in providing cardiovascular
support.[28][32]
An intra-aortic balloon pump has been used successfully in one patient and should be considered along with
cardiopulmonary bypass for those patients with refractory hypotension.[60]
Extracorporeal drug removal is useful in procainamide and NAPA toxicity, of little benefit in quinidine toxicity,
and of questionable usefulness in disopyramide toxicity. Numerous case reports of procainamide poisonings
have demonstrated clinically significant clearance by both hemoperfusion and hemodialysis and should be
considered early in any large procainamide intoxication with hemodynamic instability, especially in the
setting of renal insufficiency or failure.[3][9][17][55][57]
Case reports and studies of disopyramide intoxications demonstrated modest usefulness of hemodialysis
and hemoperfusion.[27][33][35] The role for extracorporeal drug removal in disopyramide toxicity is not well
defined.
Disposition
Because of the rapid absorption of all these drugs, symptoms of toxicity and EKG changes will be apparent
in the first few hours after ingestion. Patients who develop QRS widening, mental status changes,
hypotension, or dysrhythmias need hospital admission and telemetry monitoring. Patients who are observed
for 4 to 6 hours and do not develop QRS widening or other symptoms can be safely discharged if they are
not suicidal.
Sequelae
The QRS complex may take up to several days to return to baseline even though most of the significant
symptoms occur in the first 12 hours after ingestion. Other long-term sequelae are related to the severity of
hypotension and hypoperfusion.


CLASS IB: LIDOCAINE, TOCAINIDE, MEXILETINE
Essentials
• Confusion, coma, seizures
• Hypotension, widened QRS complex, ventricular dysrhythmias, and asystole in massive
intoxication
Class IB antidysrhythmics act primarily by inhibiting Na+ channels selectively at ischemic and rapidly
depolarizing myocytes.[5]
Pharmacology
Pathophysiology
These Na+ channel blocking agents have little electrophysiologic activity on normal cells at therapeutic or
moderately toxic doses. Because of these properties, there are no common EKG changes noted in
intoxications. Cardiac dysfunction is only noted in massive intoxications when high concentrations partially
block all cardiac sodium channels similar to type 1A agents.
CNS toxicity is more common and is manifested as confusion or seizures. Ion transport is disturbed in the
brain, and inhibitory neurons are initially blocked, causing excitatory stimulation and seizures. Higher
concentrations will inhibit both excitatory and inhibitory neurons and induce coma and respiratory
depression.
Lidocaine has been shown to develop toxicity when administered orally, mucosally, and
parenterally.[1][26][34][61] Oral lidocaine is well absorbed but undergoes significant first-pass metabolism.
Lidocaine is hepatically metabolized to two active metabolites, monoethylglycinexylidide (MEGX) and glycine
xylidine (GX), that may contribute to toxicity. The oral bioavailability of tocainide and mexiletine approaches
100 per cent, and neither compound is metabolized to any active metabolites.
The majority of these intoxications will present as confusion, agitation, or seizures (see Table 41–4 ). There
will likely be no finding other than history to differentiate this from other causes of seizure activity. Most of
these cases will have a normal EKG and relatively normal vital signs.
Severe intoxications can inhibit the Na+ channel in even normal cardiac tissue and will be similar to
quinidine toxicity with a widened QRS complex and a diminished cardiac output. Almost any dysrhythmia
can be seen in this setting. Mexiletine and tocainide intoxications are similar in presentation.[13][46][62]
The differential diagnosis includes any cause of seizures (see Chapter 18 ). The differential diagnosis of a
severe intoxication with hypotension and dysrhythmias includes other antidysrhythmics and Ca2+ channel
blockers (see Table 41–5 ).
Laboratory Studies
Determination of serum electrolyte levels is done to rule out metabolic causes of seizures. The EKG is
monitored for QRS complex widening in cases of severe intoxication. Lidocaine levels are not readily
available, but therapeutic concentrations are 3 to 5 µg/mL.
Treatment
General supportive care and control of the seizures is done first. Repetitive seizures should be controlled
with escalating intravenous doses of lorazepam. Patients whose seizures are not controlled with high-dose
lorazepam should be given intravenous phenobarbital. At this point these patients will likely require
intubation and ventilatory support. Phenytoin acts as a class IB antidysrhythmic and should not be used.
After airway management and seizure control, appropriate gastric decontamination with activated charcoal
can be accomplished if necessary.
Bradydysrhythmias may require a temporary pacemaker. Hypotension should be treated first with a normal
saline bolus, then with a vasopressor. A temporary pacemaker may be helpful in these patients.
Theoretically, NaHCO3 should be efficacious, but it has not been used clinically or studied experimentally.
Extracorporeal cardiac support to maintain blood pressure and improve hepatic metabolism has proven
useful in one experiment and one case report.[21][22]
The experience of treating tocainide and mexiletine intoxications is limited but should be similar to that of
lidocaine.
Disposition
These three agents are quickly and reliably absorbed. All patients should develop signs of toxicity in the first
1 or 2 hours. Any patient with mental status changes, seizures, hypotension, or dysrhythmias should be
admitted to a monitored bed. Patients who do not develop symptoms within 4 hours can be safely
discharged if they are not suicidal.
Sequelae
There are no sequelae.

Specific Situations
Special concern should be emphasized about the potential for toxicity with the use of oral lidocaine. Even
though there is extensive first-pass metabolism with oral ingestion, seizures have been noted to occur with
the misuse of oral lidocaine preparations.[26][34][61]
The maximal doses of subcutaneous lidocaine tolerated are 4.5 mg/kg for plain lidocaine and 7 mg/kg with
lidocaine with epinephrine.


CLASS IC: FLECAINIDE, ENCAINIDE, PROPAFENONE, AND MORICIZINE
Essentials
• Q-Tc prolongation
• Hypotension
• Bradycardia
• Coma, respiratory depression, seizures
Type IC antidysrhythmics markedly depress the phase 0 rapid action potential upstroke by blocking the Na+-
fast channels. These drugs have little or no effect on the K+ channels and thus have no effect on
repolarization. Moricizine has some features in common with type IB antidysrhythmics. [20] Propafenone also
exhibits minor ß-blocking and Ca2+ -channel blocking activities. Encainide is no longer available in the United
States after being withdrawn because of a prodysrhythmic effect.
Pharmacology
Pathophysiology
The agents in this class have much in common with the type IA antidysrhythmics. In toxicity, the Na+ channel
blocking effect will manifest itself as widened QRS and Q-Tc intervals, hypotension, and
bradycardia.[2][10][12][29][36][40][42][44][51][52][69] In addition, PR interval widening has been noted in flecainide
intoxications.[42][69]
Flecainide and encainide are both quickly absorbed, very bioavailable, and rapidly toxic. Most severe cases
have demonstrated signs of toxicity within 30 to 120 minutes of the ingestion.[40] The most prominent signs
and symptoms include hypotension, bradycardia, QRS complex widening, coma, respiratory depression, and
seizures (see Table 41–4 ).
The differential diagnosis of patients who present with a prolonged QRS interval, hypotension, relative
bradycardia, and CNS symptoms includes other agents that possess type IA properties and other cardiotoxic
agents such as Ca2+ channel blockers or ß-adrenergic blockers (see Table 41–5 ).
Laboratory Studies
The EKG is useful in predicting and following toxicity. In case reports, QRS complex widening has been
consistently useful in predicting the presence and severity of poisoning.[69]
Treatment
Cardiac monitoring, intravenous access, airway management, and early gastrointestinal decontamination
are important in managing these potentially severe intoxications. NaHCO3 boluses have been reported
useful in treating the cardiotoxic effects and preventing dysrhythmias and hypotension.[52][58]
There is no clear choice of a vasopressor for those patients who do not respond to crystalloid infusion and
NaHCO3. Rapidly escalating doses of dopamine or epinephrine should be titrated to a reasonable blood
pressure. Pacing has been successful in improving the hemodynamics in some patients. Extracorporeal
cardiac support, including balloon counterpulsation or cardiac bypass, should be considered in severe
refractory cases.
Efforts at resuscitation should be prolonged because several cases of flecainide and propafenone poisoning
survived extended periods of cardiopulmonary resuscitation with asystole or pulseless electrical activity and
were discharged with normal neurologic status.[10][36][42][51]
Disposition
Patients with significant ingestions will manifest symptoms in 30 to 60 minutes. All patients with QRS
widening, mental status changes, hypotension, or bradycardia should be monitored closely in an intensive
care unit. These patients should be monitored for 8 to 12 hours after their symptoms have resolved. There
has been one reported case of late-appearing dysrhythmias in a patient with severe flecainide
intoxication.[29] Patients who have not developed symptoms in 4 to 6 hours can be safely discharged if they
are not suicidal.
Sequelae
There are few or no long-term sequelae. One patient with an acute intoxication of propafenone had
persistent QRS complex widening and diminished cardiac function at 4 months after ingestion.[36] Most other
patients demonstrated complete recovery, with QRS widening resolving over hours to days.


CLASS III: AMIODARONE, SOTALOL, BRETYLIUM
Essentials
• Amiodarone—increased PR interval, rare sinus bradycardia
• Sotalol—rapid onset hypotension, bradycardia, Q-Tc prolongation, confusion; severe cases— respiratory
depression, ventricular dysrhythmias
• Bretylium—profound coma, occasional transient hypertension followed by hypotension
Amiodarone, sotalol, and bretylium are type III antidysrhythmics because they function by blocking K+
channels. This slows the action potential repolarization and produces Q-Tc prolongation. Despite this one
similar function, all of these drugs act differently in overdose because of their other pharmacologic properties
and their differing pharmacokinetics.[41]
Pharmacology
Pathophysiology
The toxicities of this group of antidysrhythmics cannot be predicted or explained by K+ channel blockade
alone. A pure K+ blocker would slow the action potential’s return to baseline and reset the myocardial cell at
a higher level that would make it more prone to ventricular irritability.
Amiodarone has well-documented chronic toxicities (pulmonary fibrosis, Q-Tc prolongation, and thyroid
abnormalities) but little acute toxicity because of its poor absorption.[53] The prolonged period of absorption
allows the logical use of late gastrointestinal decontamination and dictates a long observation period.
Sotalol is rapidly and completely absorbed and demonstrates toxicity within an hour of ingestion. In addition
to the K+ channel blockade, it also has a significant ß-adrenergic receptor antagonist effect that explains
most of the hemodynamic changes in overdose.
Bretylium is only available in intravenous form, and intoxication is usually iatrogenic. In addition to its type III
antidysrhythmic properties, bretylium affects the autonomic nervous system. An initial release of
norepinephrine from sympathetic ganglia results in a transient increase in blood pressure and heart rate.
Later, the drug blocks the release of norepinephrine by depressing adrenergic nerve excitability, causing
hypotension and bradycardia. The severe coma caused by bretylium remains unexplained.
Most acute amiodarone intoxications are benign and manifest little or no EKG changes. Reported EKG
abnormalities include prolongation of the PR and Q-Tc interval, mild bradycardia, and one case of self-
limited ventricular tachycardia.[7][8][25] More severe toxicity can be predicted in the future with the availability
of an intravenous form of amiodarone.
Sotalol intoxications can be expected to develop Q-Tc prolongation, bradycardia, and hypotension soon after
ingestion. More severe intoxications will manifest as coma, respiratory depression, seizures, and ventricular
dysrhythmias.[18][19][43][47][65]
There have only been three reported cases of bretylium overdose.[6][24][64] These patients developed
profound coma lasting 1 to 3 days. One patient developed transient tachycardia and hypertension, followed
by a reduced cardiac output and refractory hypotension. No specific EKG changes were noted in any of
these patients (see Table 41–4 ).
Differential Diagnosis (see Table 41–5 )
The differential diagnosis for the cardiovascular effects caused by amiodarone and sotalol include other ß-
adrenergic receptor antagonist drugs, Ca2+ channel blockers, type 1A and 1C antidysrhythmics, and the
other drugs that can cause prolonged Q-Tc and torsades. Differential considerations for bretylium toxicity
include toxicity of any sedative/hypnotic agent, clonidine, and tetrahydralazine.
Laboratory Studies
The EKG may reveal Q-Tc interval prolongation in significant amiodarone or sotalol intoxication. Serum K +,
Ca2+ , and Mg2+ levels will be helpful in gauging the extent of electrolyte replacement necessary. Serum
levels of class III antidysrhythmic drugs are not readily available.
Treatment
The slow absorption of amiodarone allows for late gastrointestinal decontamination in cases of significant
ingestion. Activated charcoal has been effective in binding amiodarone and is the therapy of choice. [39]
Cholestyramine binds amiodarone in the gastrointestinal tract as well as reduces the elimination half-life of
absorbed drug, but its role in this ingestion is currently unclear.[49] Intravenous potassium should be given
slowly to increase the serum potassium to greater than 4.5 mmol/L. K + repletion alone has been noted to
have a protective effect from the dysrhythmias caused by amiodarone.[53]
Occasionally, torsades de pointes occurs in amiodarone intoxication (usually in combination with a type IA
agent). This should be treated with intravenous magnesium and an isoproterenol infusion or overdrive
pacing to increase the heart rate.[67]
Sotalol ingestions resemble ß-blocker intoxications, with a greater propensity for ventricular dysrhythmias.
The initial treatment includes appropriate gastrointestinal decontamination, cardiac monitoring, and K+
repletion. Hypotension has been successfully treated with isoproterenol (to increase myocardial rate),
dopamine, and cardiac pacing. Glucagon, commonly employed in ß-adrenergic receptor antagonist
intoxication, is a logical choice in a patient refractory to other pressors. Patients with recurrent ventricular
dysrhythmias have been successfully treated with defibrillation and lidocaine.
The treatment of bretylium intoxication includes airway management and other supportive measures. Coma
may be prolonged and can resemble brain death. In addition, hypotension may require vasopressors or
extracorporeal cardiac support.
Disposition
Amiodarone’s prolonged absorption, up to 15 hours, dictates a long observation period and will require the
admission of all but the most trivial of ingestions. Clinical endpoints for amiodarone ingestions are unclear,
owing to limited clinical experience.
Sotalol intoxications will demonstrate EKG and vital sign changes within the first few hours. A patient
monitored for 4 to 6 hours without EKG changes, hypotension, bradycardia, or mental status changes can
be safely discharged if the patient is not suicidal. The Q-Tc prolongation can persist for days and is not a
useful endpoint of observation. Late-presenting torsades has not been reported in these cases. Patients
should be observed for 6 to 8 hours after vital sign abnormalities and dysrhythmias have resolved.
Bretylium intoxications are usually iatrogenic. These patients require admission and should be observed for
12 to 24 hours for mental status changes.
Sequelae
Q-Tc interval prolongation can persist for days. There are no other significant sequelae of these ingestions.


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Chapter 42 – Beta-adrenergic Receptor Antagonists
WILLIAM KERNS II
Essentials
• Bradycardia
• Hypotension
• Coma
• History of ß-adrenergic receptor antagonist ingestion or availability
INTRODUCTION
Beta-adrenergic receptor antagonists (ßARAs) are used to treat a broad spectrum of illnesses.
Cardiovascular applications include hypertension, angina pectoris, tachydysrhythmias, cardiac outflow
obstruction, and reduction of post–myocardial infarction mortality.[11][87] Noncardiovascular uses include
treatment of essential tremor, pheochromocytoma, glaucoma, anxiety, and migraine headaches.[30] With
such a variety of uses and drug availability, it is not surprising that a large number of toxic exposures occur.
Data from poison centers from 1997 include more than 8250 accidental and intentional exposures to ßARAs,
with 150 serious poisonings and 9 deaths.[59] With an expanding population of elderly patients who are
especially vulnerable to the toxic effects of medication, toxic exposures will likely continue to increase.[20]


( Fig.42–1 )
Figure 42-1 Schematic overview of ß-adrenergic receptor function and effects of ßARA. The activated ß receptor directly alters the
stimulatory G protein (Gs), which in turn activates adenylyl cyclase (AC), increasing cyclic adenosine monophosphate (cAMP), the
cytosolic second messenger. Cyclic AMP activates protein kinase, which phosphorylates the l-channel, resulting in extracellular
calcium entry into the cell. Ryanodine, an intermediary protein, couples plasmellemal calcium entry to release of intracellular calcium
stores from the sarcoplasmic reticulum. At the end of excitation-contraction coupling, intracellular calcium is taken up into storage
organelles. Phosphodiesterase hydrolyzes cAMP (not shown). ßARAs may cause toxicity by blocking receptor stimulation (1). There is
also evidence that ßARAs may interfere with calcium homeostasis by preventing calcium reuptake into storage organelles (2). As a
result, calcium-dependent potassium channels may open during altered calcium homeostasis, hyperpolarizing the cell. Additional
toxicity occurs through sodium channel blockade (3) by some ßARAs.
The ß-Adrenergic Receptor System
The ß receptor is a glycoprotein within the cell membrane whose stimulation ultimately results in increased
cytosolic calcium that is integral for excitation-contraction coupling. This occurs in a complex fashion. The
plasmalemmal ß receptor is coupled to an intracellular second messenger, cyclic adenosine
monophosphate (AMP), by a guanine nucleotide-binding regulatory protein within the cell membrane, the G
protein. On ß-receptor stimulation, the G protein undergoes a conformational change that activates adenylyl
cyclase, increasing intracellular cyclic AMP. Cyclic AMP stimulates protein kinase, which phosphorylates
calcium channels, leading to calcium entry into the cell. Calcium entry into the cell triggers additional calcium
release from sarcoplasmic reticulum, the primary intracellular calcium storage organelle. Phosphodiesterase
then hydrolyzes cyclic AMP.[7][42][55][93] There are at least three ß-receptor subtypes: (1) the ß1 subunit,
located in myocardium, kidney, and eye; (2) the ß 2 subunit, found in adipose, pancreas, liver, and muscle
tissue; and (3) the ß 3 subunit, located in adipose tissue. Stimulation of the ß 1 subunit produces increased
chronotropy and inotropy in the heart, as well as increased renin secretion by the kidney and aqueous
humor production in the anterior chamber of the eye. Beta2 agonism relaxes smooth muscle in blood vessels
and the bronchial tree, intestinal tract, and uterus. Additionally, ß2 activation prepares the body for increased
metabolic demands during periods of stress by stimulating lipolysis and glycogenolysis.[13] The ß 3 subunit
may alter lipid metabolism.[42]
Toxic Mechanisms of Action
It is generally accepted that the mechanism of toxicity involves excessive blockade of ß receptors, with
decreased cyclic AMP and blunting of the metabolic, chronotropic, and inotropic effects of
catecholamines.[30] This mechanism alone does not account for all the observed manifestations of ßARA
toxicity. Several investigations and clinical experience implicate additional or alternative mechanisms. For
example, ßARAs produce toxicity in catecholamine-depleted isolated, perfused hearts. [19][53] In a canine
model of acute toxicity, catecholamines did not improve survival.[48] Additionally, catecholamines frequently
fail to improve hemodynamics in human poisoning, even when given in large doses.[96]
Effects on the membrane sodium channel may contribute to ßARA toxicity. Several drugs of this class
antagonize myocardial sodium channels in a manner similar to quinidine, a class I antidysrhythmic drug.[28]
This occurs at supratherapeutic doses (1 to 3 mg/kg of propranolol in experimental animals).[35][70]
Impedance of sodium entry slows phase 0 of the action potential, resulting in prolonged QRS complex
duration and myocardial depression.
ßARAs may also result in myocardial toxicity by altering calcium and potassium homeostasis. Several
ßARAs inhibit ATPase-independent calcium uptake into sarcoplasmic reticulum and mitochondria.[21][71]
High cytosolic calcium may stimulate plasmalemmal calcium-dependent potassium channels to open,
resulting in an outward potassium current that lowers the resting membrane potential and hyperpolarizes the
cell. Treatments aimed at closing potassium channels or preventing calcium release from sarcoplasmic
reticulum reversed toxicity in isolated heart preparations.[46][47]
Central nervous system (CNS)-mediated cardiotoxicity represents another potential mechanism. In a rat
model, intracerebral administration of drug produced more respiratory depression and hypotension
compared with the intravenous route, even though both routes achieved similar plasma concentrations.[54]
Pharmacology
Pharmaceutical manufacturers market many ßARAs, each of which differs slightly in pharmacologic ( Table
42–1 ) and pharmacokinetic properties ( Table 42–2 ). Although these differences in properties may not
significantly alter drug effects during normal therapeutic dosing, they do influence manifestations of toxicity
in the overdose setting.
Table 42-1 -- ß-Adrenergic Receptor Antagonist Pharmacologic Profile

Adapted with permission from Frishman W, Jacob H, Eisenberg E, et al: Appraisal and reappraisal of cardiac
therapy: Clinical pharmacology of the new beta-adrenergic blocking drugs: VIII. Self-poisoning with beta-
adrenoreceptor blocking agents: Recognition and management. Am Heart J 1979; 98:798–811.
Table 42-2 -- ß-Adrenergic Receptor Antagonist Pharmacokinetics

Absorption Protein Onset of Volume of Metabolism & Half-
Agent Lipophilic
(%) Binding (%) Action (hr) * Distribution (L/kg) Life Elimination (hr)
Acebutolol 70 25 1–3 3 Renal/3–4 Moderate
Atenolol 50 <5 2–4 0.6–1.1 Renal/6–9 Weak
Esmolol NA 55 5 min 3.4 Blood esterase/9 min Weak
Labetalol 90 50 1–3 5.1–9.4 Hepatic/3–4 Weak
Metoprolol 90 12 1–2 5.6 Hepatic/3–4 Moderate
Nadolol 30 30 3–4 1.8–2 Renal/14–24 Weak
Oxprenolol 90 80 1–2 1.2 Hepatic/2–3 Moderate
Pindolol 90 57 1¼ 1.2–2 Renal/3–4 Moderate
Propranolol 90 93 1–1½ 3.4–6 Hepatic/3–4 High
Sotalol 70 0 2–3 0.23–0.7 Renal/9–10 Weak
Timolol 90 10 1–2 1.3–3.6 Renal/4–5 Weak
NA, not applicable.
Compiled from data from references 28 , 38 , 80 , 96 .
* Regular release preparations.
Clinically important pharmacokinetic characteristics include drug formulation (regular vs. sustained release),
rate of drug absorption, lipid solubility, and volume of distribution (Vd). Absorption of normal-release ßARAs
occurs rapidly, with peak effect in 1 to 4 hours.[96] For this reason, toxic symptoms begin soon after ingestion
of excess amounts of regular-release drug. Highly lipid-soluble agents such as propranolol penetrate the
blood-brain barrier to a greater extent than the water-soluble agents, thereby displaying a greater degree of
CNS toxicity. The extent of plasma protein binding, the Vd, and the lipid solubility predict the ability of
extracorporeal therapies such as hemodialysis to eliminate drug. Dialysis will not be useful for lipophilic
drugs with a Vd greater than 1.0 L/kg or high protein binding. Atenolol and sotalol are the only ßARAs
predicted to be dialyzable because they have little protein binding, are weakly lipophilic, and have Vds less
than 1.0 L/kg.
Pharmacologic differences between drugs also influence expression of toxicity. Propranolol, acebutolol,
labetolol, oxprenolol, and pindolol inhibit myocardial sodium channels, making these drugs potentially more
cardiotoxic. Acebutolol, atenolol, esmolol, and metoprolol are ß1-selective agents and are less likely to
produce the peripheral vasoconstriction, bronchospasm, and disturbances in glucose homeostasis that
result from ß2 inhibition. However, with acute ingestion of large amounts of drug, selectivity may be
lost.[29][64] Several ßARAs have partial agonist activity so that weak stimulation of the ß receptor occurs
concurrently with blockade. Partial agonist activity may have a protective effect in overdose. Labetolol has
the potential to cause profound hypotension owing to combined a1-and ß-receptor antagonism.


General
Patients who ingest ßARAs manifest a spectrum of clinical presentation ranging from minimal or no
symptoms to myocardial depression, hypotension, and cardiovascular collapse ( Table 42–3 ). Factors that
determine the severity of toxicity include amount and characteristics of ingested drug, underlying health of
the patient, co-ingestants, and delay until treatment. The majority of serious cases result from ingestion of
propranolol.[59][78] Symptoms typically develop within 1 to 3 hours after acute ingestion, although onset may
range from 15 minutes to 10 hours.[17][28][58][65][68][69][86][88][96] The time of onset of symptoms is affected
primarily by the drug formulation and the nature of the co-ingestants. Experience with calcium channel
antagonists[77] and lithium[16] demonstrates that delays are expected after ingestion of sustained-release
formulations. Co-ingested opioids and anticholinergics may decrease gastrointestinal motility, potentially
delaying absorption and peak drug effect. Systemic toxicity has been reported after instillation of ßARA
ophthalmic preparations.[3][24]
Table 42-3 -- Clinical Manifestations of ß-Adrenergic Receptor Antagonist Toxicity

System Manifestations
Cardiovascular Bradycardia, conduction delays, decreased contractility with systemic hypotension
Central nervous system Coma, seizures
Pulmonary Bronchospasm (unusual)
Metabolic Acidosis, hypoglycemia (rare)
Myocardial conduction delays and decreased contractility are common manifestations. Slowing of the heart
due to sinus node suppression and conduction abnormalities occurs in virtually all significant ß-blocker
intoxications. Sinus bradycardia is documented in most cases. * Exceptions include overdoses of ßARAs
that have partial agonist activity, in which case bradycardia may not be present despite other significant
symptoms.[73][92] Other reported conduction disturbances include first-degree atrioventricular
block, [26][86][88][89][96] atrioventricular dissociation,[14][85] right bundle branch block, and intraventricular
conduction delay.[18][85] QRS prolongation may occur with those ßARAs that antagonize sodium channels,
such as propranolol,[17][28][65][76] pindolol,[73] and acebutolol.[69] The electrophysiologic effect of sotalol
deserves separate attention. Unlike other ßARAs, sotalol has antidysrhythmic properties consistent with the
Vaughan Williams class III drugs, which lengthen the duration of the QT interval by prolonging action
potential duration in His-Purkinje tissue. Predictably, ventricular dysrhythmias such as multifocal premature
ventricular contractions, bigeminy, ventricular tachycardia, ventricular fibrillation, and torsades de pointes are
more common with sotalol.[2][25][33][68][94]
Hypotension results from negative inotropism.[26][40][52][57][68][86] Evidence that hypotension is directly due to
depressed contractile function, rather than rate-related dysfunction, comes from case reports of hypotension
without bradycardia[28][72][88] and from animal models demonstrating decreased myocardial performance
despite pacing at normal heart rates.[19] Together, bradycardia and decreased contractility may produce
profound cardiac failure. Occasionally, hypertension occurs with ßARAs that have partial agonist activity.[92]
* References 2 , 14 , 17 , 26 , 27 , 31 , 33 , 39 , 51 , 52 , 57 , 58 , 65 , 72 , 74 , 76 , 86 , 90 , 91 , and 96 .
The manifestations of CNS toxicity include psychosis, depressed consciousness, and seizures. The
mechanism is unclear but may be due to cellular hypoxia from poor cardiac output or direct neuronal
toxicity.[5][6] Seizures are generalized and tend to be brief, lasting seconds to minutes.[18][45][52][65][72][86][90]
Repeated seizures are rare but may be refractory to treatment. In one case, seizures recurred over 9 hours
and failed to respond to diazepam and thiopental.[89] Hydrophilic ßARAs result in fewer instances of coma
and seizures.[2][25][26][33][68][88][94][96] Acute psychosis preceded myocardial manifestations in a case of
propranolol overdose.[60] When patients survive, neurologic recovery appears to be complete.
Pulmonary System
Acute bronchospasm is an infrequent consequence despite the potential for bronchial smooth muscle
constriction due to ß2 antagonism. Occasional reports of bronchospasm appear, due to atenolol, metoprolol,
oxprenolol, and propranolol poisoning.[14][28][81][97] Systemic absorption of ophthalmic ßARA preparations
also resulted in bronchospasm.[3][24]
Metabolic System
Metabolic complications are unusual despite potential alterations in glucose homeostasis. Hypoglycemia
was reported after atenolol overdose.[1][81] Hypoglycemia also occurred 7 hours after accidental ingestion of
propranolol by two siblings.[36]
Unusual Manifestations
Rare complications of poisoning include esophageal spasm after propranolol overdose,[51] mesenteric
ischemia after propranolol overdose,[76] and acute renal failure associated with labetolol overdose.[88]


Many medications, chemicals, and natural toxins potentially result in bradycardia and hypotension similar to
ßARAs ( Table 42–4 ). The more common agents include calcium channel antagonists, clonidine, digoxin,
plant cardiac glycosides, and organophosphates. The selection of appropriate antidotal therapy, such as
digoxin-specific antibodies for digitalis intoxication or pralidoxime for pesticide exposure, requires
identification of the specific agent. However, it is often difficult to differentiate between offending agents
based on clinical grounds, especially when a patient presents with myocardial depression and a vague
history of “heart” or “blood pressure medicine” overdose. Some helpful distinguishing features are included
in Table 42–4 .
Table 42-4 -- Differential Diagnosis of Toxin-Induced Bradycardia with Hypotension

Toxin Distinguishing Features
Medications
Very similar to ß-adrenergic receptor antagonists; may respond
to calcium and glucagon
Opioid symptoms (coma, respiratory depression, miosis)
Clonidine
common; may respond to naloxone
Atrial tachycardia with slow ventricular response; hyperkalemia;
Digoxin (acute) serum level commonly available; responds to digoxin-specific
antibodies
Sodium channel blockers: cocaine, cyclic Bradycardia occurs with end-stage toxicity; prolonged QRS
antidepressants, or norpropoxyphene complex; responds to sodium bicarbonate
Type Ia (procainamide, quinidine) and Ic Prolonged QRS complex duration; may respond to sodium
antidysrhythmics (propafenone) bicarbonate
Pharmacologic diluent; may occur during intravenous infusion of
Propylene glycol
medications such as phenytoin
Natural Toxins
Digitalis-like glycoside–containing plants: Similar to digoxin toxicity; amenable to digoxin-specific antibody
oleander, foxglove treatment
Grayanotoxin-containing plants: azalea,
Homemade teas; gastrointestinal symptoms common
rhododendron
Common component of Chinese herbal remedies; toad licking;
Bufadienolides secreted by Bufo species
“love stone” aphrodisiac; amenable to digoxin-specific antibody
toads
treatment
Chemicals
Organophosphate and carbamate pesticides “SLUDGE” symptoms; responds to atropine and pralidoxime
Toxin Distinguishing Features
Profound metabolic acidosis; laboratory or biochemical
Cyanide exposure; aroma of bitter almonds; treat with nitrites and
thiosulfate
Profound metabolic acidosis; industrial accidents; treat with
Hydrogen sulfide
nitrites


LABORATORY STUDIES
A 12-lead electrocardiogram (EKG) and continuous rhythm monitoring are essential in the evaluation and
ongoing assessment. Laboratory testing is directed at supportive monitoring of renal function, glucose,
oxygenation, and acid-base status. Specific drug levels may be obtained to confirm an exposure but will not
alter acute management because symptoms do not necessarily correlate with levels and levels are not
rapidly available. Radiographs to detect pills in the gastrointestinal tract are not useful.[84]


TREATMENT
The goal of therapy is to restore perfusion to critical organ systems by improving myocardial contractility or
increasing heart rate, or both. Current therapy ( Table 42–5 ) is derived principally from anecdotes and case
series and includes adrenergic agonists, glucagon, atropine, and phosphodiesterase inhibitors. These
therapies have met with variable success. It is difficult to conclude which therapy is optimal from evaluation
of uncontrolled cases that lack uniform historical data, have varying degrees of toxicity, report different
doses of treatments, and have cumulative effects of multiple therapies. With these limitations in mind, the
utility of various therapeutic modalities is reviewed in light of available data.
Table 42-5 -- Treatment Essentials of ß-Adrenergic Receptor Antagonist Toxicity

Glucagon bolus (3.5–5 mg) followed by infusion (1–5 mg/hr)
Epinephrine infusion (1 µg/kg/min) and titrate or isoproterenol infusion (2 µg/min) and titrate
Amrinone infusion (5 µg/kg/min) and titrate
Electrical pacing. Consider aortic balloon pump
Glucagon
Rationale
Glucagon, a pancreatic polypeptide hormone, has become first-line pharmacotherapy for ßARA toxicity
based on clinical experience. Glucagon enhances myocardial performance by increasing cyclic AMP
concentrations in a manner identical to catecholamines[67] but is purported to act by means of a distinct
glucagon receptor.[44][56] Thus, glucagon may bypass the blocked ß receptor. Glucagon restores inotropy
and chronotropy in isolated, perfused myocardial tissue and in intact canines exposed to propranolol.[32][63]
Clinical experience with this antidote has generally produced favorable results, often after other treatments
have failed.[2][18][26][41][57][58][65][72][75][89][95][96][97] However, only two cases report using glucagon as the sole
pharmacologic agent to resuscitate severely toxic propranolol overdoses[41][98] and several reports contend
that glucagon failed to reverse toxicity.[27][31][40][74][86]
A few animal models of ßARA poisoning that directly compare glucagon to other therapies support the
efficacy of glucagon. In a canine model, glucagon was found to be superior to isoproterenol in reversing the
effects of 2 mg/kg of propranolol.[49] In another canine model, glucagon was compared with amrinone, a
phosphodiesterase inhibitor. Both agents reversed depressed myocardial contractility, but glucagon was
superior to amrinone in its chronotropic effects.[62]
Dose
The recommended initial dose of glucagon is 50 to 100 µg/kg as an intravenous bolus. For an average-sized
patient (70 kg), this represents 3.5 to 5 mg. This may be repeated as needed. Because glucagon’s duration
of action is 15 minutes,[99] a constant infusion of 1 to 5 mg/hr may be required to sustain its effect after the
bolus dose. There is no defined maximal therapeutic dose of glucagon. Cumulative bolus doses
administered to patients range from 1 to 30 mg,[2][57] and infusions of 2 to 10 mg/hr have been continued for
up to 26 hours.[45][72]
Reconstitute glucagon in normal saline or 5 per cent dextrose solution to avoid potential adverse effects of
the manufacturer’s diluent. Each 1-mg vial of diluent contains 2 mg of phenol. Phenol may be toxic at
amounts exceeding 50 mg, producing seizures, hypotension, and dysrhythmias.[66]
Adverse Effects
When compared with its potential benefits in ameliorating the life-threatening effects of ßARA toxicity, the
adverse effects associated with glucagon are minimal.[34] Nausea and vomiting may occur. Therefore, in a
patient with tenuous airway status, consider intubation to protect against aspiration of stomach contents.
Mild, transient hyperglycemia may develop.
Based on available research, multiple case reports, and adverse effects profile, glucagon appears to be a
safe agent alone or in combination with other drugs for the treatment of bradycardia and myocardial
depression. If glucagon fails to restore organ perfusion, the next step is to add a catecholamine.
Catecholamines
Rationale
Beta-adrenergic receptor agonists are a logical therapy for ßARA toxicity. Nevertheless, their use has met
with variable results. A review of 39 cases of overdose in which ß-adrenergic receptor agonists were used as
the primary or sole therapy during resuscitation showed that epinephrine increased the heart rate in 67 per
cent and blood pressure in 50 per cent of cases and isoproterenol did the same in 11 per cent and 22 per
cent, respectively; dopamine increased heart rate and blood pressure in 25 per cent for each.[96] Doses were
not reported, and the number of patients in which individual drugs were evaluated was small. Results may
not have been optimal because of inadequate dosing, because the doses that are required to overcome ß-
adrenergic receptor antagonism are much larger than those recommended in standard Advanced Cardiac
Life Support protocols. For example, in human volunteers, the dose of isoproterenol required to maintain
control-level hemodynamics had to be increased 26-fold after an infusion of labetolol.[79] In a canine model,
the doses of isoproterenol and dopamine had to be increased 15 and 5 times, respectively, to overcome the
hemodynamic effects of 1 mg/kg of propranolol.[12] Several case reports support the efficacy of high doses
of catecholamines. A severely propranolol-toxic patient achieved transvenous pacemaker capture and
elevation of systolic blood pressure to 80 mmHg after receiving 160 to 200 µg/min of isoproterenol.[4]
Another patient required 170 mg of isoproterenol for hemodynamic support in the first 12 hours after
acebutolol, labetalol, and trimipramine ingestion. [57] A patient with combined diltiazem and metoprolol
ingestion required 30 to 100 µg/min of epinephrine to maintain hemodynamic stability.[10]
Agents
The optimal ß-adrenergic receptor agonist should restore blood pressure and improve tissue perfusion.
Epinephrine may be beneficial in raising heart rate and increasing contractility through ß1-receptor
stimulation, as well as augmenting blood pressure through a-adrenergic receptor stimulation.[37] Like
epinephrine, isoproterenol increases myocardial contractility through ß1-receptor stimulation. Because
isoproterenol has weaker a-receptor effects, its overall effect may decrease blood pressure due to ß2
receptor–mediated vasodilation.[37] This may not be detrimental, because vasodilation theoretically improves
blood flow to tissues. Dobutamine, a ß1-selective agonist, has not been studied in this setting. Prenalterol, a
ß1-selective agonist available in Europe, has shown favorable results in a canine model of ßARA toxicity[9]
and in case reports.[58][68]
Dose
When faced with significant ßARA toxicity, epinephrine is the catecholamine of choice. It is best
administered as a constant infusion, beginning with 1.0 µg/min and titrating to maintain organ perfusion.
Potential adverse effects of treatment with epinephrine include dysrhythmia and increased myocardial
oxygen demand, which may be especially deleterious in individuals with atherosclerotic coronary disease.[37]
Phosphodiesterase Inhibitors
Rationale
Phosphodiesterase inhibitors have been used in the management of ßARA toxicity. They inhibit the
breakdown of cyclic AMP, thereby facilitating the maintenance of intracellular calcium levels.[22] In models of
congestive heart failure induced by propranolol, amrinone demonstrated positive inotropic effects,[8] with the
additional benefit of not increasing myocardial oxygen demands.[15][43] However, animal studies using
amrinone to reverse ßARA toxicity are discouraging. In canines receiving a 10 mg/kg bolus of propranolol,
amrinone and milrinone increased cardiac output but had no appreciable effect on heart rate.[62][82] When
administered with glucagon, neither amrinone nor milrinone provided additional benefit.[61][83] Thus, there is
no advantage to amrinone or milrinone over glucagon in reversing toxicity.
Use of aminophylline, another phosphodiesterase inhibitor, was reported in two cases of ßARA
overdose,[4][74] but no conclusions can be made regarding efficacy from these reports.
Atropine
Atropine is safe but frequently ineffective in the management of the bradycardia associated with ßARA
overdose.[4][10][26][45][52][57][74][96] Atropine has been successful in increasing heart rate and blood pressure in
a mildly toxic patient.[1]
Nonpharmacologic Therapy
Transvenous or external electrical pacing may be required to maintain heart rate when pharmacologic
measures fail.[2][4][10][45][81] However, electrical capture is not always successful; and if capture does occur,
blood pressure is not always restored.[65][74][96] Cardiac pacing may be most beneficial in treating the
torsades de pointes associated with sotalol.[94]
Occasionally, extreme means of resuscitation have resulted in successful treatment of patients with severe
toxicity. In a massive propranolol ingestion, extracorporeal circulation resulted in full neurologic recovery
after pacing, catecholamines, and glucagon failed.[65] Aortic balloon pump placement restored blood
pressure in a patient with persistent electromechanical dissociation and ventricular tachycardia due to
propranolol. The patient was maintained on the pump for 48 hours and subsequently had an uneventful
recovery. [52]
After the management of life-threatening problems, gastrointestinal decontamination is initiated to prevent

further systemic drug absorption. A single dose of 1.0 g/kg plain activated charcoal is given to all patients.
Volunteer studies suggest that multiple-dose activated charcoal (MDAC) may be useful in reducing
bioavailability of nadolol, probably by removal from the enterohepatic circulation.[23] Although no clinical
studies of nadolol poisoning have studied MDAC, it has minimal risk, provided that the patient does not have
an intestinal obstruction, perforation, or ileus, or compromised airway. Plain activated charcoal diluted in
water at a dose of 0.5 g/kg may be given every 4 to 6 hours. Gastric lavage may be beneficial before
instillation of charcoal if it can be accomplished within 1 to 2 hours of ingestion.[50] Syrup of ipecac is
contraindicated because ßARA-intoxicated patients may experience a rapid decline in mental status with risk
of aspiration during vomiting.
The use of hemodialysis or hemoperfusion for ßARA poisoning is unstudied in experimental models or in the
clinical setting. Based on previously described pharmacokinetic properties, these modalities are not
expected to effectively remove lipophilic drugs with large Vds. Case reports describe the use of
hemodialysis for atenolol overdose and for combined metoprolol and diltiazem overdose with coincident
patient improvement.[10][81] Effective removal of atenolol is predicted, based on its lower Vd and low degree
of protein binding.
Treatment Endpoints
Reasonable therapeutic endpoints include a heart rate greater than 60 beats per minute, blood pressure of
more than 90 mmHg systolic, and evidence of good organ perfusion (improved level of consciousness or
urine output of 1 to 2 mL/kg/hr). Monitoring of clinical responses requires repeated physical examination,
serial EKGs, and placement of a Foley catheter. Often, more invasive monitoring techniques are required.
Patients with cardiogenic shock may need an arterial catheter to accurately monitor blood pressure and a
Swan-Ganz catheter to monitor pulmonary capillary wedge pressure and cardiac output.


DISPOSITION
Patient disposition depends on the progression of clinical manifestations. Patients who develop altered
mental status, bradycardia, conduction delays, or hypotension should be managed in the intensive care
setting. Overdose patients who present initially without symptoms can be safely discharged to psychiatric
care after an observation period of 8 to 10 hours, provided that they remain asymptomatic with normal vital
signs and EKG, receive gastrointestinal decontamination, and are not expected to develop delayed
complications from sustained-release formulation or co-ingestant drugs.


SEQUELAE
Patients surviving ßARA overdose recover without obvious long-term complications.


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Publishers; 1993:11-26.


Chapter 43 – Calcium Channel Antagonists
JEFFREY A. KLINE
Essentials
• History of ingestion
• Bradycardia or hypotension in a patient with a history of hypertension or heart disease
• Metabolic acidosis with hyperglycemia
• Delayed toxicity after unknown ingestion (with sustained-release products)
INTRODUCTION
Toxicity from organic calcium channel antagonists (CCAs) causes a decrease in mechanical contraction of
heart and smooth muscle. Severe toxicity produces hypodynamic shock, characterized by bradycardia and
hypotension and often accompanied by metabolic acidosis. Because CCAs interfere with normal signaling of
stimulatory hormones in the cardiovascular system, standard cardiotonic and vasopressor treatments for
hypotension often produce ineffective or minimal effects in patients with severe toxicity. Optimal treatment is
best undertaken on an individual case basis, often requiring systematic investigation of drugs and
interventions to search for the best hemodynamic and metabolic response to treatment.


Pharmacology
CCAs are characterized by their chemical structure, which confers selectivity regarding tissue binding and
clinical effects of toxicity ( Table 43–1 ). At therapeutic concentrations, organic CCAs bind to the a-subunit of
the L-type calcium channel, causing the channel to favor the closed state, thereby decreasing calcium entry
during phase II depolarization. At very high concentrations, some CCAs (verapamil) may occupy the channel
canal and prevent calcium from entering the L-channel altogether. In general, however, the term antagonist
is more accurate than blocker for these drugs.[42][62] Pharmacokinetic data of available CCAs are listed in
Table 43–4 .
Table 43-1 -- Relative Vascular Smooth Muscle Selectivity Compared with Negative Inotropic Effect of
Calcium Channel Antagonists in Humans
Class Trade Name Vascular Selectivity *
Phenylalkylamines
Verapamil Calan, Verelan, Isoptin 1.0
Benzothiazepines
Diltiazem Cardiazem, Dilacor 1.0
Dihydropyridines
Nifedipine Procardia, Adalat 10
Amlodipine Norvasc 10
Nicardipine Cardene 100
Isradipine DynaCirc 100
Felodipine Plendil 100
Nisoldipine Baymycard (in United Kingdom) 1000
* Ratio of per cent vasodilation/per cent negative inotropy at 10-7 M in isolated organ studies. A larger index number indicates preferential
smooth muscle relaxation.[3][42]
Table 43-4 -- Pharmacokinetics of Calcium Channel Antagonists

Time to Peak
Time to
Concentration Biotransformation
Name Absorption * Peak Half-Life Elimination
(After Oral †
Toxicity
Administration)
Dihydropyridine Subgroup
Time to Peak
Time to
(After Oral †
Toxicity
Administration)
Elimination 35
hr in healthy
volunteers;
may be
Minimal
prolonged 65
presystemic
Slowly and hr in elderly,
metabolism. Slow Renal: 60%
almost 60 hr in
6–9 hr 6–12 hr but extensive (about 5%
completely hepatic
hepatic metabolism. unchanged)
absorbed. function
Metabolites lack
Amlodipine impairment;
significant activity.
not affected
by renal
function
impairment
Bioavailability Biliary/fecal:
60–65%. 20–25%
Not removed by
hemodialysis
Six metabolites
Renal: 70%
Very well identified with no
2.5–5 hr 6–12 hr Polyphasic (less than
absorbed. significant
unchanged)
vasodilating activity
Biliary/fecal:
Bioavailability Terminal 10% (less than
20%. 11–16 hr 0.5%
Felodipine
unchanged)
Bioavailability
increases
with
concentrated
grapefruit
juice.
Renal: 60–65%
Absorption
1.5 hr Six metabolites Biphasic (none
90%.
unchanged)
Biliary/fecal:
Bioavailability
Early 1.5–2 hr 25–30%
20%.
Isradipine (unchanged)
Time to Peak
Time to
(After Oral †
Toxicity
Administration)
Not likely to be
removed by
Terminal 8 hr hemodialysis
(95% protein
bound)
Vasodilating activity
Renal: 60%
Well of metabolites <1%
0.5–2 hr Biphasic (less than 50%
absorbed. of activity of parent
unchanged)
compound
Nicardipine
Early 2–4 hr
35%. 35%
Terminal 8.6
hr
Regular
release 1 Renal: 80% (as
Liquid-filled
Well hr; No known active metabolite
capsules: 0.5–1 2 hr
absorbed. extended metabolites traces
hr
release unchanged)
3–10 hr
Biliary/fecal:
Bioavailability Procardia XL 6
20% (as
60–75%. hr
metabolites)
Nifedipine
Does not
appear to be
removed by
hemodialysis or
CAPD;
however,
plasmapheresis
may be
beneficial
Rapidly Numerous inactive Terminal: 8–9 Renal (less than
Within 1 hr
absorbed. metabolites hr 1 unchanged)
Bioavailability
13% (peak Earlier, rapid
can be elimination
Biliary/fecal
doubled in rate half-life of
Nimodipine hepatic 1–2 hr
impairment).
Time to Peak
Time to
(After Oral †
Toxicity
Administration)
Unlikely to be
removed by
hemodialysis
(over 95%
protein bound)
18 metabolites;
hydroxylated
Renal: 60–80%
Absorption Immediate isobutyl ester 7–12 hr parent
(little to none
87%. release 1–1.5 hr derivative has 10% drug
unchanged)
pharmacologic
activity.
Nisoldipine
Bioavailability
extended- Extended-
Feces: 6–12%
release 4 to release 6–12 hr
8%
Not removed by
hemodialysis
Benzodiazepine Subgroup
Regular
release
Wide individual Biliary and renal
Well 1–2 hr; By cytochrome P-
variation in IV—3.4 hr (2–4%
absorbed. extended 450.
concentration unchanged)
release
3–5 hr
Desacetyl diltiazem
has one fourth to
one half of the Does not
Cardizem CD coronary dilatation appear to be
Bioavailability 10–14 hr; activity of parent Oral removed by
40% regular release compound (this (biphasic) hemodialysis or
Diltiazem
tablets 2–3 hr metabolite not peritoneal
detected after rapid dialysis
intravenous
administration)
Oral
bioavailability
nonlinear,
increases Cardizem cd
with chronic 5–8 hr
use and
increasing
Time to Peak
Time to
(After Oral †
Toxicity
increasing Administration)
dose.
Diphenylalkylamine Subgroup
Principal metabolite
is norverapamil,
which has 20% of Renal: primarily
Regular
Absorption Regular release the hypotensive Single oral as conjugated
release
90%. tablet 1–2 hr activity of verapamil. dose: 3–7 hr metabolites; 3%
1–2 hr
Eleven other unchanged
metabolites in trace
amounts.
Repetitive oral
dosage:
Extended 4.5–12 hr
Extended release (half-life
release tablets 2–7hr increases
20–35%. 9–16%
5–7hr (can be because of
Verapamil
longer) saturation of
enzyme
systems)
Bioavailability
nonlinear,
increased
Intravenous Not removed by
with chronic
(biphasic) hemodialysis
use and
increasing
dose.
Early: 4 min
Terminal: 2–5
hr
Diarylaminopropylamine Subgroup
17 or more
metabolites; 1 or Renal: 70%
Rapid and Distribution: 2
2–3 hr more with (none
complete. hr
cardiovascular unchanged)
activity
Biliary/fecal:
Bepridil Bioavailability Elimination:
22% (none
60–70%. 42 hr
unchanged)
Time to Peak
Time to
(After Oral †
Toxicity
Administration)
Decline from
peak plasma Not removed by
concentration hemodialysis
occurs rapidly.
From USPDI, Drug Information for the Health Care Professional, 18th ed. Rockville, MD: United States
Pharmacopeial Convention, 1998.
* Many calcium channel blockers are well absorbed but have a lower bioavailability because of first-pass metabolism.
† Biotransformation of current calcium channel blockers is hepatic, extensive, and rapid.
Pharmacokinetics of Long-Acting Preparations
The use of sustained-release and second-generation dihydropyridine CCA preparations is common, and
these long-acting drugs are now involved in the majority of CCA overdoses.[38] These preparations provide a
larger drug dose per tablet (especially in children), can extend the duration of clinical toxicity, and can lead to
a delay in clinical manifestation of toxicity. Drawing from available reports that provide plasma drug levels,
several management guidelines can be asserted for overdose of any long-acting CCA preparation: (1) If
significant toxicity occurs, it will initially manifest within 6 hours of overdose[24][47](although a 12-hour delay in
overt toxicity after a sustained-release verapamil overdose treated with charcoal administration has been
reported)[6]; (2) peak drug levels and associated toxicity will occur within 12 hours of overdose; and (3)
chronic use of the drug will worsen and prolong toxicity.
Pathophysiology
An increase in intracellular calcium causes smooth and cardiac muscle to contract and accelerates impulse
formation in cardiac pacemaker cells. Conversely, a deprivation of intracellular calcium causes smooth
muscle relaxation, a decrease in cardiac contraction, and a slowing of automaticity. Clinically, these effects
are recognized as hypotension, bradycardia, and shock.
Verapamil is the most potent negative inotrope of all CCAs, causing equal depression of heart contraction
and increase in smooth muscle dilation at any concentration. Because these effects are often undesirable in
humans, dihydropyridines were developed to selectively relax smooth muscle at concentrations that produce
less negative inotropy. The dihydropyridine molecule was chemically modified to yield drugs with remarkable
selectivity for vascular smooth muscle relaxation at therapeutic concentrations (see Table 43–1 ). Further
modifications of the dihydropyridine structure led to the development of second-generation drugs that are
more lipid soluble and have longer duration of action (amlodipine, in particular).[1] These drugs appear to
cause a more gradual smooth muscle relaxation, producing less reflex baroreceptor activation and less
reflex tachycardia than is observed with first-generation dihydropyridines.


As described earlier, CCAs generally produce hypotension with a slow heart rate ( Table 43–2 ). In most
cases, CCAs produce bradycardia by decreasing sinus node firing, leading to sinus arrest, with an “escape
rhythm” originating from the atrioventricular node or from a ventricular focus. Patients with severe CCA
poisoning typically manifest heart rates of 45 to 55 beats per minute with no evidence of sinus node
depolarization on a surface electrocardiogram (EKG). Information about the clinical effects of CCA overdose
are drawn largely from case reports and animal studies; as such, precise clinical descriptions of CCA toxicity
do not exist. CCAs do cause a decrease in systemic vascular resistance at all degrees of toxicity. However,
a more variable response occurs regarding overall heart performance with moderate CCA overdose (3–7
mg/kg for nifedipine, 5–10 mg/kg for diltiazem or verapamil).[15][17][18][22][23][24][49][63] Dihydropyridines are
well recognized to produce reflex increases in heart rate with an increase in left ventricular stroke volume,
leading to an increase in cardiac output at therapeutic and moderate toxic doses. Preliminary reports
suggest that all CCAs can increase cardiac output in nonfatal overdoses. [8] This finding has been
experimentally verified in healthy animals as well and has been attributed to physiologic reflexes and
neurohumoral adaptations. [55] With severe overdose, all CCAs exert a negative inotropic effect with
depressed cardiac contraction, conduction block, and hypotension with shock. Importantly, the physiologic
reflexes that can preserve heart function in healthy young patients may be inoperative in patients with
preexisting cardiomyopathy, coronary artery disease, or in the elderly.[9][53][54] Perhaps the greatest
challenge to the clinician is to recognize early which patients will develop refractory cardiogenic shock after
CCA overdose.
Table 43-2 -- Clinical Presentation of Calcium Channel Antagonist Toxicity

Bradycardia with hypotension
Altered mental status (patients may have clear sensorium early in clinical course)
Metabolic acidosis with hyperglycemia
Sinus arrest on electrocardiogram
Refractory shock
Suspect in patients with a history of hypertension or cardiac disease having access to calcium channel blockers
Other clinical manifestations of CCA toxicity stem from organ hypoperfusion and inhibition of metabolic
processes, and these may herald the onset of shock. Many patients provide inaccurate details regarding the
time and amount of ingestion; therefore, the physical examination may provide the best initial evidence of
incipient–severe toxicity. Most patients with significant toxicity are drowsy and asthenic. However, muscular
weakness does not occur from a direct effect of CCAs on skeletal muscle excitation contraction even with
massive overdoses. Mental function is often altered, with behavior ranging from agitation to coma.[48][59]
With shock, cerebral hypoperfusion can cause seizure activity or stroke.[52][53][54][55][56] Pulmonary edema
frequently complicates CCA overdose, sometimes with a normal pulmonary capillary wedge
pressure.[25][26][28][29][30][31][32][33][34][35][36][37] Hypoxemia has also been reported, presumably from
intrapulmonary ventilation-perfusion mismatch.[66] Metabolic acidosis with hyperglycemia has been
described frequently after CCA poisoning and may help differentiate CCA toxicity from toxicity from other
drug ingestions.[6][14][37][38][39][40][41][42][43][44][45][46][58][59] The mechanism of hyperglycemia is likely related to
a suppressive effect of CCAs on pancreatic beta cell insulin release coupled with whole-body insulin
resistance.[11][27]


The combination of hypotension and bradycardia can help differentiate CCA toxicity from hypovolemia,
sepsis, cyclic antidepressant toxicity, and structural causes of shock such as pulmonary embolism or cardiac
tamponade. All of these cause hyperdynamic shock in early stages. The differential diagnosis of
hypodynamic shock is outlined in Table 43–3 .
Table 43-3 -- Differential Diagnosis for Hypotension with Normal or Decreased Heart Rate
Cause Specific Examples
ß-Adrenergic receptor antagonists, calcium channel antagonists, class IA antidysrhythmic
agents (procainamide, quinidine), clonidine, agonal cyclic antidepressant toxicity,
organophosphate and carbamate pesticides, cyanide, hydrogen sulfide, propylene glycol,
Drug toxicity
magnesium overdose, cardiac glycosides (digoxin; digitalis-like glycoside–containing
plants: oleander, fox-glove, lily of the valley; bufadienolides secreted from Bufo species
toads)
Right ventricular myocardial infarction, large anterior left ventricular infarction with
Ischemia
infranodal conduction block
Cellular hypoxia Poisoning with carbon monoxide (severe) or cyanide
Paradoxical Acute peritoneal hemorrhage in young patients (e.g., ruptured ectopic pregnancy),
bradycardia hypothyroidism, hypothermia
Electrophysiologic Heart block from sick sinus syndrome, pacemaker failure, infiltrative cardiomyopathy
The toxicologic differential diagnosis of CCAs includes those pharmaceutical agents that also produce
bradycardia and hypotension in an overdose setting. Examples include digoxin and other cardioglycoside-
containing agents, ß-adrenergic receptor agonists, clonidine, organophosphates, and the type Ia
antidysrhythmic agents such as procainamide and quinidine.


LABORATORY STUDIES
In a patient presenting with a suspected or confirmed CCA overdose, key diagnostic studies include an EKG
and venous blood drawing for electrolyte and renal function determinations. In the symptomatic patient,
serum calcium and potassium levels should be serially monitored. Hypokalemia is frequently observed but
carries little prognostic meaning. However, hyperkalemia suggests severe cellular poisoning and marked
negative inotropy can be expected with hyperkalemia in CCA overdose.[26][43] Hypercalcemia is not caused
by CCA overdose, although hypocalcemia has been reported.[35] If a patient presents with hypotension and
bradycardia, a serum digoxin level should be obtained if concomitant digoxin toxicity is suspected.
Arterial blood gases should be examined to determine the base deficit and to guide the rate of oxygen
delivery and minute ventilation based on PaO 2 and PaCO2 measurements. The shock state from CCA
overdose is characterized by a decrease in left ventricular contractility, hypotension, heart block, and lactic
acidosis. Each of these manifestations can be quantified at the bedside to help gauge the severity of
overdose. Transthoracic echocardiography can estimate the left ventricular ejection fraction as an index of
contractile function. A low PO2 on arterial blood gas analysis reflects poor lung perfusion from low cardiac
output. Compensatory hypocarbia may be seen. An arterial base deficit and elevated lactate concentration
are indices of toxicity. The precise cause of the lactic acidosis remains to be elucidated, but it may occur as
a combination of skeletal muscle hypoperfusion coupled with inhibition of enzymes responsible for
carbohydrate oxidation. This lactic acidosis may be important for diagnostic and therapeutic reasons: (1) a
lactic acid concentration greater than 2.0 mmol/L may portend hemodynamic decompensation, and (2) H+
can antagonize the L-channel, thereby potentiating CCA toxicity.
Individual cardiovascular responses to an equal amount of drug are remarkably variable among
patients.[15][16][21][22][23][49][63] Although plasma concentrations of CCAs correlate well with cardiovascular
depression in the experimental setting,[9][28][40] plasma concentrations in humans show no significant
correlation with the amount of drug reportedly ingested by patients ( Fig. 43–1 ). Moreover, fatal verapamil
overdose has occurred with a peak plasma concentration slightly higher than the high-therapeutic range
(687 ng/mL).[50] Accordingly, a conservative approach to managing patients with suspected CCA overdose
should be taken.
Figure 43-1 Regression analysis applied to 27 cases that reported CCA ingestion amount (x-axis) vs. peak plasma drug level,
measured within 24 hours of ingestion. All cases are either diltiazem (triangles) or verapamil (squares) overdose. There is no
significant correlation between the variables (r = 0.29, p = 0.34). Clinical significance: Plasma CCA concentrations in humans show no
significant correlation with the amount of drug reportedly ingested by patients.


TREATMENT
The initial evaluation of a suspected CCA overdose should proceed in the resuscitation or critical care area
of the emergency department. All patients should undergo appropriate airway management and EKG
monitoring, have supplemental oxygen administered, and have one to two large-bore intravenous catheters
inserted with normal saline infusion begun. A 10- to 20-mL/kg 0.9 per cent bolus should be administered to
otherwise healthy patients with a systolic blood pressure below 90 mm Hg or to patients with a history of
hypertension who demonstrate a systolic blood pressure less than 100 mm Hg. In patients with shock, an
intra-arterial catheter should be inserted for accurate monitoring of blood pressure. A central venous or
pulmonary artery catheter should be inserted in any patient who remains hypotensive after a normal saline
bolus or for any patient with documented congestive heart failure or anuric renal failure who manifests CCA
toxicity.
Treatment of CCA overdose consists of three basic objectives: (1) providing supportive care, (2) decreasing
drug absorption, and (3) augmenting myocardial function with cardiotonic agents. Many patients are alert
and cooperative, give a history of a nontoxic CCA overdose (<3 mg/kg for nifedipine, <5 mg/kg for diltiazem
or verapamil), and demonstrate sinus rhythm with a low normal arterial blood pressure. These individuals
can be closely observed in an intensive care setting without invasive monitoring or airway protection.
Patients who are drowsy or manifest hypotension despite a 15-mL/kg normal saline bolus or show sinus
arrest on an EKG should be managed aggressively, as outlined next.
Supportive care consists of airway protection and management, adequate ventilation, and hemodynamic
monitoring. Endotracheal intubation may prevent pulmonary aspiration during gastric instillation of charcoal
or if vomiting occurs during the administration of glucagon and may improve cardiac output and survival.[5]
The minute ventilation is adjusted to produce a slight respiratory alkalosis (PaCO2 25–30 mm Hg). This will
normalize arterial pH, which, in turn, may reduce negative inotropy. A 7-French central venous catheter
should be inserted to provide a portal for pulmonary artery catheterization and to administer calcium salts,
which are irritating to peripheral veins. A Foley catheter should be inserted to monitor urine production as a
key index of organ perfusion. Experimental verapamil intoxication reduces renal perfusion proportionally to
the reduction in cardiac output.[30][55]
Decontamination
Activated charcoal should be administered after the patient’s airway is secured. In massive overdose,
sustained-release preparations can form gastrointestinal concretions (with ileus), which can persist for days,
rendering charcoal less useful.[45][60] In this situation, whole-bowel irrigation with polyethylene glycol may
accelerate removal of sustained-release CCA pill fragments.[6] CCA elimination half-life is increased in
overdose ( Table 43–4 ), and toxicity from massive overdose can last for days. Drug elimination can be
enhanced by extracorporeal removal. Charcoal hemoperfusion can lower verapamil and diltiazem
concentrations but may be less useful in nifedipine poisoning. [4][50] However, the effect on clinical outcome
is unknown, and extracorporeal technique is seldom used in CCA overdose.
Cardiotonic Drugs
No firm rules dictate the selection and sequencing of cardiotonic agents to treat CCA toxicity. Guidelines are
provided in Table 43–5 . Several basic resuscitation efforts should precede the use of an inotropic agent: (1)
provide a reasonable crystalloid bolus (10–20 mL/kg), (2) correct acidemia (keep arterial pH above 7.30 by
hyperventilation or with sodium bicarbonate infusion), and (3) correct hyperkalemia (>5.0 mEq/L), preferably
with insulin infusion. The clinician should then consider each patient individually. If shock advances despite
treatment with an individual agent, a test bolus of another inotrope should be administered. With massive
overdose, the goal is to provide adequate vital organ perfusion until toxicity resolves. Treatment goals
should focus on stabilization of urine production (1–2 mL/kg/hr), arterial blood pressure, arterial base deficit,
and cardiac output or left ventricular ejection fraction.
Table 43-5 -- Treatment of Calcium Channel Antagonist Toxicity

Ensure airway protection and adequate ventilation and oxygenation, preferably via endotracheal intubation and
mechanical ventilation.
Insert a 7 F central venous “cordis” catheter. Administer a 10- to 20-mL/kg normal saline injection.
Keep arterial pH > 7.30 with hyperventilation and potassium level < 5.0 mEq/L (particularly if considering an
insulin infusion).
Begin electrical pacing for heart rate below 40 beats per minute with shock.
Administer 10 to 20 mg/kg of 1% calcium chloride solution. If favorable response, begin infusion at 20 mg/kg/hr
(monitor ionized calcium, not to exceed two times normal baseline level).
Bolus inject 0.05 to 0.2 mg/kg glucagon. If beneficial, begin 0.1 mg/kg/hr infusion and titrate.
Consider beginning insulin/dextrose bolus/infusion at 1.0 U/kg IV bolus, followed by 1.0 U/kg/hr infusion with 40
mL 50% dextrose/hr).
Monitor glucose hourly.
Monitor potassium.
For Refractory Hypotension
Begin dopamine infusion at 10 µg/kg/min; titrate infusion.
Bolus amrinone at 750 µg/kg and begin 10 µg/kg/min infusion.
Consider intra-aortic balloon counterpulsation treament or extracorporeal cardiopulmonary bypass.
Calcium salts are the first-line treatment of CCA overdose.[51] Calcium chloride should be initiated as a 10-
to 20-mg/kg bolus injection. Calcium chloride may be preferable to calcium gluconate because the calcium
concentration is approximately three times greater, producing more reliable plasma-ionized calcium
concentrations.[69] Calcium chloride is available in a 10-mL, 10 per cent solution, which may be diluted to
100 mL in normal saline and infused over 5 minutes through a central venous catheter as a test bolus in
adults. If this infusion improves heart rate, myocardial conduction, arterial blood pressure, or urine
production, then a constant infusion of calcium chloride at 20 to 50 mg/kg/hr should be initiated. Ionized
plasma calcium concentrations should be maintained between 2.0 and 3.0 mEq/L. It has been argued that
calcium infusion should not continue in the absence of any obvious clinical improvement. This argument
centers on the notion that some CCAs (particularly verapamil) demonstrate “receptor promiscuity” in toxic
concentrations. Consequently, calcium channels in the myocardial sarcoplasmic reticulum may be
antagonized, thereby decreasing diastolic calcium reuptake. Flooding the cell with more calcium, without
improving the dynamics of sarcoplasmic reticular calcium handling, could lead to a less compliant (“stiffer”)
heart that does not fill properly during diastole. Calcium infusion may also cause vomiting, asystole, and
local irritative effects, including upper extremity compartment syndromes.[7] Calcium should not be used if
concomitant cardiac glycoside (e.g., digoxin) toxicity is possible.
If calcium produces an inadequate clinical response, glucagon should be given in a 0.05- to 0.20-mg/kg
bolus infusion. The availability of a newer preparation of glucagon (rDNA origin) with glycerin has eliminated
the previous concern about toxicity from the phenol contained in the diluent. However, if older glucagon
preparations are used, the glucagon should be diluted in normal saline rather than in the diluent provided.
Each vial of diluent contains 2 mg of phenol, and injection of multiple vials can result in phenol toxicity. The
bolus can be repeated at higher doses up to 10 mg. If a benefit is observed,[12][64][70] usually within 5
minutes, a constant infusion of glucagon should be initiated, starting at 0.05 to 0.1 mg/kg/hr. The infusion
rate should be sufficient to maintain sinus rhythm or a systolic blood pressure above 100 mm Hg with urine
production above 1 mL/kg/hr. Vomiting may occur, especially with the initial glucagon bolus, and the
physician must be prepared to manage the airway to avoid aspiration.
Atropine seldom produces any benefit as a sole treatment.[24][47][56][59] However, its administration is
acceptable in the patient initially presenting with bradycardia and hypotension.
Catecholamines are the next treatment for refractory CCA overdose. Dopamine can be used in standard
doses for cardiogenic shock (10–20 µg/kg/min).[47] Other catecholamines such as dobutamine and
isoproterenol have been used in cases and in animal studies with variable success.[19][56][65] Epinephrine
has also shown benefit in CCA-intoxicated humans and animals.[18][29][56] However, a recent clinically
relevant canine study of verapamil toxicity demonstrated that epinephrine worsened myocardial function and
did not improve survival compared with saline treatment.[31]
The phosphodiesterase inhibitor amrinone has successfully treated refractory CCA hypotension.[12][19][70]
Amrinone requires a loading bolus of 750 µg/kg followed by a constant infusion at 1 to 20 µg/kg/min.
High-dose regular insulin infusion has proven beneficial in two models of verapamil toxicity.[28][29][30][31]
Insulin apparently improves myocardial mechanical efficiency and contractility by accelerating carbohydrate
oxidation. Insulin bolus does not produce an immediate sharp improvement in hemodynamicindices but,
instead, slowly but steadily improves heart contraction with infusion. Insulin has no direct effect on
conduction but may lower plasma potassium concentrations, thereby indirectly improving automaticity and
conduction.
The efficacy of insulin in improving outcomes in CCA toxicity remains unknown, but it has been used in five
severely toxic human cases, all of whom survived.[71] These patients received multiple treatments,
confounding evaluation of insulin’s effect. If insulin is used as an adjunctive therapy for suspected massive
overdose, it is most effective when administered before profound hypodynamic shock supervenes. A regular
insulin bolus of 1.0 U/kg should be given, followed by an infusion of 1.0 U/kg/hr for the first hour, followed by
0.5 U/kg/hr until toxicity resolves.[10][71] Depending on the severity of overdose, resistance to insulin-
mediated glucose clearance may be significant. In general, adults require 20 to 30 g of glucose per hour to
maintain euglycemia with high-dose insulin infusion. Serum potassium and glucose levels should be
monitored during and after the insulin therapy is stopped. Hourly bedside glucose determinations revealed
hypoglycemia during and after insulin treatment in the five cases discussed earlier.[71] Intravenous dextrose
easily corrected the hypoglycemia.
Rescue Treatments
For patients with cardiogenic shock that is refractory to the above treatments, several options remain open.
Electrical cardiac pacing may help restore heart rate and should be considered for patients with shock and a
heart rate below 40 beats per minute. During CCA toxicity, the heart should not be paced above 60 beats
per minute. At the level of the heart cell, CCAs delay both systolic calcium transients and diastolic calcium
reuptake. The heart cell cannot be forced into normal rhythmicity with electrical depolarization. In fact,
ventricular stroke volume tends to be maximized at a heart rate of 45 to 50 beats per minute. Pacing faster
than this rate may actually reduce stroke volume. As a result, electrical pacing may fail to improve cardiac
output.
4-Aminopyridine is now available (for the treatment of multiple sclerosis) and, based on several animal
studies of verapamil toxicity, should be considered for a patient who is dying despite all efforts.[2][61]
Intra-aortic balloon counterpulsation has also been reported to improve shock from verapamil
poisoning.[41][68] Extracorporeal cardiopulmonary bypass may also provide a bridge to survival, especially if
used in conjunction with hemodialysis or hemoperfusion.[20]


DISPOSITION
In symptomatic patients or those presenting asymptomatic early in their clinical course after ingestion of a
long-acting agent, admission to a monitored setting for 24 hours of observation is recommended. Because
the majority of CCA overdoses involve long-acting agents,[38] these preparations can extend the duration of
clinical toxicity and can lead to a delay in clinical manifestation of toxicity. If significant toxicity occurs, it will
initially manifest within 6 hours of overdose[24][47] (although 12-hour delays in overt toxicity have been
reported).[6] In addition, chronic use of these drugs can worsen and prolong toxicity. In those symptomatic
patients presenting with hemodynamic compromise, admission to an intensive care setting is essential.


SEQUELAE
Toxicologic morbidity and mortality from CCAs can be significant, particularly in patients presenting late in
their clinical course. If the patient survives, it does not appear that severe CCA toxicity causes any residual
cardiomyopathy or central nervous system dysfunction from direct drug effect.


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Chapter 44 – Digitalis Glycosides
CHRISTOPHER H. LINDEN
Essentials
• Toxic effects of digitalis glycosides (DGs) involve the central nervous system (CNS) and gastrointestinal
(GI) tract as well as the cardiovascular system (CVS).
• Cardiac dysrhythmias, including both tachydysrhythmias and bradydysrhythmias, are the hallmark of
severe DG poisoning.
• Markedly elevated serum digoxin and potassium levels are characteristic of DG poisoning due to acute
overdose, whereas digoxin levels may be minimally elevated or even “therapeutic” and the potassium
level is typically low or normal in chronic toxicity due to excessive therapeutic dosing.
• Drug levels require correlation with clinical and electrocardiographic findings.
INTRODUCTION
Digitalis and digitalis-like cardiac glycosides (DGs) are found in a variety of plants, toads, and
pharmaceuticals ( Table 44–1 ).[9][24][27][29] Extracts and dried powders from these sources have been used
for centuries as medicinal agents and as arrow and ordeal poisons. Although DGs are present in all plant
parts, concentrations vary: they are highest in the leaves of foxglove; the aerial parts and flower buds of lily-
of-the-valley; the seeds, bark, and roots of oleander; the bulbs of squill; and the seeds of strophanthus. In
toads such as the cane toad and Colorado River toad, DGs are produced and secreted by specialized skin
glands.
Table 44-1 -- Natural Sources of Digitalis Glycosides *

Scientific Name
(Genus and
Family Species) Common Name Glycoside(s)
Plants
Apocyanaceae Acokanthera Ouabain, strophanthin G
schimperi
Apocynum Dogbane Apocannoside, cymarin
cannabinum
Nerium indicum Sweet-scented Unknown/unnamed
oleander
Nerium oleander Bay laurel, oleander Oleandrin
Scientific Name
(Genus and
Strophanthus Ouabain, strophanthins
species
Tanghinia Ordeal tree Unknown/unnamed
venenifera (Madagascar)
Theyetia Yellow oleander Thevetin, thevetoxin
nereifolia
Asclepias
Asclepiadaceae Milkweed Unknown/unnamed
curassavia
Tecomella
Bignoniaceae Tecomin
undulata
Brassicaceae Cheiranthus cheiri Wallflower Cheiranthin
Selenicereus
Cactaceae Night-blooming cereus Unknown/unnamed
grandifloris
Convallaria
Lily-of-the-valley Convallotoxin
majalis
Ornithogalum
Star of Bethlehem Convallotoxin, convalloside
umbellatum
Lilliaceae
Urginea(aka
Indian squill Scillaren A and A
Scilla) indica
Mediterrranean (red or
Urginea maritima Scillaren A and B
white) squill, sea onion
Adonis vernalis Pheasant’s eye Adonitoxin, cymarin, strophanthin K
Ranunculaceae
Helleborus niger Christmas rose Hellebrin
Digitalis lanata
Grecian floxglove Deslanoside, digoxin, lanatosides
Serophulariaceae (aka lantana)
Digitalis purpurea Purple floxglove Digitoxin, gitalin, gitoxin
Toads
All Bufo toads contain bufodenalides or
bufogenines (e.g., bufalin, bufotalin,
Bufo alvarius Colorado River toad cinobufagin, cinobufotalin, resibufogenin);
amounts vary by species, maturity, and
environmental factors
B. bufo-bufo European toad
B. californicus Asian toad
B. formosus
Scientific Name
(Genus and
Bufonidae B. gargarizans
Chinese toad
(aka asiaticus)
American tropical
toad; cane toad;
B. marinus
marine toad; giant
toad
Common European
B. melanosticus
toad
B. viridis
B. vulgaris
* Partial listing. Other species from these genera may also contain similar glycosides.
Although digitoxin and ouabain are still available, digoxin is the most widely prescribed drug of this class in
the United States. Digitoxin and other DGs, in both crude and purified formulations, may be used
therapeutically in other countries or for experimental purposes. Although most medicinal preparations are
derived from plants, Chinese “chan su” consists of dried toad venom. It is identical to the hard, brown,
resinous, gravel-sized material known as stone, black stone, love stone, love rock, and rock hard marketed
as a topical aphrodisiac in New York City. [6] Toad venom is also a component of the Chinese medications
“chu an wu,” “kyushin,” and “yixin wan” and the Japanese medication “sensu.”
DGs consist of a steroid (cyclopentanoperhydrophenanthrene) nucleus with an unsaturated lactone ring

attached to C17 and up to four sugar residues (glycosides) attached to C3. Removal of the glycoside(s)
leaves an aglycone or genin that is structurally similar to bile acids, adrenocortical and sex hormones, and
endogenous sterols. DGs with five- and six-membered lactone rings are also known as cardenolides and
bufadienolides, respectively.
The majority of plants contain cardenolides, whereas toad venom, squill, and the Christmas rose contain
bufadienolides. Bufadienolides in toad venom do not have attached sugars. Toad venom also contains
cardioactive catecholamines (e g., dopamine, epinephrine, and norepinephrine) and hallucinogenic
indolalkylamines (e.g., bufotenin, bufotenidin, and bufoviridin).[25] Bufotenin, for example, is an isomer of
pscilocin. Both are structurally related to the neurotransmitter serotonin (5-hydroxytryptamine).


PHARMACOLOGY AND PATHOPHYSIOLOGY
Pharmacokinetics
Pharmacokinetic data is generally available only for DGs of therapeutic importance.[3][18][28][30]

Gastrointestinal absorption appears to result from passive diffusion. Because the rate and completeness of
absorption are inversely related to molecular polarity, digoxin and ouabain, which are more polar than
digitoxin, are less rapidly and less completely absorbed. Absorption also depends on pill dissolution rate,
which tends to be slow and varies by manufacturer and formulation. Bioavailability is 60–85 per cent for
most oral and intramuscular digoxin preparations and approaches 100 per cent for oral digitoxin, intravenous
administration, and the liquid-filled capsule formulation (Lanoxicap) of digoxin.
Absorption may be decreased by agents and conditions that lead to malabsorption or increased GI motility
and increased by agents and conditions that decrease GI motility or inhibit gut flora ( Table 44–2 ).
Metabolism of digoxin to inactive products by gut flora can sometimes decrease bioavailability by 30–40 per
cent. Use of antibiotics that alter gut flora can cause increased bioavailability with resultant toxicity.
Table 44-2 -- Pharmacokinetic Interactions Involving Digitalis Glycosides

Nature of Interaction Causes DG Affected *
Decreased GI absorption Activated charcoal Dg, Dt
Alkylating agents Dg
Aminoglycosides Dg
Antacids Dg
Cholestipol Dg
Cholestyramine Dg, Dt
Cyclophosphamide Dg
Doxorubicin Dg
Food Dg
Kaolin-pectin Dg
Metoclopramide Dg
Procarbazine Dg
Sucralfate Dg
Sulfonamides Dg
Sulfasalazine Dg
Vancomycin Dg
Vincristine Dg
Anticholinergics Dg
Diphenoxylate Dg
Increased GI absorption Erythromycins Dg
Omeprazole Dg
Tetracyclines Dg
Clofibrate Dt
Heparin Dt
Phenobarbital Dt
Phenylbutazone Dt
Phenytoin Dt
Decreased protein binding
Prazosin Dt
Procainamide Dt
Sulfonamides Dt
Tolbutamide Dt
Warfarin Dt
Amiodarone Dg
Captopril Dg
Decreased tissue binding
Quinidine Dg
Reserpine Dg
Increased tissue binding Hypokalemia Dg, Dt
Decreased volume of distribution Advanced age Dg, Dt
Amiodarone Dg
Cyclosporin Dg
Hypothyroidism Dg, Dt
Quinine Dg
Renal failure Dg, Dt
Verapamil Dg
Infants Dg, Dt
Increased volume of distribution
Neonates Dg, Dt
Alprazolam Dg
Decreased metabolism Flecainide Dg
Hyperthyroidism
Aminoglutethimide Dt
Barbiturates Dt
Ethambutol Dt
Increased metabolism Isoniazid Dt
Phenytoin Dg
Rifampin Dg, Dt
Spironolactone Dt
Cholestipol Dg
Decreased enterohepatic circulation Cholestyramine Dg, Dt
Verapamil Dg
Advanced age Dg
Alprazolam Dg
Amiodarone Dg
Captopril Dg
Cyclosporine Dg
Decreased renal excretion Diltiazem Dg
Guanethidine Dg
Indomethacin Dg
Quinidine Dg, Dt
Spironolactone Dg
Trimethoprim Dg
Hydralazine Dg
Hyperthyroidism Dg
Increased renal excretion
Levodopa Dg
Nitroprusside Dg
* Dg = digoxin; Dt = digitoxin.
DGs are bound to plasma proteins (primarily albumin). Because polarity also influences protein binding,
digoxin is bound to a lesser degree than digitoxin (25 per cent versus 97 per cent). Agents that are highly
protein bound may displace digitoxin from serum proteins and increase free (i.e., active) drug levels (see
Table 44–2 ).
DGs are widely distributed in body tissues. The highest concentrations are found in muscle. Myocardial
concentrations are about 30 times higher than serum levels. The distribution of DGs conforms to a two-
(possibly three-) compartment model. Their initial apparent volume(s) of distribution (Vd) are quite small and
representative of plasma water and extracellular fluid along with highly vascular tissue. Peak serum
concentrations occur within minutes of an intravenous dose and 1–2 hours after an oral dose. The final Vd is
very large for ouabain (14–18 L/kg) and for digoxin (5–7.3 L/kg in adults), rendering hemodialysis relatively
ineffective in removing these glycosides. It is small for digitoxin (0.5–0.73 L/kg). Volumes of distribution are
higher in infants and neonates and lower in the elderly (owing to decreased muscle mass), those with renal
failure and hypothyroidism, and those taking a variety of drugs (see Table 44–2 ). Tissue distribution is slow;
it takes 6–12 hours for blood and tissue DG levels to equilibrate. Digoxin crosses the placenta; fetal drug
levels approach those of the mother.
DGs are eliminated by hepatic metabolism as well as by urinary excretion of unchanged drug. The more
polar digoxin is predominantly (60–80 per cent) eliminated by urinary excretion, whereas digitoxin is
predominantly eliminated by hepatic metabolism. About 8 per cent of digitoxin is metabolized to digoxin.
Elimination follows first-order kinetics. The elimination half-life of digoxin is about 36 hours, whereas that of
digitoxin is 5–7 days. Inactive products of hepatic metabolism (i.e., glucuronide and sulfate conjugates) are
excreted in the bile and urine. Enterohepatic recirculation appears to be responsible for the long half-life of
digitoxin.
The half-life of digoxin is increased in those with impaired renal or hepatic function. Digitoxin elimination may
be prolonged in those with impaired hepatic function. Diuresis does not appreciably enhance the elimination
of digoxin, but it may increase the elimination of digitoxin. Drugs and conditions that affect renal or hepatic
function may also alter the elimination of DGs (see Table 44–2 ).
Pharmacodynamics
Pharmacodynamic data are well characterized only for digoxin and digitoxin. [18][28][30] Digoxin is available as
a 50 µg/mL elixir; 50, 100, and 200 µg liquid-filled capsules; 125, 250, and 500 µg tablets; and 100 µg/mL
and 250 µg/mL solutions for parenteral administration. Digitoxin is available as a powder and in 100 µg
tablets.
Digoxin is more potent than digitoxin. Because of their long half-lives, it takes many days for digoxin and
several weeks for digitoxin (i.e., four to five half-lives) to achieve steady-state levels unless a loading
(digitalizing) dose is given. And because of their slow distribution, levels obtained within 6–12 hours of drug
administration do not reflect tissue levels and hence do not correlate with effect. Maximal (ceiling) effects on
cardiac contractility occur at lower levels (about 1.5 ng/mL for digoxin) than those necessary for controlling
the ventricular rate in atrial flutter or fibrillation. Supratherapeutic drug levels (as high as 4 mg/mL for
digoxin) may sometimes be required for rate control.
In undigitalized patients, the onset of effects occurs within 30 minutes of a parenteral loading dose and
within 2 hours of an oral loading dose. Peak effects are noted at 1–5 and 4–12 hours, respectively. Effects
may persist for 3–4 days after withdrawal of digoxin therapy and 3–4 weeks after stopping digitoxin.
A variety of factors may affect dose-response and concentration-effect relationships ( Tables 44–3 and 44–4
). [18][28][30][34][36][38][41] Those that increase the effect of DGs may result in clinical toxicity occurring at
therapeutic doses and drug levels. Hypokalemia and hypomagnesemia are the most common and readily
correctable causes of such toxicity. Not only does hypokalemia potentiate the electrophysiologic effects of
DGs, it increases their tissue binding and decreases their renal tubular excretion. Magnesium is important
because it blocks calcium channels and modulates sympathetic activity. Hypoxia has a variable effect: by
blocking impulse formation, it may decrease tachydysrhythmias owing to increased automaticity; by
impairing conduction, it may increase bradydysrhythmias and re-entrant tachydysrhythmias.
Table 44-3 -- Pharmacodynamic Interactions Involving Digitalis Glycosides

Underlying Mechanism Causes
Increased DG Effect
Advanced myocardial disease
Acid-base disturbances
Active myocardial ischemia
Disease/conditions
Chronic obstructive pulmonary disease
Extremes of age
Hypothyroidism
Hypercalcemia Calcium salts
Amphotericin B
ß-Adrenergic agonists
Corticosteroids
Hypokalemia Glucagon/glucose/insulin
Laxatives
Loop diuretics
Thiazide diuretics
Hypomagnesemia Diuretics
Decreased DG Effect
Captopril
Hyperkalemia Potassium salts
Potassium-sparing diuretics
Hyperphosphatemia
Hypocalcemia
Hypoparathyroidism
Variable Effect
ß-Adrenergic receptor antagonists
Underlying Mechanism Causes
Bretylium
Guanethidine
Decreased sympathetic tone
Halothane
Methyldopa
Reserpine
ß-Adrenergic receptor agonist bronchodilators
Reserpine
Increased sympathetic tone Succinylcholine
Sympathomimetics
Theophylline
Decreased vagal tone Anticholinergic agents
Increased vagal tone Cholinergic agents
Impaired excitability Hypoxemia
Table 44-4 -- Interactions with Digitalis Glycosides Which Occur by Undefined Mechanisms
Causes Drugs Affected *
Increased DG Effect or Level
Calcium-channel blockers Dg, Dt
Cimetidine Dg, Dt
Itraconazole Dg
Neuromuscular blocking agents Dg, Dt
Nonsteroidal anti-inflammatory agents Dg, Dt
Prazosin Dg
Propafenone Dg
Quinine Dg
Reserpine Dg
Sulfonylureas Dg
Tamoxifen Dt
Trazodone Dg
Decreased DG Effect or Level
Penicillamine Dg
* Dg = digoxin; Dt = digitoxin.
Pathophysiology
DGs have multiple mechanisms of action and effects on cardiovascular function.[16][18][28] Only those actions
and effects thought to be of clinical significance will be discussed here. In patients with heart failure,
therapeutic doses of DGs increase the force and velocity of myocardial contraction (i.e., contractility),
primarily by increasing the availability of cytosolic calcium ions (Ca 2+ ) to the contractile proteins actin and
myosin in the sarcoplasmic reticulum. This increased calcium availability enhances excitation-contraction
coupling during systole through the normal sarcolemmal exchange of Ca2+ for sodium ions (Na+) and the
ability of DGs to bind to and reversibly inhibit sodium, potassium adenosine triphosphatase (Na+, K+-
ATPase). Na+, K+-ATPase is the sarcolemmal enzyme that maintains the resting membrane potential by
actively transporting Na+ out of cardiac muscle cells in exchange for K+. Inhibition of this enzyme results in
increased intracellular Na+, enhanced membrane cycling of Na+ and Ca2+ , and increased intracellular Ca2+
available for uptake and release by the sarcoplasmic reticulum. Increased intracellular Ca2+ may also trigger
spontaneous calcium influx and release, resulting in transient late depolarizations (afterdepolarizations) and
enhanced automaticity.
DGs also act on vascular smooth muscle and on the nervous system. In patients with heart failure,
vasodilation results from increased vagal activity (via cholinergic inhibition of norepinephrine release at
adrenergic-smooth muscle junctions) and decreased sympathetic nervous system tone (via inhibition of
sympathetic outflow from the CNS and by enhancing baroreceptor sensitivity). Decreased afterload and
improved cardiac function are the beneficial results. DGs also reflexively blunt the neurohumoral
sympathetic activation (i.e., increased norepinephrine, renin, and vasopressin levels and resultant increases
in heart rate, contractility, systemic vascular resistance, and salt and water retention) that accompanies heart
failure by their direct effects on contractility.
In toxic amounts or with rapid administration, DGs may cause vasoconstriction as a result of increased
intracellular Ca2+ and stimulation of vasomotor centers in the area postrema of the medulla. Adverse GI
effects also appear to be centrally mediated. CNS toxicity is probably due to inactivation of Na+, K+-ATPase,
resulting in altered ionic transfer across excitable neuronal membranes with consequent membrane
irritability and instability. Adverse GI and CNS effects can occur at therapeutic as well as toxic doses.
Gynecomastia, which may occur during chronic therapy, may be due to a direct estrogenic effect or to
altered estrogen metabolism secondary to coexistent heart failure.
The electrophysiologic effects of DGs are due to their indirect action on the autonomic nervous system as
well as their direct actions on cardiac muscle, pacemaker, and conduction cells. At therapeutic doses, DGs
decrease automaticity and conduction velocity through the AV node primarily as a consequence of their
indirect sympatholytic and vagotonic effects. Vagotonic effects result from cholinergic activation of K+
currents and inhibition of Ca2+ currents and include membrane hyperpolarization, decreased atrial action
potential (AP) duration (due to shortening of the plateau or phase of the AP), and prolongation of the
effective refractory period (ERP) of the AV node.
Direct effects include reduction of the AP duration, prolongation of the ERP, and reduction (of the negativity)
of the resting membrane potential of the AV node (resulting in decreased amplitude and decreased rate of
rise of the AP). These actions are probably due to inhibition of Na+, K+-ATPase with subsequent changes in
Na+, K+, and Ca2+ concentrations and currents. Shortening of the AP duration is usually accompanied by an
increase in the slope of phase 4 (spontaneous diastolic) depolarization and enhanced automaticity of the
sinoatrial (SA) node, effects that are directly related to the intracellular Ca2+ concentration and inversely
related to the intracellular K+ concentration.
On the electrocardiogram (EKG), therapeutic effects may be manifest by prolongation of the P-R interval,
shortening of the Q-T interval, scooping and depression of the ST segment, and decreased amplitude of the
T wave. Effects on AV node conduction are generally apparent only when the atrial rate is rapid because, at
normal rates, the node has sufficient time to recover between beats. Similarly, because direct effects on the
SA node are offset by indirect effects, changes in the heart rate are negligible.
In contrast, at toxic doses, DGs directly depress SA node automatically and conduction at the AV node.
They also increase sympathetic activity and intracellular Ca2+ , resulting in an increase in automaticity and
afterdepolarizations. Increased automaticity and afterdepolarizations which reach the AP propagation
threshold may result in triggered tachydysrhythmias. Because effects on automaticity and conduction in
muscle, nodal, and conducting cells are nonuniform, they also promote the development of re-entrant
tachydysrhythmias. Following acute DG overdose, inhibition of NA+, K+-ATPase may result in increased
extracellular K+ (i.e., hyperkalemia).


DG poisoning may be acute or chronic.[4][11][13][22][23][36][39] Acute poisoning most frequently occurs in adults
following the suicidal ingestion of a single large dose of drug. It may also result from unintentional ingestion
in children. Intentional self-poisoning with intravenous digoxin has been reported. Acute poisoning, both
accidental and intentional, can also result from the consumption of plants containing DGs, extracts,
medicinals, or teas prepared from such plants,[2][33][35][42] toad toxins, or the licking of toads. [8][14][25][50] Toad
toxin exposure may result in cardiovascular toxicity from catecholamines as well as DGs. An epidemic of
poisoning in homosexual men occurred when an aphrodisiac product containing toad toxins and intended for
topical use was ingested.[6] The recreational licking of live toads in order to achieve a hallucinogenic effect is
most prevalent in the Southeastern U.S. and is primarily a practice of teenagers. Poisoning from teas is most
common in the elderly who mistake a toxic species for an edible one.
Chronic poisoning is more common than acute poisoning and typically develops in patients who are
receiving DGs for therapeutic purposes. Although rates were much higher 10 to 20 years ago, it currently
occurs in about 1 per cent of both outpatients and inpatients treated with digoxin.[37][46] Chronic poisoning
may result from excessive maintenance dosing, therapeutic substitution of one formulation or brand for
another, intercurrent illness or disease (see Tables 44–2 and 44–3 ), or a variety of drug interactions (see
Tables 44–2 , 44–3 , and 44–4 ). Impaired renal function is the most common underlying cause. The elderly,
who may have reduced renal function despite normal blood urea nitrogen (BUN) and creatinine levels, are at
greatest risk.[49] Whether or not there are age-related differences in the clinical manifestations of chronic
toxicity is unclear. Chronic poisoning may also result from self-therapy with herbal or medicinal preparations
containing DGs.
Manifestations of DG poisoning involve the CNS, GI tract, and CVS ( Table 44–5 ).[22][23][36][39] As described
by William Withering in 1785,[48]
The foxglove, when given in very large and quickly repeated doses, occasions sickness,
vomiting, purging, giddiness, confused vision, objects appearing green or yellow, increased
secretion of urine with frequent motions to part with it and sometimes inability to retain it, slow
pulse, even as low as 35 in a minute, cold sweats, convulsion, syncope, death.
Table 44-5 -- Manifestations of Digitalis Glycoside Toxicity *

Level of consciousness: confusion, lethargy, delirium, coma, convulsions
Psychiatric: depression, emotional lability, unusual dreams, hallucinations (visual), psychosis
Visual: chromatopsia, decreased acuity, photopsia, diplopia, scotomata, retrobulbar neuritis
Other: dizziness, fatigue, headache, malaise, weakness, paresthesias, vertigo, aphasia, facial neuralgia
Gastrointestinal
Anorexia, weight loss, nausea, abdominal pain, vomiting, diarrhea
Nonspecific: Diaphoresis, lightheadedness, pallor, palpitations, shortness of breath, syncope
Bradydysrhythmias: First-degree AV block; sinus bradycardia; sinus arrest or exit block; Mobitz I second-
degree AV block (Wenckebach); asystole
Tachydysrhythmias: ventricular premature beats (unifocal or multifocal; bigeminy, trigeminy); atrial premature
beats; junctional (nonparoxysmal) tachycardia; ventricular tachycardia (monomorphic, polymorphic, or
bidirectional); ventricular fibrillation; fascicular tachycardia
Both: atrial fibrillation or flutter with a slow ventricular rate or third-degree AV block; nonconducted atrial
premature beats; paroxysmal atrial tachycardia with second- or third-degree AV block; wandering atrial
pacemaker; junctional tachycardia with fixed or variable exit block; bidirectional ventricular tachycardia
Uncommon: increased congestive heart failure, mesenteric ischemia
Miscellaneous
Gynecomastic (chronic use); hyperkalemia (acute overdose), allergic reactions (rare)
* Manifestations are listed in order of decreasing frequency within each category.
Depending on the criteria used for the diagnosis of poisoning, extracardiac symptoms occur in 10–95 per
cent of patients, and cardiac dysrhythmias are present in 40–90 per cent. Worsening of congestive heart
failure may be the initial manifestation in up to 8 per cent. Although extracardiac symptoms, especially CNS
symptoms, often precede the development of cardiotoxicity, dysrhythmias may be the first sign of toxicity in
33–50 per cent.
The recognition of poisoning in those with subtle and nonspecific extracardiac symptoms prior to the onset
of cardiotoxicity remains a diagnostic challenge.[4][17] Many of the more pronounced CNS and GI symptoms
(see Table 44–5 ) are nonspecific and can be mistakenly attributed to other conditions. In contrast, visual
symptoms are relatively specific for DG poisoning.[7] They are occasionally the sole manifestation of
intoxication. Chromatopsia, the subjective perception of color, is most frequent for yellow and green but can
occur for red, brown, or blue. It can be objectively measured by color vision testing. Vision also may be
described as blurred, dim (amblyopia), or frosted. Photopsia, the perception of light that is not present, is
characterized by the presence of innumerable points of light in the peripheral visual fields and is typically
described as white borders or halos around dark objects.
Cardiovascular signs and symptoms are also nonspecific. EKG manifestations may include
bradydysrhythmias, tachydysrhythmias, or both (see Table 44–5 ). Rapid atrial fibrillation or flutter, sinus
tachycardia, and multifocal atrial tachycardia are inconsistent with DG poisoning, but almost any other
dysrhythmia may be seen.[12][31] Mobitz II second-degree AV block, paroxysmal atrial or nodal tachycardia,
ventricular parasystole, idioventricular tachycardia, and infranodal block are consistent but unlikely.
DG poisoning should be suspected in any patient taking DGs who has a normal or fast heart rate that
becomes slow, a normal heart rate that becomes fast, an irregular rhythm that becomes regular, or a
regularly irregular rhythm.[47] Nonparoxysmal junctional tachycardia with a ventricular rate greater than 70
beats per minute and the simultaneous occurrence of tachydysrhythmias and bradydysrhythmias are highly
suggestive for DG poisoning. Bidirectional ventricular tachycardia, which is a wide complex tachycardia with
a right bundle-branch morphology and alternating polarity of the QRS complex in the limb leads, may be
specific for DG poisoning. It may result from two ectopic ventricular foci, an ectopic left bundle-branch focus
with an alternating fascicular block, or junctional tachycardia with bigeminy. [31] Bundle-branch block with
bigeminy and polymorphic ventricular tachycardia may be confused with this extremely rare dysrhythmia.
Poor prognostic factors following acute poisoning include age greater than 55 years, male sex, underlying
heart disease, high-degree AV block, especially if associated with severe bradycardia (less than 40 beats
per minute), and a potassium level above 5.5 mEq/L.[39] With the exception of sex and hyperkalemia, these
conditions are probably also risk factors in chronic poisoning. The presence of renal failure, electrolyte
abnormalities, hypoxia, and acid-base derangements are additional considerations.
SDLs must be interpreted with caution (see discussion under Laboratory Studies). At a minimum, the
diagnosis of DG poisoning requires that clinical toxicity be present and that the reported SDL be consistent
with the history and clinical findings. Ultimately, the diagnosis is confirmed by excluding other etiologies and
observing the resolution of toxicity upon termination of exposure (with time) or after the administration of
specific (i.e., antidotal) therapy.
Inappropriate timing of blood sampling for SDL measurement is a common cause of diagnostic confusion.
SDLs obtained during the distribution phase (i.e., within 6–12 hours of a therapeutic dose and probably up to
24 hours following overdose) do not accurately correlate with toxicity. During this time, elevated SDLs may
be seen in the absence of poisoning. This is particularly true after acute poisoning when patients may have
markedly elevated SDLs (e.g., up to 50 mg/mL for digoxin) despite being relatively asymptomatic.
Pharmacodynamic variability (i.e., individual differences in susceptibility to drug effects) must also be
considered when interpreting SDLs. As a general rule, the higher the post-distribution SDL, the greater the
likelihood of toxicity.[26] Most patients will exhibit symptoms and signs of poisoning at digoxin levels of 3–4
ng/mL. Some patients, however, particularly those with rapid atrial fibrillation or flutter, may require a “toxic”
drug level for a therapeutic effect. Other patients will exhibit toxicity at “therapeutic” levels, particularly if they
have conditions or diseases that increase the effects of DGs (see Table 44–3 ).
Acute Versus Chronic Toxicity
Acute and chronic poisoning differ in a number of respects.[4][11][13][22][23][36][39] Patients with acute (oral)
overdose are typically asymptomatic on presentation. They may develop extracardiac symptoms within an
hour or two of ingestion, but cardiac effects do not usually develop until 6 or more hours after ingestion. In
contrast, with chronic poisoning extracardiac effects typically have been present for days or weeks, and
patients often present with signs and symptoms of dysrhythmias as well as extracardiac toxicity. Life-
threatening dysrhythmias usually occur within 24 hours of acute digoxin overdose and within 5 days of acute
digitoxin overdose but can occur at any time during chronic therapy.
Bradydysrhythmias are typically seen after acute overdose whereas tachydysrhythmias are more common in
chronic poisoning. Because acute poisoning most often occurs in children and young adults, whereas
chronic poisoning usually occurs in older patients, it is unclear whether this finding relates to the acuity of
poisoning or to the presence or absence of underlying cardiac disease.
The serum potassium may be high in patients with acute poisoning but is normal or low in those with chronic
poisoning (depending on the concomitant use of diuretics). In the setting of acute overdose, the degree of
hyperkalemia reflects the effect of DGs on target enzymes and may correlate with clinical toxicity more
accurately than drug levels.[5] Serum drug levels (SDLs) are usually markedly elevated in acute poisoning
but minimally elevated or even therapeutic in chronic poisoning. The half-life of digoxin may be shortened
following acute overdose[15] but appears to be unchanged in chronic poisoning.


A variety of diseases and intoxications can cause DG-like cardiotoxicity and visual disturbances ( Table
44–6 ). All these conditions must be considered in the differential diagnosis of DG poisoning in elderly
patients and in those with underlying cardiovascular disease, whereas other intoxications are the main
consideration in young, otherwise healthy individuals. As might be expected, most plants and drugs in the
differential diagnosis exert their cardiotoxic effects by actions on sodium channels, calcium channels, or the
autonomic nervous system. In contrast, visual disturbances are most often due to the direct effect of disease
or drugs on the cornea, lens, retina, or optic nerve. Monocular symptoms are almost always due to intrinsic
eye disease, whereas binocular symptoms suggest systemic disease or intoxication.
Table 44-6 -- Differential Diagnosis of Digitalis Glycoside Poisoning

Cardiotoxicity
Diseases/disorders
Cardiomyopathy
CNS hemorrhage/ischemia
Electrolyte abnormalities
Myocardial ischemia/infarction
Myocarditis
Pericarditis
Pheochromocytoma
Pre-excitation syndromes
Thyroid dysfunction
Drugs/chemicals
Bradydysrhythmias
Alpha-adrenergic receptor agonists
Antidysrhythmics (class Ib)
Baclofen
Bradydysrhythmias
Calcium-channel blockers
Cholinergic agonists
Cholinesterase inhibitors
Clonidine
Guanabenz
Imidazoline decongestants
Nicotine
Tachydysrhythmias
Amantidine
Antidysrhythmics (class Ia, Ic, III)
Antihistamines
Antimalarials
Baclofen
Fluoride
Metals
Local anesthetics
Meperidine
Neuroleptics
Propoxyphene
Sympathomimetics
Plants (common name)
Aconitum charmichaeli (caowu)
Aconitum kusnezoffii (chuanwu)
Aconitum napellus (monkshood)
Chelidonium majur
Cinchona calisaya
Cinchona pitayensis
Corydalis cava
Cytisus scoparius
Fagara coca
Fumaria officinalis
Kalmia angustifolia
Lobeline inflata (bluebell, Indian tobacco)
Papaver somniferum (opium poppy)
Phoradendron tomentosum (American mistletoe)
Remijia pedunculata
Remijia purdiena
Rhododendron macrophyllum
Rhododendron ponticum
Sanguinaria canadensis
Schoenocaulon officinalis (sabadilla)
Stylophorum diphyllun
Veratrum californicum
Veratrum viride (American hellebore)
Zanthoxylum brachycanthum
Visual Disturbances
Diseases/disorders
Cataracts
Cerebrovascular disease
Corneal disease or injury
Diabetes
Glaucoma
Macula degeneration
Migraine
Optic neuritis
Retinal detachment
Vasculitis
Vitreous hemorrhage
Chemicals/drugs
Antimalarials
Carbon disulfide
Carbon monoxide
Ergot alkaloids
Ethambutol
Metals
Methanol
Quinine
Salicylates
Tamoxifen
Topical irritants


LABORATORY STUDIES
The evaluation of symptomatic patients should include a 12-lead EKG, serum calcium and magnesium
levels as well as routine electrolytes, BUN and serum creatinine levels, oxygen saturation, and an SDL.
Arterial blood gases and a chest radiograph should be obtained in those with dysrhythmias, hypoxia, or
hypotension. Arterial blood gas analysis should also be considered in those with an abnormal serum
bicarbonate level. Patients who are asymptomatic after an acute exposure initially need only an EKG (or
cardiac monitoring) and an SDL. If the SDL is elevated after drug exposure or drug is detected following
nondrug exposure, liver function tests such as AST, alkaline phosphatase, and total bilirubin should also be
evaluated.
Serum Digoxin Level
The SDL ideally should be obtained at least 6 hours after the most recent dose in patients with chronic drug
exposure. It should be measured immediately in unstable patients, if chronic nonpharmaceutical DG
poisoning is suspected, and 1 to 2 hours after acute DG ingestion because the result can be used to exclude
or confirm the exposure. Serial SDLs may be useful in assessing the adequacy of GI decontamination and
enhanced elimination therapy and in determining the duration of monitoring.
The diagnosis of DG poisoning is supported by finding an elevated SDL in patients with drug exposures or
by detecting the apparent presence of drug in cases of nonpharmaceutical glycoside exposure. Drug-
specific radioimmunoassays are the most widely used methods for “measuring” SDLs. Enzyme and
fluorescence polarization immunoassays are also available. Because these assays indirectly calculate the
total (free plus protein bound) drug concentration rather than directly measuring it, the SDL does not
necessarily reflect the actual value. Assays utilize a variety of techniques and have differing degrees of
reliability and precision. They are also nonspecific and subject to interference by the presence of
compounds with which they cross-react.
Fab antibody therapy interferes with all immunoassay techniques, making SDLs unreliable for assessing
potential toxicity following the administration of antidote.[6] Depending on the assay, post-Fab SDLs may be
very low, very high, or intermediate. Although assays which utilize equilibrium dialysis or ultrafiltration for the
removal of protein can “measure” the concentration of free drug in the presence of Fab, the result does not
necessarily reflect the true value.
Immunoassays
These assays cross-react with drug metabolites and other DGs to a variable, nonlinear, and lesser degree
than they do with their target drug.[6][44] The “measured” digoxin concentration may vary as much as 0.5
ng/mL from one assay to another. Digoxin immunoassays cross-react with digitoxin and vice versa. In
nonpharmaceutical DG poisoning, immunoassays yield an apparent (false positive) target drug level that
may be subtherapeutic, therapeutic, or slightly elevated. Although the apparent drug level may correlate with
clinical toxicity for a given nonpharmaceutical glycoside measured by a particular assay, the nature of such
relationships have not been defined.
Immunoassays can also yield false positive SDLs when they cross-react with endogenous digoxin-like
immunoreactive substances (EDLIS).[21] Although the identity and function of EDLIS remain unknown,
steroidal derivatives with hormonal activity are suspected. EDLIS have been detected in neonates, seriously
ill infants, pregnant women, and those with acromegaly, congestive heart failure, hypertension, liver
dysfunction, renal failure, and subarachnoid hemorrhage. False positive SDLs caused by EDLIS in such
patients have resulted in health care workers being falsely accused of iatrogenic and even homicidal
poisoning. Although SDLs due to the presence of EDLIS are usually therapeutic or lower, apparent digoxin
levels as high as 5 ng/mL have been reported. SDLs are also unreliable following the administration of
digoxin-specific antibody fragments (see later discussion).
Hemolysis resulting from venipuncture does not significantly affect the accuracy of SDL measurements.
Complete hemolysis (e.g., due to repeated freezing and thawing), however, will result in the SDL being
falsely low. In contrast, because of redistribution from muscle and other tissues to blood, postmortem SDLs,
particularly those determined from heart blood samples, are nearly always higher than antemortem ones.
Unless blood is obtained and assayed within a few hours of death, these additional factors must be
considered when interpreting postmortem SDLs. [3]


TREATMENT
General Measures
The treatment of DG poisoning includes supportive care, prevention of further DG absorption, enhancement
of DG elimination, and in severe cases, the use of the specific antidote digoxin Fab antibodies ( Table 44–7
). [4][11][13][18][28][36][39] As always, supportive care is the highest priority. Supportive measures include the
establishment of intravenous access, continuous cardiac monitoring, and correction of acid-base and
electrolyte abnormalities (including calcium and magnesium) and oxygenation and ventilatory compromise,
as well as standard advanced cardiac life support (ACLS) therapies. Unless otherwise noted, standard
doses and contraindications should be assumed for the drugs discussed.
Table 44-7 -- Treatment of Digitalis Glycoside Poisoning

General Measures *
Supportive care: ACLS drugs for dysrhythmias (see below); Correction of acid-base, electrolyte, calcium,
magnesium, oxygenation and ventilatory abnormalities
Bradydysrhythmias † : atropine (0.5–2 mg for adults; 0.02 mg/kg for children, minimum 0.1 mg), electrical
pacing, phenytoin (1.5 mg/kg every 5 min up to 15 mg/kg); other drugs are of doubtful benefit
Ventricular tachydysrhythmias † : electrical cardioversion/defibrillation for unstable or pulseless
dysrhythmias; lidocaine (1–3 mg/kg), magnesium sulfate (2–6 g for adults; 100–200 mg/kg for children),
bretylium (5–10 mg/kg), phenytoin (1.5 mg/kg every 5 min up to 15 mg/kg), procainamide (1.5 mg/kg every 5
min or 0.5 mg/kg/min up to 15 mg/kg), amiodarone (150 mg over 10 min then 1 mg/min for 6 hr then 0.5
mg/min for 18 hr for adults), and propranolol (0.5–3 mg for adults, 10–20 µg/kg for children) for stable,
persistent, or recurrent dysrhythmias
Supraventricular tachydysrhythmias: esmolol (0.5 mg/kg over 1 min then 0.05 mg/kg/min; may repeat
loading dose and double infusion rate if no response in 5 min) and diltiazem (0.25 mg/kg for 2 min then 0.1–0.2
mg/kg/hr; may give second loading dose of 0.35 mg/kg if no response after 15 min) for rate control;
procainamide (see above) and electrical cardioversion for dysrhythmias
Prevention of DG absorption: oral activated charcoal (0.5–1 g/kg); gastric aspiration or lavage and syrup of
ipecac may increase vagal tone and precipitate bradydysrhythmias
Enhancement of DG elimination: repeated doses of activated charcoal (0.5 g/kg every 2 to 4 hr); repetitive
doses of cholestipol and cholestyramine less effective and less well tolerated; hemodialysis, hemofiltration, and
hemoperfusion are relatively ineffective
Specific Therapy with Digoxin-Specific Fab
Indications: dysrhythmias associated with hypotension or organ ischemia which are not immediately
responsive to conventional drugs, which recur despite such therapy, or require electrical
cardioverson/defibrillation or pacing; hyperkalemia (serum K+ = 5.5 mEq/L) in acute poisoning
Calculated dosage(number of 38-mg vials of Digibind):
Acute overdose(based on amount ingested)
2 × dose of oral digoxin elixir or tablets (in mg) × 0.8
2 × dose of oral digitoxin, liquid-filled digoxin capsules, or intravenous digoxin (in mg)
Chronic overdose(based on serum drug level)
2 × serum digoxin level (ng/mL) × 5.6 × body weight (kg)/1000
1.7 × serum digitoxin level (ng/mL) × 0.56 × body weight (kg)/1000
Empirical dose(number of 38-mg vials of Digibind)
Acute DG overdose: 5–15 vials
Chronic DG overdose: 1–4 vials
* Listed in order of priority and choice of therapy; drug doses refer to intravenous dose.
† Should include early consideration of digoxin-specific Fab (see specific therapy).
Supplemental Potassium and Magnesium
These electrolytes may be beneficial in patients with chronic DG poisoning who have deficits of these ions
as a result of diuretic use. They should be given cautiously if renal failure is the underlying cause of toxicity.
Hyperkalemia following acute overdose may be treated with digoxin Fab antibodies, glucose and insulin,
sodium bicarbonate, and the exchange resin sodium polystyrene sulfonate. Calcium is contraindicated due
to its potential to exacerbate dysrhythmias. The effects of glucose and insulin and sodium bicarbonate are
transient, whereas those of resin and antidotal therapy are not. Because the serum potassium level reflects
the severity of acute poisoning as well as the success of antidotal therapy, and hyperkalemia in this setting
is a result rather than a cause of poisoning and may not itself be harmful, the necessity and wisdom of
correcting it with measures other than antidotal therapy are not clear.
Dysrhythmias
Life-threatening bradydysrhythmias should be treated with digoxin Fab antibodies. Alternative therapies such
as atropine, dopamine, epinephrine, and possibly isoproterenol, with electrical pacing reserved for those
unresponsive to drug therapy should be instituted if digoxin Fab antibody therapy is not immediately
available. Even when the antidote is used, it takes time to reverse existing toxicity, and other therapies may
be useful as temporizing measures.
Only atropine and cardiac pacing have a well-documented record of success. Because the pacing wire may
increase ventricular irritability and induce ventricular fibrillation, particularly during its insertion, antidotal
therapy is currently recommended as the treatment of choice for DG-induced bradydysrhythmias
unresponsive to atropine.[40] Prophylactic pacing is without benefit and may be hazardous.
Phenytoin may also be effective in reversing DG-induced AV conduction blocks.[4][28] When used for this
indication, the adult dose is 100 mg, intravenously (IV) every 5 minutes until the desired effect is achieved or
a total dose of 15 mg/kg is given. A comparable pediatric dose would be 1.5 mg/kg every 5 minutes with a
maximal dose of 15 mg/kg.
Asystole and pulseless electrical activity should be treated in the usual fashion with epinephrine and
atropine. Because of the likelihood of hyperkalemia, the early use of sodium bicarbonate (1 mEq/kg) should
be considered in patients who develop these dysrhythmias after acute overdose and do not respond to initial
therapy.
As with bradydysrhythmias, digoxin Fab antibody therapy is the treatment of choice for life-threatening
ventricular tachydysrhythmias, with other therapies being used as interim measures. Standard ACLS
treatment for ventricular tachydysrhythmias consists of defibrillation or cardioversion for pulseless rhythms
and lidocaine, bretylium, magnesium sulfate, and procainamide for stable, persistent, or recurrent
dysrhythmias. With some qualifications, these drugs remain acceptable for patients with DG poisoning.
Classically, however, phenytoin has been advocated as the treatment of choice for DG-induced ventricular
tachydysrhythmias.[4][28] Phenytoin is theoretically attractive because it suppresses automaticity without
depressing conduction. Although it has been long recommended, data supporting its clinical efficacy are
sparse. Dosing is the same as that noted for bradydysrhythmias. Propranolol has also been used
successfully for ventricular ectopy,[11] but it can exacerbate conduction disturbances and is contraindicated
in patients with concomitant AV block. The intravenous dose, 0.5–3 mg for adults, can be repeated once
after 5 minutes if necessary. For children, 0.01–0.1 mg/kg per dose, to a maximum dose of 1 mg, infused
over 10 minutes has been recommended. Amiodarone has been reported to be effective in cases refractory
to other agents,[26] but experience is limited. The adult dose is 15 mg/minute IV for 10 minutes (i.e., a 150-
mg loading dose) followed by 1 mg/min for 6 hours and then 0.5 mg/minute. Refractory junctional or
ventricular tachycardia may also respond to overdrive pacing. If defibrillation is necessary, low energy levels
(e.g., 5–50 watt-seconds) should be used initially because electrical shock itself may precipitate
tachydysrhythmias of a more malignant and refractory nature. Postulated mechanisms for this phenomenon
include catecholamine release and altered membrane permeability leading to loss of intracellular potassium.
If time permits, the administration of antidysrhythmics prior to countershock is recommended.
Lidocaine is neither harmful nor particularly effective. Bretylium appears to be more effective and has the
theoretical advantages of positive inotropic activity, insignificant effects on AV node conduction, and the
ability to raise the ventricular fibrillation threshold (thereby facilitating defibrillation).[45] Its use is
controversial, however, because it has enhanced ventricular dysrhythmia formation in experimental DG
intoxication. Magnesium sulfate appears to be moderately effective as well as safe and is recommended for
most patients, particularly those with chronic poisoning who frequently have underlying hypomagnesemia.[19]
It may also counteract the effects of hyperkalemia. Except in patients with known or suspected
hypermagnesemia (e.g., those with chronic renal failure), magnesium sulfate, in a dose of 2 to 6 g (10–30
mL of a 20 per cent solution) over a period of 1 to 10 minutes (depending on hemodynamic stability) is
recommended for adults. The pediatric dose is 100–200 mg/kg. Because of its ability to cause and
potentiate conduction disturbances, procainamide should not be used in patients with AV blocks.
Supraventricular tachydysrhythmias resulting from DG toxicity rarely require treatment. Because they are
almost invariably accompanied by some degree of AV block, the ventricular rates usually do not
hemodynamically compromise the patient. Patients with severe underlying congestive heart failure, however,
may require sinus rhythm or a normal heart rate in order to maintain an adequate cardiac output. In such
patients, a ß-adrenergic receptor antagonist or calcium-channnel blocker may be used for ventricular rate
control. Because of the negative effects of these drugs on inotropy, short-acting agents such as esmolol and
diltiazem are preferred. Procainamide may be effective in terminating supraventricular tachydysrhythmias.
Electrical cardioversion, if required, should include consideration of the precautions described for ventricular
dysrhythmias.
This step should be accomplished as soon as possible in patients with acute overdose and in those with
chronic poisoning who have ingested a dose of DG within 6 hours. Oral administration of activated charcoal
(AC) is the preferred method. AC readily adsorbs digoxin and digitoxin (and probably other DGs).[10] Gastric
tube insertion or lavage may result in vagal stimulation and appears to have precipitated asystole in a patient
with AV block,[15] and therefore should be used with extreme caution. For the symptomatic patient who
cannot drink AC, pretreatment with atropine prior to tube placement should be considered. Simply
administering a dose of AC by gastric tube may be safer than performing gastric lavage first. Because
vomiting may also increase vagal tone and precipitate or worsen conduction disturbances, syrup of ipecac
should be reserved for asymptomatic patients with recent ingestions for whom AC is not readily available
(e.g., in a home remote from a health care facility).
The elimination of digoxin and digitoxin (and probably all DGs) is also enhanced by AC when the latter is
administered in repetitive doses.[10] Such therapy has reduced the half-lives of these drugs to 8–21 hours
and 18–53 hours, respectively. Because AC appears to be relatively more effective in enhancing the
elimination of the less polar digitoxin, it is also likely to be effective for other less polar DGs such as the
nonpharmaceutical agents. Repetitive doses of cholestyramine and to a lesser extent cholestipol can also
enhance the elimination of DGs, but these bile-acid sequestering resins are less well tolerated than AC. The
observation that AC is much more effective than resins in preventing digoxin absorption suggests that resins
enhance DG elimination primarily by interrupting enterohepatic recirculation. Although there have been no
direct comparisons between repetitive-dose regimens of AC and resins, the apparent superiority of AC is
consistent with its ability to increase enteroenteric as well as enterohepatic drug elimination. Some
pharmacokinetic data suggests that furosemide-induced diuresis can enhance the elimination of digoxin, but
the clinical efficacy of this intervention is questionable. Forced diuresis may worsen electrolyte abnormalities
and is not recommended.
Multiple-dose AC is effective in both acute and chronic poisoning and for intravenous as well as oral
overdose.[10] It is also more effective than hemodialysis, hemofiltration, and hemoperfusion and has
replaced these modalities as the method of choice for enhancing DG elimination, even in patients with renal
failure. Repetitive doses of AC should be given until the patient is asymptomatic or the SDL approaches the
therapeutic range (or is declining in cases of nonpharmaceutical glycoside poisoning).
Antidotal Therapy
Digoxin-specific antibody fragments (Fab) are indicated for the treatment of potentially life-threatening
dysrhythmias and conduction disturbances, and for hyperkalemia following acute overdose.[1][4][23][39][40]
Such rhythm disturbances include bradydysrhythmias and tachydysrhythmias associated with hypotension
or organ ischemia and Mobitz II and third-degree heart block. Hyperkalemia (i.e., peak serum potassium at
5.5 mEg/L or greater) is an independent risk factor in acute poisoning and an indication for antidotal therapy
in the absence of cardiotoxicity.[5] Because toxicity is likely to be prolonged and recurrent and may worsen
with time, particularly in those with acute overdose, all patients with potentially life-threatening dysrhythmias
should receive Fab antibody therapy, even if initial conventional therapy is successful. Fab antidotal therapy
may also be justified in patients with dysrhythmias that are not life-threatening if they have other factors
associated with a poor prognosis (see previous discussion). At a minimum, all patients with potential
poisoning should have an antidote available at the bedside.
Digoxin-specific Fab (Digibind) is a large molecule with a molecular weight of about 46,200 d. It is prepared
by isolating and purifying papain digested polyclonal IgG antibodies obtained from sheep that have been
immunized with a conjugate of hapten (digoxin) and protein (human albumin). A monoclonal Fab preparation
(Digitab) is currently undergoing clinical trials. Each vial of Digibind contains 38 mg of Fab and can bind
approximately 0.5 and 0.6 mg of digoxin and digitoxin, respectively.
Fab cross-reacts with other DGs and only binds free (unbound) DG. Although the affinity and binding
capacity of Fab for these agents is less than for digoxin and digitoxin, Digibind has been used with success
in the treatment of plant[33][35] and toad venom[6] poisoning as well as drug intoxication.
Fab is administered intravenously and distributes throughout the extracellular fluid space. Following Fab
administration, the concentration of free DG declines to undetectable levels within minutes, whereas the
concentration of total (serum-bound plus Fab-bound) DG increases. The total DG level may peak at up to
8–20 times the pre-Fab level in patients with normal renal function and up to 33 times the pre-Fab level in
those with renal failure.[43] Peak total DG concentrations occur about 12 hours after Fab administration in
patients with normal renal function and up to 30 hours in those with renal failure. A rebound increase in free
DG levels may be noted 3–24 hours following the administration of Fab in patients with normal renal function
and as long as 8 days after Fab in those with renal failure. Metabolic degradation of the Fab-DG complex
with release of free DG is the postulated mechanism. Levels exceeding the therapeutic range and
associated with recurrence of clinical toxicity have been noted in up to 4 per cent of patients, although, in
most cases, peak free DG levels do not rebound above the therapeutic range. Inadequate Fab dosing may
be associated with an increased risk of recurrent toxicity.
Fab and Fab-bound DG are eliminated by glomerular filtration and renal excretion. Elimination is biphasic,
with the terminal phase having a half-life of 16–30 hours. The terminal elimination half-life is prolonged up to
4 days in patients with renal failure.
Reversal of clinical toxicity occurs more slowly than changes in serum DG concentrations because
redistribution of tissue-bound DG is required, and this process takes time. Reversal may also depend on the
rate of Fab infusion, the dose of Fab relative to the body load of DG, the severity of poisoning, and age, and
the process is therefore highly variable. An initial response may occur within a few minutes in some patients
but may not be apparent for up to 30 minutes in others. The time to maximal response ranges from 30
minutes to 6 hours. Most patients show clinical improvement within 1 hour and complete response within 4
hours. In severe poisoning, it may take up to 13 hours for rhythm disturbances to stabilize.
Side effects of Fab therapy include worsening of underlying congestive heart failure, increased heart rate in
patients with pre-existing atrial fibrillation or flutter, hypokalemia, and rarely, allergic reactions.[1][20] Patients
with a history of allergies—particularly to antibiotics and possibly to sheep, wool, or other animals—asthma,
or prior exposure to Fab or other ovine serum products may be at increased risk of allergic reactions. Such
reactions are rare, are generally mild, and may occur during or up to several hours ater Fab infusion. They
primarily consist of pruritic rashes. Chills, periorbital edema, and thrombocytopenia have also been reported.
The manufacturer recommends skin sensitivity testing via intradermal injection or the scratch technique,
using 0.1 mL of a 1:100 dilution of reconstituted Digibind (i.e., 0.1 mL of reconstituted Digibind diluted with
9.9 mL 0.9 per cent saline), prior to therapeutic dosing. This practice, however, is of questionable value
because nearly all patients, including those who develop allergic reactions, have negative skin tests. In
addition, antibodies to Fab have not been detected in those treated with this antidote. And finally, the risk of
delaying Fab administration in order to perform skin testing in patients with life-threatening dysrhythmias is
probably far greater than the risk of an adverse reaction to Fab. Hence, this author does not routinely use
skin sensitivity testing. Instead, the Fab infusion is initially started very slowly while the patient is closely
observed for signs of an adverse reaction. If none is observed, the rate of infusion is increased, whereas it is
slowed or stopped if a reaction is noted. Equipment and drugs to manage allergic reactions should be
available at the bedside whenever Fab is given.
The dose of Fab depends on the total body load (TBL) of DG. The TBL can be calculated from the amount
of DG absorbed after an acute overdose or from the serum drug concentration following chronic exposure.
Following acute overdose, the TBL (in mg) equals the amount of digitoxin and liquid-filled capsule
formulation of digoxin ingested, the amount of intravenous digoxin administered. However, since the oral
bioavailability of digoxin ingested in elixir or tablet form is only 80 per cent, the amount ingested is multiplied
by 0.8 to obtain the amount absorbed. Following acute or chronic exposure, where the serum drug
concentration is known, the TBL (in milligrams) is calculated with the following formula:
In this formula, nanograms per milliliter

(ng/mL) is equivalent to micrograms per liter (µg/L); Vd (volume of distribution) is assumed to be 5.6 L/kg for
digoxin and 0.56 L/kg for digitoxin.
The number of vials of Digibind necessary to neutralize the TBL of DG is approximately twice this number
[divide the TBL (in mg) by 0.5 for digoxin and 0.6 for digitoxin to calculate number of vials needed].
Alternative methods of calculating the Digibind dose, along with guidelines presented in tabular format, can
be found in the package insert. In clinical practice, however, TBL calculations are of limited value because
the amount and time of drug exposure may be unknown or unreliable, drug levels may not be immediately
available, and calculations based on drug levels are accurate only if the level is drawn in the postdistribution
phase.
Clinical experience indicates that, in the vast majority of cases, 5–15 vials of Digibind are sufficient to
reverse toxicity in patients with acute overdose, whereas only 1–4 vials are necessary in those with chronic
DG intoxication. The differences in antidote dose for acute and chronic poisoning reflect the fact that the
TBL may be much greater in the former. Hence, for adults who are hemodynamically stable, this author
recommends an initial (empirical) Digibind dose of 5 vials for those with acute overdose and 1 vial for those
with chronic intoxication. For those in cardiac arrest or shock, corresponding doses of 15 and 4 vials are
recommended. For children, similar doses are appropriate for those with acute accidental ingestions, but
fractional doses based on weight should be used for those with chronic intoxication. Additional doses should
be administered if toxicity persists or recurs.
The rate of administration of Fab should also be individualized. In patients who are hemodynamically stable,
infusion over 15–30 minutes is recommended. If cardiac arrest has occurred or if signs of shock or ischemia
are present, Digibind may be given over several minutes.


DISPOSITION
Symptomatic patients should be admitted and have continuous cardiac monitoring. Those with acute
overdose, with potentially life-threatening dysrhythmias, and in whom poor prognostic factors are present
should initially be admitted to an intensive care unit (ICU). Those with chronic intoxication who do not have
life-threatening dysrhythmias and those who have received Fab antibody therapy can be admitted to a
telemetry unit. After 24 hours, patients with acute overdose or poor prognostic factors who do not manifest
life-threatening toxicity can be transferred to a telemetry unit if they remain symptomatic and then can be
discharged when they become asymptomatic. Those with potentially life-threatening dysrhythmias who have
not been treated with Fab antibodies can have a similar disposition 24 hours after the resolution of such
toxicity.
Patients who have received Fab antibodies should have close monitoring and serial SDLs. Ideally, they
should also have a free DG level measured daily (for 2 days in those with normal renal function and for up to
2 weeks in those with renal failure). Although the absolute DG level may not correlate with clinical toxicity,
trends can be used to determine its potential duration. If the patient remains asymptomatic after the peak
rebound DG level is observed, he or she can be discharged. If clinical toxicity recurs, redisposition as has
been described will be necessary. In patients who require DGs for therapeutic purposes, the reinstitution of
therapy should generally be withheld until rebound free DG levels are confirmed to be nontoxic.
Asymptomatic patients should be monitored in the emergency department, an observation unit, ICU, or
telemetry unit until serial SDLs have determined that peak levels are nontoxic, toxic levels have declined to
nontoxic ones, or for 24 hours in patients with detectable drug levels following nonpharmaceutical glycoside
exposures.
Patients with intentional overdoses should have a psychiatric evaluation prior to discharge. Those with
therapeutic misadventures should have close follow-up and SDL monitoring if treatment with a DG is
continued. Recreational toad-lickers should be referred for substance abuse counseling and treatment.
Caretakers of children with accidental ingestions should be educated about the prevention of poisoning.
Users of herbal preparations should be advised against continuing such practices.


SEQUELAE
Any sequelae from digitalis glycoside toxicity result from the ensuing complications, such as dysrhythmias
and hypotension. No sequelae result from permanent, direct drug effects on end organs.


REFERENCES
1. Antman EM, Wenger TL, Butler VP, et al: Treatment of 150 cases of life-threatening digitalis intoxication
with digoxin-specific Fab antibody fragments. Final report of a multicenter study.
Circulation 1990; 81:1744.
2. Bain RJI: Accidental digitalis poisoning due to drinking herbal tea. Br Med J 1985; 290:1624.
3. Baselt RC, Cravey RH: Disposition of Toxic Drugs and Chemicals in Man, 4th ed. Foster City
4. Bhatia SJS: Digitalis toxicity—Turning over a new leaf?. West J Med 1986; 145:74.
5. Bismuth C, Gauhier M, Conso F, et al: Hyperkalemia in acute digitalis poisoning: Prognostic significance
and therapeutic implications. Clin Toxicol 1973; 6:153.
6. Brubacher JR, Ravikumar PR, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific
Fab fragments. Chest 1996; 110:1282.
7. Butler VP, Odel JG, Rath E, et al: Digitalis-induced visual disturbances with therapeutic serum digitalis
concentrations. Ann Intern Med 1995; 123:676.
8. Chern MS, Ray CY, Wu D: Biologic intoxication due to digitalis-like substance after ingestion of cooked
toad soup. Am J Cardiol 1991; 66:443.
9. Chitton WS, Bigwood J, Jenson RE: Psilocin, bufotenine, and serotonin: Historical and biosynthetic
observations. J Psychedelic Drugs 1979; 11:61.
10. Cooney DO: Activated Charcoal in Medicinal Applications, New York: Marcel Dekker; 1995:226-229.
503–507
11. Ekins BR, Wanttabe AS: Acute digoxin poisonings: Review of therapy. Am J Hosp
Pharm 1978; 35:268.
12. Fisch C, Knoebel SB: Digitalis cardiotoxicity. J Am Coll Cardiol 1985; 5:91A.
13. Hansteen V, Jacobson D, Knudsen K, et al: Acute massive poisoning with digitoxin: Report of seven
cases and discussion of treatment. Clin Toxicol 1981; 18:679.
14. Hitt M, Ettinger DD: Toad toxicity. N Engl J Med 1986; 314:1517.
15. Hobson JD, Zettner A: Digoxin serum half-life following suicidal digoxin poisoning.
JAMA 1973; 223:147.
16. Hoffman BF, Bigger JT: Digitalis and allied cardiac glycosides.
In: Gilman AG, Goodman LS, Rail TW, et al ed. Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, . 8th ed. New York: Macmillan; 1990:716-747.
17. Joy ME, Higbee MD: Extracardiac manifestations of digitalis toxicity in the elderly. Hosp
Formulary 1985; 20:1015.
18. Kelly RA, Smith TW: Pharmacological treatment of heart failure.

In: Hardman JC, Limbird LE, Maolinoff PB, et al ed. Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, . 9th ed. New York: McGraw-Hill; 1996:809-838.
19. Kinlay S, Buckley NA: Magnesium sulfate in the treatment of ventricular arrhythmias due to digoxin
toxicity. Clin Toxicol 1995; 33:55.
20. Kirkpatrick CH, The Digibind Study Advisory Panel : Allergic histories and reactions of patients treated
with digoxin immune Fab (ovine) antibody. Am J Emerg Med 1991; 9(7(suppl 1)):
21. Koobatian TJ, Roberts JR: Falsely elevated serum digoxin levels secondary to endogenous digoxin-like
immunoreactive substances. Acad Emerg Med 1995; 2:322.
22. Lely AH, Van Enter CHJ: Large-scale digitoxin intoxication. Br Med J 1970; 3:737.
23. Lewander WJ, Gaudreault P, Einhorn A, et al: Acute pediatric digoxin ingestion: A ten-year experience.
Am J Dis Child 1986; 140:770.
24. Lewis WH, Elvin-Lewis MPF: Medical Botany: Plants Affecting Man’s Health, New York: John Wiley &
Sons; 1977:183-186.
25. Lyttle T: Misuse and legend in the “toad licking” phenomenon. Int J Addict 1993; 28:521.
26. Maheswaran R, Bramble MG, Hardisty CA: Massive digoxin overdose: Successful treatment with
intravenous amiodarone. Br Med J 1983; 287:399.
27. Marshall PG: Steroids: Cardiotonic glycosides and aglycones: Toad poisons.. In: Coffey S, ed. Rodd’s
Chemistry of Carbon Compounds, vol. 2D. 2nd ed. Amsterdam: Elsevier; 1970:360-421.
28. American Hospital Formulary Service Drug Information.

In: McEvoy GK, Litvak K, Welsh OH, ed. Bethesda, . American Society of Hospital Pharmacists; 1997:1178-
1188.
29. Moe GK, Farah AE: Digitalis and allied cardiac glycosides.. In: Goodman LS, Gilman A, ed. Goodman
and Gilman’s The Pharmacological Basis of Therapeutics, . 5th ed. New York: Macmillan; 1975:653-682.
30. Mooradian AD: Digitalis: An update of clinical pharmacokinetics, therapeutic monitoring techniques and
treatment recommendations. Clin Pharmacokinet 1988; 15:165.
31. Moorman JR, Pritchett ELC: The arrhythmias of digitalis intoxication. Arch Intern Med 1985; 145:1289.
33. Rich SA, Libera JM, Locke RJ: Treatment of foxglove extract poisoning with digoxin-specific Fab
fragments. Ann Emerg Med 1993; 22:1904.
34. The Medical Letter Handbook of Adverse Drug Interactions. In: Rizack MA, ed. New Rochelle, NY: The
Medical Letter, Inc; 1996:162-170.
35. Safadi R, Levy I, Amitai Y, et al: Beneficial effect of digoxin-specific Fab antibody fragments in oleander
intoxication. Arch Intern Med 1995; 155:2121.
36. Smith TW, Antman EM, Friedman PL, et al: Digitalis glycosides: I. Mechanisms and manifestations of
toxicity. Prog Cardiovasc Dis 1984; 26:413.
37. Steiner JF, Robbins J, Hammermeister KE, et al: Incidence of digoxin toxicity in outpatients. West J
Med 1994; 161:474.
38. Surawicz B: Factors affecting tolerance to digitalis. J Am Coll Cardiol 1985; 5:69A.
39. Taboulet P, Baud FJ, Bismuth C, et al: Acute digitalis intoxication—Is pacing still appropriate?. Clin
Toxicol 1993; 31:261.
40. Taboulet P, Baud FJ, Bismuth C: Clinical features and management of digitalis poisoning—Rationale for
immunotherapy. Clin Toxicol 1993; 31:247.
41. Drug Interaction Facts. In: Tatro DS, ed. Anesthesia for Obstetrics, . 5th ed. St. Louis: Facts and
Comparisons; 1996:347-404.
42. Tuncok Y, Kozan O, Cavdar C, et al: Urginea maritima (squill) toxicity. Clin Toxicol 1995; 33:83.
43. Ujhelyi MR, Robert S, Cummings DM, et al: Influence of digoxin immune Fab therapy and renal function
on the disposition of total and free digoxin. Ann Intern Med 1993; 119:273.
44. Valdes R, Brown BA, Graves SW: Variable cross-reactivity of digoxin metabolites in digoxin
immunoassays. Am J Clin Pathol 1984; 82:210.
45. Vincent JL, Dufaye P, Berre J, et al: Bretylium in severe ventricular arrhythmias associated with digitalis
intoxication. Am J Emerg Med 1984; 2:504.
46. Warren JL, McBean AM, Hass SL, et al: Hospitalizations with adverse events caused by digitalis therapy
among elderly medicare beneficiaries. Arch Intern Med 1994; 154:1482.
47. Wellens HJJ: The electrocardiogram in digitalis intoxication. In: Yu PN, Goodman IF, ed. Progress in
Cardiology, Vol. 5. Philadelphia: Lea & Febiger; 1976:271-290.
48. Withering W: An Account of the Foxglove and Some of Its Medicinal Uses: With Practical Remarks on
Dropsy and Other Diseases J Robinson, 1785 Reprinted in Med Class, vol. 2. London: Reprinted in Med
Class; 1937:305.
49. Wofford JL, Ettinger WH: Risk factors and manifestations of digoxin toxicity in the elderly.. Am J Emerg
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50. Ye CC, Deng JF: Toad or toad cake intoxication in Taiwan: Report of four cases. J Form Med
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Uncited reference
Ordog GJ, Benaron S, Bhasin V, et al: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg
Med 1987; 16:32.


Chapter 45 – Clonidine and Central-Acting Antihypertensives
FRED M. HENRETIG
Essentials
• Central nervous system (CNS) depression
• Miosis
• Respiratory depression and apnea
• Hypotension (rarely, early transient hypertension)
• Bradycardia
INTRODUCTION
In this chapter the class of central-acting antihypertensive agents is discussed, with emphasis on clonidine.
Guanabenz, guanfacine, and methyldopa, as well as the topical vasoconstrictor imidazoline agents, which
share similar pharmacologic and toxicologic effects, are also discussed.
Clonidine, guanabenz, and guanfacine are widely used antihypertensive agents. Clonidine is also used as
an adjunct in the treatment of migraine headaches, menopausal flushing, attention deficit disorder with
hyperactivity (ADHD), Tourette’s syndrome, and opioid withdrawal.[33] The vast majority of clinical
experience in this class of agents is with clonidine overdose. This popular medication is used in both tablet
and transdermal patch form. Thus, there are numerous opportunities for both intentional adult and accidental
pediatric exposures.[2][29][33] Several characteristics of this medication make it particularly hazardous to
young children: frequent use by grandparents, visited by their grandchildren, who may be less vigilant about
“childproofing” strategies[21]; typical daily or twice-daily dosing pattern, which may lead to the daily tablet or
two being left out on the nightstand for the “morning” or “at bedtime” dose; toxic manifestations after
ingestion of only one or two tablets by a child; rapid onset of symptoms; and significant CNS and
cardiovascular morbidity at relatively low doses. Although clonidine ingestion is a relatively uncommon
pediatric pharmaceutical exposure, it is disproportionally represented among medications causing serious
morbidity.[33]


The pharmacokinetic properties of this class of medications are summarized in Table 45–1 .[9][15] Of note,
clonidine is rapidly and almost completely absorbed after oral administration, with rapid onset and time to
peak pharmacologic effects, particularly relative to methyldopa. Clonidine has a large volume of distribution
and is widely distributed to all tissues and the CNS. The drug is metabolized in the liver, but 50 to 70 per
cent is excreted unchanged in the urine, with an elimination half-life of 12 to 16 hours (prolonged to 18 to 40
hours in patients with renal insufficiency).[7]
Table 45-1 -- Pharmacokinetics of Representative Central-Acting Antihypertensives

Agent Absorption/Onset Protein Binding Volume of Distribution Elimination Half-life
Clonidine 75–90%/30–60 min 20–40% 3–6 L/kg H 50%, R 50%/12–16 hr
Guanabenz 75%/2–5 hr 90% 7–17 L/kg H/7–14 hr
Guanfacine 81–100%/1–2 hr 72% 6 L/kg H 50%, R 50%/10–30 hr
Methyldopa 50%/3–4 hr <15% 0.24 L/kg H 50%, R 50%/0.2–1.2 hr
H, hepatic metabolism; R, renal elimination.
Clonidine and other imidazolines act predominantly as a2-adrenergic receptor agonists.[11][15][23] The
antihypertensive and CNS effects of these agents are believed to result primarily from agonism at
presynaptic a2-adrenergic receptors in the brain, particularly in the cardiovascular center of the medulla
oblongata (nucleus tractus solitarii) and in the locus ceruleus.[7][15] This results in decreased sympathetic
activity in the brain, heart, and peripheral blood vessels; decreased norepinephrine release at these sites;
and consequent sedation and decreased heart rate, peripheral vascular resistance, and blood pressure. In
addition, clonidine lowers plasma renin activity by its actions on CNS a2-adrenergic receptors, decreasing
sympathetic stimulation to the kidney, which in turn mediates renin secretion via ß-adrenergic receptors.
Animal studies have also demonstrated a direct effect on renal a-adrenergic receptors.[24] Recent evidence
indicates clonidine may also act on noradrenergic imidazoline-preferring sites, particularly imidazoline
receptors (I1 receptors) in the ventrolateral medulla. Binding at these receptors leads to diminished blood
pressure independent of central a 2-adrenergic activity.[5] In addition, a class of endogenous substances with
imidazoline receptor binding activity, termed clonidine-displacing substances (CDS), has been found, but its
physiologic role is uncertain.[27] One CDS, agmatine, which is decarboxylated arginine, does bind to both a2-
adrenergic and I1 receptors. In therapeutic dosing, clonidine does not inhibit the peripheral sympathetic
nervous system nor act as a ganglion blocker; thus, circulatory response to exercise is preserved and
orthostatic changes are not typically observed. At very high blood levels, peripheral postsynaptic a2-
adrenergic receptor–mediated vasoconstriction may predominate over the centrally mediated sympathetic
inhibition, accounting for the occasional transient hypertension noted in clonidine overdose. The topical
vasoconstrictor properties of imidazolines such as oxymetazoline and tetrahydrozoline are mediated by
peripheral a2-adrenergic receptor activity, although when ingested, predominant central a2-adrenergic
receptor agonist effects lead to manifestations of CNS and cardiovascular depression analogous to
clonidine.[14] Methyldopa is a catecholamine analog structurally unrelated to the imidazolines. Its
antihypertensive effect is believed to be mediated by the metabolite a-methylnorepinephrine, which in turn
functions similarly to imidazolines as a central a2-adrenergic receptor agonist.
The effects of imidazoline-mediated stimulation of central a2-adrenergic receptors mimic those of stimulated
opioid receptors, raising the possibility of some linkage between these sites. Clinically, imidazoline toxicity is
very similar to that of opioid intoxication, and naloxone has been reported to reverse clonidine toxicity in
some cases.[33] Furthermore, clonidine has found a therapeutic role in detoxifying patients from opioid
dependence. Both types of receptors act through G protein mediation (although specific imidazoline
receptors do not). Some communication between these receptors through G proteins may be possible, as
may some direct but incomplete binding of imidazolines to opioid receptors, but this relationship is not
clearly elucidated.[9][34]


Acute Toxicity
The toxic dose of clonidine is relatively small. Pediatric cases requiring hospitalization have been described
with as little as 0.2 mg ingested (mean, 1.6 mg; range, 0.2 to 10.2 mg).[33] Several pediatric cases of
clonidine toxicity have followed ingestion, mouthing, or even inadvertent dermal application of clonidine
transdermal patches (available in 2.5-, 5.0-, and 7.5-mg sizes).[13][18] The toxicologic profile of this class of
agents closely follows predictable exaggeration of expected therapeutic effects resulting from decreased
CNS sympathetic outflow. Significant toxicity involves depression of sensorium, respiratory drive, heart rate,
and blood pressure ( Table 45–2 ). Most patients with clonidine ingestion manifest symptoms within 30 to 90
minutes. One large pediatric series found 75 per cent of children had signs or symptoms (primarily altered
mental status) within 1 hour but 4 hours after ingestion there was no delayed progression of symptoms nor
evolution of new toxic effects.[33] The CNS and cardiovascular depression of even severe clonidine toxicity is
relatively short-lived. Most patients recover substantially within 12 to 24 hours, and nearly all recover
completely within 48 hours.[1][18][33] Compared with children, intentional overdose in adults with impaired
renal function has resulted in delayed onset and prolonged progression of symptoms. Seizures and
malignant hypertension 8 hours after ingestion of 4.5 mg of clonidine were reported in a 17-year-old girl with
renal failure.[16]
Table 45-2 -- Clinical Presentation of Clonidine and Central-Acting Antihypertensive Toxicity

Children (N = 127) Adults (N = 49)
No. % No. %
Lethargy 121 95 39 78
Miosis 50 39 5 10
Hypothermia 26 20 1/12 8
Cardiovascular
Bradycardia 58 46 25 51
Hypotension 34 27 17 35
Hypertension 37 29 7 14
Respiration
Apnea 16 * 13 1 2
Depressed 8 6 3 6
Data from references 21 and 33 for children and references 1 and 29 for adults.
* Of 10/47 patients with “apnea” from Wiley et al,[33] 6 required intubation; and 6/80 patients from Nichols et al[21] with “respiratory
depression” required intubation.
CNS depression is the most frequently observed effect, occurring in 85 to 94 per cent of children and 78 per
cent of adults. It ranges from slight lethargy to coma with marked respiratory depression and apnea.[29][33] In
my experience, the CNS depression seems more stimulus responsive than in most overdoses, particularly in
young children. A toddler may present deeply comatose, flaccid, apneic, and bradycardic, with immediate
response on the part of the emergency department staff to obtain intravenous access and endotracheal
intubation. Remarkably, the child will often respond vigorously to these stimuli with arousal, crying, effective
respiratory effort, and increased heart rate. However, within seconds of being left “undisturbed,” the child
again reverts to apparent near-cardiorespiratory arrest. A similar scenario has been described in an 18-year-
old man with an intentional overdose.[1] Pupillary changes include miosis (observed in 20 to 26 per cent of
patients), as well as occasional mydriasis or unreactive pupils. Hypothermia, hyporeflexia, hypotonia, and
irritability are additional reported manifestations of CNS toxicity, and seizures have been observed rarely. As
noted previously, the concurrence of coma and miosis with central respiratory depression closely mimics
toxicity due to opioids, and some authors have suggested an action of clonidine on opioid receptors.[7][18]
The possible role of naloxone in reversing CNS effects is discussed under Treatment.
Cardiovascular depression is the second major toxic effect. Bradycardia (24–53 per cent) and hypotension
(21–38 per cent) are most consequential. A transient 2- to 4-hour period of hypertension (but as long as 24
hours)[8] has been described in 11 to 21 per cent of patients.[7][29][33] This probably reflects a particularly high
clonidine blood level causing transient predominance of peripheral postsynaptic a2-adrenergic
receptor–stimulated vasoconstriction over centrally mediated inhibition of sympathetic outflow.
Atrioventricular conduction abnormalities occasionally occur, including PR interval prolongation, 2:1 and
Wenckebach second-degree block, and complete heart block.[6][7]
Far less clinical experience has been reported with overdoses due to guanabenz, guanfacine, methyldopa,
and the topical imidazolines, but in general these agents seem to parallel clonidine toxicity in acute
overdose.[9][12][14][17][22][28][32] Rapid onset of CNS depression, bradycardia, and hypotension are described
in both adult and pediatric exposures. One 2-year-old child developed lethargy within 35 minutes after
ingesting 4 mg of guanfacine and then became mildly hypotensive 19 hours later but did not require specific
pressor therapy and recovered by 26 hours after ingestion.[32] Methyldopa toxicity may present after a
somewhat longer interval post ingestion,[28] perhaps explained by the time required for activation by
decarboxylation to a-methylnorepinephrine. Hypothermia, along with coma and bradycardia, has been
reported in an 89-year-old woman who overdosed on guanabenz.[22] Lethargy, bradycardia, and sinoatrial
node arrest were observed in a 16-year-old boy 5 hours after ingestion of up to 15 mL of 0.05%
tetrahydrozoline (Visine) eye drops.[17]
Chronic Toxicity
This group of antihypertensive agents has a rather common profile of adverse effects at therapeutic dosing,
including drowsiness, dizziness, dry mouth, and constipation.[9][15] Methyldopa has a particularly high
incidence of such effects, and in addition may cause sexual dysfunction, orthostatic hypotension,
atrioventricular conduction abnormalities, and sodium retention with edema and weight gain. Rare but
serious adverse effects of methyldopa include leukopenia and thrombocytopenia, myocarditis,
gynecomastia, pancreatitis, parkinsonism, Bell’s palsy, depression, and mild psychosis.
There is concern about the increasingly frequent prescription of combination clonidine-methylphenidate

therapy for pediatric ADHD.[20] Several prior reports are noted of transient electrocardiographic
abnormalities in patients on relatively low-dose clonidine therapy; and three cases have been reported of
sudden death in children taking clonidine and methylphenidate, although in each case clinical or laboratory
findings cast doubt on a causal relationship between the drug therapy and fatality. Subsequent evaluation by
the U.S. Food and Drug Administration found that whereas both medications have cardiotoxic potential,
there was a lack of convincing evidence for a lethal interaction.[10][25] Cardiac evaluation of ADHD patients
before instituting clonidine and periodically during chronic therapy has been recommended.[20]
Another phenomenon of this group of agents is that of a withdrawal syndrome of sympathomimetic

overactivity with hypertension, tachycardia, diaphoresis, palpitations, and anxiety that usually appears 16 to
48 hours after abrupt discontinuation of medication. This has been observed typically in patients using more
than 1.2 mg/d of clonidine[1][3] or 48 mg/d of guanabenz.[26] Patients who are also being treated with
concomitant ß-adrenergic receptor antagonists are at higher risk for severe manifestations of clonidine
withdrawal.[30][34]


The differential diagnosis of toxin-induced depression of CNS and cardiovascular function includes several
classes of pharmaceuticals ( Table 45–3 ). The coma, miosis, and frequently associated respiratory
depression, often punctuated by apnea, are suggestive of opioid intoxication, and there may be some opioid
receptor agonism of clonidine. Additional features of hypothermia, hypotonia, bradycardia, and hypotension
may enhance suspicion of opioid toxicity. Furthermore, many patients with clonidine toxicity will have partial
or dramatic responses to naloxone therapy, although usually only at the higher end of the dosing
requirement (0.1 mg/kg).[18] Thus, opioid and clonidine toxicity may be nearly indistinguishable at times,
apart from clinical circumstances and laboratory screening for opioids, which will be negative in clonidine
patients. Clonidine and related imidazolines may be conceptualized as possessing both sympatholytic and
opioid-like effects, and thus have more severe cardiovascular depression relative to CNS and respiratory
depression as compared with opioid toxicity. For example, significant heart block might suggest clonidine
overdose rather than opioids.
Table 45-3 -- Differential Diagnosis of Clonidine and Central-Acting Antihypertensive Poisoning

Drug/Toxin Common Clinical Syndrome Distinguishing Features
Coma, miosis, respiratory
Relatively less CV depression
depression
Opioids * Hypothermia Usually dramatic response to naloxone
Rare to see AV block or paradoxic
hypertension
Organophosphates and Cholinergic syndrome (may be subtle in
Coma, miosis
carbamates children)
Phenothiazines * Coma, miosis Less CV depression
Coma, occasional miosis No response to naloxone
Respiratory depression
Barbiturates *
Hypothermia
CV depression
Ethanol * Respiratory depression
Hypothermia
Miscellaneous
sedatives/hypnotics
Beta-adrenergic receptor Marked CV depression Less CNS depression

antagonists AV block
Drug/Toxin Common Clinical Syndrome Distinguishing Features
Marked CV depression Less CNS depression
AV block
CV, cardiovascular; CNS, central nervous system; AV, atrioventricular.
* Indicates usual detection by routine hospital overdose screen.
Other intoxications associated with depressed sensorium and miosis include those from organophosphates,
phenothiazines, barbiturates, ethanol, and some sedative-hypnotic agents. Organophosphate toxicity usually
manifests as other cholinergic findings, although these may be subtle in pediatric exposures. The other
medications on this list may be noted on toxicologic screening and would not show any response to a
naloxone trial.
Bradycardia and hypotension are primary manifestations of ß-adrenergic receptor antagonist and calcium-
channel blocker toxicity and may be seen in digitalis poisoning. Severe intoxications with these agents may
also be associated with altered sensorium. However, the cardiovascular effects associated with these
agents would typically be disproportionately severe relative to CNS and respiratory depression, in contrast to
clonidine and related imidazolines.


LABORATORY STUDIES
Clonidine and congeners are not detected on routine blood or urine toxicologic screening. Acute overdose
with these agents does not affect routine blood chemistry or pH determinations, unless secondary to hypoxic
or ischemic consequences. Plasma levels of clonidine are not generally measured, and such levels do not
correlate directly with clinical severity.[18] A gas chromatography/mass spectrophotometry assay is currently
available through reference laboratories that may detect clonidine at levels as low as 0.025 ng/mL
(therapeutic range is 0.1 to 0.6 ng/mL).[9] As noted earlier, electrocardiographic abnormalities include sinus
bradycardia and all degrees of atrioventricular block.


TREATMENT
The primary emphasis in the management of clonidine and related imidazoline toxicity is on gastrointestinal
decontamination and the intensive support of cardiorespiratory status ( Table 45–4 ). The rapid onset of
CNS depression contraindicates the use of syrup of ipecac.[33][34] Oral activated charcoal is the preferred
method of gastrointestinal decontamination for all forms of ingested imidazolines. Gastric lavage is
controversial but may precede charcoal administration in severe cases that present within 1 hour of
ingestion, particularly if the patient has already undergone endotracheal intubation for airway control and
respiratory support. In such patients, a small nasogastric tube is insufficient for tablet retrieval; and if lavage
is attempted, it should be done with a 24 to 26 F orogastric tube in children and a 36 to 40 F tube in adults. A
patient who has ingested a transdermal patch will not likely benefit from lavage. A case of patch ingestion
treated with whole-bowel irrigation has been reported with successful recovery of the patch in rectal effluent
and rapid subsequent recovery.[13] Dermal adherence of clonidine patches requires prompt discovery by
careful skin inspection and removal, followed by skin cleansing with soap and water.
Table 45-4 -- Treatment of Clonidine and Central-Acting Antihypertensive Poisoning

ABCs (Airway, Breathing, Circulation)
Intensive monitoring of respiratory and cardiovascular status
Intermittent stimulation for children with mild to moderate effects
Endotracheal intubation, mechanical ventilation for severe effects
Decontamination
Activated charcoal, cathartic (consider gastric lavage rarely for rapid presentation of severe effects)
Whole-bowel irrigation for patch ingestion
Removal and skin washing for patch adherence to skin
Central Nervous System Depression
Often responds transiently to stimulation
Naloxone trial (0.1 mg/kg, or 1–2 mg per dose, up to 8–10 mg)
Apnea
Naloxone (as above)
Endotracheal intubation, mechanical ventilation
Bradycardia
Naloxone (as above)
Atropine (0.02 mg/kg, min: 0.16 mg max: 1.0 mg, pediatric; 0.5–1.0 mg adult)
Dopamine (5–20 µg/kg/min)
Hypotension
Trendelenburg position
Crystalloid fluids (20 mL/kg boluses as necessary)
Dopamine (as above)
Hypothermia
Radiant heater, blankets
Hypertension
Usually transient, resolves without therapy
If severe, consider short-acting agents
Nitroprusside (0.5–4 µg/kg/min)
Seizures (rare)
Benzodiazepines if prolonged, recurrent
Lorazepam, 0.05–0.1 mg/kg pediatric; 2–4 mg adults
Treatment of CNS and respiratory depression centers on meticulous supportive care and attempts to
reverse toxicity with naloxone.[4] Naloxone’s efficacy in clonidine poisoning remains controversial, but a trial
in all significantly affected patients is warranted. Early administration of high doses (e.g., 0.1 mg/kg, or 1- to
2-mg doses repeated to a total of 10 mg) may enhance the efficacy of naloxone.[18] Some patients may
arouse considerably, with improvement in respiratory effort, heart rate, and blood pressure, after naloxone
infusion. As in opioid poisoning, naloxone effects may only last for 30 to 60 minutes, and repeated doses or
continual infusion may be necessary. An occasional patient may develop hypertension in temporal relation
to naloxone administration, so incremental dosing with ongoing observation of vital signs is indicated.[18][33]
Other authors have failed to detect a clear response to doses in the 0.1- to 0.25-mg/kg range for the more
severely affected patients.[33] Improvement after naloxone administration does not alter the need for
subsequent vigilant monitoring of cardiorespiratory status. Some toddlers with mild to moderate clonidine
toxicity may be managed with such monitoring in a pediatric intensive care unit using intermittent stimulation
alone for respiratory support, whereas more severely affected children will require endotracheal intubation
and ventilatory support for severe apnea and/or airway protection.[21][33] Intubation might also be favored in
apneic children who require transport to a tertiary care facility. Endotracheal intubation may be problematic,
given the notable stimulus-responsiveness of even severe clonidine poisoning. Some patients may become
bradycardic or agitated during positioning and laryngoscopy, necessitating a rapid sequence induction with
atropine, neuromuscular blockade, and cricoid pressure.[33]
Bradycardia may improve with atropine (pediatric dose: 0.02 mg/kg, minimum 0.16 mg, maximum 1 mg;
adult dose: 0.5–1.0 mg) or catecholamine support. Hypotension may respond to simple maneuvers such as
Trendelenburg positioning and crystalloid infusions. More severe cases of bradycardia or hypotension may
respond to dopamine infusion (5–20 µg/kg/min), which has been reported to be successful in clonidine
toxicity.[2][33]
Early reports of clonidine intoxication suggested use of the imidazoline a-adrenergic receptor antagonist
tolazoline (pediatric dose: 1 mg/kg to maximum 10 mg; adult dose: 5–10 mg IV, repeated as necessary
every 10–15 minutes, up to 40 mg total) as a physiologic antidote for the cardiovascular effects. However,
only variable success has been reported with use of this drug, its dosage is not easily titratable, and most
physicians currently in practice have had little experience with its use, particularly in pediatric patients. Thus,
it is not recommended as a first- or second-line agent in clonidine or related-agent intoxication. Some
authors still advocate its use as a last resort if bradycardia or hypotension fails to respond to atropine and
traditional catecholamine support.[7][9]
Paradoxical hypertension may occur early in severe cases or after naloxone treatment. The hypertension is
usually transient, is of little to no clinical significance, and is frequently followed by a hypotensive phase.
Thus, aggressive therapy is not warranted. In the occasional severe case, a short-acting antihypertensive
may be indicated, such as nitroprusside infusion in a closely monitored setting.[7][9] One hypertensive adult
patient was successfully treated with nifedipine,[7] and one similar child responded to hydralazine.[33]
Seizures, which rarely occur, may require benzodiazepine therapy if persistent or recurrent. Hypothermia
usually responds to external warming techniques (radiant heater and/or blankets). Both clonidine and
guanabenz have large volumes of distribution, and extracorporeal methods of enhanced elimination are not
thought to be useful. Forced diuresis may exacerbate hypotension and is not recommended. The
pharmacokinetics of methyldopa suggest possible benefit from hemodialysis, but there are little data
supporting its use in this context.[9]


DISPOSITION
All acute pediatric exposures to clonidine should be referred for emergent physician evaluation and
monitored for at least 4 hours, because minimal doses may result in rapid onset of significant toxicity.[18][33]
If symptoms evolve, children should be hospitalized for careful monitoring of CNS, respiratory, and
cardiovascular status. Adult patients should be similarly managed with careful medical observation before
transfer to a psychiatric unit. Symptomatic patients should be admitted to a medical or pediatric intensive
care unit. In most patients, symptoms resolve within 24 to 48 hours. Although there is less clinical
experience on which to base similar triage and disposition recommendations for the related imidazoline and
central-acting antihypertensives, similar guidelines should be followed. In the case of methyldopa, delayed
onset of toxicity is more characteristic, and thus all patients with significant overdose (pediatric dose > 50
mg/kg, adult dose > 2 g) should probably be hospitalized.[9]
An increasingly common occurrence is the inadvertent ingestion of one or two extra doses of clonidine by
children with ADHD on chronic three- or four-times-a-day dosing regimens (e.g., an extra 0.05 mg in a child
on 0.05 mg four times a day). There is little published experience on which to make firm triage guidelines,
but it seems reasonable to observe children at home if they take only one extra dose, are in the older,
school-age range (> 5 years), and have competent parents available to monitor them closely for several
hours. Further doses that day are probably best withheld. Any evidence of toxicity should prompt immediate
emergency department evaluation. Younger children (< 5 years), those who take two or more doses, those
without available home observation, or those with any evidence of toxicity warrant urgent referral to the
emergency department.


SEQUELAE
Fortunately, few deaths have been observed, despite the potential for severe morbidity for this class of
agents. No pediatric clonidine fatalities have been reported, and only two fatal adult intentional overdoses of
clonidine are cited in the annual reports of the American Association of Poison Control Centers from 1987 to
1996. One case occurred in a 37-year-old man who overdosed on an unknown number of clonidine tablets
and died of cardiac arrest despite attempts at treatment with naloxone, tolazoline, conventional resuscitation,
defibrillation, and external pacing. [19] At least one death from methyldopa overdose has been reported.[31]
Most reports and series of clonidine poisonings have emphasized complete recovery with good supportive
care and avoidance of complications.


REFERENCES
1. Anderson RJ, Hart GR, Crumpler CP, et al: Clonidine overdose: Report of six cases and review of the
literature. Ann Emerg Med 1981; 10:107-112.
2. Artman M, Boerth RC: Clonidine poisoning: A complex problem. Am J Dis Child 1983; 137:171-174.
3. Bailey R, Neale TJ: Rapid clonidine withdrawal with blood pressure overshoot exaggerated by beta-
blockade. BMJ 1976; 1:942-943.
4. Banner W, Lund ME, Clawson L: Failure of naloxone to reverse clonidine toxic effect. Am J Dis
Child 1983; 137:1170-1171.
5. Bousquet P, Feldman J, Tibirica E, et al: Imidazoline receptors: A new concept in central regulation of the
arterial blood pressure. Am J Hypertens 1992; 5:47S-50S.
6. Connor CS, Watababe AS: Clonidine overdose: A review. Am J Hosp Pharm 1979; 36:906-910.
7. Dire DJ, Kuhns DW: The use of sublingual nifedipine in a patient with a clonidine overdose. J Emerg
Med 1988; 6:125-128.
8. Domino LE, Domino SE, Stockstill MS: Relationship between plasma concentrations of clonidine and
mean arterial pressure during an accidental clonidine overdose. Br J Clin Pharmacol 1986; 21:71-74.
9. Ellenhorn MJ, Barceloux DG: Centrally acting agents Medical Toxicology., New
York: Elsevier; 1988:287-300.
10. Fenichel RR: Post-marketing surveillance identifies three cases of sudden death in children during
treatment with clonidine and methylphenidate. J Child Adolesc Psychopharmacol 1995; 5:157-166.
11. Guyenet PG: Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites?.
Am J Physiol 1997; 273:R1580-R1584.
12. Hall AH, Smolinske SC, Kulig KW, et al: Guanabenz overdose. Ann Intern Med 1985; 102:787-788.
13. Henretig F, Wiley J, Brown L: Clonidine patch toxicity: The proof’s in the poop. [Abstract]. J Toxicol Clin
Toxicol 1995; 33:520-521.
14. Higgins GL, Campbell B, Wallace K, et al: Pediatric poisoning from over-the-counter imidazoline-
containing products. Ann Emerg Med 1991; 20:655-658.
15. Hoffman BB, Lefkowitz RJ: Catecholamines, sympathomimetic drugs, and adrenoreceptor antagonists..
In: Hardman JG, Limbird LE, ed. The Pharmacologic Basis of Therapeutics, . 9th ed. New York: McGraw-
Hill; 1996:217-219.
16. Hunyor SN, Bradstock K, Somerville PJ, et al: Clonidine overdose. [Letter]. BMJ 1975; 4:23.
17. Jones DG, Osterhoudt K, Stone M, et al: Sinoatrial node dysfunction following tetrahydrozoline (Visine)
ingestion. [Abstract]. J Toxicol-Clin Toxicol 1996; 34:564.
18. Knapp JF, Fowler MA, Wheeler CA, et al: Case 01-1995: A two-year-old female with alteration of
consciousness. Pediatr Emerg Care 1995; 11:62-65.
19. Litovitz TL, Schmitz BF, Holm KC: 1988 Annual Report of the American Association of Poison Control
Centers National Data Collection System. Am J Emerg Med 1989; 7:495-545.
20. Maloney MJ, Schwam JS: Clonidine and sudden death. Pediatrics 1995; 96:1176-1177.
21. Nichols MH, King WD, James LP: Clonidine poisoning in Jefferson County, Alabama. Ann Emerg
Med 1997; 29:511-517.
22. Perrone J, Hoffman RS, Jones B, et al: Guanabenz induced hypothermia in a poisoned elderly female.
J Toxicol Clin Toxicol 1994; 32:445-449.
23. Pettinger WA: Clonidine, a new antihypertensive drug. N Engl J Med 1975; 293:179-180.
24. Pettinger WA: Pharmacology of clonidine. J Cardiovasc Pharm 1980; 2(suppl 1):S21-S28.
25. Popper CW: Combined methylphenidate and clonidine: News reports about sudden death. J Child
Adolesc Psychopharmacol 1995; 5:155-166.
26. Ram VCS, Holland B, Fairchild C, et al: Withdrawal syndrome following cessation of guanabenz
therapy. J Clin Pharmacol 1979; 19:148-150.
27. Regunathan S, Reis DJ: Imidazoline receptors and their endogenous ligands. Ann Rev Pharm
Toxicol 1996; 36:511-544.
28. Shnaps Y, Almog S, Halkin H, et al: Methyldopa poisoning. J Toxicol Clin Toxicol 1982; 19:501-503.
29. Stein B, Volans GN: Dixarit overdose: The problem of attractive tablets. BMJ 1978; 2:667-668.
30. Strauss FG, Franklin SS, Lewin AJ, et al: Withdrawal of antihypertensive therapy: Hypertensive crisis in
renovascular hypertension. JAMA 1977; 238:1734-1736.
31. Tamminen V, Alha A: Fatal methyldopa poisoning. Bull Int Assoc Toxicol 1970; 7:2.
32. VanDyke MW, Bonace AL, Ellenhorn MJ: Guanfacine overdose in a pediatric patient. Vet Hum
Toxicol 1990; 32:46-47.
33. Wiley II JF, Wiley CC, Torrey SB, et al: Clonidine poisoning in young children. J
Pediatr 1990; 116:654-658.
34. Wiley II JF: Clonidine and related imidazoline derivatives..

In: Haddad LM, Shannon MW, Winchester JF, ed. Clinical Management of Poisoning and Drug Overdose, .
3rd ed. Philadelphia: WB Saunders; 1998:1049-1054.


Chapter 46 – Antihypertensives
ROY A. PURSSELL
Essentials
• Hypotension
• Bradycardia
• Tachycardia, electrocardiographic (EKG) abnormalities with vasodilator overdose
• Sedation
• Electrolyte abnormalities with diuretic overdose
INTRODUCTION
Although antihypertensive agents are used extensively, relatively few cases of overdose are reported in the
literature. As newer agents, such as angiotensin-converting enzyme (ACE) inhibitors, replace older agents,
the pattern of drug overdose can be expected to change as well. Central-acting agents, ß-adrenergic
receptor antagonists, mixed-adrenergic blocking agents, calcium channel blockers, and nitroprusside are
covered in separate chapters.


SPECIFIC AGENTS
Diuretics
Overdose with diuretics is uncommon. There are three classes of diuretics in common use: (1) thiazides and
thiazide-like diuretics, (2) loop diuretics, and (3) potassium-sparing diuretics. Carbonic anhydrase inhibitors
and osmotic diuretics have limited and specific uses. Mercurial diuretics are no longer used.
Pharmacologic data are contained in Table 46–1 . Diuretics often produce effects by interfering with
adenosine triphosphate (ATP)-mediated renal epithelial transport of solutes. This may require symport,
cotransport of solutes in the same direction, or antiport, countertransport of solutes in opposite directions.[31]
Thiazide diuretics act on the distal convoluted tubule segment of the nephron. They inhibit the
sodium/chloride (Na+/Cl-) symporter, thereby increasing the excretion of Na+ and Cl-. Thiazide diuretics also
increase potassium (K+) excretion, owing to its exchange with the increased Na+ in the distal tubule, and
cause arteriolar dilatation. Loop diuretics inhibit the Na+/K+/2Cl- symporter in the thick ascending limb of the
nephron, blocking the reuptake of Na + and Cl- as well as calcium (Ca2+ ) and magnesium (Mg2+ ). Potassium-
sparing diuretics are not very efficacious as diuretics or antihypertensive agents and are used primarily for
their potassium-sparing quality. Amiloride and triamterene block Na+ channels in the distal tubule and
collecting duct, preventing the exchange of K+ (excretion) for Na+ (reabsorption) and also blocking the
elimination of hydrogen (H+), Ca2+ , and Mg2+ at these sites. Spironolactone produces a similar effect on K+
and H+ excretion by inhibiting aldosterone binding in the distal tubule and collecting duct, which then inhibits
the activity of Na+ channels. Carbonic anhydrase inhibitors inhibit carbonic anhydrase, which catalyzes the
formation of H2CO3 from CO2 and H2O. Normally, the H2CO3 formed would ionize to H+ and HCO3- in the
cytoplasm, and the H + formed would be exchanged for luminal Na+ by the Na+/H+ antiporter. By inhibiting
H2CO3 formation, carbonic anhydrase inhibitors prevent this Na+/H+ exchange; the net result is increased
renal excretion of HCO3-, Na+, K+, Cl-, and water in the urine. Osmotic diuretics are freely filtered at the
glomeruli and undergo minimal tubular reabsorption. They act predominantly at the loop of Henle and
produce diuresis by extracting intracellular water and decreasing renal medullary tonicity. Excretion of all
electrolytes is increased.[31]
Table 46-1 -- Antihypertensive Drugs: Pharmacokinetics and Therapeutic Dose

Duration of
Drug Onset (min) Peak Effect (hr) Action (hr) Elimination
Diuretics
=120 Single dose: 6–10 Single dose: R 20–50% (U); fecal 40% (U)
Amiloride
24
Acetazolamide
(extended release 120 8–12 18–24 R (U)
capsules)
Duration of
Bumetanide (oral) 30–60 1–2 4–6 H; R (81%; 45% U); biliary/fecal
H; R (67%); biliary/fecal (33%);
Ethacrynic acid (oral) 30 2 6–8
20% U
R (88%); biliary/fecal (12%);
Furosemide (oral) 20–60 1–2 6–8 nonrenal clearance increased
in renal impairment
Hydrochlorothiazide 120 4 6–12 R (U)
Multiple doses: Multiple H; metabolites eliminated
Spironolactone Gradual onset
48–72 doses: 48–72 mainly R (<10% U)
Torsemide (oral) =60 1–2 6–8 H; R (24% U)
Single dose: Multiple doses: 24 Single dose: H; biliary/fecal; R secondary
Triamterene
120–240 hr to several days 7–9 route
Sympatholytics
H; fecal U 5%, metabolites
Doxazosin 60–120 5–6 24
65%; R 9%
Single dose:
Guanadrel 120 4–6 H; R 85% (40% U)
9
Single dose: 8; Multiple
Guanethidine multiple doses: doses: 1–3 H; R 25–50% (U)
1–3 wk wk
Effects cumulative
Phenoxybenzamine Several hours over 168 hr with 72–96 H; R/biliary
daily dosing
Half-life 19 Not completely known; R 13%
Phentolamine
min U
H; bile and feces; R 6–10%;
Prazosin 30–90 Single dose: 2–4 7–10
5–11% excreted U
Several days to 3
3–6 wk (multiple
wk (multiple
doses);
doses); H; fecal more than 60% mainly
Reserpine catecholamine 1–6 wk
catecholamine U; R 8% (1% U)
depletion within 24
depletion =60 min
hr (single dose)
(1 dose)
2–3 hr (single
H; fecal (biliary) 40%; fecal (U)
Terazosin 15 dose); up to 6–8 24 hr
20%; R 40% (10% U)
wk (multiple dose)
Duration of
May be metabolized by
Trimethaphan IV immediate 10–15 min pseudocholinesterase; R,
mostly U
Vasodilators
H extensive; R (2–4% U after
Hydralazine Oral 45 IV 0.25–0.5 Oral or IV 3–8
oral; 11–14% U after IV)
IV 10–20
Diazoxide (IV) 1 0.03–0.08 2–12 H; R (50% U)
H 90%; fecal 3% (may increase
Single dose: 2–3; 24–48; up to
in severe renal function
Minoxidil 30 multiple doses: 75 in some
impairment); R 97%, mostly as
72–168 patients
metabolites
Angiotensin-Converting Enzyme Inhibitors
Benazepril =60 Single dose: 2–4 Single dose: H to active metabolite; R mainly
24 biliary (11–12%)
Single dose:
Captopril 15–60 Single dose: 1–1.5 6–12; dose H; R >95% (40–50% U)
related
H to enalaprilat, active
Single dose: metabolite; R 60% (20% U and
Enalapril 60 Single dose: 4–6
24 40% as enalaprilat); fecal 33%
(6% U and 27% enalaprilat)
Single dose:
Enalaprilat (IV) 15 Single dose: 1–4 R 100% U
6
H, gastrointestinal mucosa;
Single dose:
Fosinopril =60 Single dose: 2–6 fosinoprilat active metabolite; R
24
44–50%; fecal 46–50%
Single dose:
Lisinopril 60 Single dose: 6 R 100% U
24
H, gastrointestinal tract,
extravascular tissue; by
Single dose
hydrolysis to quinaprilat, the
Quinapril =60 Single dose: 2–4 =24; dose
active metabolite; R 61% (56%
related
as quinapril and quinaprilat);
fecal 37%
Single dose: H to active metabolite; R 60%;
Ramipril 60–120 Single dose: 4–6.5
24 fecal 40%
Multiple doses: 1 Single dose: H to active metabolite; R 33%;
Trandolapril
wk 24 feces 66%
Duration of
Angiotensin II Receptor Antagonist
24; multiple
doses: 2/3 of
Single dose: 4; blood
H; R 20% (U and metabolites);
Irbesartan multiple doses: 2 pressure
biliary
wk effect still
present 1 wk
after last dose
H; metabolite responsible for
much of activity; R 35% (4% U
Losartan 6 =24
and 6% active metabolite);
fecal (biliary) 60%
H; 20% eliminated as
Valsartan 120 6 =24
metabolite; R 13%; feces 83%
H, Hepatic; R, renal; U, unchanged.
Data from USPDI Drug Information for the Health Care Professional, 17th ed. If drug is newly marketed, data
from package insert.
The pathophysiologic effects of diuretics are predominantly due to alterations in fluid and electrolyte
balance. In addition to systemic effects, loop diuretics alter electrolyte composition in the endolymph of the
inner ear, which can lead to ototoxicity.[31] The potassium-sparing diuretics can produce hyperkalemia,
especially in predisposed patients such as those with renal failure or who take ACE inhibitors or potassium
supplements. Carbonic anhydrase inhibitors produce urinary alkalinization and systemic metabolic acidosis,
which can worsen other systemic acidotic states; increase the formation of renal calcium phosphate stones;
and increase systemic ammonia levels, thereby worsening hepatic cirrhosis. Acutely, osmotic diuretics
increase extracellular fluid and can precipitate pulmonary edema.
Overdose with diuretics, either intentional or iatrogenic, generally has a benign outcome. Although rare, the
following can occur: coma, cardiac dysrhythmias, dehydration, and electrolyte abnormalities. Overdose of
thiazide diuretics resulting in coma has been described in children[5][67] and adults.[84] Two children, aged 14
months and 2½years, ingested a large quantity of chlorothiazide. They became drowsy 3½hours after the
ingestion, and at 12 hours were deeply comatose. The children did not appear dehydrated, had normal
electrolyte levels, and did not have dysrhythmias. Both children were asymptomatic 3 days after ingesting
the medication.[6] A 22-month-old child who ingested 3 g of chlorothiazide developed lethargy 4 to 5 hours
after the ingestion, which completely resolved by 24 hours. Although the child urinated large amounts of
urine, he did not appear dehydrated and did not develop electrolyte abnormalities. A patient with renal failure
on chronic hemodialysis accidentally received high-dose hydrochlorothiazide. He became increasingly
confused, forgetful, ataxic, and tremulous over the 4 days that he received the medication. His symptoms
improved after his first dialysis following discontinuation of the medication, and they had completely resolved
in 6 days.[84] In these cases the patients did not develop dehydration or electrolyte abnormalities, and it has
been postulated that thiazide diuretics may have a direct central nervous system (CNS) depressant effect.[84]
Seizures have been reported after self-poisoning with bendrofluazide.[23] Drowsiness, confusion, and coma
have been described in children who received large doses of chlorothiazide to treat nephrogenic diabetes
insipidus.[57][76]
Table 46-2 -- Clinical Presentation of Antihypertensive Drug Toxicity

Drug Class Signs and Symptoms
Diuretics Hearing loss (loop diuretics)
Rare: Drowsiness, coma, cardiac dysrhythmias, dehydration, hypotension,
electrolyte abnormalities
Hypotension
Bradycardia or tachycardia
Sympatholytics
CNS depression (reserpine)
Rare: Coma, seizures, respiratory depression
Hypotension
Vasodilators
Tachycardia
Hypotension
ACE inhibitors Hyperkalemia (uncommon)
Adverse effects: cough, angioneurotic edema
Angiotensin II receptor Hypotension *
antagonists Adverse effects: cough, angioneurotic edema less than that with ACE inhibitors
* Hypotension anticipated but no overdose cases reported.
A patient reported by Zahid and associates[84] developed cardiac dysrhythmias and conduction blocks.
Frequent premature atrial contractions, brief runs of paroxysmal supraventricular tachycardia, and
occasional premature ventricular contractions and varying degrees of atrioventricular block were noted. The
dysrhythmias were not associated with decreased cardiac output and did not appear to cause the
confusional state. They resolved in 6 days. This is the only reported case in which dysrhythmias developed
in the absence of electrolyte abnormalities. Ventricular tachycardia in association with profound
hyperkalemia developed in a patient who took an overdose of cyclopenthiazide and potassium chloride.
Several cases of profound hyperkalemia have been reported after overdose with a combination of thiazide
diuretics and potassium.[28][30] Hypokalemia, hyponatremia, hypercalcemia, and hypomagnesemia have
also occurred.[49] Hyperkalemia developed after an overdose of potassium-sparing agents.[35]
Gastrointestinal symptoms may occur after a diuretic overdose,[49] and renal failure has been reported after
an overdose of Dyazide.[14] The loop diuretics can cause ototoxicity; patients with renal insufficiency who
receive a rapid intravenous infusion of a large dose of these agents are at increased risk. The total dose of
furosemide received by patients before hearing loss ranged from 40 mg to 21.6 g and occurred in 6 patients
who received a total of 200 mg or less of furosemide.[15] The ototoxicity is usually reversible, although a few
cases of permanent hearing loss have been described.[26]
Therapeutic use of thiazide diuretics is associated with an increase in sudden cardiac death. This is
probably related to diuretic-induced potassium loss.[7][19][25][72] Sudden death has also been reported after
ingestion of furosemide, but it is unclear if the furosemide was responsible.[10] Noncardiogenic pulmonary
edema is a very uncommon but potentially life-threatening condition related to therapeutic use of
hydrochlorothiazide.[18][34][36]
In a minority of cases, dehydration and hypotension can occur.[49] A fatal thrombosis of the left internal
carotid artery has been described after diuretic abuse.[68] Therapeutic use of thiazide diuretics can cause
hypokalemia, hyponatremia, hypercalcemia, and hypomagnesemia.[1][3][49] Significant metabolic acidosis
may occur in patients taking acetazolamide. [21]
Other complications described include renal failure after large therapeutic doses of mannitol.[12][27][62]
Thiazide use is associated with cholecystitis,[66] and one case each of thrombocytopenia[13] and of hemolytic
anemia[82] have been reported.
Sympatholytic Drugs
Six types of sympatholytic drugs are used in the treatment of hypertension[56]:

1. Central-acting agents (methyldopa, clonidine, guanabenz, guanfacine)
2. Ganglionic blocking agents (trimethaphan)
3. Adrenergic blocking agents (guanethidine, guanadrel, reserpine)
4. Beta-adrenergic receptor antagonists (e.g., propranolol, metoprolol)
5. Alpha-adrenergic receptor antagonists (prazosin, terazosin, doxazosin, phenoxybenzamine,
phentolamine)
6. Mixed adrenergic receptor antagonists (labetalol)
Beta-adrenergic receptor antagonists and the central-acting agents are discussed in Chapters 42 and 45
and are not covered here. The other drugs in this category are not used commonly and, hence, are rarely
taken in overdose.
Pharmacology/Pathophysiology (see Table 46–1 )
Trimethaphan produces ganglionic blockade by competing with acetylcholine for postganglionic nicotinic
receptor sites. Ganglionic blockade causes reversal of adrenergic-mediated vasoconstriction of arterioles
and venules. Trimethaphan also acts as a direct vasodilator[20] and stabilizes postsynaptic nerve
membranes. Overdose of ganglionic blocking agents is characterized by hypotension and tachycardia, as
well as by effects of both sympathetic and parasympathetic blockade.
Guanethidine and guanadrel interfere with the function of peripheral postganglionic adrenergic neurons by
acting as inactive substitute “neurotransmitters.” They are transported into neurons by the transporter that
reuptakes norepinephrine, and they replace norepinephrine in neurosecretory vesicles. When given in large
doses, guanethidine can also block neuronal excitation or the associated release of neurotransmitters.[70]
Guanethidine administered intravenously can initially release norepinephrine, causing hypertension. Chronic
treatment with guanethidine or guanadrel sensitizes neuronal cells to norepinephrine.[56] Reserpine binds to
and inactivates storage vesicles for norepinephrine and dopamine in both central and peripheral adrenergic
neurons.[16] As a result, these neurotransmitters leak into the neuronal cytoplasm and are inactivated by
monoamine oxidase. The a-adrenergic receptor antagonists such as prazosin and phentolamine selectively
block peripheral a1-adrenergic receptors without affecting peripheral a2-adrenergic receptors. Arteriolar
resistance is reduced and venous capacitance is increased, resulting in a sympathetically mediated reflex
increase in heart rate and plasma renin activity.[47] Labetalol is a mixture of stereoisomers. One isomer is an
a-adrenergic receptor antagonist, and another is a nonselective ß-adrenergic receptor antagonist with partial
agonist activity. Labetalol lowers blood pressure by blockade of a-adrenergic receptors and stimulation of
ß2-adrenergic receptors.[51]
Clinical Presentation (see Table 46–2 )
One case of massive trimethaphan overdose in a 7½-month-old girl has been described. This infant had
pneumococcal meningitis and presented with a heart rate of 160 beats per minute and a blood pressure of
190/110 mmHg. A 1000-fold dosage error resulted in the child being given trimethaphan, 20 mg/kg. The
infant had no detectable blood pressure for several seconds, followed by a normalization of the blood
pressure over a period of several hours. The child also had dilated pupils that were poorly responsive to
light. [20] Respiratory arrest has also been reported after high doses of trimethaphan.[11] The following side
effects have occurred in patients receiving ganglionic blocking agents on a chronic basis: interstitial fibrosis,
seizures, and psychosis. [60]
Guanethidine can produce dizziness, blurred vision, bradycardia, nausea, vomiting, and diarrhea. Profound
hypotension lasting up to a week has been reported after the use of intravenous guanethidine for the
treatment of neuralgia after neural injury.[33] Apnea and syncope have also been reported in this
setting.[32][71]
Reserpine overdose is characterized by CNS depression, bradycardia, and hypotension. Three children who
ingested reserpine became drowsy 3 hours after ingestion, were comatose after 10 hours, and completely
recovered in 36 hours.[50] One child developed hypertension. The children had constricted, nonreactive
pupils, and the recovery phase was characterized by tremor and clonic movements. McKown and
colleagues reviewed 151 cases of Rauwolfia alkaloid overdose.[54] Twenty-five patients had CNS
depression, one adult became comatose, two patients became hypotensive, 20 patients developed flushing,
one had vertigo, and four vomited. Sixty-eight patients (48 per cent) had no symptoms.
Prazosin overdose is characterized by tachycardia, hypotension, and alterations in level of consciousness

that can vary from drowsiness to coma. [46][47][69] Respiratory failure, metabolic acidosis, and pulmonary
edema have occurred.[46] The onset of symptoms occurs within 3 hours of ingestion with full recovery in 48
hours.[47] Priapism develops rarely during therapeutic use of these agents and has been reported after
deliberate overdose of prazosin.[63] A 43-year-old woman took an overdose of indoramin and was
unconscious 1 hour after the overdose. She developed seizures, respiratory depression, metabolic acidosis,
pulmonary edema, and bradycardia. Treatment with fluid support, atropine, and isoproterenol was
unsuccessful, and the patient died 7 hours after the ingestion.[29]
Labetalol overdose is characterized by bradycardia, conduction blocks, and hypotension.[22][39] Drowsiness,

seizures, and coma have been described, and renal failure has occurred.[40][73] Symptoms develop within 2
hours of the ingestion and, with the exception of renal failure, resolve in less than 48 hours.
Vasodilators
There are three arterial vasodilators: hydralazine, minoxidil, and diazoxide. Very few overdoses of
hydralazine or diazoxide are reported in the literature. Minoxidil is also available as a topical preparation to
treat male pattern baldness, and overdoses of this agent are more common. Nitroprusside causes both
arterial and venous vasodilation, and toxicity from this agent is discussed in Chapter 47 .
Pharmacology
Hydralazine directly relaxes arteriolar smooth muscle by a mechanism that involves cyclic guanosine
monophosphate. It is well absorbed from the gastrointestinal tract, and peak plasma levels occur in 1 to 2
hours. Plasma concentrations of the drug do not correlate with toxicity. The rate of elimination is dependent
on the genetically determined activity of N-acetyl-transferase. When treated with the same dose of drugs,
slow acetylators have higher serum concentrations of hydralazine than fast acetylators. Slow acetylators
have a greater lowering of blood pressure. With doses of hydralazine in excess of 200 mg/d, slow
acetylators are more likely to develop antinuclear antibodies and develop a lupus erythematosus-like
syndrome.[38]
Minoxidil sulfate activates adenosine triphosphatase (ATPase)–sensitive K+ channels, producing

vasodilation by hyperpolarizing arteriolar smooth muscle cells.[43] It is a potent vasodilator with almost no
effect on the venous system. It is well absorbed from the gastrointestinal tract, and peak serum
concentration occurs in 1 hour. The maximum hypotensive effect develops later and is likely due to
conversion to an active metabolite, minoxidil N-O sulfate. The majority of the drug is eliminated by hepatic
metabolism, and only 20 per cent of the absorbed drug is excreted unchanged in the urine. The elimination
half-life of minoxidil in plasma is 4 hours or less, but its duration of action can exceed 24 hours due to active
metabolites.
Diazoxide activates ATPase-sensitive K+ channels, producing vasodilation by hyperpolarizing arteriolar

smooth muscle cells.[77] It does not affect capacitance vessels. It is only administered intravenously in
clinical practice. Twenty to 50 per cent of the drug is renally eliminated, and the rest is hepatically
metabolized to 3-hydroxymethyl and 3-carboxy derivatives. Although the half-life of diazoxide is 20 to 60
hours, the hypotensive effect lasts for as little as 4 hours. This may be related to stimulation of renin with
subsequent production of angiotensin II.[37]
Pathophysiology
The predominant pathophysiologic effects are due to the hypotension caused by these drugs. Hydralazine
produces a tachycardia that has been attributed to a simple baroreceptor mechanism. However, evidence
from animal studies suggests that hydralazine has direct chronotropic and inotropic effects that can be
blocked by calcium channel antagonists or ß-adrenergic receptor antagonists.[4] Myocardial ischemia can
occur; it is unclear if this is caused by increased myocardial oxygen consumption due to tachycardia,
decreased coronary perfusion, or direct toxicity due to the drug.[74] Therapeutic use of hydralazine can also
induce several immunologically mediated effects whose underlying mechanisms remain unknown.
Minoxidil ingestion leads to increases in heart rate, myocardial contractility, and myocardial oxygen
consumption. The cardiac output may quadruple. These effects are due to baroreceptor-mediated activation
of the sympathetic nervous system and enhancement of venous return due to increased flow in vascular
beds. Flattened and inverted T waves in the electrocardiogram, described in both acute overdose and
therapeutic use, are probably related to activation of myocardial potassium channels. Retention of sodium
and water results from increased proximal renal tubular resorption secondary to decreased renal perfusion
pressure.[58]
Diazoxide causes baroreceptor-mediated sympathetic stimulation, thus increasing myocardial contractility

and producing tachycardia. Changes in intrarenal hemodynamics and stimulation of renal sympathetic
nerves result in significant sodium and water retention. Stimulation of ATPase-sensitive K+ channels also
inhibits release of insulin from pancreatic beta cells, producing hyperglycemia.[37]
Hydralazine
Hydralazine toxicity is normally characterized by mild hypotension and tachycardia. Marked, transient ST-
segment depression has been described in a young woman who overdosed on hydralazine.[73]
Two types of side effects occur with therapeutic use. Pharmacologic effects include headache, nausea,
flushing, hypotension, palpitations, tachycardia, dizziness, and angina. Hydralazine may precipitate
myocardial infarct in patients with coronary artery disease.[38] The second type, immunologic, can include a
lupus-like syndrome, vasculitis, serum sickness, hemolytic anemia, and rapidly progressive
glomerulonephritis. The lupus syndrome is the most common. An unusual side effect is a pyridoxine-
responsive polyneuropathy.[56]
Minoxidil
The oral and topic minoxidil exposures reported to the American Association of Poison Control Centers
(AAPCC) from 1985 to 1991 have been reviewed. Only minor effects were reported after topical exposure.
Of 224 ingestions reviewed, 16 (7.1 per cent) developed moderate to major effects according to AAPCC
criteria. The most frequent effects were hypotension (69 per cent), tachycardia (38 per cent), and lethargy
(31 per cent). One death was reported, but this patient had ingested hydralazine, prazosin, and paracetamol
as well as minoxidil.[65] A young woman who took an overdose developed labile hypotension, tachycardia,
and EKG changes of diffuse T wave inversions and ST segment depression. The patient’s blood pressure
dropped 3 hours after she ingested the tablets and returned to normal after 30 hours. The changes in the
EKG started to resolve in 8 hours.[61] Ingestion of minoxidil has also resulted in a non–Q wave myocardial
infarction.[52] Prolonged hypotension requiring inotropic support for 48 hours has been described; the blood
pressure did not normalize for 72 hours.[53]
Therapeutic use of minoxidil can have significant cardiovascular effects. Myocardial ischemia can occur in
patients with coronary artery disease. Congestive heart failure has been reported, and pericardial effusion is
an uncommon, but serious, complication.[41] Fluid retention is especially problematic if the patient has any
degree of renal impairment. Hypertrichosis is an almost universal side effect in patients on long-term
therapy. Topical use of minoxidil can also produce cardiovascular effects.[45]
Diazoxide
Diazoxide is used only parenterally for treatment of hypertensive emergencies. Diazoxide infusion will lower
the blood pressure within 30 seconds, with maximum effect occurring in 3 to 5 minutes. When diazoxide was
introduced, a bolus of 300 mg was recommended. This practice resulted in myocardial and cerebral
infarction.[37] Severe hyperglycemia with hyperosmolar nonketotic coma has been described. Diazoxide may
cause arrest of labor, owing to its effect on smooth muscles, if given in the peripartum period. Diazoxide
displaces warfarin from serum albumin, and it may be necessary to lower the anticoagulant dose once
diazoxide is given.[37]
Angiotensin-Converting Enzyme Inhibitors
The ACE inhibitors are widely used in the treatment of hypertension and congestive heart failures. This class
of drugs includes alacepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, moexipril, pentopril, perindopril,
quinapril, ramipril, spirapril, trandolapril, and zofenopril. Some of these may not be available in the United
States. Captopril was the first agent to be developed. Overdose has been reported with captopril, enalapril,
and lisinopril. A review of the literature [48] reports 12 cases of overdose in the English language literature.
Another study reviewed cases reported to five regional poison control centers in the United States over a 6-
month period. Nineteen cases of overdose with captopril, 19 overdoses with enalapril, and 12 overdoses
with lisinopril were reported.[9]
Pharmacology/Pathophysiology (see Table 46–1 )
Some agents in this class, including pentopril, alacepril, ramipril, and enalapril, are prodrugs. The prodrugs
are converted to active drug in the liver. They have an increased rate of absorption and longer duration of
action than the other drugs in this class. Ingestion of food can reduce the absorption of an active drug, such
as captopril, by 30 per cent but has little effect on the absorption of a prodrug such as enalapril. Captopril
levels peak 1 hour after ingestion. Enalapril is converted to enalaprilat, which reaches peak levels in serum 4
hours after ingestion. These drugs have polyphasic elimination kinetics. The prolonged terminal elimination
phase is probably related to persistent binding of the drug to ACE. After a minor overdose of enalapril, the
plasma ACE activity did not normalize for 147 hours. Captopril is eliminated from the body more rapidly, and
ramiprolat, the active metabolite of ramipril, is eliminated more slowly, than other ACE inhibitors. The
primary route of elimination for all is the kidney.
The pathophysiologic effects are related to the pharmacologic mechanisms by which these drugs ameliorate
hypertension. ACE inhibitors work by blocking ACE, located primarily in the pulmonary vascular
endothelium, which is an important enzyme in the renin-angiotensin system. All ACE inhibitors have a
common 2-methyl propranolol-L-proline moiety. This moiety binds to the active site of the ACE and prevents
the conversion of angiotensin I to angiotensin II, which is the primary antihypertensive effect.
Angiotensin II directly acts on blood vessels to cause vasoconstriction. Angiotensin II also stimulates
aldosterone secretion, causing salt and water retention, and participates in the breakdown of bradykinin to
inactive compounds. ACE inhibitor use results in accumulation of bradykinin, which may also reduce blood
pressure, either by direct vasodilation or by stimulation of prostaglandin synthesis. Unlike other vasodilators,
ACE inhibitors do not produce a reflex tachycardia. This is likely due to centrally mediated effects.
Angioedema is a rare, potentially life-threatening complication associated with the use of ACE inhibitors.
Marked edema of the tongue can obstruct the airway, resulting in respiratory arrest. This phenomenon is
mediated through the kallikrein-kinin system.[64]
The hemodynamic response to ACE inhibitors is mediated by substances that bind to opiate receptors.[83]
Hypotension can occur with the first therapeutic dose of an ACE inhibitor, and this effect can be blocked by
naloxone administration. ACE inhibitors can cause renal damage by (1) reducing glomerular filtration
pressure, (2) decreasing renal blood flow due to systemic hypotension, and (3) producing
glomerulonephritis. Reduced aldosterone production can result in electrolyte abnormalities, specifically
hyperkalemia, hyponatremia, and metabolic acidosis.
Hypotension is the most common symptom after overdose.[48] The hypotension may be profound, and
systolic pressures as low as 40 mmHg have been reported. Symptoms did not occur until 6 hours after
ingestion[42] in a 46-year-old woman who took an overdose of enalapril. In most cases, the hypotension
responds to supportive measures and resolves in less than 24 hours. However, persistent hypotension
developed in a 33-year-old woman who overdosed on captopril. The patient was given 5.6 L of saline and
required dopamine until 53 hours after admission.[2] Most cases are characterized by a normal pulse.
Bradycardia has been described in a patient who ingested verapamil as well as enalapril.[32] The level of
consciousness may be depressed; this is likely caused either by co-ingested medications or by hypotension.
A woman presented alert, with a blood pressure of 120/70 mmHg, 6 hours after an ingestion of enalapril.
She developed hypotension and stupor simultaneously.[42]
Overdose may produce dramatically different symptoms and outcomes in different patients.[81] A 73-year-old
man was found dead in his residence after ingesting 1125 mg of captopril. There were no known co-
ingestants, and the patient had an elevated postmortem plasma captopril concentration of 60.4 mg/L.[59] A
66-year-old man ingested 5000 to 7500 mg of captopril and remained asymptomatic despite a calculated
maximal plasma level of 59.9 mg/L.[44] Two patients who ingested large doses of captopril (1500 mg and
5000 mg) did not develop any symptoms.[79]
In children, possible small ingestions of subtherapeutic adult doses of ACE inhibitors have been reported to
have benign outcomes. However, reliance on these poison center studies is limited by the lack of hard data
(documented witnessed ingestion or serum drug levels). Spiller and coworkers reported a series of 48
asymptomatic ACE inhibitor ingestions in children.[75] Hogue-Murray and associates reported 110 pediatric
exposures. One child had a 10 per cent decrease in blood pressure, and the other children remained
asymptomatic.[24]
Hypotension can occur with the first therapeutic dose of an ACE inhibitor. Syncope and myocardial infarction
have occurred in this setting.[8] In approximately 10 per cent of patients, the systolic blood pressure drops by
more than 50 mmHg. Patients with renovascular hypertension or volume depletion are at increased risk.
Reversible acute renal failure resulting from hypoperfusion has occurred with both drug overdose and
therapeutic drug use. Hyperkalemia, hyperphosphatemia, hyponatremia, and metabolic acidosis have been
described.
Adverse drug effects reported with therapeutic ACE inhibitor use include angioedema, chronic cough,
rhinitis, azotemia, rash, nephrotic syndrome, hypotension, arthralgia, hypokalemia, and agranulocytosis.
Angioedema has an overall incidence of 0.1 to 0.2 per cent. The tongue and soft tissues of the neck are
often affected,[64] but the clinical presentation is unpredictable. Some cases resolve spontaneously or with
standard therapies for allergic reactions, including antihistamines, corticosteroids, and epinephrine. Other
cases may progress rapidly and not respond to therapy. A fatality has been reported.[17] In this case,
massive edema led to airway obstruction, requiring a surgical airway.
Severe hyperkalemia can occur if ACE inhibitors are taken with potassium supplements or potassium-
sparing diuretics. Animal studies suggest that captopril may accentuate the respiratory depressive and
analgesic properties of morphine.[78] No clinical studies have been completed.
Angiotensin II Receptor Antagonists
These drugs include losartan, valsartan, and irbesartan. They diminish the effect of angiotensin II at its
receptor. The incidence of cough is less than with ACE inhibitors.[59a] Angioneurotic edema has been
reported in patients taking losartan.[79a]


Differential diagnoses for the cardiovascular effects and electrolyte abnormalities caused by
antihypertensive drugs can be found in Chapters 10 and 20 .


LABORATORY STUDIES
Blood levels of antihypertensive agents are not routinely available or clinically useful. The following may be
useful in the investigation and treatment of these patients, depending on the clinical situation: complete
blood cell count, electrolytes, blood urea nitrogen, creatinine, glucose, electrocardiogram, chest radiography,
and arterial blood gases.


Supportive care constitutes the primary treatment for these patients. Oral activated charcoal, 1 g/kg, should
be administered. The patient’s airway and ventilation should be maintained by standard methods.
Continuous cardiac monitoring is necessary for detection of dysrhythmias. Electrolyte abnormalities should
be corrected.
Table 46-3 -- Treatment of Antihypertensive Toxicity

Indication Treatment Dose Notes
Maintain airway
General and ventilation
management
Activated charcoal 1 g/kg PO
Caution—pulmonary edema described
Crystalloids 0.9% NaCl
with diuretic overdose
Adult: 200-mL boluses. Repeat
as needed. Central pressure
monitoring may be required.
Pediatric: 20 mL/kg
Useful for postural hypotension in
Positioning Reverse Trendelenburg
prazosin overdose
Vasopressors
Use caution when treating hypotension
secondary to a-adrenergic receptor
Norepinephrine IV infusion
antagonists. Response may be
unpredictable or exaggerated.
Hypotension
Adult: 8–12 µg/min (initial)
Pediatric: 0.1 µg/kg/min, titrate
to effect
Use caution when used with ß-
adrenergic receptor antagonist; may get
Epinephrine Adult: IV infusion 1–4 µg/min
exaggerated hypertension and
bradycardia
Pediatric: 0.1–1 µg/kg/min
Dopamine IV infusion, 5–20 µg/kg/min
Load: 0.75 mg/kg IV over 2–3
Amrinone May be useful in overdose of labetalol
minutes
Infusion: 5–10 µg/kg/min
Indication Treatment Dose Notes
1 mg/kg IV bolus, followed by
Lidocaine
infusion
Adult: 1–4 mg/min
Dysrhythmias Pediatric: 20–50 µg/kg/min

20 mg/min IV until dysrhythmia
controlled, QRS widens = 50%, Cautious use in diuretic overdose,
Procainamide
hypotension develops, or a especially if hypokalemia is present.
maximum dose of 1 g given
Adult: 0.5–1 mg IV (maximum 3
Atropine Treat bradycardia
mg)
Pediatric: 0.02 mg/kg (minimum
0.1 mg) to maximum single dose
of 0.5–1 mg/dose
Other
Naloxone Adult: 2 mg May be useful in ACE inhibitor overdose
Pediatric: =20 kg: 0.1 mg/kg; =20
kg: 2 mg
Angiotensin amide Has been used in ACE inhibitor
8.5–18 µg/min
infusion overdose
ACE, angiotensin-converting enzyme.
Hypotension
Hypotension is treated initially with an intravenous crystalloid bolus. Caution should be exercised because
pulmonary edema occurs uncommonly in the setting of diuretic use. If fluid replacement is ineffective, a
vasopressor such as dopamine or norepinephrine is started. Vasopressor use may be risky, because
dysrhythmias have been reported in cases of diuretic overdose. Vasopressors may be necessary to treat
hypotension due to adrenergic neuronal blocking agents (guanethidine, guanadrel, reserpine) but should be
used cautiously. Severe hypertension has occurred when patients taking guanethidine were treated with
sympathomimetic drugs.[70] Postural hypotension is a significant problem with prazosin overdose; patients
may require the reverse Trendelenburg position.[49] In the setting of vasodilator overdose, vasopressors with
prominent ß-adrenergic receptor agonist effects should be avoided.[61] In one case, an a-agonist,
phenylephrine, was used successfully to treat severe hypotension due to minoxidil overdose.[52]
Bradycardia
Symptomatic bradydysrhythmias should be treated with atropine, isoproterenol, or cardiac pacing.

Isoproterenol must be used with caution, because ß2-adrenergic receptor-mediated vasodilation may
exacerbate hypotension.
Dysrhythmias
Cardiac dysrhythmias should be treated with standard antidysrhythmic agents, including lidocaine and
procainamide.
Theoretically, hemodialysis may be a useful option in selected cases of antihypertensive agent overdose,
especially patients with renal failure or those refractory to standard treatment. Based on pharmacokinetic
data, captopril could be removed by hemodialysis. Captopril has a volume of distribution of 0.7 L/kg, and
only 25 to 30 per cent is bound to serum proteins. However, removal of captopril with hemodialysis has not
been reported in the literature.
Toxin-Specific Therapies
Vasodilators
Calcium channel antagonists and ß-adrenergic receptor antagonists may be useful in treating myocardial
ischemia due to direct inotropic or chronotropic effects of these agents in overdose.[61][73]
ACE Inhibitors
A trial of naloxone should be used to treat hypotension due to ACE inhibitor overdose. One case reported
prompt resolution of severe hypotension[80]; however, failure of response to naloxone has also been
reported.[5] Two cases of enalapril overdose, with profound hypotension unresponsive to other treatment,
responded promptly to an infusion of intravenous angiotensin II.[32][55] Angioedema can rapidly obstruct the
airway, which can be lethal and must be treated aggressively.[64] The following drugs or treatments may be
helpful: antihistamines, corticosteroids, and epinephrine. Some cases of angioedema are very resistant to
aggressive medical therapy. The airway should be secured very early in the management of these patients.
Later, both endotracheal intubation and cricothyroidotomy may be technically impossible due to massive
swelling.
Sympatholytic Agents
A cavernospongiosum shunt was used in the treatment of priapism due to prazosin.[63]


DISPOSITION
Patients who overdose or who have a significant adverse effect, such as angioedema, should be admitted
for at least 24 hours of monitoring. Cardiac dysrhythmias and hemodynamic instability are common, and
symptoms may be delayed [5][42] and persistent. Hypotension due to severe minoxidil overdose may persist
for up to 72 hours.[53]


SEQUELAE
Acute renal failure can occur after large infusions of mannitol, and spontaneous recovery is the usual
outcome.[12][62] Ototoxicity from rapid infusion of large doses of loop diuretics is usually transient, but a few
cases of irreversible hearing loss have been reported.[15][26] Renal failure has been described after overdose
of labetalol. In both cases, the patients regained normal renal function.[40][73] Profound hypotension due to
overdose of antihypertensive agents can lead to myocardial infarction or stroke.[52]


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Chapter 47 – Nitroprusside
SARALYN R. WILLIAMS RICHARD F. CLARK
Essentials
Cyanide Toxicity
• Increasing anion gap metabolic acidosis due to lactate
• Decreasing arteriovenous oxygen (AVO2) difference
• Alteration in mental status
• Cardiovascular instability
• Elevated erythrocyte or plasma cyanide levels with clinical
deterioration
Thiocyanate Toxicity
• Gastrointestinal symptoms
• Altered mental status
• Absence of metabolic acidosis
• Elevated thiocyanate level with clinical syndrome
INTRODUCTION
Sodium nitroprusside (NTP) is a potent vasodilator that has important applications in the management of
critically ill patients. It was first introduced as a therapeutic agent in the 1950s.[21] The development of a
stable, freeze-dried preparation in the 1970s led to widespread utilization. Its rapid onset of action and short
half-life allow close titration of blood pressure effects in patients with hypertensive emergencies. NTP is also
used to induce hypotension during neurosurgical procedures and for afterload reduction in patients with left
ventricular failure.[6][13]
Continuous infusion of NTP is associated with two distinct toxic effects. The more commonly recognized
poisoning associated with NTP is caused by the liberation of cyanide.[11] The other results from
accumulation of thiocyanate. The toxic effects of thiocyanate are less well recognized and often
misdiagnosed. The following two sections will discuss these two distinct types of toxicity from NTP therapy.


CYANIDE
Pathophysiology
Each NTP molecule is composed of a ferrous iron center complexed with 5 cyanide moieties and a nitrosyl
group ( Fig. 47–1 ). Cyanide comprises approximately 44 per cent of the weight of the molecule. Although
some cyanide is released from NTP through photodegradation, the majority is released by a nonenzymatic
in vivo reaction.[1][20] After infusion, NTP rapidly breaks down to cyanide and nitric oxide. This reaction was
initially thought to occur in erythrocytes,[29][34] but more recent information indicates that the primary location
of cyanide production is in the extracellular space.[17] This process is initiated by contact with sulfhydryl
groups on vessel walls.[26]
Figure 47-1 Structure of nitroprusside molecule.
NTP is really a prodrug, and its metabolite, nitric oxide, is its functional mediator. Nitric oxide exerts its
vasodilatory effects by interacting with guanylate cyclase, an enzyme found in smooth muscle. Stimulation of
guanylate cyclase by nitric oxide raises intracellular levels of cyclic guanosine monophosphate (GMP), which
leads to a decreased influx of calcium into the cell. This results in a decrease in smooth muscle tone that
causes vasodilation to occur.[19] These vasodilatory effects are nonspecific and seem to occur in pulmonary
vasculature as well.[13]
Cyanide released from NTP is detoxified by the enzyme-mediated transfer of sulfur from thiosulfate to
cyanide ( Fig. 47–2 ) (see Chapter 86 ). This irreversible reaction results in the synthesis of thiocyanate,
which is then eliminated by the kidneys.[37] Whereas rhodanese is the best characterized enzyme involved in
the process of cyanide detoxification, other enzymatic and nonenzymatic reactions have also been
implicated.[37][38][39]
Figure 47-2 Transulfuration of cyanide.
The rate-limiting factor in cyanide detoxification is the availability of thiosulfate.[8] Healthy humans have
enough endogenous thiosulfate to detoxify approximately 50 mg of NTP.[15] Patients who are critically or
chronically ill have limited reserves of thiosulfate and may be more susceptible to cyanide poisoning at lower
doses of NTP.[8] Children are also more susceptible to cyanide poisoning since they are less able to
mobilize their thiosulfate stores.[15]
Cyanide that accumulates during NTP infusion is sequestered primarily in erythrocytes, although an
equilibrium exists between erythrocytes and plasma.[32] Toxic effects occur when plasma cyanide distributes
into tissues. Cyanide binds avidly to metals. In the cell it inhibits critical biochemical processes by combining
with metalloenzymes. Enzyme systems that contain iron, molybdenum, zinc, or copper may be inhibited.[30]
Cytochrome oxidase (cytochrome a3) is an iron-containing metalloenzyme on mitochondrial membranes that
facilitates synthesis of adenosine triphosphate by oxidative phosphorylation. The binding of cyanide to the
iron moiety of this enzyme blocks the ability of cells to utilize oxygen, resulting in anaerobic metabolism and
severe lactic acidosis.[37]
Other affected metalloenzymes include xanthine oxidase and succinate dehydrogenase. In animal models,
cyanide reduces -aminobutyric acid concentrations in the brain by inhibiting glutamate decarboxylase.[31]
When NTP solutions are exposed to sunlight, photodegradation occurs, resulting in the release of cyanide in
vitro. Exposure to bright sunlight may result in release of 40 per cent of the cyanide into solution. As the
photochemical breakdown of NTP solution progresses, its therapeutic effects decline. Two hours of
exposure to direct sunlight may reduce the efficacy of NTP by 50 per cent. Artificial light does not have this
same degradative effect.[1][12]
Protection of NTP solution from sunlight by placement of aluminum foil or other covers over the infusion bag
prevents this photochemical reaction. Protected NTP solutions are stable for months.[8]
The amount of NTP that can be infused before the development of cyanide toxicity varies with the availability
of thiosulfate stores. Most healthy individuals can detoxify an infusion of 1 to 2 µg/kg/min.[28] Cyanide
concentrations may rise rapidly at higher infusion rates when thiosulfate stores are depleted.[28] Prolonged
infusions or rates greater than 2 µg/kg/min can result in significant morbidity and mortality due to cyanide
toxicity.[25] Patients with low thiosulfate stores are at greater risk.
The organ systems most commonly affected by cyanide poisoning are those most sensitive to hypoxia, the
heart and brain. Cyanide poisoning should be considered in any patient receiving NTP who develops
cardiovascular instability or central nervous system abnormalities in the setting of an anion gap acidosis.
One of the earliest and most consistent findings in patients with NTP-induced cyanide poisoning is the
development of an anion gap metabolic acidosis.[7] The presence of an anion gap metabolic acidosis in a
patient on NTP should prompt evaluation for cyanide poisoning. Likewise, the absence of a metabolic
acidosis excludes significant cyanide poisoning.
Early NTP-induced cyanide poisoning frequently presents as unexplained sinus tachycardia. Sinus
bradycardia develops as the myocardium becomes more hypoxic. Pump failure, asystole, or ventricular
dysrhythmias may be terminal events.
Another early sign of cyanide toxicity that may not initially be recognized is the development of tachyphylaxis
to NTP. This results in progressively resistant hypertension that requires increasing doses of NTP,
enhancing cyanide production.[8][13] Hypotension and shock develop as cyanide concentrations rise.
Cyanide-induced central nervous system dysfunction initially begins as restlessness and agitation and may
progress to convulsions. Encephalopathy, coma, and cerebral death often occur simultaneously with the
terminal cardiovascular events.[8] The brain appears to be more sensitive to cyanide poisoning than the
heart, although critically ill patients will demonstrate multiorgan effects (see Chapter 86 ).[37]
Mixed venous oxygen content rises and the AVO2 difference declines as clinical deterioration due to cyanide
poisoning progresses. In the patient with a pulmonary artery catheter, this parameter may help the clinician
to distinguish the patient with lactic acidosis caused by cardiovascular instability from the one with lactic
acidosis and cardiac instability caused by cyanide toxicity. In contrast to the patient with cyanide toxicity, the
patient with lactic acidosis due to shock manifests an increase in the AVO2 difference and a fall in central
mixed venous oxygen.[8] The PO 2 and arterial oxygen saturation remain normal in cyanide poisoning.
Cyanosis, when it occurs, is due to diminished cardiac output and intrapulmonary shunting.[8][23]
Clinical findings of cardiovascular instability, mental status changes, and metabolic acidosis in patients on
NTP infusion should suggest cyanide poisoning. An increase in the mixed venous oxygen concentration in
the setting of increased lactate production supports this diagnosis. The presence of lactate indicates an
increase in oxygen demand and the shift to anaerobic metabolism. Other diagnoses that may similarly result
in increased mixed venous oxygen and a lactic acidosis include sepsis and hepatic failure. Sepsis will
decrease the AV O 2 difference, provided that there is an increase in the cardiac output. Intracranial pathology
such as a hypertensive hemorrhage also causes a change in mental status and may alter cardiovascular
hemodynamics especially when intracranial pressure is increased. A primary decrease in cardiac output
results in lactic acidosis due to decreased tissue perfusion. As previously noted, this typically results in an
increase in the AVO 2 difference as more oxygen is extracted by the poorly perfused tissue. Review of the
medication list may reveal use of drugs with propylene glycol as a diluent such as nitroglycerin, diazepam,
and phenytoin. Large concentrations of propylene glycol have been reported to cause lactic acidosis and
mental status changes.[4][10] Other causes of an anion gap metabolic acidosis should be considered, but a
high suspicion for cyanide poisoning must be maintained in the patient on a NTP infusion and a new lactic
acidosis ( Table 47–1 ) (see Chapter 11 ).
Table 47-1 -- Clinical Presentation and Differential Diagnosis of Nitroprusside Toxicity

Increased Mixed Venous Oxygen Saturation
Cyanide poisoning
Increased cardiac output
High arterial oxygen content
Sepsis
Hepatic failure
Altered Mental Status
Hypoxemia
Cyanide poisoning
Thiocyanate poisoning
New-Onset Metabolic Acidosis While on Nitroprusside Infusion
Ketoacidosis
Uremia
Lactic acidosis
Cyanide poisoning
Hypoxemia
Decreased cardiac output
Phenformin
Metformin (rarely)
Thiamine deficiency
Seizures
Propylene glycol infusion (diazepam, phenytoin, nitroglycerin)
Laboratory Studies
Laboratory studies that are most useful in evaluating a patient for suspected cyanide toxicity include arterial
blood gas analysis and serum chemistries. An anion gap metabolic acidosis with rising lactate levels is an
early indicator of NTP-induced cyanide toxicity. The absence of an acidosis should suggest another cause
for the deteriorating condition. A rise in mixed venous oxygen levels may also provide a clue to the diagnosis
of cyanide toxicity, especially when this occurs in the setting of a stable or declining cardiac output in the
patient monitored with a pulmonary artery catheter.
Cyanide levels are helpful, but results are usually not rapidly available. The erythrocyte cyanide
concentration is usually the most available test; however, plasma cyanide correlates best with tissue burden
and toxicity.[26] Cyanide poisoning, however, is diagnosed by the effects the cyanide is having on the tissues
rather than the absolute level.
Erythrocyte cyanide levels are typically much higher than plasma levels, although they are in equilibrium and
maintain a consistent relationship. As the red cell concentrations rise, plasma levels and tissue levels also
increase. After an acute poisoning with inorganic cyanide, erythrocyte concentrations are typically two to
three times higher than plasma levels. However, during NTP infusions, an even greater proportion of
cyanide is concentrated in red blood cells so that erythrocyte cyanide levels in poisoned patients on NTP are
much higher than those found in patients with a similar degree of toxic symptoms after poisoning with
inorganic cyanide. The earliest symptoms of cyanide poisoning in patients on NTP infusions begin to be
seen at erythrocyte levels of 40 µmol/L (1 mg/L), levels that are compatible with death when they follow an
acute ingestion of a cyanide salt.[8][28] Short-term NTP infusions will result in cyanide levels that correlate
with the total dose infused. Conversely, cyanide levels from long-term infusions appear to correspond with
the rate of infusion rather than the total dose.[32]
Serum thiocyanate levels are not useful in diagnosing or excluding cyanide poisoning because there is no
correlation between plasma thiocyanate levels and cyanide toxicity. Normal thiocyanate concentrations may
be present in the setting of severe cyanide toxicity.[2][18][33]
Treatment
Discontinuation of the NTP infusion is the first step in the management of suspected cyanide poisoning. The
patient should also be placed on oxygen supplementation. In all cases, sodium thiosulfate should be given
immediately to enhance transulfuration of cyanide to thiocyanate ( Table 47–2 ). In severe cases, the
administration of sodium nitrite is indicated. The dosage should be adjusted for weight and hemoglobin in
pediatric patients. Amyl nitrite need not be used since intravenous access is available. In patients with mild
to moderate manifestations of cyanide poisoning or those with contraindications to the induction of
methemoglobinemia (e.g., glucose-6-phosphate dehydrogenase deficiency), treatment is limited to
discontinuation of NTP and administration of thiosulfate.[8]
Table 47-2 -- Treatment of Suggested Cyanide Toxicity from Nitroprusside Infusions

Prevention
Thiosulfate, 1 g/100 mg nitroprusside infused
Treatment of Cyanide Poisoning
Discontinue nitroprusside infusion
Administer 100% oxygen
Administer sodium thiosulfate, 25% solution
Adult dose: 50 mL (12.5 g)
Pediatric dose: 1.65 mL/kg up to 50 mL
When severe manifestations are present: Sodium nitrite, 3% solution
Adult dose: 10 mL (300 mg)
Pediatric dose: 0.33 mL/kg up to 10 mL
Treatment of Thiocyanate Toxicity
Benzodiazepines for agitation or convulsions
Hemodialysis
Prevention
Detoxification of the cyanide molecule is enhanced in the presence of thiosulfate. Co-administration of

thiosulfate with the NTP infusion has been shown to prevent a rise in cyanide concentrations[15][18][26] and to
limit cyanide-induced toxicity.[18][24] One gram of thiosulfate (10 mL of a 10 per cent sodium thiosulfate
solution) may be mixed with each 100 mg of NTP solution. This mixture is stable when protected from
light. [28]
Hydroxycobalamin also binds cyanide and has been used to prevent cyanide poisoning during NTP
infusions.[6] Animal data suggest that thiosulfate is a more effective prophylactic agent.[16] The cost and lack
of availability of hydroxycobalamin in the United States also limit its use.[40]
Sequelae
Cyanide poisoning from NTP infusions has been associated with unexpected deaths and cardiopulmonary
arrests. Neurologic sequelae including encephalopathy, coma, and irreversible focal deficits have been
described.[25]


THIOCYANATE
Pathophysiology
As previously noted, the detoxification of cyanide by transulfuration results in the production of thiocyanate,
which is eliminated primarily by renal excretion. The half-life of thiocyanate in patients with normal renal
function is 2.7 days. Although patients with normal renal function rarely accumulate thiocyanate with less
than 2 weeks of NTP infusion, moderate infusions of 2 to 5 µg/kg/min in patients with normal renal function
have resulted in thiocyanate toxicity after 7 to 14 days.[8] Thiocyanate concentrations may rise more quickly
when thiosulfate is infused with NTP to prevent cyanide poisoning, occasionally producing clinical evidence
of thiocyanate toxicity in as soon as 6 days.[8] Patients with renal insufficiency who are not on hemodialysis
accumulate thiocyanate.[27] Thiocyanate toxicity may develop in these patients in 3 to 6 days during
moderate NTP infusions.[26]
The pathophysiology of thiocyanate toxicity is poorly understood, although it is distinctly different from that of
cyanide. It is not reconverted to cyanide. [35] Individuals with thiocyanate poisoning do not develop metabolic
acidosis or diminished oxygen uptake because thiocyanate does not inhibit cytochrome oxidase. Central
nervous system and gastrointestinal effects predominate. In addition, thiocyanate causes hypothyroidism by
competing with iodine for thyroidal uptake. This is most common after ingestion of thiocyanate salts;
however, the antithyroid effects of thiocyanate should be considered after prolonged infusions of NTP.[8]
Most descriptions of severe thiocyanate toxicity are from older studies of its use in treatment of
hypertension.[3] These reports describe a multitude of symptoms particularly involving the central nervous
system. Mild toxicity is manifest as weakness, tinnitus, and agitation. Tremor and hallucinations also occur.
Progression to more severe toxicity results in disorientation, lethargy, coma, and death. Abdominal pain and
vomiting are also noted.[9][14][36] Metabolic acidosis does not occur as a primary manifestation of thiocyanate
toxicity, although it may follow seizures.
Laboratory Studies
Although thiocyanate levels are not predictive of cyanide poisoning, they do correlate with thiocyanate
poisoning. Normal serum levels less than 4 mg/L are detected in nonsmoking patients, whereas smokers
often have levels up to 8 mg/L, owing to cyanide released from the burning tobacco. Levels of 80 mg/L have
been associated with fatigue. [2][3][9][14] Thiocyanate concentrations may approach 100 mg/L before serious
signs of toxicity occur. Critically ill patients who are deficient in total-body thiosulfate stores can still
accumulate toxic concentrations of thiocyanate when renal insufficiency is present.
Treatment
Hemodialysis removes thiocyanate, resulting in improved central nervous system function.[5][22] Although
hemodialysis is considered most frequently in the setting of renal insufficiency or renal failure, it may also be
effective in patients with adequate renal function and severe manifestations of thiocyanate toxicity due to
prolonged infusions of NTP. Benzodiazepines can be used to manage seizures or agitation.
Sequelae
Altered mental status, convulsions, and coma are reported in the literature describing the use of thiocyanate
as an antihypertensive. Death was also reported in the older literature.[9][14][36]


REFERENCES
1. Arnold WP, Longnecker DE, Epstein RM: Photodegradation of sodium nitroprusside: Biologic activity and
cyanide release. Anesthesiology 1984; 61:254-260.
2. Ballantyne B: Toxicology of cyanides. In: Ballantyne B, Marrs TC, ed. Clinical and Experimental
Toxicology of Cyanides., . Bristol, England: IOP Publishing; 1987:217-247.
3. Barker MH: The blood cyanates in the treatment of hypertension. JAMA 1936; 106:762-767.
4. Cate JC, Hedrick R: Propylene glycol intoxication and lactic acidosis. N Engl J Med 1980; 303:1237.
5. Christensen J, Willliams BJ: Thiocyanate psychosis treated by extracorporeal hemodialysis.

JAMA 1962; 181:340-342.
6. Cottrell JE, Casthely P, Brodie JD, et al: Prevention of nitroprusside-induced cyanide toxicity with
hydroxocobalamin. N Engl J Med 1978; 298:809-811.
7. Curry SC: Hydrogen cyanide and inorganic cyanide salts.. In: Sullivan Jr JB, Krieger GR, ed. Hazardous
Materials Toxicology Clinical Principles of Environmental Health, . Baltimore: Williams & Wilkins; 1992:698-
710.
8. Curry SC, Arnold-Capell P: Nitroprusside, nitroglycerin, and angiotensin-converting enzyme inhibitors.

Crit Care Clin 1991; 7:555-581.
9. Domalski CA, Kolk LC, Hines EA: Delirious reactions secondary to thiocyanate therapy of hypertension.
Proc Mayo Clin 1953; 28:272-280.
10. DrugFacts and Comparisons, St. Louis: Facts and Comparisons; 1994:633. 1505, 1515
11. Food and Drug Administration : New labeling for sodium nitroprusside emphasizes risk of cyanide
toxicity. JAMA 1991; 265:847.
12. Frank MJ, Johnson JB, Rubin SH: Spectrophotometric determination of sodium nitroprusside and its
photodegradation products. J Pharm Sci 1976; 65:44-48.
13. Friederich JA, Butterworth JF: Sodium nitroprusside: Twenty years and counting. Anesth
Analg 1995; 81:152-162.
14. Garvin CF: The fatal toxic manifestations of the thiocyanates. JAMA 1939; 112:1125.
15. Ivankovich AD, Braverman B, Stephens TS, et al: Sodium thiosulfate disposition in humans: Relation to
sodium nitroprusside toxicity. Anesthesiology 1983; 58:11-17.
16. Krapez JR, Vesey CJ, Adams L, Cole PV: Effects of cyanide antidotes used with sodium nitroprusside
infusions: Sodium thiosulphate and hydroxocobalamin given prophylactically to dogs. Br J
Anaesth 1981; 53:793-804.
17. Kreye VAW, Reske SN: Possible site of the in vivo disposition of sodium nitroprusside in the rat.
Naunyn-Schmiedegergs Arch Pharmacol 1982; 320:260-265.
18. Michenfelder JD, Tinker JH: Cyanide toxicity and thiosulfate protection during chronic administration of
sodium nitroprusside in the dog: Correlation with a human case. Anesthesiology 1977; 47:441-448.
19. Moncada S, Palmer RM, Higgs EA: Nitric oxide: Physiology, pathophysiology, and pharmacology.
Pharmacol Rev 1991; 43:109-142.
20. Norris JC, Hume AS: In vivo release of cyanide from sodium nitroprusside solution. Br J
Anaesth 1987; 59:236-239.
21. Page IH, Corcoran AC, Dustan HP, Koppanyi T: Cardiovascular actions of sodium nitroprusside in
animals and hypertensive patients. Circulation 1955; 11:188-198.
22. Pahl MV, Vaziri ND: In-vivo and in-vitro hemodialysis studies of thiocyanate. J Toxicol Clin
Toxicol 1983; 19:965-974.
23. Peters CG, Mundy JVB, Rayner PR: Acute cyanide poisoning. Anaesthesia 1982; 37:582-586.
24. Piantadosi CA, Sylvia AL: Cerebral cytochrome a, a3 inhibition by cyanide in bloodless rats.
Toxicology 1984; 33:67-79.
25. Robin ED, McCauley R: Nitroprusside-related cyanide poisoning: Time (long past due) for urgent,
effective interventions. Chest 1992; 102:1842-1845.
26. Schulz V: Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate, and thiocyanate. Clin
27. Schulz V, Bonn R, Kindler J: Kinetics of elimination of thiocyanate in seven healthy subjects and in eight
subjects with renal failure. Klin Wochenschr 1979; 57:243-247.
28. Schulz V, Gross R, Pasch T, et al: Cyanide toxicity of sodium nitroprusside in the therapeutic use with
and without sodium thiosulfate. Klin Wochenschr 1982; 60:1393-1400.
29. Smith PR, Kruszyna H: Nitroprusside produced cyanide poisoning via a reaction with hemoglobin. J
30. Solomonson LP: Cyanide as a metabolic inhibitor.. In: Vennesland B, Knowles Conn E, et
al ed. Cyanide in Biology., . London: Academic Press; 1981:11-28.
31. Tursky T, Sajter V: The influence of potassium cyanide poisoning on the aminobutyric acid level in rat
brain. J Neurochem 1962; 9:519-523.
32. Vesey CJ: Nitroprusside cyanogenesis.. In: Ballantyne B, Marrs TC, ed. Clinical and Experimental
Toxicology of Cyanides, . Bristol, England: IOP Publishing; 1987:184-208.
33. Vesey CJ, Cole PV, Simpson PJ: Cyanide and thiocyanate concentrations following sodium
nitroprusside infusion in man. Br J Anaesth 1976; 48:651-660.
34. Vesey CJ, Krapez JR, Cole PV: The effects of sodium nitroprusside and cyanide on haemoglobin
function. J Pharm Pharmacol 1980; 32:256-261.
35. Vesey CJ, Wilson J: Red cell cyanide. J Pharm Pharmacol 1978; 30:20-26.
36. Wald MH, Lindberg HA, Barker MH: The toxic manifestations of the thiocyanates.
JAMA 1939; 112:1120-1124.
37. Way JL: Cyanide intoxication and its mechanism of antagonism. Ann Rev Pharmacol
Toxicol 1984; 24:451-481.
38. Way JL, Sylvester D, Morgan RL, et al: Recent perspectives on the toxicodynamic basis of cyanide
antagonism. Fundam Appl Toxicol 1984; 4:S231-S239.
39. Westley J, Adler A, Westley L, et al: The sulfur transferases. Fundam Appl Toxicol 1983; 3:377-382.
40. Zerbe NF, Wagner BKJ: Use of vitamin B12 in the treatment and prevention of nitroprusside-induced
cyanide toxicity. Crit Care Med 1993; 21:465-467.


Chapter 48 – Theophylline
CHRISTINE M. STORK MARY ANN HOWLAND
Essentials
• Physical examination: nausea, repeated vomiting, tachycardia, tachypnea, restlessness, tremors, wide
pulse pressure, hypotension, seizures, status epilepticus
• Laboratory findings:
° Theophylline serum concentrations (repeated)
° Acid-base balance: anion gap metabolic acidosis, respiratory
alkalosis
° Blood chemistry: hypokalemia, low bicarbonate, hyperglycemia
° White blood cell analysis: leukocytosis
• Electrocardiography: sinus tachycardia, supraventricular tachycardia, multifocal atrial tachycardia in

chronic obstructive pulmonary disease (COPD), ventricular dysrhythmias
INTRODUCTION
Theophylline has been used since the early 1900s for the management of pulmonary disorders such as
COPD and asthma. Although the indications for theophylline in the routine management of asthma recently
have been questioned, it is still frequently prescribed in those patients with COPD, severe persistent asthma,
and nocturnal symptoms. The morbidity and mortality associated with the use of theophylline has risen due
to the development of sustained-release formulations. According to the 1998 Annual Report of the American
Association of Poison Control Centers Toxic Exposure Surveillance System, there were 2079 exposures to
theophylline, 22 per cent of which resulted in moderate to severe toxicity, and 16 of which resulted in
death.[21]


Pharmacology
Theophylline, a methylxanthine, in therapeutic serum concentrations (5–15 mg/L) may produce beneficial
effects in asthma through adenosine antagonism and modulation of intracellular calcium concentrations.[8]
Theophylline is well absorbed from the gastrointestinal tract. After therapeutic doses, peak serum
concentrations are achieved within 2 hours after regular-release formulations and within 4 to 12 hours after
sustained-release formulations. Absorption is slowed in the overdose setting, and peaks may be delayed for
12 to 24 hours or longer. The volume of distribution of theophylline is approximately 0.5 L/kg, and it is well
distributed to all body compartments within 45 minutes after dosing.[20] Hepatic metabolism through the
cytochrome P-450 1A2, 3A4, and 2E1 isoenzymes accounts for the majority of elimination, with only
approximately 10 per cent excreted unchanged in the urine.[44] In the overdose setting, theophylline exhibits
saturable pharmacokinetics where only a constant amount of drug can be eliminated per unit of time,
resulting in prolonged elimination. The three major metabolites in adults are 3 methyl xanthine, 1-methyl uric
acid, and 1,3-dimethyluric acid (active metabolite). Neonates metabolize theophylline slower than children
and adults. Neonates metabolize a consequential amount of theophylline to caffeine by n-methylation, and
caffeine serum concentrations may achieve 25 per cent of theophylline serum concentrations. Theophylline
serum concentrations can increase or decrease depending on changes in the hepatic microsomal P-450
enzyme activity influenced by age, liver function, and drug interactions ( Table 48–1 ).
Table 48-1 -- Factors Influencing Theophylline Clearance

Inhibitors * Enhancers
Acute ethanol Carbamazepine
Allopurinol Cigarette smoke
Cimetidine Phenobarbital
Ciprofloxacin, norfloxacin Phenytoin
Erythromycin, clarithromycin Primidone
Heart failure (congestive) Rifampin
Liver failure
Propranolol (?other ß-adrenergic receptor antagonists)
Pulmonary disease
Tacrine
Ticlodipine
Verapamil
Modified from Stork AM, Howland MA, Goldfrank LR: Concepts and controversies of bronchodilator overdose.
Emerg Med Clin North Am 1994; 12:421.
* Any drug that inhibits the cytochrome P-450 isoenzyme (1A2, 3A4, 2E1) would be expected to inhibit the metabolism of theophylline.
Pathophysiology
The nausea and vomiting seen after theophylline poisoning may result from direct central nervous system
(CNS) stimulation of the chemoreceptor trigger zone, relaxation of lower esophageal sphincter tone,
phosphodiesterase inhibition, and increases in gastric acid secretion.[7][14]
Adenosine receptor antagonism in the brain has been implicated in the seizures and status epilepticus
associated with severe theophylline poisoning.[40] Peripheral adenosine receptor antagonism may also be
partially responsible for the tachycardia and cardiac dysrhythmias seen after theophylline poisoning.[40][44]
Theophylline in the overdose setting causes increases in cyclic adenosine monophosphate through
phosphodiesterase inhibition and the release of catecholamines.[10][17] These catecholamines, especially
epinephrine with resulting ß-adrenergic receptor stimulation, contribute to theophylline-induced tachycardia,
hypokalemia (due to an intracellular shift), lactic acidosis, and hyperglycemia. Hypophosphatemia and
hypomagnesemia may also result, although these findings are less common. A widened pulse pressure
occurs due to increased ß2-adrenergic receptor stimulation, with resultant relaxation of arteriolar tone.
Increased catecholamines may also contribute to the agitated alert mental status, seizure activity, and
cardiac dysrhythmias (supraventricular and ventricular) seen after poisoning. Findings in a reported case of
theophylline toxicity suggest myocardial function remains intact but systemic vascular resistance is low.[18]
Other pharmacologic effects apparent after theophylline poisoning include direct respiratory stimulation,
gastric acid secretion, positive cardiac inotropy and chronotropy, and cerebrovascular vasoconstriction.
Direct respiratory stimulation causes a respiratory alkalosis. With chronic toxicity the metabolic abnormalities
typical after acute theophylline poisoning may be blunted or absent.


Patients who acutely overdose with theophylline often present with nausea, vomiting, and sinus tachycardia (
Table 48–2 ). These manifestations begin within 1 hour for immediate-release preparations (oral regular
release tablets, liquid preparations, and parenteral aminophylline) and within 2 to 4 hours for sustained-
release dosage forms. Patients often complain of feeling jittery. In addition to tachycardia, vital signs may
reveal a widened pulse pressure and an elevated respiratory rate. This widened pulse pressure is an early
clue to toxicity. Physical examination is significant for repeated vomiting, tremor, and hyperreflexia with an
intact sensorium. As the theophylline serum concentration approaches 90 to 100 mg/L, the pulse pressure
may further widen, followed by life-threatening manifestations of toxicity, including generalized tonic-clonic
seizures, status epilepticus, and supraventricular and ventricular tachydysrhythmias. Seizures secondary to
theophylline poisoning are difficult to manage and often progress to status epilepticus.[47] Hypokalemia,
hyperglycemia, and an anion gap metabolic acidosis are typically present.
Table 48-2 -- Clinical Presentation of Theophylline Toxicity

Nausea, repeated vomiting
Tachycardia, tachypnea, wide pulse pressure
Restlessness, tremors, seizures, status epilepticus
Anion gap metabolic acidosis, respiratory alkalosis
Electrolytes: hypokalemia, low bicarbonate, hyperglycemia
Leukocytosis
Electrocardiogram: sinus tachycardia, supraventricular tachycardia, multifocal atrial tachycardia in chronic
obstructive pulmonary disease, ventricular dysrhythmias
Patients develop chronic theophylline toxicity as a result of accumulation secondary to inappropriate dosing
over several days, liver disease, drug-drug interactions, or other processes that inhibit the elimination of
theophylline.[28] The chronically poisoned patient is typically older, is on concomitant medications, and has
some degree of organ dysfunction. In renal failure patients, the active metabolite, 1,3-dimethyluric acid, may
accumulate to cause toxicity.[22] Chronically poisoned patients often have more subtle signs and symptoms
of toxicity and demonstrate the severe manifestations of toxicity—seizures and cardiac dysrhythmias—at
lower serum concentrations. Gastrointestinal findings may be mild, with anorexia or nausea occurring in only
50 per cent of patients.[39] In one study, seizures were the first manifestation of toxicity.[45] The most
common dysrhythmia seen in patients with COPD who develop chronic toxicity is multifocal atrial
tachycardia. The catecholamine-mediated hypokalemia and metabolic acidosis classically associated with
acute toxicity are absent with chronic toxicity, perhaps as a result of tolerance.[39]
Patients on therapeutic doses of theophylline who take an acute overdose (acute poisoning on therapeutic
dosing) develop symptoms that most closely resemble those in the acute overdose. However, elevated
baseline theophylline serum concentrations (5–15 mg/L) facilitate earlier development of life-threatening
serum concentrations.
Pediatric patients poisoned with theophylline are unique in presentation. These patients may not appear
clinically to have tachypnea or hyperpnea due to a decreased respiratory reserve.[29] In 28 theophylline-
poisoned pediatric patients ages 3½ to 21 months having serum theophylline concentrations greater than
125 mg/L, 1 patient had a seizure, 17 patients had a sinus tachycardia, and no patients died.[9] In another
study, life-threatening events occurred in 12 of 125 patients.[37] Seizures occurred with serum theophylline
concentrations of 85 to 195 mg/L (mean, 125 mg/L) in the acute setting and approximately 42 mg/L in the
chronic setting. Children ages 1 to 12 years have higher metabolic clearances of theophylline compared with
those 12 years and older, 1.45 mL/kg/min versus 0.65 mL/kg/min.


The differential diagnosis of a patient with theophylline poisoning should include toxin-related and non–toxin-
related causes of nausea and vomiting, tachycardia, metabolic acidosis, respiratory alkalosis, hypokalemia,
and hyperglycemia ( Table 48–3 ). Iron, salicylates, and sympathomimetics head the toxin differential list.
Iron and salicylates consistently cause nausea and vomiting as their chief complaint, although with iron the
vomitus may be bloody. They both cause an anion gap metabolic acidosis; and salicylates, like theophylline,
cause a direct respiratory alkalosis. However, significant poisoning with iron or salicylates will often result in
an altered mental status, whereas theophylline-intoxicated patients usually remain alert and oriented, but
restless. Beta-adrenergic receptor agonists like albuterol and epinephrine (parenterally) cause a tachycardia,
hypokalemia, metabolic acidosis, leukocytosis, and some minor gastrointestinal symptoms without affecting
the mental status. However, unlike theophylline these agents rarely cause seizures. The ß-adrenergic
receptor agonists with a-agonist activity, such as ephedrine, may cause consequential vasoconstriction and
severe hypertension. Caffeine is a xanthine derivative, like theophylline, and in very large doses would be
indistinguishable from theophylline in presentation and management. Finally, agents that are capable of
causing status epilepticus such as isoniazid, amoxapine, chlorinated hydrocarbons (e.g., lindane), and
cicutoxin should be included in the differential diagnosis.
Table 48-3 -- Differential Diagnosis of Theophylline Toxicity

Toxin Mediated Non–Toxin Mediated
Salicylates Severe asthma
Iron Sepsis
ß-adrenergic agonists Diabetic/alcoholic ketoacidosis
a-adrenergic agonists Hypoglycemia
Central nervous system infection/subarachnoid
Cocaine
hemorrhage
Metals: arsenic, thallium
Mercury salts
Status epilepticus initiators: isoniazid, amoxapine,
bupropion, lindane, cicutoxin
A non–toxin-related differential diagnosis includes diabetic ketoacidosis and alcoholic ketoacidosis. The
presence of ketones and an altered mental status in these conditions are differentiating factors. In both the
medical and toxicologic differential of theophylline poisoning, examination of all pertinent discriminators of
patient presentation is often sufficient to allow for a clear diagnosis.


LABORATORY STUDIES
Theophylline Levels
Acute Overdose
Patients with a history of theophylline overdose or who have a toxidrome consistent with theophylline toxicity
should have theophylline serum concentration measured urgently. If positive, the serum concentration
should be repeated every 1 to 2 hours initially to determine the rate of rise or decline. In cases in which
expeditious laboratory results are not anticipated (within 1 hour) a second theophylline level should be sent
before the results of the first level are received. Theophylline serum concentrations of 90 to 100 mg/L in
acute poisoning (therapeutic, 5–15 mg/L) place the patient at significant risk for the life-threatening
complications related to theophylline toxicity: seizures, status epilepticus, and cardiovascular collapse.[25][43]
Rapidly rising levels are also of concern, because they indicate that absorption is occurring much faster than
elimination.
Chronic Toxicity
In chronic poisoning, theophylline levels do not necessarily correlate with the development of life-threatening
signs and symptoms of toxicity.[38] However, serum theophylline levels greater than 40 mg/L should be
considered consequential and interpreted in conjunction with the patient’s risk factors for toxicity (i.e., organ
function, age older than 60 years, concurrent illnesses, and medications).[1][25][35]
Other Studies
An arterial blood gas, serum electrolytes, glucose, and complete blood cell count may be helpful in
differentiating an acute theophylline overdose from a chronic overdose. Patients symptomatic after acute
theophylline exposure will have results of an arterial blood gas analysis consistent with a primary respiratory
alkalosis and a primary metabolic acidosis. Laboratory evaluation typically reveals a high anion gap
metabolic acidosis, hypokalemia, and hyperglycemia.[33] Hypophosphatemia and hypomagnesemia are also
noted, but less consistently. These findings are usually absent in the chronic setting. A leukocytosis is
common after acute overdose. An electrocardiogram and rhythm monitoring are useful to record
cardiovascular manifestations. Concurrent exposures to salicylate and acetaminophen should be ruled out
using a bedside urine ferric chloride test or rapid salicylate serum concentration, and a 4-hour serum
acetaminophen level, respectively. Creatine kinase or amylase and lipase can be measured for suspected
rhabdomyolysis or pancreatitis, respectively.


TREATMENT
General Measures
The first rule of good poison management is to ensure the ABCs—airway, breathing, and circulation. These
patients usually have an adequate airway and are breathing on their own unless there are co-ingestants or
other mitigating circumstances. Vital signs should be carefully monitored, and two large-bore intravenous
lines placed. An initial fluid bolus (10–20 mL/kg in children, 200 to 500 mL in adults) (divided and titrated
incrementally in patients at risk for pulmonary edema) should be administered at this time for a widened
pulse pressure or low mean arterial pressure.
Toxin Specific ( Table 48–4 )
Activated charcoal is the mainstay of therapy for acute and chronic theophylline poisoning.[23][24][34] The
dose of activated charcoal is 1 g/kg orally given initially, followed by 0.25 to 1 g/kg orally every 1 to 6 hours
depending on the severity of toxicity and the patient’s tolerance of activated charcoal. Plain activated
charcoal should be used; one dose of a cathartic such as sorbitol may be used initially, but repeated
cathartic doses are to be avoided. Activated charcoal not only binds drug remaining in the gastrointestinal
tract to decrease absorption but also enhances elimination of drug already absorbed or administered
intravenously. A healthy human volunteer study, in which subjects were given intravenous aminophylline and
repeated doses of oral activated charcoal, demonstrated dramatic lowering of serum theophylline
concentrations secondary to effects termed “gastrointestinal dialysis.”[2] Activated charcoal administration
should be continued throughout the patient’s course, even while other therapeutic measures such as
extracorporeal removal are taking place, unless contraindicated (e.g., ileus).
Table 48-4 -- Theophylline Toxicity: Decision Analysis for Critical Management Indications
Intervention Indication
Rarely
Syrup of ipecac
Early in large ingestions (<1 hr), at home
Rarely
Gastric lavage
Early in large ingestions (<1 hr)
In all toxic ingestions, unless contraindicated
Multiple doses of
activated charcoal Continue until systemic symptoms abate and drug levels fall to the therapeutic
range
Early in large ingestions of sustained-release preparations
Whole-bowel irrigation With rapidly increasing serum concentrations and when high levels persist despite
multiple doses of activated charcoal or extracorporeal removal
Intervention Indication
Electrolytes Repeated as indicated
Antiemetic therapy For emesis interfering with the administration of activated charcoal
>90 mg/L for acute intoxication
Charcoal hemoperfusion With levels > 40 mg/L and significant risk factors in chronic poisoning
With poor response to multiple doses of activated charcoal
See charcoal hemoperfusion
Hemodialysis
Unavailability of charcoal hemoperfusion
Peritoneal dialysis None
Infants < 6 mo and neonates requiring extracorporeal removal who will not tolerate
Exchange transfusion
hemodialysis, hemoperfusion, or activated charcoal
Plasmapheresis None
Adapted from Stork AM, Howland MA, Goldfrank LR: Concepts and controversies of bronchodilator overdose.
Emerg Med Clin North Am 1994; 12:425.
Repeated vomiting, a common feature of theophylline intoxication, can interfere with the effective use of
activated charcoal. Several antiemetics have proven successful in treating the intractable vomiting.
Metoclopramide, starting with doses of 10 mg intravenously in an adult (pediatric 0.1 mg/kg) and titrating to a
dose of 1 to 2 mg/kg (currently employed in cancer chemotherapy regimens) may be used to treat vomiting.
More recently, ondansetron (0.15 mg/kg intravenously), granisetron (10 µg/kg intravenously), and other 5-
HT3 receptor antagonists have been successful after the failure of other antiemetics.[30][32]
Orogastric lavage, using the largest tube possible, should be considered for all life-threatening acute
overdoses of theophylline who present early (usually within 1 hour after ingestion) and have not vomited.
Some sustained-release formulations of theophylline may not pass through the holes in a lavage tube, but
solubilized particles may be retrieved. Syrup of ipecac is rarely indicated and should be reserved for patients
presenting immediately after a witnessed acute ingestion of large amounts of theophylline (greater than 40
mg/kg) not combined with other agents that would contraindicate the use of ipecac. Later implementation
delays the time to administration of activated charcoal with no clear advantage.
Whole-bowel irrigation (WBI) using a polyethylene glycol electrolyte neutral solution may be considered
under some circumstances. This mode of gastrointestinal decontamination is not universally accepted due to
the success of multiple-dose activated charcoal and to the in vitro ability of WBI solution to displace
theophylline from activated charcoal binding sites.[13][31] WBI should be reserved for those patients who are
failing adequate activated charcoal therapy as evidenced by rising theophylline levels. Activated charcoal
should be continued throughout the patient’s course.
Extracorporeal Removal
To expedite treatment, it is essential that nephrologist involvement and the ability to institute extracorporeal
treatment such as hemoperfusion or hemodialysis be ensured early. Any patient at risk for having seizures
or life-threatening cardiac dysrhythmias or who has a rapidly rising theophylline level (greater than 50
mg/mL) is a potential candidate for extracorporeal removal. These patients should be transferred to a
medical center with appropriate expertise and capabilities. The goal of therapy is to prevent life-threatening
toxicity in the acute setting through timely institution of extracorporeal removal when theophylline levels
approach 90 mg/L. This is extremely important and cannot be overemphasized.
Definitive therapy for life-threatening theophylline poisoning includes extracorporeal removal of the toxin,
which greatly enhances elimination ( Table 48–5 ). Hemoperfusion (blood filtered through a cartridge
containing microencapsulated charcoal) is the preferred method. However, hemodialysis removes significant
amounts of theophylline and should be performed when hemoperfusion is not readily available. Indications
for the removal of theophylline using these methods include an acute theophylline level greater than 90 mg/L
or rapidly approaching 90 mg/L in the acute setting, a theophylline level of greater than 40 mg/L in the
chronic setting in a patient with a poor response to oral activated charcoal, and any patient with ongoing or
imminent seizures, cardiac ventricular dysrhythmias, cardiac ischemia, or poorly responsive
hypotension.[27][46] In infants younger than 6 months of age, exchange transfusion can be considered when
hemoperfusion or hemodialysis cannot be performed. For all patients, plasmapheresis and peritoneal
dialysis are not considered management options because they do not remove substantial amounts of
theophylline.[19]
Table 48-5 -- Theophylline Clearances with Endogenous and Exogenous Techniques of Elimination *
Clinical Situation Clearance Half-Life(hr)
Neonatal (endogenous) 0.055–0.63 mL/kg/min 20–30
Children (1–12) (endogenous) 1.45 mL/kg/min 1.5–9.5
Adults (>12) (endogenous) 0.65 mL/kg/min 8.3
Multiple-dose activated charcoal † 167 mL/min 3.3
Hemoperfusion ‡ 200 mL/min 2.0
Hemodialysis ‡ 125 mL/min 4.7
Peritoneal dialysis ‡ 9.5 mL/min 31
High flux hemodialysis ‡ 142 mL/min 3.8
* Extracorporeal clearances are based on scant data, and newer hemodialysis technologies are being studied.
† The clearance with multiple doses of activated charcoal includes endogenous clearance.
‡ The endogenous clearance or the multiple-dose activated charcoal clearance should be added to the extracorporeal removal clearance to
calculate total clearance.
Other Treatment
End organ manifestations of toxicity including seizures, cardiac dysrhythmias, and severe hypotension can
be treated supportively. Seizures should be treated aggressively with benzodiazepines and, if required,
barbiturates, followed by protocols for status epilepticus including continuous IV infusion of midazolam,
propofol, or general anesthesia as needed.[4][12] Phenytoin is considered relatively ineffective. In an animal
model it was not useful in the treatment of seizures and actually decreased the dose of theophylline required
to induce cardiac dysrhythmias.[4] Treatment of life-threatening supraventricular dysrhythmias includes the
correction of hypoxia and any fluid and electrolyte abnormalities, cardioversion, and diltiazem if needed.
Adenosine (Adenocard) may not be effective in this setting, with larger doses required to overcome
theophylline’s adenosine receptor antagonism. Ventricular dysrhythmias may be treated with lidocaine,
cardioversion, or defibrillation as needed. Electrical reversal of dysrhythmias may not be sustained due to
the persistence of toxic theophylline levels. These recommendations for dysrhythmia treatment are based on
theoretical considerations and not on studies. Hypotension should initially be treated with an adequate
crystalloid fluid challenge followed by peripheral a-adrenergic receptor agonists, such as norepinephrine, to
mitigate the hypotensive effects of excess peripheral ß2-adrenergic receptor stimulation.
Beta-adrenergic receptor antagonists such as propranolol and esmolol have been used successfully in a few
cases to reverse refractory hypotension and supraventricular and ventricular dysrhythmias attributed to
theophylline toxicity.[3][6] In an animal model, ß 1-adrenergic receptor antagonism with esmolol transiently
decreased the heart rate and increased the systemic vascular resistance.[17] However, these agents may
worsen hypotension and should only be used cautiously in cases refractory to maximal standard therapies. If
time allows, use of these agents should be discussed with a regional poison control center or toxicologist.
Caution must also be used when considering ß-adrenergic receptor antagonists in patients with underlying
bronchospastic disease.
Chronic Toxicity
The chronically poisoned patient may not exhibit the warning signs for impending life-threatening toxicity that
can occur at lower serum theophylline concentrations, as previously mentioned. In the chronic setting,
patient factors such as hepatic dysfunction, cardiovascular instability, poor oxygenation, and prior neurologic
dysfunction are more important than theophylline levels alone. It is impossible to accurately predict which
patients with chronic toxicity will proceed to life-threatening toxicity.
Stable patients can be treated initially with multiple doses of activated charcoal. Serum theophylline levels
should be checked every 4 to 6 hours. Patients older than 60 years or who have serum theophylline
concentrations persistently greater than 40 mg/L, despite multiple-dose activated charcoal, should be
considered for hemoperfusion or hemodialysis. Other indications for extracorporeal elimination are similar to
those for acute toxicity.


DISPOSITION
Theophylline poisoned patients who are either symptomatic or have elevated or rising serial theophylline
serum concentrations should remain closely monitored while in the emergency department and be admitted
to an intensive care unit. Patients whose serial theophylline levels remain therapeutic over 6 hours or decline
into the therapeutic range are not considered theophylline toxic, assuming clinical symptoms either have
resolved or never developed. In those institutions where expeditious extracorporeal removal is not available,
patient transfer should be considered early in symptomatic patients and in any patient with rapidly rising
levels greater than 50 mg/L.


SEQUELAE
The most serious manifestations of theophylline toxicity include seizures (including status epilepticus),
cardiac dysrhythmias, and profound hypotension leading to death. These may result in hypoperfusion of vital
organs. Neurologic dysfunction, rhabdomyolysis, myocardial infarction, acute renal dysfunction, and, rarely,
pancreatitis have been reported.[5][22] Elderly patients may be at increased risk for serious end-organ toxicity
after theophylline overdose. Two studies found that age alone, specifically an age greater than 60 years or
75 years respectively, was directly correlated with a poor outcome regardless of theophylline serum
concentrations.[35][38] In reality, this may be a consequence of organ function and not a direct relationship
with age.


SPECIFIC SITUATIONS
Neonates appear to be at increased risk for severe toxicity after theophylline overdose. In a childhood risk
assessment series, the authors found very young patients to be at increased risk for the development of
seizures and cardiac dysrhythmias.[37] The reasons for increased risk are unclear but may include a higher
cerebrospinal fluid fractionation of drug in neonates, limited cytochrome P-450 isoenzyme activity, altered
metabolism, and poor renal function, all of which may enhance the development of theophylline
toxicity.[41][42]
The risk of necrotizing enterocolitis in neonates receiving therapeutic doses of theophylline orally may be
increased.[15] Notwithstanding this concern, activated charcoal is successfully and safely used in children as
young as 2 days, and multiple doses of activated charcoal have been used safely in children as young as 2
weeks. [16][36] The risk of necrotizing enterocolitis should be weighed against the risk of the degree of
theophylline poisoning when considering activated charcoal therapy in this population. In some cases of
severe theophylline poisoning, exchange transfusion has been used with success.[26]


REFERENCES
1. Barr JT, Schumacher GE, Luks DB, Karpel J: Mild theophylline-related adverse reactions and serum
theophylline concentration. Am J Hosp Pharm 1994; 51:688-692.
2. Berlinger WG, Spector R, Goldberg MJ, et al: Enhancement of theophylline clearance by oral activated
charcoal. Clin Pharmacol Ther 1983; 33:351-354.
3. Biberstein MP, Zeigler MG, Ward DM: Use of ß-blockade and hemoperfusion for acute theophylline
poisoning. West J Med 1984; 141:485-490.
4. Blake KV, Massey KL, Hendeled L, et al: Relative efficacy of phenytoin and phenobarbital for the
prevention of theophylline induced seizures in mice. Ann Emerg Med 1988; 17:76-77.
5. Burgan THS, Gupta I, Rate CM: Fatal overdose of theophylline simulating acute pancreatitis.
BMJ 1982; 284:939-940.
6. Farrar KT, Dunn AM: Beta blockers in the treatment of theophylline overdose. Lancet 1985; 1:983.
7. Foster LJ, Trudeau WL, Goldman AL: Bronchodilator effects on gastric acid secretion.
JAMA 1979; 241:2613-2615.
8. Fredholm BB: Theophylline actions on adenosine receptors. Eur J Respir Dis (suppl) 1980; 109:29-36.
9. Gaudreault P, Wason S, Lovejoy FH: Acute pediatric theophylline overdose: A summary of 28 cases. J
Pediatr 1983; 10:474-476.
10. Serafin WE: Drugs used in the treatment of asthma. In: Gilman AG, Rall TW, Nies AS, et
al ed. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, . 9th ed. New York: McGraw-
Hill; 1996:672-676.
12. Hoffman A, Pinto E, Gilhar D: Effect of pretreatment with anticonvulsants on theophylline-induced

seizures in the rat. J Crit Care 1993; 8:198-202.
13. Hoffman RS, Chiang WK, Howland MA, et al: Theophylline desorption from activated charcoal caused
by whole bowel irrigation solution. J Toxicol Clin Toxicol 1991; 29:191-202.
14. Howell RE, Muehsam WT, Kinnier WJ: Mechanism for the emetic side effect of xanthine
bronchodilators. Life Sci 1990; 46:563-568.
15. Hufnal-Miller CA, Blackmon L, Baumgart S, et al: Enteral theophylline and necrotizing enterocolitis in the
low-birthweight infant. Clin Pediatr 1993; 32:647-653.
16. Jain R, Tholl DA: Activated charcoal for theophylline toxicity in a premature infant on the second day of
life. Dev Pharmacol Ther 1992; 19:106-110.
17. Kearney TE, Manoguerra AS, Curtis GP, et al: Theophylline toxicity and the beta adrenergic system..
Ann Intern Med 1985; 102:766-769.
18. Kempf J, Rusterholtz TH, Ber C, et al: Hemodynamic study as a guideline for the use of beta blockers in
acute theophylline poisoning. Intens Care Med 1996; 22:585-587.
19. Laussen P, Shann F, Butt W, et al: Use of plasmapheresis in acute theophylline toxicity. Crit Care
Med 1991; 19:288-290.
20. Levy G, Koysooko R: Pharmacokinetic analysis of the effect of theophylline on pulmonary function in
asthmatic children. J Pediatr 1975; 86:789-793.
21. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 Annual report of the American Association of
Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1999; 17:435-487.
22. Maaten JC, Hoorntje SJ: Acute renal failure in theophylline poisoning. Netherlands J
Med 1993; 42:61-64.
23. Minton NA, Glucksman E, Henry JA: Prevention of drug absorption in simulated theophylline overdose.
Hum Exp Toxicol 1995; 14:170-174.
24. Minton NA, Henry JA: Prevention of drug absorption in simulated theophylline overdose. J Toxicol Clin
Toxicol 1995; 33:43-49.
25. Olson KR, Benowitz NL, Woo OF, et al: Theophylline overdose, acute single ingestion versus repeated
over medication. Am J Emerg Med 1985; 3:386-394.
26. Osborn HH, Henry G, Wax P, et al: Theophylline toxicity in a premature neonate—elimination kinetics of
exchange transfusion. J Toxicol Clin Toxicol 1993; 31:639-644.
27. Park GD, Spector R, Roberts RJ, et al: Use of hemoperfusion for treatment of theophylline intoxication.
Am J Med 1983; 74:961-966.
28. Pashko S, Simons WR, Sena MM, Stoddard ML: Rate of exposure to theophylline-drug interactions.
Clin Ther 1994; 16:1068-1077.
29. Powell EC, Reynolds SL, Rubenstein JS: Theophylline toxicity in children: A retrospective review.
30. Roberts JR, Carney S, Boyle SM, Lee DC: Ondansetron quells drug-resistant emesis in theophylline
poisoning. Am J Emerg Med 1993; 11:609-610.
31. Rosenberg PJ, Livingstone DJ, McLollan BA: Effect of whole bowel irrigation on the antidotal efficacy of
activated charcoal. Ann Emerg Med 1988; 17:681-688.
32. Sage TA, Jones WN, Clark RF: Ondansetron in the treatment of intractable nausea associated with
theophylline toxicity. Ann Pharmacother 1993; 27:584-585.
33. Sawyer WT, Caravati M, Ellison MJ, et al: Hypokalemia, hyperglycemia, and acidosis after intentional
theophylline overdose. Am J Emerg Med 1985; 3:408-411.
34. Sessler CN, Glauser FL, Cooper KR: Treatment of theophylline toxicity with oral activated charcoal.
Chest 1985; 87:325-329.
35. Shannon M: Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993; 119:1161-
1167.
36. Shannon M, Amitai Y, Lovejoy FH: Multiple dose activated charcoal for theophylline poisoning in young
infants. Pediatrics 1987; 80:368-370.
37. Shannon M, Lovejoy FH: Effect of acute versus chronic intoxication on clinical features of theophylline
poisoning in children. J Pediatr 1992; 121:125-130.
38. Shannon M, Lovejoy FH: The influence of age versus serum concentration on life-threatening events
after chronic theophylline intoxication. Arch Intern Med 1990; 50:2045-2048.
39. Shannon M, Lovejoy FH: Hypokalemia and theophylline intoxication: The effects of acute vs chronic
poisoning. Arch Intern Med 1989; 149:2725-2729.
40. Shannon M, Maher T: Anticonvulsant effect of intracerebroventricular Adenocard in theophylline induced

seizures. Ann Emerg Med 1995; 26:65-68.
41. Skopnik H, Bergt U, Heimann G: Neonatal theophylline intoxication: Pharmacokinetics and clinical
evaluation. Eur J Pediatr 1992; 151:221-224.
42. Somani SM, Khanna NN, Bada HS: Caffeine and theophylline: Serum/CSF concentration in premature
infants. J Pediatr 1980; 98:1091-1093.
43. Tsai J, Chern TL, Hu SC, et al: The clinical implication of theophylline intoxication in the emergency
department. Hum Exp Toxicol 1994; 13:651-657.
44. Ujhelyi MR, Hulula G, Skau K: Role of exogenous adenosine as a modulator of theophylline toxicity.
Crit Care Med 1994; 22:1639-1646.
45. Weinberger M, Henderles L: Theophylline in asthma. N Engl J Med 1996; 334:1380-1388.
46. Woo OF, Pond SM, Benowitz NL, et al: Benefit of hemoperfusion in acute theophylline intoxication. J
47. Zwillich CW, Sutton FD, Neff TA, et al: Theophylline-induced seizures in adults. Ann Intern
Med 1975; 82:784-787.


Uncited reference
Henderson A, Wright DM, Pond S: Management of theophylline overdose patients in the intensive care unit.
Anaesth Intens Care 1992; 20:56-62.


Chapter 49 – Selective Beta-Adrenergic Agonists
JEANMARIE PERRONE
Essentials
• Profound tachycardia
• Emesis
• Tremor
• Absence of hypertension
• Normal mental status
• Hypokalemia, hyperglycemia, leukocytosis
INTRODUCTION
The principal therapeutic use of ß-adrenergic agonists is in the management of asthma. They are also used
to inhibit preterm labor in the pregnant patient. A decline in the use of theophylline in the pharmacotherapy
of asthma as well as the development of selective long-acting ß2-agonists with fewer side effects has led to
a proportionate increase in the therapeutic administration of ß-agonists. In addition, the use of home
nebulizer systems has proliferated, increasing the availability of ß-agonist solutions available for accidental
or intentional self-administration. The American Association of Poison Control Centers (AAPCC) Toxic
Exposure Surveillance System reported 14,150 ß-agonist exposures in 1995.[13] Eighty-four per cent of
these exposures were unintentional and occurred predominantly in children younger than age 6 years (70
per cent).


Pharmacology
Endogenous catecholamines have very short half-lives, owing to rapid metabolism by monoamine oxidase
and catechol-O-methyltransferase. Orally administered catecholamines are inactivated in the intestinal wall
and by hepatic conjugation and exhibit no pharmacologic activity. The pharmacochemistry of the synthetic
selective ß-adrenergic agonists is therefore directed at avoiding these pathways of degradation, allowing for
a longer-acting drug and one that may have oral activity. All of the derived ß-agonists share the
phenylethylamine base structure and contain various substitutions both to prevent degradation and to
increase selectivity for the ß 2-adrenergic receptor.
Bioavailability of these drugs available in oral formulations varies: metaproterenol, 40 per cent; albuterol, 50
per cent; terbutaline, 10 to 33 per cent; and ritodrine, 30 per cent. Metabolic transformation occurs to varying
degrees in the liver, with both metabolites and unchanged drug excreted by the kidney. Peak effect of the
drugs generally occurs 1 to 4 hours after ingestion. The oral formulations of these medications contain about
10 times more drug than the nebulizer solution formulations, to compensate for the gut and first-pass hepatic
metabolism. For this reason, nebulizer solutions ingested intentionally or accidentally tend to cause less
toxicity, especially pediatric ingestions.[7]
Pathophysiology
Beta-adrenergic receptors mediate the effects of the sympathetic nervous system throughout the body.
Beta1-receptors are located solely on the myocardium, whereas ß2-receptors are found on vascular,
bronchial, gastrointestinal, and uterine smooth muscle as well as on skeletal muscle, hepatocytes, and also
the myocardium. At the cellular level ß2-adrenergic receptors are located in the plasma membrane ( Fig.
49–1 ). They consist of a transmembrane protein linked to a stimulatory guanyl nucleotide-binding protein
(Gs ). [15] After activation of the ß2-adrenergic receptor, conformational changes occur in the Gs , initiating
activation of adenylate cyclase.[15] Adenylate cyclase converts adenosine triphosphate (ATP) to cyclic 3'5'-
adenosine monophosphate (cAMP), which mediates bronchodilation and smooth muscle relaxation through
activation of protein kinases.[14]
Figure 49-1 The ß-adrenergic receptor is a transmembrane protein coupled to an intermediary, stimulatory guanyl-nucleotide-binding
protein (Gs), which is composed of (1) a, ß, and subunits. When the ß-adrenergic receptor is unbound, the receptor-Gs complex is
inactive, the Gs subunits are associated, and adenylate cyclase (AC) is inactive. When a ß-agonist binds to the ß-adrenergic receptor,
(2) guanosine triphosphate (GTP) is exchanged for guanosine diphosphate (GDP). The a-GTP subunit then dissociates from the ß
subunit to activate AC. Adenylate cyclase catalyzes the transformation of adenosine triphosphate (ATP) to cyclic adenosine
monophosphate (cAMP), which functions as a second messenger for the ß-agonist. Finally, cAMP activates protein kinases to
produce the ß-adrenergic effects.
The ß-adrenergic agents used in the management of asthma are directed at the ß2-adrenergic receptors in
the lung and cause bronchial smooth muscle relaxation, inhibition of secretions, and decreased histamine
release. Stimulation of ß2-adrenergic receptors found on uterine smooth muscle inhibits the onset of labor.
Increased specificity for the ß2-adrenergic receptor has diminished the side effects of these agents, but this
selectivity is lost in overdose.
Cardiovascular toxicity, especially tachycardia, occurs with both the selective and nonselective ß-agonists.
The ß 2-specific agents mediate tachycardia through several mechanisms: (1) reflex tachycardia results from
ß2-mediated vascular smooth muscle relaxation and peripheral vasodilation; (2) direct stimulation of the
small number of ß2-adrenergic receptors that are found in the left ventricle and right atrium also results in
tachycardia[19]; and (3) in the overdose setting, loss of selectivity for ß2-receptors results in direct stimulation
of ß1-receptors as well.[12] Ventricular tachycardia has been reported in the setting of myocardial infarction in
a patient treated with terbutaline for bronchospasm.[9] Myocardial ischemia and infarction have been
associated with excessive tachycardia in elderly patients treated with ß2-agonists.[3][12][18] Supraventricular
tachycardia after overdose of albuterol has also been reported.[17]
The characteristic tremor associated with the ß-agonist agents is attributed to excessive stimulation of
peripheral skeletal muscle, because most of the ß-adrenergic agonists used today do not cross the blood-
brain barrier.[1] Beta2-receptor–mediated release of glucagon, which inhibits insulin release and stimulates
glycogenolysis, produces hyperglycemia in toxic states.[10] Hypokalemia results from intracellular shifts of
potassium due to stimulation of membrane-bound Na+,K+-ATPase.[4]
Specific Agents
Metaproterenol, a derivative of isoproterenol, is less potent but is active orally and has a longer duration of
action when administered by inhalation. Substitutions on the structure of metaproterenol led to terbutaline, a
compound with increased ß2-receptor selectivity. Albuterol retains ß2-receptor selectivity, is active after oral
administration, and has a duration of effect of several hours. Ritodrine, a ß2-specific agonist designed to be
a uterine relaxant, can be administered either intravenously or orally. Other selective ß-adrenergic agonists
available only in inhalation form include isoetharine, pirbuterol, bitolterol, fenoterol, formoterol, procaterol,
and salmeterol. Fenoterol, formoterol, and procaterol are not available in the United States.[7]


Overdoses of ß-adrenergic agonists have commonly resulted from excess self-administration, iatrogenic
dosing errors,[3][12] intentional suicide attempts,[16] and accidental pediatric ingestions.[20] One case report
describes systemic toxicity after application to excoriated skin.[8] The patient history may reveal ingestion of
ß-adrenergic agonists or “asthma medications.” At all times one must consider the possible co-ingestion of
theophylline, the toxicity of which may initially be clinically indistinguishable from that of a ß-adrenergic
agonist overdose but may result in more significant morbidity or even mortality.
Table 49-1 -- Clinical Presentation of ß-Adrenergic Agonist Toxicity

Signs Symptoms
Tachycardia Vomiting
Wide pulse pressure Agitation
Tremor Palpitations
Dysrhythmias (rare) Tremulousness
Seizures (very rare)
Patients usually present with tachycardia and a wide pulse pressure. Children (aged 2–8) ingesting
salbutamol have been reported to tolerate heart rates of 140 to 220 beats per minute without
compromise.[16] Hypotension may occur due to excessive peripheral vasodilation resulting from ß2-receptor
induced relaxation of vascular smooth muscle. This also exacerbates the tachycardia but can be managed
easily with fluids. These agents do not cause significant hypertension, and its occurrence should prompt
consideration of other sympathomimetic agents such as cocaine or amphetamines ( Table 49–2 ). Cardiac
dysrhythmias including ventricular tachycardia have only rarely been reported.[11][17] Vomiting, headache,
tremors, palpitation, and agitation may also occur. Vomiting is not as intractable as with theophylline
overdose and usually abates spontaneously. There is only one reported case of seizures after exposure to
ß-agonists[6]: a 7-year-old girl with a history of asthma had a seizure temporally related to therapeutic doses
of terbutaline on three separate occasions.
Table 49-2 -- Differential Diagnosis of ß-Adrenergic Agonist Toxicity

Conditions Drugs
Psychosis Theophylline
Withdrawal (ethanol, barbiturates, benzodiazepines, other sedative-hypnotics) Caffeine
Thyrotoxicosis Ephedrine
Pheochromocytoma Amphetamines
Hypoglycemia Cocaine


Toxicity due to many sympathomimetic agents may present as similar vital-sign abnormalities as well as the
associated findings of headache, tremor, agitation, and vomiting (see Table 49–2 ). Other sympathomimetic
signs, such as diaphoresis and mydriasis, are not as prominent with ß-agonist toxicity. Their presence
suggests another sympathomimetic agent. Patients with seizures, altered mental status, or significantly
elevated blood pressure are not poisoned with ß-adrenergic agonists, and other agents and conditions
should be considered. In the setting of suspected ß-adrenergic overdose, it is prudent to send a theophylline
level because these agents are often prescribed together and early clinical manifestations are
indistinguishable.


LABORATORY STUDIES
The confirmation of ß-adrenergic toxicity is largely clinical. No specific drug levels are necessary, with the
exception of a theophylline level, to rule out concomitant theophylline ingestion. Other characteristic findings
on laboratory screening include ß-receptor–mediated hypokalemia, hyperglycemia, mild lactic acidosis,
hypophosphatemia, and hypercalcemia. Although one case report describes rhabdomyolysis after a
terbutaline sulfate ingestion in a young woman, other features of this case are not consistent with a pure ß-
agonist overdose; and this has not been reported again.[2] Dipstick analysis of urine is a quick and
inexpensive screen for this rare possible complication. If a urine dipstick test is positive for heme and the
microscopic examination shows no red blood cells, myoglobinuria secondary to rhabdomyolysis should be
suspected. In that case, serum creatinine and creatine kinase values should be obtained.


Gastric emptying by ingestion of syrup of ipecac or with gastric lavage for suspected overdose of any of the
ß-adrenergic agonists can be omitted because serious toxicity from these agents is extremely rare. These
drugs adsorb well to activated charcoal, and gastrointestinal decontamination can be confined to one to two
doses of activated charcoal.
Table 49-3 -- Treatment Essentials of ß-Adrenergic Agonist Toxicity

1. Provide gastrointestinal decontamination
a. Activated charcoal
b. Gastric emptying unnecessary
2. Rule out concomitant theophylline ingestion
3. Correct hypokalemia
4. Hypotension
a. Intravenous 0.9% NaCl
b. Vasopressors, ß-adrenergic blockers rarely required
5. Treat dysrhythmias
a. Tachycardia resolves spontaneously
b. Ventricular dysrhythmias: ß-adrenergic blockers
Myocardial and Vascular Effects
Beta-adrenergic blockers are best reserved for the management of profound tachydysrhythmias or
hypotension refractory to crystalloid supplementation in known ß-agonist overdoses. Beta-adrenergic
blockers have rarely been used for symptomatic treatment of palpitations and tachycardia. In one
retrospective series of 40 patients with salbutamol toxicity, 10 were treated with ß-adrenergic blockers
without complications. However, the indications for treatment were not revealed.[16] A case report described
the successful use of intravenous propranolol to treat supraventricular tachycardia in a young woman after
albuterol overdose.[17] Beta-adrenergic blockers should be used cautiously in patients with a history of
bronchospasm. Additionally, ß-adrenergic blockers are contraindicated in the setting of cocaine or
amphetamine poisoning, owing to an exacerbation of unopposed a-receptor–mediated effects, which may
result in severe paradoxical hypertension. Labetalol, a mixed a- and ß-receptor antagonist, may also be
associated with unopposed a effects because its a-adrenergic blocking capacity is relatively weak. Beta-
adrenergic blockers have been used to treat hypokalemia and hyperglycemia secondary to salbutamol
poisoning,[5] but the necessity of using these drugs to treat these toxic effects is unclear.
Hypotension or a widened pulse pressure occurs due to diminished venous return resulting from ß2-
mediated peripheral vasodilation. This finding often resolves with intravenous crystalloids and rarely requires
vasopressors or ß-adrenergic blockers.
Hypokalemia
Potassium supplementation may be necessary to correct serum (extracellular) hypokalemia resulting from
increased intracellular uptake of potassium. Although total-body stores of potassium are usually normal,
supplementation to correct extracellular hypokalemia will not lead to hyperkalemia in patients with normal
renal function.


DISPOSITION
Most toxicity from acute exposures will resolve completely during a 4- to 6-hour observation period in the
emergency department. Patients may be medically cleared when their vital signs normalize and other more
serious exposures have been excluded. It is possible with the longer-acting agents to anticipate a longer
period of toxicity; and, rarely, a toddler with an accidental ingestion may warrant hospitalization for persistent
tachycardia.


SEQUELAE
There are no long-term effects of an accidental exposure to a ß-adrenergic agonist.


REFERENCES
1. Bengtsson B, Fagerstrom PO: Extrapulmonary effects of terbutaline during prolonged administration.
Clin Pharmacol Ther 1982; 31:726-732.
2. Blake PG, Ryan F: Rhabdomyolysis and acute renal failure after terbutaline overdose.
Nephron 1989; 53:76-77.
3. Brandstetter RD, Gotz V: Inadvertent overdose of parenteral terbutaline. Lancet 1980; 1:485.
4. Clausen T, Flatman JA: The effect of catecholamines on Na-K transport and membrane potential in rat
soleus muscle. J Physiol 1977; 270:383-414.
5. Connell JMC, Cook GM, McInnes GT: Metabolic consequences of salbutamol poisoning reversed by
propanolol. BMJ 1982; 285:779.
6. Friedman R, Zitelli B, Jardine D, et al: Seizures in a patient receiving terbutaline. Am J Dis

Child 1982; 136:1091-1092.
7. Hoffman BB, Lefkowitz RJ: Catecholamines, sympathomimetic drugs, and adrenergic receptor
antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al ed. Goodman and Gilman’s The Pharmacologic
Basis of Therapeutics, 9th ed. New York: McGraw-Hill; 1996:199-248.
8. Ingrams GJ, Morgan FB: Transcutaneous overdose of terbutaline. BMJ 1993; 307:484.
9. Insel PA: Adrenergic receptors—evolving concepts and clinical implications. N Engl J

Med 1996; 334:580-585.
10. Jarvie DR, Thompson AM, Dyson EH: Laboratory and clinical features of self-poisoning with salbutamol
and terbutaline. Clin Chim Acta 1987; 168:313-322.
11. Kinney EL, Trautlein JJ, Harbaugh CV, et al: Ventricular tachycardia after terbutaline.
JAMA 1978; 240:2247.
12. Lawyer C, Pond A: Problems with terbutaline. N Engl J Med 1977; 296:821.
13. Litovitz TL, Felberg L, White S, et al: 1995 Annual report of the American Association of Poison Control
14. Nelson HS: Beta adrenergic agonists. Chest 1982; 1(suppl):33-38.
15. Nelson HS: ß-adrenergic bronchodilators. N Engl J Med 1996; 333:499-506.
16. Prior JG, Cochrane GM: Self poisoning with oral salbutamol. BMJ 1981; 282:1932.
17. Ramoska EA, Henretig F, Joffe M, et al: Propranolol treatment of albuterol poisoning in two asthmatic
patients. Ann Emerg Med 1993; 22:1474-1476.
18. Santo M, Sidi Y, Pinkhas Y: Acute myocardial infaction following intravenous salbutamol. S Afr Med
J 1980; 58:394.
19. Stiles GL, Taylor S, Lefkowitz RJ: Human cardiac beta adrenergic receptors: Subtype herogeneity
delineated by direct ligand binding. Life Sci 1983; 33:467-473.
20. Spiller HA, Ramoska EA, Henretig FM, et al: A two-year retrospective study of accidental pediatric
albuterol ingestions. Pediatr Emerg Care 1993; 9:338-340.


Chapter 50 – Oral Hypoglycemic Agents
LESLIE R. WOLF FRANK SMEEKS MICHAEL POLICASTRO
Essentials
• Excess adrenergic output: anxiety, tremulousness, flushing, tachycardia, hypertension,
diaphoresis
• Altered mental status, including any neuropsychiatric abnormality or seizure
• Decreased serum glucose level
• History of diabetes mellitus or access to oral hypoglycemic agents
• Lactic acidosis (biguanides)
INTRODUCTION
Diabetes mellitus (DM) affects 14 to 16 million Americans, and 90 per cent of this population have type II or
non–insulin-dependent diabetes mellitus (NIDDM).[13][67] NIDDM affects 2 to 3 per cent of adults residing in
Western countries.[54] Obesity-induced insulin resistance and a resulting decrease in insulin secretion
accounts for 80 per cent of cases of NIDDM.[21][54] The first-generation sulfonylureas were discovered by a
French clinician, Marcel Janbon. He was studying the effects of these agents as a treatment for typhoid
when he accidentally discovered their hypoglycemic effect.[38] Sulfonylureas, biguanides, and a-glucosidase
inhibitors are all oral agents used for the treatment of NIDDM. Hypoglycemia, or the failure to maintain
adequate glucose homeostasis, most commonly occurs after unintentional overdose or therapeutic use of
oral hypoglycemic (OHG) agents with inadequate food intake. However, self-inflicted (suicidal), occult,
malicious, or factitious administration must also be considered.
The use of hypoglycemic agents accounts for 54 per cent of cases of hypoglycemia with an established
cause.[11] Forty-seven per cent of drug-induced hypoglycemia results from OHG agents. [50] In 1998, there
were 4581 exposures to OHG agents, 831 of which were intentional.[48] Ten deaths, 96 major outcomes,
and 623 moderate outcomes occurred.[48] The incidence of hypoglycemia in patients taking sulfonylureas is
1.81/100 patient-years[78] with the risk for severe hypoglycemia of 1.4 to 20 per cent.[85] Combined insulin
and sulfonylurea therapy carries a risk of hypoglycemia of 3.38/100 patient-years. The majority of patients
(52 per cent) with hypoglycemia present with altered sensorium,[50] and in an urban emergency department,
9 per cent of all cases of altered mental status were secondary to hypoglycemia.[31] Hypoglycemia
secondary to OHG agent exposure should be considered in any patient who presents with altered mental
status, particularly those with a history of DM, family members with DM, or health care professionals with
access to these medications.


PHYSIOLOGY
Normal Glucose Regulation
Plasma glucose is maintained within a narrow range (72–144 mg/dL) by neural, hormonal, and substrate
mechanisms. When glucose levels rise above this range, the pancreatic beta cells secrete insulin. Insulin
production is the result of a two-step cleavage process of the preproinsulin precursor. [16] After translocation
across the endoplasmic reticulum, preproinsulin loses the N-terminal signal peptide to produce proinsulin.[16]
Approximately 10 per cent of circulating insulin is in the form of proinsulin, which has a half-life of 44 minutes
and only 5 per cent of the metabolic activity of insulin.[16] Initial conversion of proinsulin to insulin begins in
the Golgi apparatus by calcium-dependent endopeptidases, PC2 and PC3. Transformation is completed in
secretory granules, with a loss of the connector peptide (C peptide).
Insulin is composed of two peptide chains (A and B), each containing ordered a-helical regions connected
by one intrasubunit and two intersubunit disulfide bonds. Insulin exists in three forms: monomeric, dimeric,
or hexameric. The monomer is biologically active, whereas the hexamer is the storage form. Zinc is required
in both the conversion of proinsulin to insulin and in the formation of the hexamer.[16] Insulin secretion is
biphasic, first peaking in 1 to 2 minutes, followed by a delayed peak of longer duration. Normal basal insulin
secretion is 0.5 to 1 unit/hr with daily insulin production of 0.2 to 0.5 unit/hr. Insulin binds to the extracellular
portion of the a subunit of the insulin transmembrane receptor, resulting in autophosphorylation of the
tyrosine residues of the ß subunit and signal transduction. The biological activity of insulin results in a
decrease in plasma glucose. This occurs by inhibition of hepatic glucose production, increased glucose
uptake, and increased glycogen stores in insulin-sensitive tissues, muscle, and adipose tissue. Insulin also
causes amino acid storage, suppression of proteolysis, increased triglyceride formation, fatty acid
deposition, and decreased lipolysis.
Insulin metabolism occurs predominantly in the liver, kidney, and muscle. Forty to 50 per cent of insulin
secreted by the pancreas is destroyed by first-pass hepatic metabolism and never reaches the general
circulation.[16][69] Thiol metalloprotease is the primary degrading enzyme in the hepatocytes. The kidney
clears 30 to 80 per cent of insulin, 50 per cent of proinsulin, and 70 per cent of C peptide by glomerular and
peritubular clearance.[69] Glomerular clearance is the major route of elimination and is determined by size,
shape, and charge of the filtrate, glomerular permeability, and renal plasma blood flow.[69] Insulin crosses
the glomerulus intact, and 99 per cent of the filtered insulin is absorbed in the proximal tubules. Sixty per
cent of the amount resorbed is metabolized.[34][69] Brush-border luminal absorption occurs by stereospecific
binding of insulin and endocytosis. Insulin is degraded in the proximal tubules by two different mechanisms:
insulin protease hydrolysis (may be defective in patients with DM) and reductive cleavage by glutathione
insulin transhydrogenase. The second mechanism is peritubular, accounts for one third of total renal insulin
clearance, and occurs when insulin quantities greater than physiologically normal are present in the proximal
tubules.[69] Insulin can be degraded at the contraluminal side or in the cell.[69] Binding of insulin to receptors
results in stimulation of sodium-potassium adenosine triphosphatase (Na +,K+-ATPase) and increased
sodium reabsorption.[69]
Response to Hypoglycemia
The counterregulatory substances released in response to hypoglycemia include glucagon, epinephrine,
norepinephrine, cortisol, growth hormone, and adrenocorticotropic hormone. [17] The initial response to
hypoglycemia is glucagon release, the major acute defense. Glucagon is secreted from the pancreatic alpha
cells and acts on the liver to increase glycogenolysis and gluconeogenesis. [52]
Epinephrine, synthesized in the adrenal medulla, constitutes 85 per cent of the total molar increase in
catecholamines circulating in response to hypoglycemia.[15][52] Epinephrine acts primarily through ß 2-
adrenergic receptors to increase plasma glucose[52] by indirect stimulation of lipolysis.[29] Catecholamines
also directly stimulate glycogenolysis and gluconeogenesis. In addition, epinephrine contributes significantly
to recovery in long-term hypoglycemia.[33] Norepinephrine is also synthesized in the adrenal medulla and
functions as both a hormone and a neurotransmitter.[15][52] When hypoglycemia occurs, norepinephrine
accounts for 35 per cent of the catecholamine concentration in adipose tissue and 50 per cent in muscle.[52]
Cortisol is necessary for the liver to respond appropriately to glucagon and epinephrine. Antecedent
hypoglycemia raises plasma cortisol levels, reducing the autonomic adrenomedullary response to
subsequent hypoglycemia.[17] If the rise in plasma cortisol is blocked, the catecholamine response to
hypoglycemia is restored.[18] The combination of autonomic failure associated with antecedent
hypoglycemia and glucagon depletion that occurs in patients with DM increases the risk for severe
hypoglycemia by a factor of 25,[14] as well as decreasing awareness of the symptoms of hypoglycemia.[25]
Without glucagon and epinephrine release, lipolysis is blunted, resulting in a 40 per cent decrease in hepatic
glucose production, a 70 per cent decrease in gluconeogenesis, and a 15 per cent increase in peripheral
glucose utilization.[14]
In addition to hormone release, neural and hepatic autoregulation contributes significantly to the response to
hypoglycemia, especially in the event of autonomic failure. Hepatic autoregulation and direct neural input
during insulin-induced hypoglycemia are estimated to be responsible for 25 per cent of the change in net
hepatic glucose output.[58] If the brain maintains euglycemia, despite systemic hypoglycemia, glucagon
release is not stimulated.[17] However, the liver continues to produce glucose.[58] The liver achieves this
primarily by glycogenolysis, if glycogen stores are adequate, followed by gluconeogenesis from the
peripheral tissue.[58]
Diabetics have increased cerebral blood flow to the frontal cortex in the basal state, which may represent a
chronic adaptation.[51] When acute hypoglycemia develops, a 20 per cent increase in total cerebral blood
flow occurs.[51] The risk of thrombosis and infarct can increase with hypoglycemia, owing to activation of von
Willebrand factor.[26] The developing brain is the most susceptible to hypoglycemia because of a decreased
ability to enhance cerebral blood flow.[51]
Factors Affecting Response to Hypoglycemia
Sex and age influence counterregulatory mechanisms in response to hypoglycemia. Women have both an
increased threshold and an attenuated hormonal response in comparison with men.[7][15] Children have a
more vigorous and earlier response to hypoglycemia than young adults. [17] However, diabetic children have
a higher threshold as well as an attenuated response compared with healthy children.[7] Diabetic children
with a higher body mass index (BMI) report autonomic symptoms at higher glucose levels than those with
low BMI.[7] In one study hypoglycemia in diabetic children was due to dietary errors in 27 per cent, exercise
in 12.2 per cent, and incorrect insulin dose in 10.8 per cent.[8] Severe hypoglycemia occurred in
approximately 15 per cent of diabetic adolescents and children.[8] Frequent, severe hypoglycemia is more
common in young children than adolescents, and 50 per cent of severe hypoglycemia occurs during sleep.[5]
The risk of nocturnal hypoglycemia for patients taking insulin twice daily is greater in children than adults.[5]
Young adults report symptoms of hypoglycemia at glucose levels of 3.6 ± 0.1 mmol/L (64.6 mg/dL), whereas
an elderly male will not report symptoms until the glucose falls to 3.0 ± 0.2 mmol/L (53.8 ± 3.6 mg/dL).[55]
It was previously thought that elderly males had an attenuated hormonal response to hypoglycemia, but this
has proven to be false.[55] In aged men, cognitive dysfunction occurs before autonomic symptoms, resulting
in more severe episodes of hypoglycemia and a slower rate of recovery than in younger males.[55]
Ethanol ingestion can be associated with hypoglycemia.[50] Ethanol metabolism by alcohol dehydrogenase
impairs gluconeogenesis by increasing the NADH/NAD+ ratio.[56] Concomitant glycogen depletion after
chronic alcohol use significantly increases the risk of hypoglycemia.[56] The form of alcohol ingested also
influences blood glucose levels. Beer and spirits are absorbed more quickly than wine, resulting in earlier
peaks in the ethanol level.[56] Co-ingestion of food decreases the peak ethanol level and the time to this
peak. When beer is ingested with an evening meal, a delayed hypoglycemic effect can occur 7 to 14 hours
after ingestion.[56] Alcohol ingestion also decreases awareness, which may exaggerate the severity of
neuroglycopenia.[12][83]
Renal failure, often associated with DM, results in decreased insulin extraction, decreased insulin
elimination, and glycogen depletion, [3][69] all of which contribute to an increased risk of hypoglycemia.
Salicylate ingestion has also been associated with hypoglycemia. Salicylates also displace tolbutamide and
chlorpropamide from plasma proteins, resulting in an increased concentration of free drug.[43] Salicylates
affect the pharmacokinetics of glyburide, decreasing peak concentrations of glyburide by 35 per cent. Total
glyburide clearance increases by 85 per cent, and the mean free fraction of glyburide is increased by 29 per
cent with concomitant salicylate therapy. [43] Beta-adrenergic receptor antagonists inhibit the
counterregulatory epinephrine response, contributing to an increased risk of hypoglycemia.[50] Conditions
associated with glycogen depletion, such as fasting, anorexia nervosa, and malnutrition also increase the
risk of hypoglycemia. Other agents have also been implicated in causing hypoglycemia ( Table 50–1 ).[3][50]
Table 50-1 -- Differential Diagnosis of Other Agents That Cause Hypoglycemia

Ethanol
Sulfinpyrazone
Ackee fruit (unripe)
Opioids
Insulin
Ritodrine
Pentamidine
Tetracycline
Alloxan
Quinine
Streptozocin
Propoxyphene
Vacor
Salicylates
Valproic acid
Cocaine
Quinidine
Sulfonamides
Haloperidol


Sulfonylureas
Pharmacology
Sulfonylureas reduce plasma glucose levels by 8 to 43 per cent.[21] Their effects occur secondary to
stimulation of insulin secretion from pancreatic beta cells, reduction of hepatic glucose production, and
increasing peripheral insulin sensitivity.[16][21][47] Sulfonylureas bind to the sulfonylurea receptor and inhibit
the pore-forming unit of the ATP-sensitive potassium channel, which subsequently results in depolarization
and calcium influx with resulting insulin secretion from the beta cell.[16][32][76] After chronic sulfonylurea
therapy, insulin receptors can also become down-regulated.[16] Insulin secretion may also contribute to
weight gain, further contributing to peripheral insulin resistance in obese patients.[67]
Two generations of sulfonylureas exist: first and second generation ( Table 50–2 ). Sulfonylureas are
metabolized in the liver and renally excreted.[28] They are highly protein bound (>90 per cent) and have
volumes of distribution ranging from 10 to 15 L/kg.[43]
Table 50-2 -- Pharmacokinetics of Oral Hypoglycemic Agents, Therapeutic Doses

Agent Onset (hr) Peak (hr) Duration (hr)
Sulfonylureas
First Generation
Acetohexamide 1 4 12–24
Chlorpropamide 1 3–6 24–72
Tolazamide 3–4 4–6 12–24
Tolbutamide 1–3 5–8 6–12
Second Generation
Glimepiride 1–2 2–3 24
Glipizide
Regular 1–1.5 1.5–2 12–24
Extended Release 2–3 6–12 24
Glyburide
Nonmicronized 2–4 2–4 24
Micronized 0.25–1 2–3 24
Biguanides
Agent Onset (hr) Peak (hr) Duration (hr)
Metformin 2–2.5 5–6
Phenformin 6–8
Alpha-Glucosidase Inhibitors
Acarbose 1 2
Miglitol 2–3 2
Thiazolidinediones
Troglitazone * 2–3 16–34
Rosiglitazone 1.3–3.5
Pioglitazone 2–4
Meglitinides
Repaglinide 0.25–0.5 0.5–1 1
* Withdrawn from U.S. market on 3/21/2000 due to severe hepatotoxicity.
First Generation
First-generation sulfonylureas exhibit ionic protein binding and are displaced by various drugs, including
phenylbutazone, salicylates, sulfonamides, and warfarin.[43] They include acetohexamide (Dymelor),
chlorpropamide (Diabenese), tolazamide (Tolinase), and tolbutamide (Orinase).
Second Generation
The second-generation sulfonylureas include glimeperide (Amaryl), glipizide (Glucotrol, Glucotrol XL),
glyburide (DiaBeta, Micronase, Glynase), and glibenclamide. They are 100 times more potent than the first-
generation agents and offer an improved safety profile, especially in patients simultaneously receiving drugs
that are highly bound to albumin.[16][43] Glyburide, responsible for 70 per cent of sulfonylurea use, has been
found to be more effective than glipizide for hepatic insulin sensitivity.[79] However, glipizide lowers blood
glucose more effectively in response to meals.[79] A 50 per cent risk for hypoglycemia occurs in patients with
renal failure taking glibenclamide.[28]
Pathophysiology
Several side effects have been noted with sulfonylurea use. Chlorpropamide can induce hyponatremia. [16]
Because of the possibility of accumulation of parent drug or metabolites with resulting hypoglycemia,
acetohexamide, tolazamide, and chlorpropamide should be avoided in patients with renal failure.[28] In
general, renal impairment is associated with a fourfold higher risk of hypoglycemia in patients taking
sulfonlyureas.[28] Sulfonylureas should also be avoided in patients with severe liver disease.[43]
Hypoglycemic risk generally increases as the drug half-life increases.[16] Glyburide has the highest rate of
serious hypoglycemia (16.6/1000 patient-years) and tolbutamide the lowest (3.5/1000 patient-years).[79]
Thirty-one per cent of patients treated with glibenclamide experience hypoglycemia.[85] Other conditions that
increase the risk for hypoglycemia in patients taking sulfonylureas include advanced age, polypharmacy,
alcohol use, microalbuminuria, hypertension, and counterregulatory failure.[17][72]
Nonsulfonylureas
Biguanides
Pharmacology
Biguanides are a class of antihyperglycemic agents that were introduced in the 1950s.[16][49] Buformin was
introduced in 1958 but had limited use. However, phenformin and metformin (Glucophage) have been used
worldwide.[16] Phenformin, a monosubstituted long-chain lipophile guanidine derivative, reduces glucose
levels without stimulating insulin production. Phenformin hydroxylation occurs in the liver by cytochrome P-
450.[49][75]
Metformin is a bisubstituted, short-chain hydrophilic guanidine derivative. Oral absorption of metformin

occurs within 6 hours, with a bioavailability of 50 to 60 per cent.[21] The bioavailability decreases by 24 per
cent with concomitant food administration, and peak plasma concentrations are delayed.[73] It undergoes
negligible hepatic metabolism and is excreted by the kidney.[21][75] Metformin does not stimulate insulin
secretion.[21] It lowers plasma glucose 7 to 45 per cent by inhibiting lipolysis.[1][16][21] The lower free fatty
acid concentrations result in increased glucose uptake by 18 to 29 per cent, decreased hepatic glucose
production by 9 to 30 per cent, decreased intestinal absorption of glucose, decreased gluconeogenesis, and
increased insulin-receptor binding. Triglyceride and cholesterol levels are also lowered.[1][16][21] Metformin
also stimulates the hexose monophosphate transport in vascular cells, increases fibrinolysis, and decreases
platelet aggregation.[21][74] Metformin may be added to other diabetic therapy regimens for better glucose
control. When added to sulfonylureas, the combination reportedly decreases fasting plasma glucose levels
by 31 per cent.[21]
Pathophysiology
Lactic acidosis is the most serious side effect associated with metformin use, although the incidence is less
common than with phenformin. The estimated incidence is 0.03/1000 patient-years with a 50 per cent
associated mortality.[10] Lactic acid may accumulate owing to decreased gluconeogenesis from precursors,
including alanine, pyruvate, and lactate. Three types of lactic acidosis can occur in a patient taking
metformin: type A, hypoxic and not related to metformin; type B, a result of metformin accumulation; and
type C, which is a mixture of A and B and the most common.[45] In one report, 10 of 14 patients with
metformin-associated lactic acidosis had significantly elevated metformin blood levels (4.1–84.9 mg/dL).[75]
Although not clinically available, erythrocyte metformin levels obtained in patients who present with lactic
acidosis may implicate metformin as the etiologic agent. Because of the incidence of spontaneous lactic
acidosis (0.4/1000 patient-years) associated with a high mortality rate (30–50 per cent), phenformin was
removed from the U.S. market in 1977.[21][22][49] However, phenformin continues to be used in other
countries, including China and Italy, and in other European markets.[22][49]
Contraindications to metformin use include congestive heart failure, metabolic acidosis, drug
hypersensitivity, and renal impairment (creatinine greater than 1.5 mg/dL [male] or greater than 1.4 mg/dL
[female]). The most common feature associated with serious lactic acidosis is renal dysfunction, defined by
an abnormal creatinine clearance or serum creatinine of 1.5 mg/dL or more.[37] Use of iodinated
radiographic contrast dyes can also precipitate metformin-associated lactic acidosis, owing to the risk of
renal failure.[37][75]
Precautions include conditions that result in tissue hypoxia and thus predispose to lactic acidosis, including
coronary artery disease, chronic obstructive pulmonary disease, and peripheral vascular disease. Liver and
kidney disease can also result in decreased lactate clearance.[21] Drugs that affect creatinine clearance or
compete with renal tubular secretion of metformin should be avoided. The latter category includes
vancomycin, trimethoprim, triamterene, quinidine, quinine, morphine, digoxin, amiloride, ranitidine, and
cimetidine.[37] Other agents that can impair renal function include nifedipine, furosemide, nonsteroidal anti-
inflammatory drugs, and loop diuretics.[37] Patients with age-associated renal impairment should also avoid
metformin. Cimetidine increases plasma metformin AUC by 50 per cent and decreases 24-hour urine
excretion of metformin by 27 per cent.[75] Guar gum reduces metformin concentrations by 40 per cent 6
hours after administration.[75]
Metformin does not cause hypoglycemia when it is the sole agent involved, even after overdose. However,
when combined with insulin or sulfonylureas it may increase the risk of hypoglycemia from these agents.[21]
Gastrointestinal side effects, including abdominal pain, nausea, and diarrhea, occur in 5 to 20 per cent of
patients taking metformin.[21] Chronic use can also be associated with decreased absorption of vitamin B12
and folate, and rare cases of megaloblastic anemia have been reported with metformin use.[21]
Alpha-Glucosidase Inhibitors
Pharmacology
Acarbose is a water-soluble pseudotetrasaccharide that differs from dietary oligosaccharides by the

attachment of an amino sugar to the a-D-glucopyranose unit.[13] This structure results in reversible
competitive inhibition of the a-glucosidase on the brush border of the small bowel. The resultant delayed
carbohydrate absorption and redistribution throughout the intestines yields a decreased, constant insulin
production due to lowered postprandial glucose concentrations. Acarbose also results in lowered cholesterol
and triglyceride concentrations.[13][36]
Only 1 to 2 per cent of acarbose is absorbed by the gut, and the serum half-life is 2.7 to 9 hours. The half-life
is increased in patients with renal failure.[13][54] Although acarbose monotherapy is associated with a
decrease in hemoglobin A1C and a reduction in postprandial glucose, it is not a single substitute for
biguanide/sulfonylurea failure.[54] When acarbose is coupled with insulin, postprandial glucose levels
decrease, allowing insulin injections closer to meals and an overall decrease in insulin requirement.[13][54]
Pathophysiology
Acarbose does not cause hypoglycemia when administered alone. However, when it is added to insulin or
sulfonylurea regimens, hypoglycemia can occur in 2 per cent.[54] The beneficial effects of acarbose are
diminished by concomitant administration of intestinal absorbing agents, such as charcoal or carbohydrate-
splitting enzymes (amylase, pancreatin).[54] The most common side effects are gastrointestinal and include
flatulence, borborygmi, abdominal pain, and diarrhea. Rarely, elevated liver transaminases and decreases in
serum iron concentrations have occurred. [13][54][67] Liver biopsies in two patients with acarbose-associated
hepatic injury demonstrated infiltration of inflammatory cells, ceroid-containing macrophages, Councilman
bodies, liver cell regeneration, and mild fibrosis in portal areas.[23] Because the liver injury seems to be
idiosyncratic, serum aminotransferase levels should be periodically monitored in patients taking acarbose.
Thiazolidinediones
Pharmacology
Troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos) belong to a new class of
thiazolidinedione derivatives used for the oral treatment of NIDDM. These agents decrease insulin
resistance by binding to nuclear peroxisome proliferator-activated receptors involved in transcription of
insulin-responsive genes and in regulation of adipocyte differentiation and lipid metabolism.[46] Because
insulin sensitivity is increased by troglitazone, its prophylactic use was suggested for patients at high risk for
developing NIDDM (patients with gestational diabetes, polycystic ovary syndrome).[6][20][86] In the presence
of insulin, these drugs (1) decrease gluconeogenesis, glucose output, and triglyceride synthesis in the liver,
(2) increase glucose uptake and utilization in skeletal muscle, (3) increase glucose uptake, and (4) decrease
fatty acid output in adipose tissue. They do not affect insulin secretion.
Peak levels of troglitazone occur 3 hours after ingestion with a half-life of 16 to 34 hours. The agent is
metabolized in the liver by CYP3A4 and excreted primarily in feces. Troglitazone is generally given in
addition to insulin and results in decreases in hemoglobin A1C and insulin requirement.[44] Two newer
congeners of troglitazone, rosiglitazone and pioglitazone, exhibit tighter receptor binding. Peak levels of
rosiglitazone occur at 1.3 hours (fasted) and 3.5 hours (fed), with an elimination half-life of 3.64–3.78 hours.
Pioglitazone peaks at 2 (fasted) to 3–4 (fed) hours. It has an active metabolite; elimination half-lives are 3–7
hours (parent drug) and 16–24 hours (total).
Pathophysiology
The major toxicity associated with troglitazone is hepatic. One to 2 per cent of patients taking troglitazone
developed mild, reversible increases in aminotransferase activity, and 2 of 2510 patients developed
jaundice. Since the introduction of troglitazone in March 1997, the reported rate of death or live transplant in
patients receiving the drug is 1 in 60,000.[70] Close monitoring of liver function tests is recommended. In a
canine model, thiazolidinediones caused cardiac hypertrophy,[24] but this has not been documented in
humans.[24] Concomitant use of troglitazone decreases metabolism of other agents that are metabolized by
the CYP3A4 system. Troglitazone has been removed from the market in the United Kingdom, and the drug
was withdrawn from the United States market in March 2000 because of hepatotoxicity. Two cases of
hepatotoxicity in patients taking rosiglitazone have been reported. Pioglitazone has not been reported to
produce hepatotoxicity, but its use has been limited.
Repaglinide
Pharmacology
Although structurally different from sulfonylureas, repaglinide also binds to ATP-sensitive potassium
channels on pancreatic beta cells and increases insulin secretion.[53] The drug is well-absorbed when taken
orally, with peak plasma levels occurring within 30 to 60 minutes and a half-life of 1 hour. It is metabolized by
the CYP3A4 system and primarily excreted in bile. Repaglinide is more effective when used with metformin
than either drug alone.[59]
Pathophysiology
Hypoglycemia does occur with repaglinide, although less frequently than with sulfonylureas. No significant
drug interactions have been reported. However, concomitant use of other agents that affect the CYP3A4
system should be done with caution.


As hypoglycemia develops, a normal biological response occurs ( Table 50–3 ). Initially, at 2.8 mmol/L (50
mg/dL), neurogenic symptoms are perceived due to autonomic counterregulatory stimulation.[15] Adrenergic
symptoms include tremulousness, palpitations, anxiety, and diaphoresis.[15][57][62] Signs include tachycardia,
increased systolic blood pressure, and decreased diastolic pressure.[15] Cases of hypoglycemia presenting
with bradycardia have been reported. This may be caused by catecholamine depletion, postsynaptic ß-
adrenergic receptor down-regulation, vagal stimulation, thyroid dysfunction, adenosine accumulation, or
electrophysiologic abnormalities.[65] Hypothermia can also occur. With glucose concentrations of 2.5 mmol/L
(45 mg/dL), core body temperature falls after 40 minutes.[40]
Table 50-3 -- Clinical Presentation of Oral Hypoglycemia Toxicity

Vital Signs
Hypothermia
Tachypnea
Hypertension
Tachycardia
Bradycardia (neonates)
Pupils
May be normal or fixed and dilated
Cardiovascular
Dysrhythmias (atrial fibrillation, ventricular ectopy)
Skin
Decreased turgor
Diaphoresis
Pallor
Neurologic
Tremor
Altered mental status: agitation, depression, coma
Seizures
Focal neurologic deficits
Neuroglycopenic symptoms follow as the plasma glucose falls below 1.1 mmol/L (20 mg/dL), depriving the
brain of glucose.[15][50] The brain, unable to synthesize glucose, requires approximately 150 mg/dL of
continuous glucose.[41][50] Symptoms include weakness, fatigue, behavioral and cognitive dysfunction, and
coma.[15] Severe hypoglycemia can also result in hemiplegia, decerebrate posturing, ataxia,
choreoathetosis, and seizures.[15] Fifty per cent of neurologic symptoms in cases of nonfatal hypoglycemia
are transient.[26] Whereas the cerebral cortex and hippocampus are the most sensitive to neuroglycopenia,
the brain stem and spinal cord are the most resistant.[51] The onset and duration of symptoms can be
predicted if the type of oral hypoglycemic agent and the time of ingestion are known. Although hypoglycemia
can occur early after ingestion of oral hypoglycemic agents, hypoglycemia delayed up to 48 hours after
ingestion as well as recurrent hypoglycemia 94 hours postingestion have been reported.[42] Hypoglycemia is
not expected with biguanides.
Lactic acidosis from biguanide use should be suspected in patients presenting with lethargy, vomiting,
diarrhea, and an elevated anion gap metabolic acidosis.[22][49] In patients presenting with nausea, vomiting,
fatigue, dark urine, or jaundice, hepatic failure secondary to troglitazone should be considered.


Hypoglycemia should be considered in any patient who presents with sympathomimetic signs and
symptoms, altered mental status, and/or focal neurologic signs. High-risk patients include anyone with a
history of diabetes mellitus or relatives of a diabetic and those in the health care profession with access to
oral hypoglycemic agents. Although structural, infectious, toxicologic, and other metabolic abnormalities can
alter mental status, hypoglycemia is the most common cause. Hypoglycemia must also be considered in any
trauma patient, particularly after motor vehicular collision.[50] Despite symptoms of hypoglycemia, 26.5 per
cent of patients reportedly will operate a vehicle.[27] Seizures precipitated by hypoglycemia can also result in
orthopedic injuries.[50] The nonsulfonylurea agents do not generally cause hypoglycemia, even after
overdose, although it can occur with replaglinide.
After the diagnosis of hypoglycemia is established, the cause must be determined. Nontoxicologic causes of
hypoglycemia include postprandial, idiopathic, insulinoma, extrapancreatic neoplasms, endocrine
insufficiency, hepatic disease, sepsis, renal failure, starvation, exercise, and autoimmune disease.
Hypoglycemia can also result after exposure to insulin, oral hypoglycemic agents, ethanol, ß-adrenergic
receptor antagonists, salicylates, and other miscellaneous agents (see Table 50–1 ). Lactic acidosis
secondary to biguanide use must be considered in patients presenting with an elevated anion gap metabolic
acidosis. Troglitazone should be added to the differential diagnosis in any patient who presents with hepatic
dysfunction.


LABORATORY STUDIES
Glucose
Rapid bedside glucose testing is required to diagnose hypoglycemia and prevent delay in treatment. This
monitoring has become rapid, reliable, and efficient. Visually interpreted Chemstrip bG reagent strips are
accurate in detecting hypoglycemia, with a sensitivity of 97 per cent and specificity of 94 per cent.[77] Blood
glucose monitoring units employ glucose oxidase or hexokinase enzymatic techniques.[80] Fingerstick blood
glucose results obtained with Chemstrip (bG) are 91.7 per cent sensitive and 92.4 per cent specific when
compared with laboratory samples.[35] The Glucoscan 2000 monitor has a reported accuracy of 79.8 per
cent, with the greatest inaccuracy occurring in the low plasma glucose ranges.[84] The accuracy of the
AccuChek II monitor is 87.9 per cent. Glucose test strips can produce inaccurate results if stored
inappropriately (high humidity, high temperatures, exposure to sunlight).[77] Inaccurate bedside glucose
measurements can also occur in patients with abnormal hematocrits or those with hypotension or if the
sample is obtained from capillary heel stick.[2] Capillary glucose values can exceed venous levels by up to
80 mg/dL.[77]
Insulin
At plasma glucose concentrations of 45 mg/dL (2.5 mmol/L), pancreatic insulin secretion is normally
suppressed.[66] If insulin levels are measurable at this level, insulinoma, factitious insulin or oral
hypoglycemia exposure, or insulin antibody production should be considered.[66] Because exogenous insulin
does not produce C-peptide fragments, elevated insulin levels with normal C-peptide levels indicate
factitious insulin use.[66] If the insulin used is of animal origin, high-pressure liquid chromatography can
identify the source. [66] Exposure to sulfonylurea oral hypoglycemic agents also induces insulin secretion,
resulting in elevations of C peptide, insulin, and proinsulin.[66] Definitive diagnosis must be made using gas
chromatography mass spectrometry evaluation for these agents.
When insulin is produced by an insulinoma, C peptide, proinsulin, and insulin levels will all be increased.[66]
Elevated C-peptide levels cannot be properly interpreted in the presence of renal failure because they are
renally excreted.[65] Because levels of insulin-like growth factor binding protein-1 (IGFBP-1) are suppressed
during fasting in children with hyperinsulinism, IGFBP-1 levels less than 125 mg/dL in combination with
ketones and decreased free fatty acid secretion indicate insulinoma.[4] Insulin antibodies may also result in
elevated insulin levels, despite hypoglycemia.[66] In Japan, autoimmune hypoglycemia is the third leading
cause of hypoglycemia.[39] If hypoglycemia was preceded by postprandial hyperglycemia and levels of C
peptide are low, insulin antibody production should be suspected.[66]
Other Studies
Arterial blood gas and anion gap determination should be made in any patient with suspected acidosis from
biguanide use. An elevated anion gap metabolic acidosis and an elevated lactate level support the
diagnosis. Liver function tests should be obtained in patients with suspected hepatic dysfunction related to
troglitazone use and will initially demonstrate an elevation in the transaminases.


Stabilization of airway, breathing, and circulation is the first priority in treatment. Because the consequences
of hypoglycemia can be devastating and an antidote is readily available, rapid diagnosis and treatment must
be performed in any
Table 50-4 -- Treatment of Hypoglycemia

General
Supportive care
Bedside glucose monitoring
Thiamine, 100 mg IV (adult)
Naloxone, 0.4–2.0 mg IV, repeat prn
Hypoglycemia
Dextrose
Adult: 50 mL (25 g) D50% IV bolus
Child: 0.5 g/kg (2 mL/kg) D25% IV bolus
Neonate: 200 mg/kg (2 mL/kg) D10% IV bolus
Continuous infusion of D5%, D10%, or D20% while monitoring serum glucose
Glucagon
Adult: 0.5–2.0 mg IM, SC, IV. May repeat twice.
Child: 0.03–0.1 mg/kg IV, SC (concentration = 1.0 mg/mL). Can repeat in 20 minutes.
Neonate: 0.3 mg/kg IV, SC (concentration = 1.0 mg/mL). Can repeat in 4 hours.
Diazoxide
Adult: 300 mg over 30 minutes IV every 4 hours.
Child:
Oral—3 to 8 mg/kg/day divided in two to three doses, given every 8 to 12 hours.
Newborn/infant: oral—8 to 15 mg/kg/day divided in two to three doses, given every 8 to 12 hours.
Octreotide
Adult: 50 µg every 12 hours SC
patient with suggested hypoglycemia, regardless of the cause. Gastric lavage with airway protection should be
considered if the patient presents within 1 hour after overdose.[47] Activated charcoal should be administered
unless contraindicated. Because of the enterohepatic recirculation of glipizide, multiple-dose activated charcoal
may be useful, although the clinical benefit has never been demonstrated. Hypoglycemia
Rapid bedside testing should be used to confirm the diagnosis. Empirical treatment with intravenous
dextrose can be given if bedside testing is unavailable or the results are questionable. However, because
neurologic outcomes are worse when hyperglycemia occurs with cerebral infarction, severe hypotension, or
cardiopulmonary resuscitation,[50] empirical administration of glucose to patients with altered mental status
should be avoided if possible. In an adult, initial treatment consists of the intravenous administration of 1
g/kg, D50W solution.[50] In children, the dose is 0.5 to 1.0 g/kg D 25W; neonates receive the same dose as
D10W. Recovery usually occurs within 5 to 10 minutes. Prophylactic administration of glucose when there is
no evidence of hypoglycemia is generally not recommended after oral hypoglycemic ingestion, because
development of toxicity will be difficult to assess. If there is no intravenous access, glucagon can be
administered by the intramuscular route, although glucagon will have no effect if glycogen stores are
depleted. Whereas the basal glucose requirement is 2 mg/kg/min, this increases to 10 to 11 mg/kg/min in
the presence of insulin-induced hypoglycemia, with a requirement of up to 375 to 660 mg/kg/min with severe
insulin-induced hypoglycemia.[71]
Diazoxide has been successfully used to reverse sulfonylurea-induced hypoglycemia refractory to

intravenous glucose administration (non–Food and Drug Administration–approved use).[61] Diazoxide
inhibits insulin secretion by opening K+ channels, increases hepatic glucose production, and decreases
cellular glucose utilization. In an adult, 300 mg diazoxide is administered intravenously over 30 minutes and
can be repeated every 4 hours. Its use should be reserved for refractory hypoglycemia.[9][19][30][64]
Octreotide, an analog of somatostatin, inhibits insulin release from the pancreatic beta cells. Its successful
use has been reported in several cases of hypoglycemia. The adult dose is 50 µg administered
subcutaneously every 12 hours. Glucose infusion should be maintained when treating with diazoxide or
octreotide.
After reversal of hypoglycemia, one must attempt to maintain euglycemia. The frequency of recurrent
hypoglycemia after treatment varies from 2 to 30 per cent,[33] and some patients may require continued
intravenous glucose administration. Ten per cent dextrose should be given to maintain serum glucose at 5.6
to 7.7 mmol/L (100–250 mg/dL). Some patients may require 20 per cent dextrose infusion with intermittent
50 per cent dextrose boluses.
Acidosis
Lactic acidosis should be treated early and intensively. Sodium bicarbonate should be administered if the
serum pH falls below 7.1. Hemodialysis should be performed for cases of severe refractory acidosis.
Hemodialysis not only corrects the metabolic acidosis but also removes lactate, ketones, and
metformin.[37][75] Continuous venovenous hemodiafiltration using a non–lactate-containing replacement fluid
has been successfully used in cases in which sodium bicarbonate alone fails to correct pH.[82]
Other Measures
Urinary alkalinization is recommended for chlorpropamide toxicity because it significantly reduces the half-
life of the drug.[60] Because of the high protein binding of most oral hypoglycemic agents, extracorporeal
removal is of little benefit. Thiamine, 100 mg, should be administered to adults receiving glucose; it may
prevent Wernicke’s encephalopathy in patients with a history of chronic alcohol abuse and/or malnutrition.[50]
Troglitazone should be discontinued in any patient with evidence of hepatic dysfunction.


DISPOSITION
Because of their long half-life and duration of action, sulfonylurea agents can cause prolonged and
refractory hypoglycemia. A patient who ingests sulfonlyureas should be admitted if (1) hypoglycemia
develops; (2) it is a deliberate overdose; and (3) the patient is a child, even in the absence of hypoglycemia.
The ingestion of just one tablet of chlorpropamide, glipizide, or glyburide can produce hypoglycemia in a
child younger than 4 years of age. The absence of hypoglycemia within the first 8 hours of ingestion may be
predictive of a benign outcome in accidental pediatric sulfonylurea ingestion.[81] However, in one study of
sulfonylurea ingestions in children, hypoglycemia occurred from 30 minutes to 16 hours after ingestion.[68]
Other indications for admission include continued neuropsychiatric symptoms despite correction of
hypoglycemia and any suspicion of suicidal, homicidal, or factitious hypoglycemia. Although the
nonsulfonylurea oral agents generally do not cause hypoglycemia, even after overdose, patients who
develop hypoglycemia from these agents should be admitted. Patients who present with lactic acidosis
secondary to biguanide use should also be admitted.
If euglycemia is achieved in the emergency department and the patient is asymptomatic, patients can be
admitted to a general medical unit with the capability of frequent glucose monitoring. Patients with metabolic
acidosis, continued neurologic symptoms/signs, and continued episodes of hypoglycemia despite treatment
should be admitted to an intensive care unit.


SEQUELAE
Delay in treatment may result in profound sequelae, including death. The most common sequelae are
neurologic, and the risk increases with prolonged hypoglycemia. The central nervous system areas most
sensitive to hypoglycemia are the cerebral cortex, hippocampus, basal ganglia, thalamus, brain stem, and
spinal cord.[83] Fifty per cent of the neurologic symptoms in nonfatal hypoglycemia are transient.[26]
Recurrent, severe hypoglycemia is associated with electroencephalographic changes and cognitive
impairment particularly in the young, with reported IQ deficiencies of 6 points.[63][83] Electroencephalographic
activity also differs between diabetics with awareness of hypoglycemia and those without awareness.[63][83]
Cortical atrophy has been demonstrated in patients with recurrent, severe hypoglycemia. Permanent
sequelae may include hemiparesis, memory impairment, diminished language skills, decreased abstract
thinking, and ataxia.


ACKNOWLEDGMENT
The authors want to thank Lynn DeWine for her help on this chapter.


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Chapter 51 – Insulin
LESLIE R. WOLF REBECCA PERRY MICHAEL POLICASTRO
Essentials
• Excess adrenergic output: anxiety, tremulousness, flushing, tachycardia, hypertension,
diaphoresis
• Altered mental status, including any neuropsychiatric abnormality or seizure
• Decreased serum glucose level
• History of diabetes mellitus or access to insulin
• Injection site on physical examination
INTRODUCTION
Diabetes mellitus (DM) affects 14 to 16 million Americans, and 10 per cent of this population have type I or
insulin-dependent diabetes mellitus (IDDM). [9][42] Hypoglycemia, or the failure to maintain adequate glucose
homeostasis, most commonly occurs after unintentional overdose or therapeutic use of insulin with
inadequate food intake. However, self-inflicted (suicidal), occult, malicious, or factitious administration must
also be considered. Three to 4 per cent of patients with IDDM experience severe hypoglycemia
(hypoglycemia with neuroglycopenia).[11][12] Conventional insulin therapy is associated with a 19 per cent
risk of severe hypoglycemia, whereas patients on intense insulin therapy have a 62 per cent risk.[12] The use
of hypoglycemic agents results in 54 per cent of cases of hypoglycemia with an established cause.[28] In
1996, 1229 exposures to insulin were reported by the American Association of Poison Control Centers, and
321 of these were intentional.[30] Two cases were fatal, 28 resulted in a major outcome, and 200 resulted in
a moderate outcome. Since 1922, 17 cases of suicide with insulin have been confirmed.[45] In an urban
emergency department study, 9 per cent of all cases of altered mental status were secondary to
hypoglycemia.[27] Hypoglycemia secondary to insulin exposure should be considered in any patient who
presents with altered mental status, particularly those with a history of DM, family members with DM, or
health care professionals with access to insulin.


Pharmacology
Insulin is classified by species of origin (human, bovine, porcine, bovine/porcine), preparation (standard,
buffered, purified, recombinant, or combinations), and duration of action (rapid, short, intermediate, long) (
Table 51–1 ). Insulin may be administered intravenously, intramuscularly, or subcutaneously, but the
majority of injections are given by the subcutaneous route. Several factors affect the rate of subcutaneous
absorption.[12] The site of injection affects absorption, with the abdomen being the site of fastest absorption,
followed by the arm and thigh.[12] Lipohypertrophy or lipoatrophy and regional blood flow also influence
absorption. Combining preparations also has an impact on absorption. Intermediate-acting insulin
preparations are crystallized with protamine (NPH, neutral protamine Hagedorn) or zinc (Lente).[3] Human
origin intermediate agents have a more rapid onset and shorter duration than porcine agents.[12] When
insulin Lispro (Humalog), a rapid-acting insulin, is combined with NPH, the normally rapid effect is delayed,
owing to a tendency for crystallization. [3] Intermediate and long-acting preparations have the largest variation
in absorption. The presence of insulin antibodies further delays absorption. Variation of peak hypoglycemic
effects of insulin can vary by up to 50 per cent because of changes in subcutaneous absorption.[12]
Table 51-1 -- Pharmacokinetics of Representative Insulin Preparations

Insulin Preparation Onset (hr) Peak (hr) Duration (hr)
Rapid acting Lispro 0.25–0.5 0.5–2.5 3–6.5
Short acting Regular 0.5–1 1–5 6–10
NPH 1–2 6–14 16–24+
Intermediate acting
Lente 1–3 6–14 16–24+
Ultralente 4–6 8–20 24–28
Long acting PZI 4–8 14–20 36
70/30 0.5 4–8 24
Pathophysiology
A discussion of normal glucose regulation is necessary to understand some of the pathophysiologic changes
that occur with hypoglycemia, the predominant pathophysiologic effect of insulin.
Normal Glucose Regulation
Plasma glucose is maintained within a narrow range (72–144 mg/dL) by neural, hormonal, and substrate
glucose. When glucose levels rise above this range, the pancreatic beta cells secrete insulin. Insulin
production is the result of a two-step cleavage process of the preproinsulin precursor. [12] After translocation
across the endoplasmic reticulum, preproinsulin loses the N-terminal signal peptide to produce proinsulin.[12]
Approximately 10 per cent of circulating insulin is proinsulin, which has a half-life of 44 minutes and only 5
per cent of the metabolic activity of insulin.[12] Initial conversion of proinsulin to insulin begins in the Golgi
apparatus by calcium-dependent endopeptidases, PC2 and PC3. Transformation is completed in secretory
granules, with a loss of the connector peptide (C peptide).
Insulin is composed of two peptide chains (A and B), each containing ordered a-helical regions connected
by one intrasubunit and two intersubunit disulfide bonds. Insulin exists in three forms: monomeric, dimeric,
or hexameric.[12] The monomer is biologically active, whereas the hexamer is the storage form. Zinc is
required in both the conversion of proinsulin to insulin and the formation of the hexamer. Insulin secretion is
biphasic, first peaking in 1 to 2 minutes, followed by a delayed peak of longer duration. Normal basal insulin
secretion is 0.5 to 1 unit/hr with daily insulin production of 0.2 to 0.5 unit/hr. Insulin binds to the extracellular
portion of the a subunit of the insulin transmembrane receptor, resulting in autophosphorylation of the
tyrosine residues of the ß subunit and signal transduction. The biologic activity of insulin results in a
decrease in plasma glucose. This occurs by inhibition of hepatic glucose production, increased glucose
uptake, and increased glycogen stores in insulin-sensitive tissues, muscle, and adipose tissue. Insulin also
causes amino acid storage, suppression of proteolysis, increased triglyceride formation, fatty acid
deposition, and decreased lipolysis.
Insulin metabolism occurs predominantly in the liver, kidney, and muscle. Forty to 50 per cent of insulin
secreted by the pancreas is destroyed by first-pass hepatic metabolism and never reaches the general
circulation.[12][43] Thiol metalloprotease is the primary degrading enzyme in the hepatocytes. The kidney
clears 30 to 80 per cent of insulin, 50 per cent of proinsulin, and 70 per cent of C peptide by glomerular and
peritubular clearance.[43] Glomerular clearance is the major route of elimination and is determined by size,
shape, and charge of the filtrate, glomerular permeability, and renal plasma blood flow.[43] Insulin crosses
the glomerulus intact, and 99 per cent of the filtered insulin is absorbed in the proximal tubules. Sixty per
cent of the amount resorbed is metabolized.[22][43] Brush border luminal absorption occurs by stereospecific
binding of insulin and endocytosis. Insulin is degraded in the proximal tubules by two different mechanisms:
insulin protease hydrolysis (may be defective in patients with DM) and reductive cleavage by glutathione
insulin transhydrogenase. The second mechanism is peritubular, accounts for one third of total renal insulin
clearance, and occurs when insulin quantities greater than physiologically normal are present in the proximal
tubules.[43] Insulin can be degraded at the contraluminal side or in the cell.[43] Binding of insulin to receptors
results in stimulation of sodium-potassium adenosine triphosphatase (Na +,K+-ATPase) and increased
sodium reabsorption.[43]
Response to Hypoglycemia
The counterregulatory substances released in response to hypoglycemia include glucagon, epinephrine,

norepinephrine, cortisol, growth hormone, and adrenocorticotropic hormone. [13] The initial response to
hypoglycemia is glucagon release. Glucagon is secreted from the pancreatic alpha cells and acts solely on
the liver, increasing glycogenolysis and gluconeogenesis.[33] This response is defective in IDDM, with a
decrease in glucagon occurring a few years after the onset of the illness.[11][21][50] Therefore, in IDDM, the
loss of the glucagon counterregulatory mechanism makes epinephrine release exceedingly important in
response to hypoglycemia.
Epinephrine, synthesized in the adrenal medulla, constitutes 85 per cent of the total molar increase in
catecholamines circulating in response to hypoglycemia.[11][33] Epinephrine acts primarily through ß 2-
adrenergic receptors to increase plasma glucose[33] by indirect stimulation of lipolysis.[19] Lipolysis is
responsible for 50 per cent of hepatic glucose production and 85 per cent of suppression of peripheral
glucose utilization (skeletal muscle and adipose tissue).[19][33] Catecholamines also directly stimulate
glycogenolysis and gluconeogenesis. In addition, epinephrine contributes significantly to recovery in long-
term hypoglycemia.[21] Norepinephrine is also synthesized in the adrenal medulla and functions as both a
hormone and a neurotransmitter.[11][21][33] When hypoglycemia occurs, norepinephrine accounts for 35 per
cent of the catecholamine concentration in adipose tissue and 50 per cent in muscle.[21]
Cortisol is necessary for the liver to respond appropriately to glucagon and epinephrine. Antecedent
hypoglycemia raises plasma cortisol levels, reducing the autonomic adrenomedullary response to
subsequent hypoglycemia.[13] If the rise in plasma cortisol is blocked, the catecholamine response to
hypoglycemia is restored.[14] The combination of autonomic failure associated with antecedent
hypoglycemia and glucagon depletion that occurs in patients with IDDM increases the risk for severe
hypoglycemia by a factor of twenty-five[10] as well as decreasing awareness of the symptoms of
hypoglycemia.[16] Without glucagon and epinephrine release, lipolysis is blunted, resulting in a 40 per cent
decrease in hepatic glucose production, a 70 per cent decrease in gluconeogenesis, and a 15 per cent
increase in peripheral glucose utilization.[10]
In addition to hormone release, neural and hepatic autoregulation contribute significantly to the response to
hypoglycemia, especially in the event of autonomic failure. Hepatic autoregulation and direct neural input
during insulin-induced hypoglycemia are estimated to be responsible for 25 per cent of the change in net
hepatic glucose output.[37] If the brain maintains euglycemia, despite systemic hypoglycemia, glucagon
release is not stimulated.[13] However, the liver continues to produce glucose.[37] The liver achieves this
primarily by glycogenolysis, if glycogen stores are adequate, followed by gluconeogenesis from the
peripheral tissue.[37]
Diabetics have increased cerebral blood flow to the frontal cortex in the basal state, which may represent a
chronic adaptation.[32] When acute hypoglycemia develops, a 20 per cent increase in total cerebral blood
flow occurs.[32] The risk of thrombosis and infarct can increase with hypoglycemia, owing to activation of von
Willebrand factor.[17] The developing brain is the most susceptible to hypoglycemia because of a decreased
ability to enhance cerebral blood flow.[32]
Factors Affecting Response to Hypoglycemia
Sex and age influence counterregulatory mechanisms in response to hypoglycemia. Adult females have
both an increased threshold and an attenuated hormonal response in comparison with men.[6][11] Children
have a more vigorous and earlier response to hypoglycemia than young adults.[13] However, diabetic
children have a higher threshold as well as an attenuated response compared with healthy children.[6]
Diabetic children with a higher body mass index (BMI) report autonomic symptoms at higher glucose levels
than those with low BMI.[6] In one study, hypoglycemia in diabetic children was due to dietary errors in 27 per
cent, exercise in 12.2 per cent, and incorrect insulin dose in 10.8 per cent. [7] Severe hypoglycemia occurred
in approximately 15 per cent of diabetic adolescents and children.[7] Frequent, severe hypoglycemia is more
common in young children than adolescents, and 50 per cent of severe hypoglycemia occurs during sleep.[5]
The risk of nocturnal hypoglycemia for patients taking insulin twice daily is greater in children than adults.[5]
Young adults report symptoms of hypoglycemia at glucose levels of 3.6 ± 0.1 mmol/L, whereas an elderly
male will not report symptoms until the glucose concentration falls to 3.0 ± 0.2 mmol/L.[34]
It was previously thought that elderly males had an attenuated hormonal response to hypoglycemia, but this
has proven to be false.[34] In aged men, cognitive dysfunction occurs before autonomic symptoms, resulting
in more severe episodes of hypoglycemia and a slower rate of recovery than in younger males.[34]
Ethanol ingestion can be associated with hypoglycemia.[31] Ethanol metabolism by alcohol dehydrogenase
impairs gluconeogenesis by increasing the NADH/NAD+ ratio.[35] Concomitant, glycogen depletion after
chronic alcohol use significantly increases the risk of hypoglycemia.[35] The form of alcohol ingested also
influences blood glucose levels. Beer and spirits are absorbed more quickly than wine, resulting in earlier
peaks in the ethanol level.[35] Co-ingestion of food decreases the peak ethanol level and the time to this
peak. When beer is ingested with an evening meal, a delayed hypoglycemic effect can occur 7 to 14 hours
after ingestion.[35] Alcohol ingestion also decreases awareness, which may exaggerate the severity of
neuroglycopenia.[8][49]
Renal failure, often associated with DM, results in decreased insulin extraction, decreased insulin
elimination, and glycogen depletion, [2][43] all of which contribute to an increased risk of hypoglycemia.
Salicylate ingestion has also been associated with hypoglycemia. Beta-adrenergic receptor antagonists
inhibit the counterregulatory epinephrine response, contributing to an increased risk of hypoglycemia.[31]
Conditions associated with glycogen depletion, such as fasting, anorexia nervosa, and malnutrition also
increase the risk of hypoglycemia. Other drugs and toxins have also been implicated in causing
hypoglycemia ( Table 51–2 ).[2][31]
Table 51-2 -- Agents Associated with Hypoglycemia

Ackee fruit (unripe)
Alloxan
Cocaine
Ethanol
Haloperidol
Opioids
Oral hypoglycemics
Pentamidine
Propoxyphene
Quinidine
Quinine
Ritodrine
Salicylates
Streptozocin
Sulfinpyrazone
Sulfonamides
Tetracycline
Vacor
Valproic acid


As hypoglycemia develops, a normal biologic response occurs. Initially, at 2.8 mmol/L (50 mg/dL),
neurogenic symptoms are perceived, owing to autonomic counterregulatory stimulation. Adrenergic
symptoms include tremulousness, palpitations, anxiety, and diaphoresis.[11][36][38] Signs include tachycardia,
increased systolic blood pressure, and decreased diastolic pressure.[11] Cases of hypoglycemia presenting
with bradycardia have been reported and may be caused by catecholamine depletion, post-synaptic ß-
adrenergic receptor down-regulation, vagal stimulation, thyroid dysfunction, adenosine accumulation, or
electrophysiologic abnormalities.[40] Hypothermia can also occur. With glucose concentrations of 2.5 mmol/L
(45 mg/dL), core body temperature falls after 40 minutes.[25]
Neuroglycopenic symptoms follow as the plasma glucose level falls below 20 mg/dL, depriving the brain of
glucose.[11][31] The brain, unable to synthesize glucose, requires approximately 8.4 mmol/L (150 mg/dL) of
continuous glucose.[26][31] Symptoms include weakness, fatigue, behavioral and cognitive dysfunction, and
coma.[11] Severe hypoglycemia can also result in hemiplegia, decerebrate posturing, ataxia,
choreoathetosis, and seizures.[11] Fifty per cent of neurologic symptoms in cases of nonfatal hypoglycemia
are transient.[7] Whereas the cerebral cortex and hippocampus are the most sensitive to neuroglycopenia,
the brain stem and spinal cord are the most resistant.[32] The onset and duration of symptoms can be
predicted if the type of insulin and the time of administration are known. If intermediate or long-acting insulin
preparations are involved, symptoms may not occur for 18 to 24 hours after administration. Signs and
symptoms of hypoglycemia are listed in Table 50–3 .
Hypoglycemia must be considered in any trauma patient, particularly after motor vehicle collision.[31] Despite
symptoms of hypoglycemia, 26.5 per cent of patients will reportedly operate a vehicle.[18] Seizures
precipitated by hypoglycemia can also result in orthopedic injuries.[31]


Hypoglycemia should be considered in any patient who presents with sympathomimetic signs and
symptoms, altered mental status, and/or focal neurologic signs. High-risk patients include anyone with a
history of diabetes mellitus or relatives of a diabetic and those in the health care profession with access to
insulin. [45] Discovery of an erythematous or boggy injection site may be a clue that insulin administration has
occurred.[29][44] Although structural, infectious, toxicologic, and other metabolic abnormalities can alter
mental status, hypoglycemia is the most common cause.
After the diagnosis of hypoglycemia is established, thecause must be determined. Nontoxicologic causes of
hypoglycemia include postprandial, idiopathic, insulinoma, extrapancreatic neoplasms, endocrine
insufficiency, hepatic disease, sepsis, renal failure, starvation, exercise, and autoimmune disease.
Hypoglycemia can also result after exposure to insulin, oral hypoglycemic agents, ethanol, ß-adrenergic
receptor antagonists, salicylates, and other miscellaneous agents (see Table 51–2 ).


LABORATORY STUDIES
Glucose
To rapidly diagnose hypoglycemia and prevent delay in treatment, bedside glucose testing is required, and
monitoring has become rapid, reliable, and efficient. Visually interpreted Chemstrip bG reagent strips are
accurate in detecting hypoglycemia, with a sensitivity of 97 per cent and specificity of 94 per cent. Blood
glucose monitoring units employ glucose oxidase or hexokinase enzymatic techniques.[48] Fingerstick blood
glucose results obtained with Chemstrip (bG) are 91.7 per cent sensitive and 92.4 per cent specific when
compared with laboratory samples.[23] The Glucoscan 2000 monitor has a reported accuracy of 79.8 per
cent, with the greatest inaccuracy occurring in the low plasma glucose ranges.[51] The accuracy of the Accu-
Chek II monitor is 87.9 per cent. Glucose test strips can also produce inaccurate results if stored
inappropriately (high humidity, high temperatures, exposure to sunlight).[46] Inaccurate bedside glucose
measurements can also occur in patients with abnormal hematocrits and those with hypotension or if the
sample is obtained from capillary heel stick.[1] Capillary glucose values can exceed venous levels by up to
80 mg/dL.[46]
Insulin
At plasma glucose concentrations of 2.5 mmol/L (45 mg/dL), pancreatic insulin secretion is normally
suppressed.[41] If insulin levels are measurable at this level, insulinoma, factitious insulin or oral
hypoglycemia exposure, or insulin antibody production should be considered.[41] When insulin is produced
by an insulinoma, C peptide, proinsulin, and insulin levels will all be increased.[41] Elevated C-peptide levels
cannot be properly interpreted in the presence of renal failure because they are renally excreted.[40]
Because levels of insulin-like growth factor binding protein-1 (IGFBP-1) are suppressed during fasting in
children with hyperinsulinism, IGFBP-1 levels of 125 mg/dL or less in combination with ketones and
decreased free fatty acid secretion indicate insulinoma.[4] Exposure to sulfonylurea oral hypoglycemic
agents also induces insulin secretion, resulting in elevations of C peptide, insulin, and proinsulin.[41]
Definitive diagnosis must be made using gas chromatography mass spectrometry evaluation for these
agents.
Because exogenous insulin does not produce C-peptide fragments, the diagnosis of surreptitious insulin use
is made in the presence of elevated insulin levels with normal C-peptide levels.[41] If the insulin used is of
animal origin, high-performance liquid chromatography can be used to identify the source. [41] Insulin
antibodies may also result in elevated insulin levels, despite hypoglycemia.[41] In Japan, autoimmune
hypoglycemia is the third leading cause of hypoglycemia.[24] If hypoglycemia was preceded by postprandial
hyperglycemia and levels of C peptide are low, insulin antibody production should be suspected.[41]


Stabilization of airway, breathing, and circulation is the first priority in treatment, followed by treatment of
hypoglycemia. Rapid bedside testing should be used to confirm the diagnosis. Empirical treatment with
intravenous dextrose can be given if bedside testing is unavailable or the results are questionable. Because
neurologic outcomes are worse when hyperglycemia occurs with cerebral infarction, severe hypotension, or
cardiopulmonary resuscitation,[31] empirical administration of glucose to patients with altered mental status
should be avoided if rapid measurement of glucose can be accomplished.[20]
In an adult, initial treatment consists of the intravenous administration of 1 g/kg, D50W solution.[31] In
children, the dose is 0.5 to 1.0 g/kg D25W (neonates D10W). Recovery usually occurs within 5 to 10 minutes.
If there is no intravenous access, glucagon can be administered by the intramuscular route, although
glucagon will have no effect if glycogen stores are depleted. Despite glucagon administration, attempts
should still continue to establish intravenous access and administer dextrose. Whereas the basal glucose
requirement is 2 mg/kg/min, this increases to 10 to 11 mg/kg/min in the presence of insulin-induced
hypoglycemia, with a requirement of up to 375 to 660 mg/kg/min with severe insulin-induced
hypoglycemia.[41] After large injections of insulin, particularly in a suicide attempt, excision of the boggy
injection site has been reported. However, this therapy is not advocated.[15][47] Thiamine, 100 mg, should be
administered; it may prevent Wernicke’s encephalopathy in patients with a history of chronic alcohol abuse
and/or malnutrition.[31]
After reversal of hypoglycemia, one must attempt to maintain euglycemia. If the cause of hypoglycemia is
determined to be a one-time dose of insulin, the patient should be able to eat an adequate diet, assuming
the insulin effect has already peaked. The frequency of recurrent hypoglycemia
Table 51-3 -- Treatment of Hypoglycemia

General
Supportive care
Bedside glucose monitoring
Thiamine, 100 mg IV (adult)
Naloxone, 0.4–2.0 mg IV, repeat prn
Hypoglycemia
Dextrose
Adult: 50 mL (25 g) D50% IV bolus
Child: 0.5 g/kg (2 mL/kg) D25% IV bolus
Neonate: 200 mg/kg (2 mL/kg) D10% IV bolus
Continuous infusion of D5, D10, or D20% while monitoring serum glucose
Glucagon
Adult: 0.5–2.0 mg IM, SC, IV. May repeat twice.
Child: 0.03–0.1 mg/kg IV, SC (concentration = 1.0 mg/mL). Can repeat in 20 minutes.
Neonate: 0.3 mg/kg IV, SC (concentration = 1.0 mg/mL). Can repeat in 4 hours.
after treatment varies from 2 to 30 per cent,[21] and some patients may require continued intravenous glucose
administration. Ten per cent dextrose should be given to maintain serum glucose levels at 100 to 250 mg/dL.
Some patients may require 20 per cent dextrose with 50 per cent dextrose boluses intermittently.


DISPOSITION
Patients who develop hypoglycemia after administration of long-acting insulin preparations should be
admitted for observation. Patients with a history of recurrent hypoglycemic episodes may also benefit from
admission and adjustment of insulin dose. Other indications for admission include continued
neuropsychiatric symptoms despite correction of hypoglycemia and any suspicion of suicidal, homicidal, or
factitious hypoglycemia. Children who have been given an inappropriate dose of insulin should be admitted
for 24 hours because inadequate data exist to predict occurrence of hypoglycemia. All children suspected to
be victims of Munchausen’s by proxy should also be admitted.


SEQUELAE
Delay in treatment may result in profound sequelae, including death. The most common sequelae are
neurologic, and the risk increases with prolonged hypoglycemia. The central nervous system areas most
sensitive to hypoglycemia are the cerebral cortex, hippocampus, basal ganglia, thalamus, brain stem, and
spinal cord.[49] Recurrent, severe hypoglycemia is associated with electroencephalographic changes and
cognitive impairment, particularly in the young, with a reported IQ deficiency of 6 points. [39][49]
Electroencephalographic activity also differs between diabetics with awareness of hypoglycemia and those
without awareness.[49] Cortical atrophy has been demonstrated in patients with recurrent, severe
hypoglycemia.[39] Permanent sequelae may include hemiparesis, memory impairment, diminished language
skills, decreased abstract thinking capabilities, and ataxia.


ACKNOWLEDGMENT
The authors thank Lynn DeWine for her help with this chapter.


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18. Gonder-Frederick L, Cox D, Kovatchev B, et al: A biopsychobehavioral model of risk of severe

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20. Hoffman JR, Schriger DL, Votey SR, Luo JS: The empiric use of hypertronic dextrose in patients with
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21. Hvidberg A, Christensen JN, Hilsted J: Counterregulatory hormones in insulin-treated diabetic patients
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22. Insulins General Statement. AHFS Drug Information 1998; 98:2568.
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24. Kim MR, Sheeler LR, Mansharamani N, et al: Insulin antibodies and hypoglycemia in diabetic patients.
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25. King P, Kong MF, Parkin H, et al: Intravenous lactate prevents cerebral dysfunction during
hypoglycaemia in insulin-dependent diabetes mellitus. Clin Sci 1998; 94:157-163.
26. King P, Parkin H, Macdonald IA, et al: The effect of intravenous lactate on cerebral function during
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OH: Lexi-Comp, Inc.; 1998. pp QV 600 L529P
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36. Moberg E, Hagstrom-Toft E, Bolinder J: Detection of hypoglycaemia by microdialysis measurements of

glucose in subcutaneous adipose tissue. Horm Metab Res 1997; 29:440-443.
37. Moore MC, Connolly CC, Cherrington AD: Autoregulation of hepatic glucose production. Eur J
Endocrinol 1998; 138:240-248.
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Physiol 1996; 80:1021-1032.
39. Perros P, Frier BM: The long-term sequelae of severe hypoglycemia on the brain in insulin-dependent
diabetes mellitus. Horm Metab Res 1997; 29:197-202.
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three cases. Acad Emerg Med 1996; 3:700-707.
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44. Roberge RJ, Martin TG, Delbridge TR: Intentional massive insulin overdose. Ann Emerg
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47. Siesjo BK: Basic mechanisms of traumatic brain damage. Ann Emerg Med 1993; 22:959-969.
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establishing a diagnosis and treatment. Ann Intern Med 1989; 110:125-137.
49. Tribl G, Howorka K, Heger G, et al: EEG Topography during insulin-induced hypoglycemia in patients
with insulin-dependent diabetes mellitus. Eur Neurol 1996; 36:303-309.
50. Tsui EYL, Chasson J-L, Tildesley H, et al: Counterregulatory hormone responses after long-term
continuous subcutaneous insulin infusion with Lispro insulin. Diabetes Care 1998; 21:93-96.
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Pathol 1991; 95:247-252.


Chapter 52 – Isoniazid and Other Antituberculous Drugs
GLENDON C. HENRY SANDRA HAYNES
Essentials
• Consider toxicity in at-risk tuberclosis patients: patients with human immunodeficiency virus,
malnourished patients, homeless patients, immigrants from endemic areas
• Acute overdose:
° Tonic-clonic seizures that may lead to status
epilepticus
° Severe lactic acidosis
° Coma
• Chronic toxicity
° Hepatitis
° Peripheral neuropathy
° Optic neuritis
° Niacin deficiency resulting in
pellagra
INTRODUCTION
Twenty years ago, the incidence of tuberculosis was on a steady decline. However, between 1985 and 1993,
an increase of 64,000 cases beyond the projected figures marked a comeback for this disease. [26] Many
factors contribute to this resurgence, including the emergence of human immunodeficiency virus, continued
drug abuse, homelessness, crowded living quarters, and inadequate or incomplete treatment programs.
Along with these factors, immigration from endemic areas of the world has also led to this increase.
Consequently, there is increased utilization of the older agents, such as isonicotinic acid hydrazine (isoniazid
[INH], rifampin, and ethambutol), as well as increased emphasis on newer and, unfortunately, more toxic
drug regimens. The onset of multiple drug–resistant tuberculosis has also necessitated the addition of newer
agents that are fraught with their own intrinsic, yet unknown, complications and toxicity. Despite increased
efficacy, these drugs exhibit toxicity both at therapeutic doses and in overdose. Unfortunately, as their use
increases, so does the incidence of adverse effects.


ISONIAZID
Introduction
Isoniazid is the primary antituberculin agent employed for prophylaxis and initial therapy in single- and
multiple-drug regimens. When the drugs are used appropriately for a short period of time, acute toxicity is
minimal; however, when they are used for extended periods of time, even correct use can cause chronic
toxicity. In addition, idiosyncratic reactions can also occur.
Isoniazid is readily available and is frequently prescribed to patients who may be at risk for overdose of INH,
including the poor, the homeless, and patients with poor social support. The toxic clinical course can be
rapid and devastating and can result in significant morbidity.
Pharmacology
Isoniazid can be administered in tablet form, as an elixir, or by intramuscular injection. It is rapidly absorbed
from the small intestine, reaching peak serum level within 2 hours of administration.[31] INH has a volume of
distribution similar to that of total body water at 0.6 L/kg and minimal protein binding.[3] Seventy-five per cent
of INH is metabolized via acetylation and hydrolysis, and a small amount is excreted unchanged by the
kidneys. INH is metabolized at different rates, depending on the genetic makeup of the patient,[16] and this
difference may contribute to its toxicity. Slow acetylators are homozygous for the recessive gene and have a
relative lack of N-acetyltransferase. Slow acetylators include those of Jewish or Scandinavian descent and
some whites in Africa, whereas those of Chinese, African American, Japanese, and Inuit descent are fast
acetylators.[30] Slow acetylators excrete up to 25 per cent of the drug unchanged, whereas fast acetylators
excrete less than half of this amount unchanged. The elimination half-time of INH also differs for these two
groups, with slow acetylators having a half-time of 4 hours in the serum, whereas that of fast acetylators may
be only 1 hour.[29] The vast majority of the parent compound and the metabolites is excreted in the urine.[10]
Isoniazid crosses the blood-brain barrier and the placenta and is found in breast milk. The concentration in
the central nervous system is 20 per cent of the serum concentration, but breast milk and plasma
concentrations are equal to plasma concentration.[8][55] Because of its small molecular weight, small volume
of distribution, and minimal protein binding, INH is an excellent candidate for hemodialysis, although this
procedure is rarely needed in clinical practice.[20] It is also removed by peritoneal dialysis and theoretically
by hemoperfusion.[10][32]
Pathophysiology
Isoniazid induces toxicity either directly by inducing hypersensitivity (hepatitis, rash, fever) or indirectly by
depleting pyridoxine (vitamin B6) and niacin.
Isoniazid induces toxicity primarily through its many interactions, especially with pyridoxine-5'-phosphatase
and nicotinamide adenine dinucleotide. These interactions may explain the more important complications
from this agent, namely seizures and acidosis ( Fig. 52–1 ). Tonic-clonic seizures are the most severe acute
manifestation of overdose. These seizures can occur rapidly, and status epilepticus can develop. The
underlying mechanism is a decrease in the primary central nervous system inhibitory neurotransmitter
gamma aminobutyric acid (GABA). [26] GABA is normally synthesized from glutamic acid via two enzymes, L-
glutamic acid decarboxylase and pyridoxine-5'-phosphatase. INH-induced GABA deficiency occurs by at
least three different mechanisms:
1. INH is converted to hydrazones, which block pyridoxine phosphokinase, the enzyme that activates
pyridoxine to pyridoxal-5'-phosphate.
Figure 52-1 Mechanisms for isoniazid (INH)–induced seizures and acidosis. INH decreases pyridoxine effect by (1)
increasing pyridoxine excretion in the urine; (2) blocking the pyridoxine phosphokinase conversion of pyridoxine to
pyridoxal-5-phosphate (P-5'-P), a cofactor necessary for (3) the conversion of glutamate to gamma aminobutyric acid
(GABA). The resultant decrease in GABA predisposes to seizures. Administering pyridoxine increases GABA, and
pyridoxine is used to treat INH-induced seizures. The metabolic acidosis results from (4) lactate produced during the
seizures and from (5) INH inhibition of kynureninase, an enzyme necessary for the ultimate conversion of tryptophan to
NAD+. (6) NAD+, an electron acceptor, is required for the conversion of lactate to pyruvate; a decrease in NAD+ results in
a build-up of lactate. GAD, glutamic acid decarboxylase.
2. INH metabolites directly inhibit the activity of pyridoxal-5'-phosphate.

3. INH increases the excretion of pyridoxine through the formation of isonicotinylhydrazide complexes,
which are renally eliminated.[2]
Because GABA levels depend on pyridoxal-5'-phosphate activity, these three mechanisms deplete the
absolute level of GABA, which leads to a relative GABA deficiency in the central nervous system. This
deficiency leads to a state of generalized excitement that can manifest as confusion, agitation, and seizures.
The seizures can be prolonged and associated with metabolic changes, such as hyperglycemia and lactic
acidosis.
Lactate rapidly accumulates during generalized seizures, resulting in a metabolic acidosis. With INH-
induced seizures, the lactic acidosis is usually excessive for the duration of the seizure and clears more
slowly than expected. INH may contribute to this disproportionate lactic acidosis by inhibiting nicotinamide
adenine dinucleotide, a cofactor required for the conversion of lactate to pyruvate. In addition, INH may
decrease the metabolism of beta hydroxybutyric acid, which can also contribute to the metabolic acidosis.[42]
( Table 52–1 ).
Table 52-1 -- Clinical Presentation of Isoniazid Poisoning

Acute
Nausea and vomiting
Seizures, including status epilepticus
Lactic acidosis (typically severe in patients with seizures)
Obtundation, coma
Chronic
Rash
Fever
Hepatitis
Peripheral neuropathy
Optic neuritis
Arthritis, vasculitis, lupus-like syndrome
Pellagra-like syndrome (diarrhea, dementia, dermatitis)
The unresponsiveness during the postictal phase of INH-induced seizures can be prolonged. Case reports
suggest that these comatose patients may awaken when given a larger than usual dose of
pyridoxine.[4][22][45]
On a long-term basis, INH depletes pyridoxine, resulting in peripheral neuropathy. Co-administration of

pyridoxine can avoid this problem. Hepatitis can occur when the cytochrome P-450 system converts the INH
metabolite monoacetylhydrazine to a toxic intermediate that binds to hepatocytes. Both fast and slow
acetylators are at risk for this complication. INH may induce niacin deficiency and a pellagra-like state, as a
result of a decrease in pyridoxal phosphate, which is necessary for the production of niacin from
tryptophan.[54]
Acute Toxicity
In the early stages of an acute overdose, the patient may present with gastrointestinal disturbances, such as
nausea and vomiting, that develop within 30 minutes of ingestion.[5] Diaphoresis, tachycardia, and increased
blood pressure can also occur. Circulation disturbances are rare but may become prominent if the patient
has seizures and develops acidosis.[5][23] The seizures are usually generalized, prolonged, and refractory to
standard therapies and may lead to status epilepticus, hyperthermia, and death. Patients who ingest more
than 3.9 g are at higher risk for seizures. [52] Agitation with altered mental status and hallucinations have also
been reported.[57] Coma occurs and may persist after other symptoms resolve (see Table 52–1 ).
Chronic Toxicity
Hypersensitivity manifested as hepatitis, fever, rash, and joint and muscle pain may develop at any time
during the course of INH treatment. The drug should be discontinued and the hypersensitivity manifestations
treated symptomatically. Occasionally, INH can induce a syndrome resembling systemic lupus
erythematosus with a positive antinuclear antibody titer,[44] serositis, arthritis, thrombocytopenia, and
anemia.[43] Hematologic disturbances, including agranulocytosis, eosinophilia, and thrombocytopenia, have
also been reported and are reversible with discontinuation of INH.
Hepatic dysfunction, peripheral neuropathy, optic neuritis dysfunction, or a pellagra-like syndrome can
develop with prolonged administration of INH. The hepatic dysfunction usually appears within the first 2
months of INH therapy but can also develop much later.[17] INH may cause an asymptomatic rise in hepatic
enzyme levels[39] but can also induce hepatitis with nausea, vomiting, anorexia, and jaundice. [51] Hepatitis
occurs in only 0.3 per cent of patients younger than 35 years but increases to 2.3 per cent in patients older
than 50 years.[14] Baseline liver function tests should be performed in any patient started on this agent and
monitored as therapy proceeds. Patients at increased risk for hepatotoxicity include the elderly and those
who consume ethanol, have chronic liver disease, or are malnourished. This hepatitis was originally believed
to be related to the patient’s genetic makeup, which determines the rate of acetylation. However, although
rapid acetylators may accumulate the toxic metabolite faster, they also excrete this metabolite faster and
therefore are not at increased risk for hepatotoxicity. Now, both rapid and slow acetylators are assumed to
have the same risk.[12][22]
Peripheral neuropathy secondary to pyridoxine deficiency may develop in patients taking high doses of INH
(>6 mg/kg) for a protracted period of time.[1][13] Slow acetylators are at greater risk because they metabolize
the toxic intermediate acetylhydrazine more slowly. Patients with malnutrition (e.g., those with acquired
immunodeficiency syndrome, alcoholism), liver disease, or diabetes mellitus are at increased risk. Pregnant
women with hyperemesis gravidarum may be at risk if they are not getting proper nutrition. Because INH
appears in breast milk in about the same concentration as plasma, it may be prudent to have infants use
formula milk rather than breast feed.[8]
Isoniazid can also induce an optic neuritis that is similar in its course to peripheral neuropathy. There is a
loss in vision, although color vision remains intact, compared with the ocular toxicity induced by other
antituberculin medications. Eye pain can occur.
The conversion of tryptophan to nicotinic acid also requires the active form of pyridoxine, pyridoxine-5'-
phosphatase. In the absence of this active form, nicotinic acid is not formed. The resulting niacin deficiency
leads to pellagra, which is a complication that develops after months of INH therapy. Patients present with
chronic wasting, dermatitis, and diarrhea and may also have dementia. The disease is ameliorated with
niacin replacement.
Chapter 18 contains an extensive discussion of the toxic cause of seizures. Considerations include central
nervous system hemorrhage, infection, tumor, and noncompliance with antiepileptic medications. Other
differential diagnoses include hypoglycemia, ethanol withdrawal, sedative-hypnotic and barbiturate
withdrawal, and ingestion of toxins, such as cocaine and other sympathomimetic agents ( Table 52–2 ).
Theophylline, hypoglycemic agents, lead, arsenic, monomethylhydrazine-containing mushrooms, water
hemlock, sodium monofluoroacetate, and cyanide ingestion or exposure must also be considered. Although
strychnine does not cause generalized seizures or status epilepticus, its toxicity may mimic seizures and
may also induce a severe metabolic acidosis secondary to muscle contractions.
Table 52-2 -- Differential Diagnosis of Acute Isoniazid Toxicity

Seizures
CNS infections, structural lesions, trauma
Electrolyte disorders, e.g., hyponatremia
Hypoglycemia
Toxins (see Chapter 18 )
Withdrawal—alcohols, sedative-hypnotic drugs, barbiturates
Metabolic Acidosis
Hypoxia
Hypoperfusion
Status epilepticus
Toxins, e.g., salicylates, ethylene glycol, methanol, metformin, phenformin, carbon monoxide, cyanide, toluene
Laboratory Analysis
Isoniazid and its metabolites can be assayed; however, levels are not readily available, nor are they
necessary for treatment of the acutely poisoned patient. Levels in the range of 4 to 8 µg/mL are considered
normal for patients on the agent therapeutically. In the acutely poisoned patient, arterial blood gases and
electrolyte, serum glucose, creatinine, and blood urea nitrogen levels are important to guide therapy and to
rule out correctable causes of seizures. Other diagnostic considerations dictate further testing. In
asymptomatic patients, INH can cause hyperglycemia and elevated hepatic aminotransferase levels.
Treatment
Acute Toxicity
Aggressive airway management and seizure treatment are the cornerstones of therapy ( Table 52–3 ).
Patients should be placed on a cardiac monitor and bedside pulse oximeter while intravenous access is
established. Because decreased mental status and seizures can begin at any time, it is critical that the
airway is protected at all times [49] and that the physician is able to perform rapid-sequence intubation if
necessary (see Chapter 2 ).
Table 52-3 -- Treatment of Acute Isoniazid Toxicity

Airway
Consider if patient presents within 1 hour of ingestion
Activated charcoal, 50–75 g PO adult; 1 g/kg pediatric
Status epilepticus
Initial
Lorazepam
Adult—4–8 mg IV; repeat prn
Pediatric—0.5–0.1 mg/kg IV; repeat prn
PLUS
Pyridoxine IV over 15 to 30 minutes
Adult—5 g IV; can repeat prn (alternatively can administer 1 g of pyridoxine for each gram of INH ingested;
realistically, this amount is seldom known)
Pediatric—70 mg/kg IV, up to 5 g
For Continued Seizures
Phenobarbital
20 mg/kg IV; additional 5 to 10 mg prn
Anesthesia *
Midazolam: load 0.2 mg/kg, followed by infusion of 0.75–10 mg/kg per minute
Propofol: load 1–2 mg/kg, followed by infusion of 2–10 mg/kg per hour
Barbiturate coma with thiopental or pentobarbital
INH, isoniazid.
* Monitor for respiratory depression and hypotension; obtain bedside continuous electroencephalographic monitoring if available.
Gastric decontamination of these patients is important and must be performed early. INH is rapidly absorbed
from the small intestine (usually within 30–60 minutes, with peak level occurring within 2–4 hours).[30] Oral
activated charcoal is beneficial because it adsorbs INH well.[50] Adults should receive 50 to 75 g and children
can receive 1 g/kg body weight.
The treatment for seizures is geared toward augmenting and replacing GABA because INH-induced
seizures result from inhibition of GABA production. Pyridoxine provides the substrate to replenish pyridoxal-
5'-phosphate, which in turn facilitates increased GABA production and should be given as soon as possible.
One gram of pyridoxine is administered, for every gram of INH ingested, over 15 to 30 minutes. When the
amount of INH ingested is unknown, an empirical pyridoxine dose of 5 g pyridoxine can be administered
intravenously and repeated if the seizures continue or recur.[31] The pediatric dose is 70 mg/kg, up to 5 g.[58]
Although human data on the maximum safe dose of pyridoxine are lacking, some patients given more than
300 mg/kg did not have any permanent untoward side effects.[5][58] However, in other case reports, patients
have experienced ataxia, inability to ambulate, and peripheral neuropathy after doses of pyridoxine as low
as 117 mg daily for 3 years.[11][47] Although pyridoxine is used mainly to terminate seizures, it was reported
to shorten the duration of coma in three patients.[4][31]
Standard anticonvulsant drug therapies include benzodiazepines, barbiturates, and anesthesia as

necessary.[35] Benzodiazepines are the first-line therapeutic agents. They augment the effects of the
remaining GABA and any produced after the administration of pyridoxine. Although diazepam at an initial
dose of 10 to 20 mg has been the traditional drug of choice, lorazepam also has a rapid onset, within 3
minutes, and has the added advantage of an anticonvulsant effect for 12 to 24 hours. The initial dose of
lorazepam is 4 to 8 mg initially and may be repeated. If a benzodiazepine is unsuccessful, phenobarbital, at
a loading dose of 20 mg/kg at 50 to 70 mg/min, should be started immediately, with an additional 5 to 10 mg
given if necessary. Phenobarbital potentiates GABA and in high doses can directly open chloride channels
associated with GABA receptor. Refractory seizures at this point benefit from anesthesia with anesthetic
doses of midazolam or propofol. Initial intravenous loading doses (midazolam, 0.2 mg/kg; propofol, 1–2
mg/kg) should be followed by an infusion (midazolam, 0.75–10 µg/kg per minute; propofol, 2–10 mg/kg per
hour). Hypotension may occur with this treatment and should be countered with fluids and augmented if
necessary with dopamine and dobutamine. Continuous electroencephalographic monitoring should be in
place as soon as possible to detect ongoing cerebral seizures, even after motor activity is controlled. In
patients in whom this continues, barbiturate coma with pentobarbital or thiopental may be needed. Both of
these drugs induce serious hypotension, limiting their usefulness.[35] Respiratory depression and
hypotension must be monitored whenever any benzodiazepine or barbiturate is used. Phenytoin or
fosphenytoin, a normal treatment in status epilepticus, would not be expected to terminate seizures induced
by INH, because it does not potentiate the deficient agent, GABA.
Because INH has a low volume of distribution and low protein binding, it is dialyzable.[32] However, because
the half-life is short, dialysis is necessary only with renal failure.
Chronic Toxicity
Peripheral neuropathy is preventable with administration of pyridoxine in doses of 10 to 25 mg per day.

Pyridoxine should be given in patients who are at risk for neuropathy, such as patients older than 65 years,
pregnant women, and those with diabetes mellitus, alcoholism, malnutrition, and renal failure. INH should be
discontinued if the patient experiences hepatitis, ocular neuritis, or hypersensitivity symptoms, such as
vasculitis. Otherwise, treatment for these symptoms is symptomatic and supportive.
Disposition
Because the course of an acute overdose is rapid, asymptomatic patients can be released from a toxicologic
point of view if no symptoms develop within several hours. Patients may require further evaluation for suicide
potential or counseling about medication use. Patients who have a seizure or are comatose should be
admitted for close observation to prevent complications, and some patients may require admission with
minor symptoms, such as nausea and vomiting, if the ingestion is unclear because of language barriers or
unclear histories.
Sequelae
Deaths are rare, occuring in only about 1 in 500 actual exposures annually and are almost always
associated with intentional overdoses.[34] Nonfatal complications of coma and status epilepticus include
rhabdomyolysis, aspiration, and respiratory depression.


OTHER ANTITUBERCULOUS AGENTS
Rifampin
Rifampin, one of the older antituberculous agents, is a semisynthetic derivative of rifamycin B that is
produced by the bacterium Streptomyces mediterranei.[38] It inhibits the action of bacterial DNA-dependent
RNA polymerase at the B-subunit, leading to a suppression of the initial chain formation in RNA synthesis.
Rifampin is bactericidal for both intracellular and extracellular organisms. Resistance is achieved if the drug
is used alone, through alteration of the B-subunit of DNA-dependent RNA polymerase.[38]
Acute overdose occurs less than 50 times a year nationally and rarely results in serious toxicity. [34] A dose of
14 g should be considered potentially lethal, resulting in cardiac arrest. [25] Nausea, vomiting, abdominal
cramps, and diarrhea are common gastrointestinal effects with ongoing use of this agent. If these effects
become severe and persistent, discontinuation of the drug may be necessary. Cases of hepatotoxicity have
also been reported.[48] Elevations in hepatic serum transaminases occur predominantly in patients who are
beginning therapy. These transaminase elevations can resolve even with continuation of the drug.[46]
Jaundice occurs in only 0.6 per cent of patients, but it is an indication for discontinuation of therapy.[56]
Patients with underlying liver dysfunction, such as chronic liver disease and alcoholism, and, potentially,
patients who are elderly may exhibit severe hepatotoxicity when the drug is used alone or in combination
with other drugs.
A nontoxic but potentially distressful side effect is the orange discoloration of the patient’s urine. Permanent
staining of clothing and permeable, soft contact lens may occur. Patients should be warned of these side
effects. Overdosage may lead to the characteristic “redman syndrome.”[41]
Patients receiving intermittent therapy (=1200 mg/day and/or less than twice weekly) may experience a
flulike syndrome, with fevers, chills, and myalgias as well as eosinophilia, interstitial nephritis, acute tubular
necrosis, thrombocytopenia, hemolytic anemia, and shock.[18] These patients should be given a constant
daily dose to prevent these potential complications. Hypersensitivity reactions, including fever, pruritus,
urticaria, skin rashes, and soreness of the mouth and tongue, are also associated with this agent.
Rifampin induces hepatic microsomal enzymes.[36] Thus, it may decrease the serum concentrations and
therapeutic effects of other agents that are metabolized via the liver, such as warfarin, oral hypoglycemics,
theophylline, and some oral contraceptives. Metabolism of corticosteroids, opioids, cyclosporine, quinidine,
dapsone, barbiturates, benzodiazepines, calcium channel antagonists, beta-adrenergic receptor antagonists,
mexiletine, and chloramphenicol has also reportedly been altered by this agent. The effect appears 5 to 8
days after initiation of the drug and continues for 5 to 7 days after discontinuation. Therefore, careful serum
monitoring is necessary when patients are receiving combinations of these agents.
Ethambutol
Ethambutol is a water-soluble, tuberculostatic, antimicrobial agent that is effective only against

Mycobacterium species. Although the exact mechanism of action is unknown, it is thought to inhibit
incorporation of mycolic acid into the mycobacterial cell wall.[53] The ability of ethambutol to suppress the
growth of isoniazid and streptomycin-resistant bacilli makes it an invaluable antituberculosis agent. Seventy-
five to 80 per cent of the drug is absorbed from the gastrointestinal tract, and peak concentration occurs 2 to
4 hours after ingestion. Most of the drug is excreted unchanged in the urine. Therefore, unlike rifampin and
isoniazid, ethambutol does not induce hepatic disease or alter the metabolism of other drugs.
Ethambutol is associated wtfh retrobulbar optic neuritis[38] causing central scotoma, tunnel vision, decreased
visual acuity, and loss of red/green differentiation. It appears to be dose related and occurs in 15 per cent of
patients receiving 50 mg/kg/day, decreasing to 5 per cent of patients receiving 25 mg/kg/day, and is
reversible with cessation of therapy. [56]
Ethambutol may also cause a peripheral neuropathy manifested by numbness and tingling of the
extremities. Other adverse effects include pruritus, skin rashes, joint pain, gastrointestinal disturbances,
malaise, headache, dizziness, confusion, disorientation, and hallucinations. Use of the drug results in
hyperuricemia and increased risk of gout in approximately 50 per cent of patients because of decreased
renal excretion of uric acid.[56] In overdose, the only cases reported are co-ingestions with other drugs.[13][28]
Pyrazinamide
Pyrazinamide is a synthetic pyrazine analog of nicotinamide.[38] Its precise mechanism of action is unknown,
but it exhibits bactericidal activity against Mycobacterium tuberculosis in vitro. It is well absorbed from the
gastrointestinal tract and is widely distributed throughout the body. It is metabolized by the liver and excreted
by the kidneys.
Hepatotoxicity is the most commonly reported adverse effect, with elevated transaminase levels being the
earliest indication of toxicity. In patients receiving combination therapy of isoniazid, rifampin, and
pyrazinamide, the reported incidence ranges from 1 to 5 per cent.[56] Pyrazinamide decreases the tubular
excretion of uric acid, which may induce an acute gouty arthritis. Other adverse reactions include nausea,
vomiting, dysuria, malaise, fever, and skin rashes.
Streptomycin
Streptomycin is an aminoglycoside antibiotic derived from the bacterium Streptomyces griseus.[38] It is

bactericidal and initially was shown to inhibit the growth of the tubercle bacilli and most aerobic gram-
positive and gram-negative organisms. However, drug resistance and adverse effects have limited its
usefulness as a first-line antituberculosis drug. It is poorly absorbed from the gastrointestinal tract but is
rapidly absorbed intravenously, and peak plasma concentrations occur within 30 to 90 minutes of
intramuscular injection. The drug is polar in nature and poorly distributed in most cells, including the central
nervous system and the eye. It is excreted almost entirely by the kidney.
Ototoxicity following administration of the drug is a result of progressive accumulation and prolonged
exposure, leading to destruction of vestibular and cochlear sensory cells. [6] Sustained loss of sensory hair
cells results in auditory nerve degeneration and irreversible hearing loss. Streptomycin has been reported to
cause a preferential, irreversible vestibular toxicity in 20 per cent of patients receiving 500 mg/day for 1
month. Additionally, 75 per cent of patients receiving 2 g per day for more than 2 months have demonstrated
nystagmus or postural imbalance.[59]
Streptomycin does not accumulate in the renal cortex and is the least nephrotoxic of all the
animoglycosides.[33] Less common adverse reactions include peripheral neuritis, perioral paresthesias, and
skin rashes. Scotomata have also been associated with the use of streptomycin. The mechanism is
unknown. Streptomycin has caused deafness in infants exposed in utero and is rated category D in
pregnancy.
Para-Aminosalicylic Acid
Para-aminosalicylic acid is a synthetic antimicrobial analog of para-aminobenzoic acid.[38] It is bacteriostatic

and acts by inhibiting folic acid synthesis in the tubercle bacilli. It is readily absorbed from the
gastrointestinal tract and is distributed widely throughout the body, with the exception of the cerebrospinal
fluid. Eighty per cent of the drug is excreted in the urine.
Anorexia, nausea, epigastric pain, abdominal distress, and diarrhea occur in 10 to 30 per cent of patients. A
lupus-like hypersensitivity reaction occurs in 5 to 10 per cent of patients and is manifested by fever,
generalized malaise, joint pains, sore throat, leukopenia, thrombocytopenia, agranulocytosis, eosinophilia,
and hemolytic anemia. A mononucleosis-like syndrome may also occur.
Cycloserine
Cycloserine is a broad-spectrum antibiotic derived from the bacterium Streptomyces orchidaceus.[38] It is

bacteriostatic for M. tuberculosis in vitro. It is rapidly absorbed through the gastrointestinal tract and
distributed throughout body fluids. About 50 per cent of the drug is excreted unchanged in the urine in the
first 12 hours, and about 35 per cent is metabolized.
Cycloserine produces mostly central nervous system toxicity,[43] which can manifest as somnolence,
headache, tremor, dysarthria, vertigo, confusion, nervousness, irritability, psychosis, paranoia, catatonia,
depression, visual disturbances, and paresis. Death occurred in one case after 500 days of treatment. [40]
There are also reports of patients having tonic-clonic or absence seizures. Patients may also develop a
peripheral neuropathy manifested by numbness and tingling of the extremities.
Ethionamide
Ethionamide is a synthetic derivative of isonicotinic acid.[38] It is bacteriostatic-inhibitory to M. tuberculosis.

Readily absorbed from the gastrointestinal tract and widely distributed throughout the body, it is metabolized
by the liver into active and inactive metabolites that are excreted in the urine.
Ethionamide causes significant gastrointestinal distress, producing anorexia, nausea, and vomitus having
the taste of rotten eggs. Postural hypotension, mental depression, drowsiness, asthenia, hepatitis, allergic
skin rashes, stomatitis, gynecomastia, menorrhagia, and impotence have also been reported.[38] Seizures,
peripheral neuropathies, and psychiatric disturbances may occur. The concomitant use of pyridoxine may
alleviate this side effect, and its use is therefore recommended.[38]
Capreomycin
Capreomycin is a cyclic peptide produced by Streptomyces capreolus.[38] It is administered parenterally and

is used in combination with ethambutol and isoniazid for the treatment of drug-resistant tuberculosis.
Capreomycin use results in ototoxicity, reversible proteinuria, cylindruria, and nitrogen retention.
Hypersensitivity reactions and blood dyscrasias are also reported.
Viomycin
Viomycin is a polypeptide antibiotic that is available only in parenteral form. [27] It is a second-line
antituberculous drug. Viomycin causes nephrotoxicity.
Clofazimine
Clofazimine is a derivative of aniline dyes and is used primarily in the treatment of leprosy.[38] It
demonstrates activity against other species of Mycobacterium and is part of multidrug therapy in the
treatment of Mycobacterium avium-intracellulare.[27] It is not used routinely in patients with tuberculosis.
Adverse reactions include gastrointestinal upset, bowel obstruction, splenic infarction, and red/black skin
discoloration.
Treatment of Toxicity Due to Non-INH Antituberculous Drugs
Experience with overdose of non-INH drugs is unusual. As with most drug overdoses, supportive care and
gastrointestinal decontamination with activated charcoal are the mainstays of therapy. Pyridoxine may be
useful for ethionamide-related seizures, and hemodialysis may offer some benefit for cycloserine.[60]


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3. Bennett WM, Singer I, Golper T, et al: Guidelines for drug therapy in renal failure. Ann Intern
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4. Brent J, Vo N, Kulig K, et al: Reversal of prolonged isoniazid-induced coma by pyridoxine. Arch Intern
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5. Brown A, Mallett M, Fisher D, et al: Acute isoniazid intoxication: Reversal of CNS symptoms with large
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8. Cavalieri SJ, Biehele JR, Sanders Jr WE: Synergistic activities of clarithromycin and antituberculous
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10. Cocco AE, Teutelbaum DT: Isoniazid intoxication: Management by peritoneal dialysis. N Engl J
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12. Dickerson DS, Bailey WC, Hirschowitz BI, et al: Risk factors for INH induced liver dysfunction. J Clin
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liver transplantation. Dig Dis Sci 1994; 39:2255-2259.
18. Flynn CT, Rainford DJ, Hope E: Acute renal failure and rifamycin: Danger of unsuspected intermittent
dosage. Br Med J 1974; 2:482.
20. Gold CH, Buchanan N, Tringham V, et al: Isoniazid pharmacokinetics in patients in chronic renal failure.
Clin Nephrol 1976; 6:365-369.
22. Gurnani A, Chawla R, Kundra P, et al: Acute isoniazid poisoning. Anaesthesia 1992; 47:781-783.
23. Hankins DG, Saxena K, Faville RJ, et al: Profound acidosis caused by isoniazid ingestion. Am J Emerg
Med 1987; 5:165-166.
25. Holdiness MR: A review of the Redman syndrome and rifampin overdosage. Med Toxicol Adverse
Drug Exp 1989; 4:444-451.
26. Holtz P, Palm D: Pharmacological aspects of B6. Pharmacol Rev 1964; 16:113-178.
27. Honsburg Jr CR: MAI. N Engl J Med 1991; 324:1332-1338.
28. Jack DB, Knepil J, McLay WD, et al: Fatal rifampin-ethambutol overdosage. [Letter].
Lancet 1978; 2:1107-1108.
29. Jeanes CWL, Schaefer O, Eidus L: Inactivation of isoniazid by Canadian Eskimos and Indians.
CMAJ 1972; 106:331-335.
30. Katz BE, Carver MW: Acute poisoning with isoniazid treated by exchange transfusion.
Pediatrics 1956; 18:72-76.
31. Katz GA, Jobin EC: Large doses of pyridoxine in the treatment of massive isoniazid ingestion. Am Rev
Respir Dis 1970; 101:991-992.
32. Konigshausen TH, Altrogge G, Hein D, et al: Hemodialysis and hemoperfusion in the treatment of most
severe INH poisoning. Vet Hum Toxicol 1979; 21(Suppl 1):12-15.
33. Leitman PS, Smith CR: Aminglycoside nephrotoxicity in humans. Rev Infect Dis 1993; 5(Suppl
2):S284-S292.
35. Lowenstein DH, Alldredege BK: Status epilepticus. N Engl J Med 1998; 338:970-976.
36. Loudon RG: Rifampin. In: Kagan BM, ed. Antimicrobial Therapy, 2nd ed. Philadelphia: WB
Saunders; 1974:131-138.
38. Mandell GL, Sande MA: Antimicrobial agents: Drugs used in the chemotherapy of tuberculosis and
leprosy. In: Gilman AG, Rall TW, Nies AS, Taylor P, ed. Goodman & Gilman’s The Pharmacological Basis
of Therapeutics, 8th ed. New York: Pergamon Press; 1990:1146-1164.
39. Meyers BR, Halpern M, Sheiner P, et al: Acute hepatic failure with seven patients after prophylaxis and
therapy with antituberculosis agents. Transplantation 1994; 58:372-376.
40. Miyakawa Tsuzuki T, Nakamura K, et al: Folia Psychiatr Neurol Jpn 1977; 31:235-241.
41. Newton RW, Forest ARW: Rifampicin overdosage: The red man syndrome. Scott Med J 1975; 20:55-
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42. Pahl MV, Jaziri NG, Ness R, et al: Association of beta hydroxybutyric acidosis with isoniazid intoxication.
Clin Toxicol 1984; 22:167-176.
43. Pitts FW: Tuberculosis: Prevention and Therapy. In: Hook EW, Nardell GL, Gwaltney Jr JM, et
al ed. Current Concepts of Infectious Diseases, New York: John Wiley & Sons; 1977:181-194.
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45. Salkind AR, Hewitt CC: Coma from long-term ingestion of isoniazid. Arch Intern Med 1997; 137:2518-
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46. Sanders Jr WE: Rifampin. Ann Intern Med 1976; 85:82-86.
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48. Schever PJ, Summerfield JA, Lal S, et al: Rifampicin hepatitis: A clinical and histological study.
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49. Shah BR, Santucci K, Sinert R, et al: Acute isoniazid neurotoxicity in an urban hospital.
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51. Singh J, Arora A, Garg PK, et al: Antituberculosis treatment-induced hepatotoxicity: Role of predictive
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52. Sullivan EA, Geoffroy P, Weisman R, et al: Isoniazid poisoning in New York City. J Emerg
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Chemother 1995; 39:2692-2695.


Chapter 53 – Anticancer and Other Cytotoxic Drugs
TIMOTHY ERICKSON MICHAEL WAHL
Cancer patients can present as toxicologic challenges. These patients are at risk for drug overdose from
exposure to highly toxic chemotherapeutic agents, adverse drug interactions, underlying disease states, and
emotional lability due to their potentially terminal condition.
In the treatment of cancer, drug dosage is critical for maximizing antitumor effect while minimizing normal
tissue toxicity. Pharmacokinetic parameters of anticancer drugs vary considerably from patient to patient.
Most clinically useful drug regimens consist of a combination of drugs with different mechanisms of action
and hence different toxicity profiles. Variability in the pharmacokinetic profile of anticancer agents in
individual patients can be further complicated by drug interactions between different chemotherapeutic drugs
or other concomitant medication.[50] In addition to the dose, the schedule and route of administration can
significantly determine the incidence and outcome of antineoplastic agent toxicity.[39] Because the majority
of chemotherapeutic agents are administered intravenously, the incidence of acute oral exposures is low.
Finally, the patient’s age and renal and hepatic function must be considered in any overdose setting.[29][58]
Numerous antineoplastic agents are presently being used, and more drugs are currently under investigation.
This chapter will discuss the more common anticancer and cytotoxic agents, focusing on their toxicologic
profiles, clinical presentation, and management.
METHOTREXATE
Essentials
• Nausea, vomiting, and mucositis are common side effects.
• Elevation of liver enzymes and renal failure have been reported.
• Anemia and leukopenia can appear in 1–2 weeks.
• Intrathecal administration may result in headache, fever, and delayed neurotoxicity.
Introduction
Methotrexate (MTX) is used in the treatment of a variety of tumors, psoriasis, rheumatoid arthritis, placenta
accreta, ectopic pregnancy, and recently, in the termination of first trimester pregnancy. The routes of
administration vary with the type and location of the disease being treated. MTX is given by oral,
intravenous, or intrathecal routes.
MTX is a folic acid analog that affects the enzymes dihydrofolate reductase (DHFR) and thymidylate
synthetase ( Table 53–1 ), resulting in decreased production of purines and deoxythymidylate, which are
essential in the synthesis of RNA and DNA. Folic acid derivatives are essential in one-carbon transfer
reactions in the body. These transfer reactions are necessary in the production of purines, which are needed
for RNA and DNA production and in the production of thymidylate from uridylate. Folate is actively
transported into the cell, where it is reduced to dihydrofolate (FH2). The enzyme dihydrofolate reductase
converts FH2 to tetrahydrofolate. The tetrahydrofolate derivatives methylene tetrahydrofolate and N-10-
formyl tetrahydrofolate are needed for the formation of the basic two-ring structures of purines. N-5, 10-
methylene tetrahydrofolate is needed for the conversion of deoxyuridylate (dUMP) to deoxythymidylate
(dTMP). Leucovorin is d, 1-N-5-formyltetrahydrofolate and can reverse the effects of methotrexate on one-
carbon transfer reactions ( Fig. 53–1 ). MTX interferes with dihydrofolate reductase, blocking the conversion
of dihydrofolate to tetrahydrofolate, thereby disrupting the synthesis of DNA and RNA components. MTX
also inhibits thymidylate synthetase, preventing the production of dTMP.
Table 53-1 -- Pharmacology of Anticancer Drugs

Methotrexate
Folic acid antagonist, which produces inhibition of dihydrofolate reductase. Limits cell production
Mechanism: of tetrahydrofolate, blocking conversion of deoxyuridylate to thymidylate, which is required for
DNA synthesis.
Small doses (0.1 mg/kg) are more readily absorbed from the GI tract than large doses exceeding
Absorption: 80 mg/m2. Further decrease in oral bioavailability if food is consumed prior to ingestion. Peak
levels are reached 1 to 2 hours after ingestion and 30 minutes after IM injection.
Distribution: 50% protein-bound. Volume of distribution 0.6–0.9 L/kg.
Metabolism: After high doses, a nephrotoxic metabolite (7-hydroxymethotrexate) may accumulate.
Clearance: 1.5 mL/min/kg. Renal clearance in 2 hours. 40–90% of absorbed drug is excreted
unchanged in the urine. Undergoes both glomerular filtration and tubular secretion. 5% of drug is
Elimination: eliminated through biliary excretion. Elimination T1/2 of parent compound is 5–9 hours. High
doses may produce T1/2 greater than 10 hours. In toxic patients with renal failure, the T1/2 can be
as high as 45 hours.
Vinblastine/Vincristine
Acts by arresting mitosis at metaphase. The arrest is reversible and is produced from
crystallization of the microtubules and spindle contractile proteins. Inhibits purine synthesis and
Mechanism:
urea formation via Kreb cycle by blocking cellular utilization of glutamic acid. Neurotoxicity from
disruption of axoplasmic transport.
Not well absorbed from the GI tract. Rapid distribution and tissue binding following IV
Absorption:
administration. Time to steady state is 15–30 hours after continuous therapeutic infusion.
Distribution: 75% protein-bound. Poor penetration into the CNS.
Metabolized in the liver. Active metabolite: Deacetylvinblastine. No active metabolite identified for
Metabolism:
vincristine.
Elimination T1/2 of approximately 8 hours. Up to 20% is excreted in the urine within 72 hours of
Elimination:
administration. Major route of excretion of unchanged parent compound is via the bile and feces.
Doxorubicin
Doxorubicin forms a complex with DNA, thereby interfering with nucleic acid synthesis.
Mechanism: Accumulates in the cardiac tissue. Myocardial cells are not adequately equipped to handle the
free radicals produced by an oxidative mechanism.
Absorption: Doxorubicin is administered IV. It is rapidly and widely distributed.
Distribution phase with 30 minutes. Plasma T1/2 of approximately 4 hours. Exhibits “first pass”
Distribution: effect with liver metabolism. 50–80% protein-bound. Volume of distribution ranges from 9–66
L/kg.
Majority metabolized in the liver. Remainder metabolized in the plasma. Active metabolite:
Metabolism:
Doxorubicinol.
Elimination T1/2 of 24–28 hours. Approximately 40% of administered dose is recovered in the bile
Elimination:
or feces within 7 days. 5% recovered in the urine within 5 days.
Bleomycin
Metabolites of bleomycin are extremely cytotoxic through the promotion of lipid peroxidation and
Mechanism: formation of free radicals. The enzyme that detoxifies bleomycin, hydrolase, is only present in low
concentrations in the lung and skin.
Absorption: Because administered IV, serum peak levels are achieved within minutes.
High concentrations are found in skin, lungs, peritoneum, and lymphatics. Low concentrations are
Distribution:
found in hematopoietic tissue and bone marrow.
Metabolism: In humans, 60–70% of an administered dose is recovered in the urine as active bleomycin.
Follows first-order kinetics. Terminal elimination T1/2 is approximately 120 minutes. As creatinine
Elimination:
clearance decreases, elimination T1/2 increases exponentially.
Alkylating Agents/Cyclophosphamide
Mechanism: Forms an imonium ion, which attacks the nucleophilic center on the DNA chain.
Well absorbed after oral administration with a bioavailability greater than 75%. Concentrations of
Absorption:
metabolites peak in plasma 2 hours after IV administration.
Distribution: Plasma protein binding of unchanged drug is low, but some metabolites are bound up to 60%.
Several cytotoxic metabolites have been identified in the plasma and urine. It has not been
Metabolism:
established that any single metabolite is responsible for the toxic effects.
The unchanged drug has an elimination T1/2 of 3–12 hours. Eliminated primarily in the urine in
Elimination:
form of active metabolites (up to 75%).
Cisplatin/Carboplatinum
Mechanism: Greatest activity in cell neoplasias of germinal cell origin. Inhibits DNA and RNA precursors.
Absorption: Peak plasma levels within 1 hour of infusion.
Greater than 90% protein-bound. Concentrates in kidneys, liver, and intestines. Poor CNS/blood
Distribution:
brain barrier penetration.
Metabolism: Initially excreted unchanged and later as biotransformation products. No known active metabolite.
Elimination: Elimination T1/2 reported in range of 60–72 hours.
Paclitaxel
Mechanism: Inhibits cell division by promoting microtubule stabilization and assembly.
Peak serum levels range from 3–8 hours depending on concentration of infusion. Serum
Absorption:
concentrations decline rapidly following infusion.
Distribution: Highly (95%) protein-bound. Large volume of distribution.
Metabolism: No active metabolites have been detected in the blood or urine.
Elimination T1/2 ranges from 1–9 hours. Only 5% of initial dose is recovered in the urine. High
Elimination:
concentrations in the bile.
Figure 53-1 The effects of methotrexate on one-carbon transfer reactions.
The clinical presentation depends on the route of administration. Intravenous (IV), oral, and intrathecal
overdoses have different treatments and toxicities.
Patients with acute oral and IV toxicities may exhibit nausea and vomiting (66 per cent), mucositis (33 per
cent), rash (18 per cent), transient increased liver enzymes (81 per cent), creatinine elevation, and
decreased leukocyte and platelet counts ( Table 53–2 ).[56] The acute gastrointestinal (GI) symptoms in the
first 2 days are due to the drug itself, and chronic effects are secondary to the mucositis (typically lasting up
to 1 week). There are very few reports of acute oral overdose in the literature. An acute oral toxic ingestion
by a 2-year-old child was reported secondary to a family member’s MTX prescribed for rheumatoid
arthritis.[67] There was no evidence of adverse symptoms and no mucositis, hepatoxicity, or nephrotoxicity
reported after therapeutic interventions. Two siblings, ages 3 and 4 years, ingested an unknown amount of
MTX and subsequently developed elevated liver enzymes but recovered uneventfully.[55] An 80-year-old
female with severe rheumatoid arthritis mistakenly ingested a weekly oral dose of 10 mg MTX every morning
for 4 consecutive days. She developed mucositis, fever, and pancytopenia, but survived without long-term
sequelae.[9] Oral overdose is unlikely to cause neurologic damage, but it has been reported in 5–15 per cent
of patients receiving high IV doses.[47]
Table 53-2 -- Anticancer Drugs: Clinical Presentations
Drug Clinical Features
Vomiting, GI bleeding, stomatitis, esophagitis; delayed leukopenia,
Methotrexate
thrombocytopenia, and anemia; elevated liver enzymes, rise in serum creatinine
Vinca alkaloids, vinblastine, Neurotoxicity (vincristine), bone marrow depression (vinblastine); fever, vomiting
vincristine within 24 hours of overdose; local tissue injury with extravasation
Doxorubicin, daunorubicin, Bone marrow suppression with acute exposure, cardiotoxicity with chronic,
dactinomycin cumulative dose; stomatitis, vomiting, diarrhea; allergic skin reaction, alopecia
Bleomycin Pulmonary toxicity, fibrosis; dermal toxicity; minimal bone marrow suppression
Nitrogen mustards, Myelosuppression with leukopenia and thrombocytopenia; GI symptoms,
cyclophosphamide nausea, vomiting; alopecia; hearing loss; powerful skin vesicants
Nephrotoxicity, peripheral neuropathy, ototoxicity; vomiting, diarrhea; some
Cisplatin, carboplatinum
cardiotoxicity
Myelosuppression, neutropenia; sensory neuropathy; alopecia, cardiac
Paclitaxel
dysrhythmias; GI irritation, diarrhea; hypersensitivity reactions
Intrathecal administration, however, can cause significant morbidity. The most common reactions are
headache, fever, meningismus, and vomiting.[38] More severe toxic effects of paresis, paraplegia, nerve
palsies, and central ataxia have also been described, although these problems generally occur after
administration and may last from months to years.[31] Death has been reported in cases of massive
intrathecal overdose (50 times the recommended dose).[25]
The GI side effects of MTX are similar to those caused by other antineoplastic agents such as doxorubicin,
nitrogen mustards, cyclophosphamide, cisplatin, carboplatinum, and paclitaxel. Although less severe, renal
toxicity should be differentiated from cisplatin. Neurotoxicity from intrathecal administration of MTX may
resemble that induced by vincristine. Other nonchemotherapeutic agents included in the toxic differential
diagnosis are summarized in Table 53–3 .
Table 53-3 -- Differential Diagnosis: Antineoplastic Drug Toxicities

Neurologic manifestations Bone marrow suppression Cardiac manifestations
Vincristine Vinblastine Doxorubicin
Methotrexate Methotrexate Dactinomycin
Cisplatin Doxorubicin Fluorouracil
Paclitaxel Dactinomycin Cisplatin
Doxorubicin Carboplatinum Mitroxantrone
Carboplatinum Cyclophosphamide Paclitaxel
Strychnine Paclitaxel Digitalis/digoxin
Tetrodotoxin Asparaginase Oleander/foxglove/lily of the valley
Saxitoxin Chloramphenicol Cocaine/amphetamines
Curare Fluorouracil Tricyclic antidepressants
Botulism Gold salts Emetine
Organophosphates Phenothiazines Calcium channel blockers
Arsenic Phenylbutazone Beta blockers
Lead Sulfonamides Type I antiarrhythmics
Mercury Colchicine Chloral hydrate
Thallium Benzene Hydrocarbon solvents
Carbon disulfide Radiation Fluorocarbon aerosols
Acrylamide Pulmonary manifestations Theophylline/caffeine
Ethylene oxide Bleomycin Phenylpropanolamine
N-Hexane Methotrexate MAO inhibitors
Methyl bromide Busulfan Chloroquine/quinine
Manganese Cyclophosphamide Propoxyphene
Lithium Chlorambucil Potassium
Tetanus toxin Melphalan Renal manifestations
Dermal irritants Nitrosoureas Cisplatin
Vincristine Diquat Carboplatinum
Vinblastine Paraquat Cyclophosphamide
Cyclophosphamide Organophosphates Streptomycin
Daunomycin Sulfur dioxide Nitrosoureas
Doxorubicin Radon Mithramicin
Nitrogen mustards Opioids Ifosfamide
Bleomycin Sedative hypnotics Methotrexate
Capsaicin Cholinergic agents Arsenic
Cobalt Hydrocarbons Cadmium
Copper Salicylates Chromium
Nickel Ammonia Copper
Platinum Chlorine Ethylene glycol
Zinc Isocyanates Vancomycin
Vanadium Nitrogen dioxide Gentamicin
Thallium Phosgene Inorganic mercury
Silver Gastrointestinal manifestations Cortinarius mushrooms
Gold Methotrexate NSAIDs
Beryllium Doxorubicin Toluene
Arsenic Mechlorethamine Acetaminophen
Chromate Cyclophosphamide Radiocontrast agents
Aluminum Cisplatin Cocaine/amphetamines/PCP
Cadmium Carboplatinum Paraquat/diquat
Plants (urushiol) Paclitaxel Alopecia
Sulfa drugs Busulfan Cyclophosphamide
Alkyl mercury Fluorouracil Doxorubicin
Cements Vinblastine/vincristine Dactinomycin
Caustics Bleomycin Paclitaxel
Hydrofluoric acid Tamoxifen Bleomycin
Phenol Acids Nitrogen mustards
White phosphorus Alkalis Cisplatin
Selenium Colchicine Fluorouracil
Ethylene oxide Iron Arsenic
Hexachlorobenzene Salicylates Thallium
Carbon monoxide Acetaminophen Gold
Epoxy resins Theophylline Mercury
Plastics Ethanol Lead
Hydrocarbons NSAIDs Chloroquine
Digitalis Selenium
Ipecac Allopurinol
Copper sulfate Valproic acid
Laboratory Studies
Electrolytes, renal and hepatic function, and peripheral blood counts should be followed. Increased levels of
serum creatinine and liver enzymes are common. Acute liver enzyme elevations usually normalize within 10
days of administration, although chronic elevation and fibrosis have been reported. Leukopenia and
thrombocytopenia may also be seen in 1–2 weeks. MTX levels can be followed and used to guide leucovorin
rescue dosages ( Fig. 53–2 ).
Figure 53-2 Methotrexate nomogram. (Adapted from Young LY, Kimble M [eds]: Applied Therapeutics: The Clinical Use of Drugs, 4th
ed. Vancouver, WA, Applied Therapeutics; 1988.)
Treatment
Oral overdoses need prompt gastric decontamination ( Table 53–4 ). Multiple doses of charcoal,[30] charcoal
hemoperfusion, and cholestyramine[26] may be beneficial in this setting. Activated charcoal was
administered to the 2-year-old child mentioned earlier, 7 hours postingestion following an acute overdose of
up to 100 2.5-mg tablets of MTX.[67]
Table 53-4 -- Anticancer Drugs: Treatment Essentials

Multidose activated charcoal, urinary alkalinization with sodium bicarbonate to a pH of
7.5–8.0
Methotrexate
Leucovorin rescue: 10 mg/m2 q 6 h (IV or oral)
Thymidine infusion: 8 g/m 2/d
Treatment is supportive, no specific antidote, possible role for glutamic acid; control
Vinca alkaloids,
neurotoxicity/seizures with benzodiazepines/phenobarbital; if extravasation occurs,
vincristine, vinblastine
stop infusion immediately
Doxorubicin, Treat symptomatically, support and monitor cardiac activity; transfuse RBCs, platelets
daunorubicin, if bone marrow suppression; if fever or infection, start appropriate antibiotics; possible
dactinomycin role for iron chelator dexrazoxane
Support airway, low flow oxygen or room air suggested, high flow oxygen contributes
Bleomycin
to pulmonary toxicity, decontaminate skin if dermal exposure
Nitrogen mustards, Decontaminate skin with soap and water. If dermal spillage, irrigate with 2–4% sodium
cyclophosphamide thiosulfate; if oral ingestion, treat like acid/alkali burns, consider endoscopy
Treatment is symptomatic and supportive, no specific antidote; hydration may reduce
risk of nephrotoxicity, hemodialysis ineffective. Fosfomycin may be protective against
Cisplatin, toxic effects (dose: 2 g bid × 4 d); possible role for sodium thiosulfate (dose: 12 g/m 2
carboplatinum infusion in 1 L 0.9/NS over 6 h)
MESNA therapy for hemorrhagic cystitis, dose: 1500 mg/m2/d (approx 37 mg/kg/d)
Treatment is supportive, no specific antidote; cardiac monitoring for signs of
dysrhythmias; if cardiotoxicity, treat with standard dysrhythmic agents (epinephrine,
Paclitaxel
lidocaine, atropine); hypersensitivity reactions treated with epinephrine,
diphenhydramine, and corticosteroids
High-dose IV methotrexate toxicity requires treatment with urinary alkalinization and leucovorin rescue.
Additionally, adjunctive therapy with thymidine may help prevent systemic toxicity in larger overdoses.[54]
Urinary alkalinization is recommended because 90 per cent of MTX is significantly less dissociated at a
urinary pH of 7.5 compared to 5.5. Hydration and good urinary output are also important for adequate renal
elimination and to prevent renal toxicity.
Leucovorin rescue therapy limits bone marrow, GI, and renal toxicities and has allowed for higher
therapeutic doses of MTX to be used clinically. For cancer chemotherapy, leucovorin is used in the smallest
dose possible, in a delayed time frame, to allow the largest effect possible against tumor cells, yet still
salvage normal cells. In an inadvertent massive overdose, large doses of leucovorin in a timely manner may
be critical, and should not be delayed while awaiting a serum MTX level. The standard recommended dose
is 10 mg/m2 (IV or oral) every 6 hours after overdose, though high MTX levels may need up to 100 mg/m2. In
the case described earlier, the 2-year-old child received urine alkalinization and leucovorin rescue 5 hours
after ingestion and recovered uneventfully.[67]
Intrathecal overdose can be treated with cerebrospinal fluid (CSF) drainage, CSF exchange, or
ventriculolumbar perfusion. If the overdosage is noted early in an intrathecal exposure, the patient should be
placed in a dependent position and 20 to 40 mL of CSF removed.[1] In large overdoses of greater than 100
mg, CSF exchange with preservative-free normal saline can be performed. If the patient has neurologic
symptoms, then ventriculolumbar perfusion should be done.[41][66]
Disposition
Patients with oral or IV overdose often require admission to an intensive care setting with close monitoring of
urine output, renal function, and hepatic function. If not already managed by a hematologist/oncologist,
consultation is highly recommended. Patients with an intrathecal overdose will need monitoring and
neurosurgical consultation, particularly if ventriculolumbar perfusion is being considered.
Sequelae
Leukopenia and thrombocytopenia may occur in 1–2 weeks. Central nervous system complications of
intrathecal administration may not manifest for several weeks and may last for years.


VINCRISTINE AND VINBLASTINE
Essentials
• Neurotoxicity can result after both therapeutic and toxic doses (particularly with vincristine).
• Severe bone marrow depression may occur with vinblastine.
• Fever and vomiting are common within 24 hours of overdose.
Introduction
Vincristine and vinblastine are alkaloids isolated from Vinca rosea (periwinkle). The biologic properties of
vinca alkaloids were first recognized in the 1950s when the periwinkle plant was studied as a potential
treatment for diabetes.[52] Currently, they have clinical importance for the treatment of leukemias,
lymphomas, and specific solid tumors.
Vinca alkaloids are cell-cycle–specific, metaphase-dependent agents.[22] These agents inhibit microtubule
formation in mitotic spindle, causing cell division arrest.[48] Neurotoxicity may be explained by the disruption
of axoplasmic transport and secretory functions involving the microtubules.
The major toxicity in therapeutic and toxic doses is neurotoxicity, particularly with vincristine. [51] Neurotoxicity
appears to be cumulative. Neuropathies, loss of deep tendon reflexes, delirium, hallucinations, coma, and
seizures may occur during the first week following an overdose.[48] Although the preferred route is IV,
inadvertent intrathecal administration of vincristine has produced ascending paralysis, coma, and death.[24]
Fever, stomatitis, nausea, and vomiting can occur within 24 hours of overdose. Bone marrow suppression
(particularly with vinblastine) may be delayed but severe.[11] Neutropenia is the primary effect, typically
occurring 7–10 days after IV administration, with full recovery in 2–3 weeks. Anemia and thrombocytopenia
can also result, but are less common. These agents can also cause local tissue injury after extravasation
and splash contact.
The mechanism of the vinca alkaloids is similar to that of colchicine, ricin, abrin, and podophyllotoxin.
Vincristine is more neurotoxic but less bone marrow suppressive than vinblastine. Mucositis is more
commonly seen with vinblastine. Routine doses of vinblastine will cause nausea and vomiting, whereas toxic
doses of vincristine are required to produce similar GI symptoms.
Laboratory Studies
Electrolytes and peripheral blood counts should be followed. Monitor laboratory data for signs of bone
marrow depression and infection for 2–3 weeks after toxicity, or until parameters normalize to the patient’s
previous baseline values. Serum vincristine and vinblastine levels can be determined by radioimmunoassay
techniques but are not clinically practical or readily available.[68]
Treatment
Treatment is primarily supportive because there is no specific antidote for either vinblastine or vincristine.
Vinca alkaloids are administered IV and not well absorbed orally. Management of neurotoxicities are
supportive with control of seizures using benzodiazepines or phenobarbital. Pyridoxine, thiamine, folinic
acid, and leucovorin have not proved beneficial in the treatment of peripheral neuropathy. [5][54] Glutamic
acid, which competitively inhibits a common cellular transport mechanism of the vinca alkaloids, may be
efficacious in lessening neurotoxicities while producing minimal side effects.[40]
If significant bleeding occurs, transfusion of packed red blood cells and platelets may be required. With
signs of infection, the patient should be cultured and appropriate antibiotics started. If extravasation occurs,
the infusion should be stopped and the site evaluated for skin necrosis. Application of heat can be beneficial
( Table 53–5 ).[21] Severe injuries may require surgical débridement. Skin splashings should be thoroughly
washed with soap and water. If inadvertent intrathecal administration occurs, the patient should be placed in
a dependent position. The rapid removal of 25–50 mL of CSF and equal volume replacement of intrathecal
lactated Ringer’s solution has been reported to lessen potential toxicity.[23] Finally, recent cancer research in
an animal model has reported a reduction in vinca alkaloid toxicity by the administration of an anti-vinca
alkaloid antibody.[34]
Table 53-5 -- Vesicant Chemotherapeutic Drugs and Extravasation Treatment

Chemotherapeutic Agent Treatment
Nitrogen mustards, Mix 4 mL of 10% sodium thiosulfate with 6 mL sterile water for local and IV
mechlorethamine injection; apply cold compresses to extravasation site
Inject 1–6 mL hyaluronidase 150 U/mL sq into extravasation site; apply warm
Vincristine/vinblastine
compresses
Doxorubicin, daunorubicin Apply 1–2 mL of 1 mmol topical DMSO 50–100%; apply cold compresses
Discontinue IV infusion; apply ice compresses for first 24 hours; apply moist
Other vesicants
heat thereafter until inflammation subsides
Disposition
Following an overdose of either vincristine or vinblastine, the patient should be monitored for 24–72 hours.
There should be outpatient follow-up for neurologic effects and leukopenia for up to 1 month or until blood
counts return to normal. If severe poisoning has resulted, observe for signs of delayed neurotoxicity for up to
1 week following larger overdoses.
Sequelae
The symptoms of acute toxicity usually last up to 1 week, and the neurologic sequelae may be present for
months with slow resolution.


DOXORUBICIN (ADRIAMYCIN)
Essentials
• Bone marrow suppression is the dose-limiting toxicity for acute exposure to doxorubicin.
• Cardiotoxicity is the dose-limiting toxicity associated with a chronic or total cumulative dose.
• Doxorubicin can be a dermal irritant and usually produces alopecia.
• Red urine occurs and can be mistaken for hematuria.
Introduction
The red anthracycline antibiotics isolated from Streptomyces peucetius include doxorubicin, daunorubicin,
and dactinomycin. These agents, particularly doxorubicin, are most often noted for their cardiotoxicity.
Doxorubicin (Adriamycin) is useful for treatment of acute leukemias, metastatic breast carcinomas, and
specific solid tumors.
Doxorubicin forms a complex with DNA and interferes with nucleic acid synthesis. It accumulates in cardiac
tissue, inducing toxicity by an oxidative mechanism. Cytotoxic metabolites are produced by the promotion of
lipid peroxidation. The cardiac tissue is not adequately equipped to neutralize the quantity of free radicals
produced.[20]
Doxorubicin is available in IV and liposomal forms. Bone marrow suppression develops after acute overdose
of doxorubicin resulting in leukopenia, thrombocytopenia, and anemia.[14] Stomatitis, nausea, vomiting, and
diarrhea are also reported. Acute oral toxicity is very unlikely because the agent is administered
intravenously. An oral exposure was reported in a 79-year-old woman who, when given a vial of doxorubicin
for outpatient, clinic administration, mistakenly took the medication home. She used pliers to remove the vial
cap and ingested the unreconstituted powder. No adverse reactions were reported or observed and the
patient recovered uneventfully.[15] The likelihood of cardiac failure is related to the toxic and cumulative total
dose administered.[7] Acute cardiovascular effects include EKG changes, dysrhythmias, pericarditis, and
myocardial infarction.[7][10] Cumulative and chronic effects include congestive heart failure, which may not
respond to conventional therapy. Doxorubicin also exhibits irritant properties. An “Adriamycin flare” is a
benign local allergic reaction easily mistaken for extravasation.[74] Finally, alopecia is almost universally
reported with therapeutic and toxic doses of doxorubicin.
Other antineoplastic agents that are cardiotoxic include fluorouracil, cisplatin, mitoxantrone, and
paclitaxel.[75] Chronic use or exposure to cocaine, ethanol, and cobalt can result in a similar
cardiomyopathy. Other cardiotoxins in the differential diagnosis are summarized in Table 53–3 .
Laboratory Studies
Peripheral blood counts should be monitored for 24–72 hours for signs of bone marrow suppression.
Cardiac monitoring includes radionuclide evaluation of left ventricular ejection fraction (MUGA). This is
reported to be more reliable than electrocardiography or echocardiography.[7] Chemotherapy should be
discontinued when the ejection fraction falls below 50 per cent. Serum doxorubicin levels are not readily
available.
Treatment
Treatment for doxorubicin overdose is largely symptomatic and supportive with close cardiac monitoring. If
fever or infection develops during the leukopenic phase, cultures should be obtained and appropriate
antibiotics started. Thrombocytopenia and bleeding may occur from doxorubicin-induced bone marrow
suppression. Bleeding may require transfusions of PRBCs and platelets. Heart failure should be treated with
diuretics and digoxin to reduce afterload. However, some patients may be unresponsive to digoxin, and may
require inotropic agents and vasodilators. If extravasation occurs, the infusion of doxorubicin should be
stopped immediately. Limb elevation and cold compresses may be beneficial.[65] Severe injury may
necessitate surgical débridement.
Hemodialysis is ineffective because doxorubicin is highly protein bound, has a large volume of distribution
and only 5 per cent is renally excreted. However, if charcoal hemoperfusion is initiated within 1 hour after an
overdose, a reduction in serum levels can be achieved.[14] The iron chelator ICRF-187 (dexrazoxane) has
been shown in human trials to limit the cardiotoxic effects of doxorubicin.[44][63] The liposome encapsulation
of doxorubicin may also significantly decrease its cardiotoxicity.[2]
Disposition
The patient should be admitted for cardiac monitoring for 24–72 hours and observed for signs of acute bone
marrow suppression and delayed infection.
Sequelae
Clinical resolution from chronic cardiotoxicity may take as long as 1–7 years.[28] Doxorubicin-induced heart
failure and cardiomyopathy can carry a poor prognosis. Fatalities have been reported within 1–16 days after
overdose,[14] although complete clinical recovery has been reported in patients with severe left ventricular
dysfunction due to acute and chronic toxicity.[60]


BLEOMYCIN
Essentials
• Both pulmonary and dermal toxicity occur.
• Pulmonary toxicity results in the development of fibrosis.
• Oxygen therapy contributes to toxicity by increasing the formation of oxygen-free radicals.
• Bone marrow suppression is minimal.
• Fever is common after administration.
Introduction
Bleomycin, an antitumor antibiotic, is frequently used in combination chemotherapy because of its lack of
myelosuppressive activity.[73] Like doxorubicin, bleomycin is derived from the bacteria Streptomyces and is
used against lymphomas, squamous cell carcinomas, and testicular cancer. It can be administered
intravenously, subcutaneously, or intramuscularly.
Metabolites of bleomycin are extremely cytotoxic through the promotion of lipid peroxidation and formation of
free radicals. The enzyme that detoxifies bleomycin, hydrolase, is only present in low concentrations in the
lung and skin.[62]
Patients present with fever, cough, dyspnea, and generalized malaise. Pulmonary toxicity results in the
development of pulmonary fibrosis.[19] The development of pulmonary toxicity may present acutely after
administration but is usually delayed, occurring 4–10 weeks after initiation or completion of therapy.[12]
Death may eventually result from respiratory failure. Dermal toxicity occurs in nearly half of patients treated
with bleomycin which may include alopecia, hyperpigmentation, erythema, and streaking or inflammation of
the skin at the injection site. A reaction including hyperpyrexia, hypotension, and sudden cardiac arrest has
been described in the treatment of lymphomas with bleomycin. This phenomena has been attributed to the
release of pyrogens, not anaphylaxis.[12]
The mechanism of pulmonary toxicity with bleomycin is very similar to that of the herbicide paraquat. Other
pulmonary toxic antineoplastic drugs include MTX, and alkylating agents such as busulfan,
cyclophosphamide, chlorambucil, melphalan, and nitrosoureas.[4]
Laboratory Studies
Oxygenation status (arterial blood gas or pulse oximetry) is monitored if signs of pulmonary toxicity develop.
Serial chest radiographs should be obtained. Pulmonary function tests are not predictive of outcome. [73]
However, most patients have a 10–15 per cent decrease in DLCO over the course of treatment and
chemotherapy should be stopped if DLCO falls greater than 20 per cent. Serum bleomycin levels are not
readily available.
Treatment
Because high oxygen therapy contributes to toxicity by increasing the formation of oxygen-free radicals,[69]
the use of low flow oxygen or room air is suggested. Although controversial, the use of glucocorticosteroids
may be effective in the treatment or reversal of bleomycin-induced pulmonary fibrosis.[46] Although not
currently FDA approved for use with bleomycin, the iron chelator ICRF-187 (dexrazoxane) may be protective
against the reactive oxygen radicals responsible for causing pulmonary damage.[36]
Disposition
It is recommended that patients treated with bleomycin receive a pretreatment dose and extended
observation for 3–4 hours to rule out adverse pulmonary effects. In any patient demonstrating significant
pulmonary compromise from acute or chronic toxicity, admission to an intensive care setting for airway
management is advised.
Sequelae
Pulmonary fibrosis occurs in 10 per cent of cases with an overall mortality rate of 1 per cent.[69] The risk of
bleomycin-induced pulmonary toxicity increases with cumulative drug doses, increasing age and previous
pulmonary radiation therapy.[12]


ALKYLATING AGENTS
Essentials
• Myelosuppression with resultant leukopenia and thrombocytopenia
• GI symptoms, nausea, and vomiting
• Alopecia and hearing loss
• Hemorrhagic cystitis with cyclophosphamide overdose
• Powerful skin vesicants
Introduction
Sulfur mustards were used during World War I as chemical agents for their vesicant properties. Between
World Wars I and II, nitrogen derivatives were synthesized for their cytotoxic actions on lymphoid tissues.[71]
Mechlorethamine was the first nitrogen mustard discovered and is still used in MOPP (mechlorethamine,
oncovin, procarbazine, prednisone) therapy for Hodgkin’s disease.[18] Cyclophosphamide and its analog
ifosfamide are the most commonly used alkylating agents.
Alkylating agents form an imonium ion, which attacks a nucleophilic center. The activity of these agents
results from the formation of reactive intermediates that bind to nucleophilic moieties on the DNA chain.
Alkylating agents are most toxic to cells that undergo high turnover (epithelial and bone marrow), as there is
less time for self repair of the DNA chain.[75]
Cyclophosphamide and ifosfamide commonly cause a severe hemorrhagic cystitis in acute overdose.[24]
Nausea and vomiting occur acutely due to destruction of the intestinal epithelium. Myelosuppression with
resultant leukopenia, anemia, and variable thrombocytopenia has been reported. Leukocyte counts fall
within 1 week after therapeutic treatment; platelets decline soon afterward. Maximum depression occurs in
2–3 weeks, followed by quick recovery.[42] Hair and hearing loss with tinnitus have been reported.[13]
Nitrogen mustards are powerful vesicants causing severe inflammation and tissue necrosis if
extravasated.[22] Mechlorethamine has the greatest blistering power of the nitrogen mustards in vapor form,
but is intermediate as a liquid blistering agent.[54] Respiratory tract irritation, if severe, can progress to
pulmonary edema which may be delayed in onset up to 24–72 hours after exposure. Neurotoxicity and
hyperthermia have been reported when high doses and regional perfusion methods are used.[75]
Nitrogen mustards should be differentiated from the various acids or alkali. Other alkylating agents of clinical
significance include alkyl sulfonates, ethylenimine, nitrosoureas, and triazenes. Derivatives of nitrogen
mustards also include melphalan and chlorambucil.
Laboratory Studies
Monitor complete blood counts with platelet and reticulocyte counts in patients with significant exposure.
Obtain arterial blood gases and chest radiograph with significant inhalation exposures to assess for
chemical pneumonitis. Colorimetric reaction can be used to determine free mechlorethamine levels.[54]
Treatment
Exposed skin should be thoroughly washed with soap and water and then irrigated with a 2–4 per cent
sodium thiosulfate solution. Extravasations can cause significant injury and should be managed by
infiltrating the area with isotonic sodium thiosulfate followed by intermittent application of iced compresses.[6]
Ingestions of mechlorethamine should be managed as a caustic exposure. As a result, emesis should not be
induced, and gastric lavage is discouraged. Immediate dilution with milk or water might be beneficial. If signs
or symptoms of esophageal irritation or burns are present, endoscopy should be performed to determine the
extent of injury.
Victims of inhalation exposure should be evacuated from the toxic environment and 100 per cent humidified
oxygen administered. Systemic administration of corticosteroids have been recommended for treatment of
respiratory tract injury caused by other alkylating agents such as mustard gas.[57] No studies have
addressed the utilization of extracorporeal elimination techniques in poisoning with these agents.
For significant toxicity with cyclophosphamide or ifosfamide resulting in hemorrhagic cystitis, the bladder
protectant 2-mercaptoethanesulfonate (MESNA) is routinely administered.[24]
Disposition
Depending on the route of exposure, symptomatic patients are generally admitted and closely observed until
all signs and symptoms have fully resolved. For dermal exposures, serial skin examinations are
recommended.
Sequelae
Chronic GI scarring may result from ingestion. Scarring and contractures from dermal exposures or
extravasation have been reported. Although uncommon, cyclophosphamide can cause severe pulmonary
toxicity. The onset of lung fibrosis can present within 2 weeks after initiation of therapy and may continue
several years after termination of therapy.[70]


CISPLATIN AND CARBOPLATINUM
Essentials
• Nephrotoxicity is the dose-limiting toxicity, particularly with cisplatin.
• Neurotoxicity becomes the dose-limiting toxicity if nephrotoxicity is prevented.
• Vomiting and diarrhea are common early and late postexposure symptoms.
• Ototoxicity is common, but rarely causes deafness.
Introduction
The cytotoxic action of platinum compounds was first observed when platinum electrodes were immersed in
a culture medium. Since this discovery, several platinum-containing compounds have been developed.
Those of clinical relevance include cisplatin and carboplatinum. These agents are administered
intravenously and intraperitoneally.
Cisplatin and carboplatinum have their greatest activity in treatment of cell neoplasias of germinal cell origin
and ovarian cancers. They appear equally effective in all phases of the cell cycle by inhibiting DNA and RNA
precursors.[22] These agents may be activated in the cell to a bifunctional alkylating agent. This targets the
neoplastic cells so the immune system can recognize and destroy them. The predominant toxic
pathophysiologic actions of these agents include renal impairment, peripheral neuropathy, and auditory
dysfunction.
Nausea, vomiting, and diarrhea are common as early as 1 hour postexposure. A metallic taste is often
described. Delayed nausea and vomiting may be exacerbated by electrolyte abnormalities such as
hypomagnesemia and hypokalemia. Mild cardiotoxicity has been reported,[27] and bone marrow depression
may occur.[8] Nephrotoxicity, particularly with cisplatin, is a common dose-limiting toxicity, which can be
minimized by adequate hydration. Carboplatin’s toxicity is similar to, but less severe than, that of cisplatin.
However, its myelosuppressive effects are usually more significant, particularly thrombocytopenia.[75]
Neurotoxicity, more common with carboplatinum, becomes the dose-limiting toxicity if nephrotoxicity is
prevented.[16]
A neurotoxic syndrome has been characterized most commonly by gait difficulties, loss or reduction of deep
tendon reflexes, peripheral glove stocking sensory neuropathy, but also with seizures, autonomic
neuropathy, and central extrapyramidal disorders[32] Ototoxicity is most often associated with single, high-
dose, rapid bolus or infusions.[45] High-frequency ototoxicity is common but rarely causes deafness. There
appears to be age-related differences in the toxicity associated with cisplatin overdose, as children seem to
be less susceptible to the neurologic and ototoxic side effects.
Other antineoplastic agents that are nephrotoxic include streptomycin, the nitrosoureas, methotrexate,
mithramycin, and ifosfamide.[64] Cisplatin is the only antineoplastic agent in which renal damage is the dose-
limiting toxicity. Other nephrotoxic agents in the differential diagnosis include arsenic, cadmium, ethylene
glycol, toluene, and the aminoglycosides.
Laboratory Studies
Electrolytes, calcium, magnesium, phosphorus, blood urea nitrogen (BUN), serum creatinine, creatinine
clearance, and peripheral blood counts should be measured. Audiologic and liver functions should be
monitored. Cardiac function can be monitored with serial EKGs and cardiac enzymes. Elevated lead levels
have been reported following overdoses of cisplatin and should be measured if toxicity is suspected.[35] Free
or total platinum in plasma and tissues can be determined by flameless atomic absorption spectrometry.[3]
Treatment
Treatment is symptomatic and supportive. There is no specific antidote for cisplatin. IV hydration with 3–6 L
of normal saline per day may reduce the risk of nephrotoxicity.[64] Cisplatin is rapidly and highly protein-
bound. Hemodialysis was reported to be ineffective in removing cisplatin following an overdose. [8] Plasma
exchange has been suggested to reduce the body burden, but has not been adequately studied. The
antibiotic fosfomycin may be protective against renal, auditory, and hematotoxicity.[72] A newly introduced
drug, amifostine, protects the kidneys from cumulative cisplatin toxicity by preventing DNA-adduct formation
and by scavenging oxygen-free radicals. [43] Sodium thiosulfate and diethyldithiocarbamate (DDTC) may also
inactivate the drug and limit its neurotoxic effects, by preventing cisplatin-induced hypomagnesemia,[17][53]
although the role of these agents in overdose settings is not reported.
Disposition
Patient should be observed closely for signs of renal toxicity following acute overdose. Admission for
adequate hydration to lessen toxicity is recommended.
Sequelae
Severe vomiting, renal tubular function impairment, and hematologic toxicity have been reported. These side
effects typically resolve within several weeks with supportive care and hydration.


PACLITAXEL (TAXOL)
Essentials
• Myelosuppression, especially neutropenia, appears to be the dose-limiting toxicity.
• Neurotoxic effects most commonly include sensory neuropathy.
• Cardiac dysrhythmias and bradycardia have been reported.
• Hypersensitivity reactions are frequent.
• Painful myalgias and arthalgias are commonly described.
Introduction
Paclitaxel is the generic name for the chemical formerly called Taxol. Taxol is a diterpene alkaloid isolated
from the bark of the Pacific yew, Taxus brevifolia. It has been shown to be effective in treating neoplasms
that are resistant to the vinca alkaloids and cisplatin and as first-line therapy in certain malignancies,
including advanced ovarian carcinoma, metastatic breast carcinoma, advanced small cell lung cancer, head
and neck cancers, and malignant melanomas. [33]
The drug is an antimitotic agent that promotes the formation of microtubule polymers in the cell by reversibly
and specifically binding the beta subunit of tubulin.[33] The tubulin-binding site is believed to be different from
that of the vinca alkaloids and inhibits further use of the microtubule through prolonged stabilization.[61]
Regarding cardiotoxicity, taximes appear to block sodium and calcium channels, resulting in the slowing of
cardiac conduction.[78] The mechanism for neuropathy is related to both axonal degeneration and
demyelination.[49]
Transient asymptomatic bradycardia and progressive atrioventricular blocks have been described during
infusion and acute toxicity. Ventricular tachycardia and ectopy have been reported in patients receiving
Taxol and cisplatin combined.[59] Myelosuppression, especially neutropenia, appears to be the dose-limiting
toxicity. Neurotoxic effects most commonly include a sensory neuropathy, muscle weakness, and motor
degeneration.[45] GI mucosal erosion and mild renal and liver damage have been reported.[37] Fever,
myalgias, and hypersensitivity reactions are other side effects.[77]
Other antineoplastic agents with cardiotoxicity include doxorubicin, cisplatin, fluorouracil, and mitoxantrone.
In addition to the yew, other plants that cause cardiotoxicity include the cardioglycoside-containing flowers
such as oleander, lily of the valley, and foxglove. Other similar naturally occurring compounds include
ouabain-like products secreted from the skins of certain toads (Bufo viridis and B. marinus).
Laboratory Studies
Serial electrocardiograms should be obtained if there is evidence of acute cardiotoxicity. Complete blood
counts, liver and renal function tests, serum lipids, and creatine phosphokinase levels can be abnormal.
There is no standard laboratory test that will identify paclitaxel.
Treatment
The drug is given intravenously; therefore, oral exposures are not expected. Treatment is symptomatic and
supportive. No specific antidote exists. Cardiac monitoring is indicated in overdose, and cardiac
dysrhythmias should be treated with standard antidysrhythmic agents. Hypersensitivity reactions can be
managed with discontinuation of the drug and standard doses of epinephrine, diphenhydramine, and
corticosteroids. Pretreatment with steroids, cimetidine, and diphenhydramine is common because allergic
reactions occur frequently.
Disposition
If toxicity is suspected, the patient should be admitted to a monitoring setting for observation of cardiac
dysrhythmias. In addition, progression of GI symptoms and neurotoxicity should be anticipated within the
first 24–48 hours.
Sequelae
Patients typically recover if they survive the initial cardiovascular insult. Long-term sequelae from paclitaxel
have not been reported.


CONCLUSION
Management of anticancer drug toxicity can be challenging because of the chemotherapeutic agent
complexity, adverse drug reactions, and the underlying disease state of the patient. Most antineoplastic
agents are administered intravenously; therefore, oral exposures are uncommon. As a result of the cytotoxic
mechanisms of these agents to alter and destroy cancer cells, adverse effects on other tissue organs are not
unexpected. The particular organs targeted vary, depending on the specific chemotherapeutic agent.


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Chapter 54 – Ergot Alkaloids
FRED P. HARCHELROAD JR. ANDREW R. TOPLIFF
Essentials
• Nausea/vomiting
• Peripheral ischemia (e.g., extremity pain, claudication, gangrene)
• Central ischemia (e.g., hypertension, cerebrovascular accident, myocardial infarction, mesenteric
ischemia)
• Smooth muscle contraction (vasculature, bronchi, bowel, uterus)
INTRODUCTION
Poisoning with ergot alkaloids is noted as early as 600 BC in Assyrian tablets that referred to the “noxious
pustules in the ear of grain.” [11] This first recognized mycotoxicosis was later found to be produced by eating
rye products that had been infected by the fungus Claviceps purpurea. The fungus would produce the ergot
alkaloids, and other biogenic amines (histamine, tyramine, serotonin, isoamyl amine, acetylcholine, and
acetaldehyde), in different quantities depending on weather conditions. Unfortunately, this Assyrian taboo of
eating contaminated rye was lost during the Roman times; and from the ninth to nineteenth centuries,
recurrent epidemics of ergot poisoning, termed ergotism, ravaged Europe.
Three types of ergotism were noted: (1) the rare convulsive type, (2) a more common abortive type, and (3)
the most common gangrenous type, characterized by severe hyperesthesias, paresthesias, and
hemorrhagic bullae that progressed to dry gangrene. The term ignis sacer (holy fire or St. Anthony’s fire)
was given to this gangrenous type because of its debilitating paresthesias, its mummification of affected
limbs that were as blackened as charcoal before falling off, and its sometimes spontaneous resolution on
pilgrimage to St. Anthony’s shrine (most likely because the afflicted ate a diet free of contaminated grain
during their pilgrimage).[6][9]
Since the 1950s, the main medical indications for use of ergot preparations have been for vascular
headaches, pituitary adenomas with hyperprolactinemia, and obstetrical use. Perhaps because of its limited
medical usage there are very few reported toxic exposures to ergot preparations. Cumulative data from 1990
to 1997 report 5431 toxic exposures to ergot preparations in the United States and only 1 death over this
same time period.[36][37][38][39][40][41][42][43] The most recent epidemic of ergot toxicity related to grain
consumption occurred in 1978 in Ethiopia.


Pharmacology
Ergot alkaloids are derivatives of the tetracyclic compound 6-methylergoline. Classically, these alkaloids are
divided into three groups based on their side chain substitution: the amino acid alkaloid group
(ergopeptines), the amine alkaloids, and the dihydrogenated amino acid alkaloids ( Table 54–1 ). Ergot
alkaloids exhibit a complex variety of pharmacologic properties, acting as partial agonists/antagonists at the
a-adrenergic, serotonergic (5-HT), and dopaminergic receptors.[57 ] They were the first adrenergic receptor
antagonists to be discovered, and much of their clinical pharmacology was disclosed by the now classic
studies of Dale.[11 ] Much of the literature before 1920 is confusing because of the inability to obtain pure
preparations. The term ergotoxine used in the early literature is, in fact, a combination of ergocortine,
ergocristine, a-ergocryptine, and ß-ergocryptine.
Table 54-1 -- Toxic Effects of Ergot Alkaloids

Amines
Ergonovine
+
-
+++
+
Fetal death
Methysergide (Sansert)
Preterm labor
Methylergonovine (Methergine, Myomergin)
Hypertension
Lisuride
Pergolide
Amino acids
Ergotamine (Wigraine, Cafergot, Ergostat, Ercatab)
+++
++
+++
+++
Thrombosis
Bromocriptine (Parlodel)
Vasospasm
Gangrene
Vascular stasis
Dihydrogenated amino acids
Dihydroergotamine (DHE 45)
++
+++
+
++
Nausea/vomiting
Dihydroergocornine/dihydroergocristine/dihydroergocryptine (Hydergine, Hydergine LC, Germinal, Niloric)
Vasospasm
Class of Alpha-Adrenergic
Myometrial Vasoconstriction and Clinical
Ergot Example Emesis Receptor
Stimulations Endothelial Damage Toxidrome
Alkaloid Antagonism
The pharmacologic actions of the ergots are varied and complex. Some actions are unrelated or even
mutually antagonistic. The ergot alkaloids interact with serotonergic, dopaminergic, a-adrenergic, and
myometrial receptors; and they may act as partial agonists or partial antagonists within different regions of
the body on the same receptor locus. Its effect at a-adrenergic receptors is that of both partial agonist and
antagonist depending on the vascular bed.[47 ] Because of these differences in pharmacologic effect and the
baseline physiologic state of the patient, the clinical signs and symptoms and the intensity of effects are
variable.
The more common ergot alkaloid preparations are noted in Table 54–1 . The hydrogenated ergot alkaloids
are among the most potent a-adrenergic receptor antagonists known. The peptide ergot alkaloids, however,
can reverse epinephrine from a pressor response to depressor (via a-adrenergic receptor antagonism), and
they can convert isoproterenol from vasodilator to pressor.[57 ] All of the natural-occurring ergot alkaloids can
cause hypertension as a result of peripheral postcapillary vasoconstriction. This pharmacologic effect of
arterial constriction can cause any organ to suffer ischemia, whether it is the heart, intestines, kidney,
tongue, or extremities. Although arterial constriction will result in increased peripheral vascular resistance,
this does not always translate into systemic hypertension.
Ergots may be given orally, sublingually, rectally, via inhalation, intramuscularly, or intravenously.
Ergotamine has less than a 1 per cent bioavailability when given orally because of extensive first-pass
metabolism. More than 90 per cent is excreted in the bile, and it is metabolized through still unknown
pathways.[8 ] A 2-mg oral dose will give a serum concentration of about 20 pg/mL. Plasma levels in excess of
1.8 ng/mL have been associated with an increased incidence of adverse effects.[21 ] [58 ] Although the
plasma elimination half-life of oral ergotamine is only 2 hours, clinical effects, including vasoconstriction,
may last for over 24 hours. This discrepancy between serum concentrations and clinical adverse effects is
true for all of the ergot alkaloids.[2 ] [23 ] Many ergot preparations are also mixed with other pharmaceutical
agents. These preparations may contain caffeine, belladonna alkaloids, or phenobarbital that cause other
symptoms.
Pathophysiology
The prominent features of chronic ergot poisoning—vascular stasis, thrombosis, and gangrene—are due to
peripheral vasoconstriction and to direct damage to the capillary endothelium. Both medial and intimal
proliferation have been reported.[21 ] Although this peripheral vasoconstrictive effect is interwoven with the
inhibition of nitric oxide synthetase, there have been no studies to evaluate the efficacy of the newer nitric
oxide donors in the treatment of ergot-induced vasoconstriction. [30 ] [49 ] [62 ]
In view of their variable effects, central and peripheral, on a-adrenergic, serotonergic, and dopaminergic
receptors, combinations of ergot alkaloids with pharmaceutical agents with similar pharmacologic properties
may result in severe symptoms. Likewise, administration of drugs that follow the same metabolic pathway
may also lead to signs and symptoms of ergotism secondary to decreased metabolism of the ergot.
The ergot alkaloids usually induce bradycardia, even when the blood pressure is not increased. This may be
due to increased vagal activity, decreased central output of sympathetic tone, and direct myocardial
depression. The natural and hydrogenated ergot alkaloids all inhibit epinephrine-induced hepatic
glycogenolysis and hyperglycemia; however, glycogenolysis in skeletal muscle is not inhibited.
Many drug interactions have been ascribed to ergot preparations, as noted in Table 54–2 , and care must be
taken to ensure that ergotism is not induced when prescribing medications. Similarly, patients’ medication
lists should be reviewed to ensure that their symptoms are not exacerbated by a drug interaction eliciting
ergotism. [20 ] [21 ] [26 ] [32 ] [33 ]
Table 54-2 -- Drug-Drug Interactions with Two Common Ergot Alkaloids
Bromocriptine with:
Chlorprothixene
Inhibits effect of bromocriptine
Erythromycin
Increased bioavailability of bromocriptine; increased adverse effects
Isometheptene
Increased bromocriptine toxicity
Phenylpropanolamine (PPA)
Increased bromocriptine and PPA toxicity
Methyldopa
Hypotension
Procarbazine
Increased antimuscarinic effect
Ethanol
Increased nausea (vomiting)
Tacrolimus
Increased adverse effect from tacrolimus
Ergotamine with:
Albuterol
Pulmonary edema
Beta blockers
Increased peripheral ischemia
Dirithromycin
Increased ergot toxicity
Dopamine
Peripheral ischemia
Erythromycin
Sumatriptan
Vasospasm
Troleandomycin
Drug Effect


The most clinically important effects in overdose are due to actions on the central nervous system and
through direct stimulation of smooth muscle.[3] The broad spectrum of effects depends on the specific ergot
alkaloid, its dosage, the tissue affected, the baseline physiologic state, and a variable time of onset. Acute
overdose of ergot alkaloids usually causes nausea and spontaneous emesis, which may be followed by
seizure or coma. Increased contraction of smooth muscle with signs and symptoms related to this, such as
uterine contractions, may be seen. The delayed-effects ischemia occurring peripherally or in other
vasculature may not be noted for 12 to 24 hours. Likewise, this vascular insufficiency/arterial spasm may
persist for as long as 3 days, well beyond the persistence of ergot in the serum.[27][48]
Although there are differences in the clinical effects of the various ergotamines, these may be masked in
overdose. For example, rectal ergotamine will cause a progressive increase in peripheral vascular
resistance that will last for 24 hours, [8] and dihydroergotamine has little capacity to produce this effect.
However, at high doses both ergotamine and dihydroergotamine cause a rapid increase in blood pressure.[3]
The dose of ergot alkaloids required to produce a toxic effect is unknown.[23] Even therapeutic doses (e.g.,
as little as 5 mg of ergotamine sublingually) may be fatal in those with underlying cardiovascular disease.
Toxicity from therapeutic or chronic overdoses will generally manifest as signs and symptoms of arterial
spasm with end-organ ischemia. Chronic ergot poisoning typically causes ischemia of the extremities;
however, involvement of any vascular bed is possible. Patients may present with symptoms of a
cerebrovascular accident, myocardial infarction, abdominal pain, or renal failure ( Table 54–3 ).
Table 54-3 -- Common Findings of Ergotism

Ischemic Effects Central Effects
Angina/myocardial infarction Nausea
Cerebrovascular accident Vomiting
Mesenteric infarction Agitation
Renal infarction Headache
Limb ischemia/gangrene Miosis
Vasospasm/ischemic pain Seizures
Hypercoagulability Bradycardia
Hemorrhagic skin lesions Hallucinations
Dyspnea Lethargy
Peripheral paresthesias
Ergotism should be considered in every patient with even therapeutic doses of any naturally occurring or
semisynthetic ergot preparation with any of the manifestations outlined in Table 54–3 . Although
manifestations of ergotism are classically reported as either acute signs and symptoms or chronic
presentations, acute ergot toxicity is very rare. Acute symptoms (vomiting, headache, and nausea) are
frequently the presenting symptoms, although evidence of any vascular insufficient organ is sufficient
evidence of ergot toxicity (see Table 54–3 ). The chronic effects are primarily ischemic and may cause
insufficiency to almost every vascular bed in the human body.
The most common presentation of ergot toxicity is peripheral ischemia. Arterial spasms of the lower
extremities are most frequently reported, causing cool mottled extremities often with distal pain, claudication,
and loss of digits.[44][53][64] Systemic vascular effects such as arterial spasm of the extremities are well-
documented complications of ergotamine abuse, with the lower extremities being most commonly
affected.[46] Evidence of peripheral vasoconstriction, with subsequent pain, pallor, paresthesias, and
pulselessness, is common and should cause one to suspect ergotism. This may be seen in the single
ingestions after 12 to 24 hours of an asymptomatic period. Vasoconstriction with subsequent end-organ
ischemia can be seen in the absence of hypertension. Ischemic injury occurs not only from vasoconstriction
but also from subsequent thrombosis.[25]
The cardiovascular effects of ergotism are perhaps most confusing because hypertension, normotension or
hypotension, and bradycardia or occasionally tachycardia may exist. [15][26][45][54] A case is reported of an
unobtainable blood pressure via sphygmomanometry with a normal blood pressure noted with an intra-
arterial monitoring device.[13] No single cardiovascular parameter should be used to prove or disprove the
clinical diagnosis of ergotism.
There are many cases of acute myocardial infarction and ventricular dysrhythmias occurring up to 36 hours
after a therapeutic dose of ergot preparations.[4][5][10][12][19][31][55][68] Patients presenting with evidence of
myocardial ischemia should be questioned about the ingestion of ergot preparations. This is especially true
in conjunction with other pharmaceutical agents that may exacerbate this effect. Severe bronchospasm may
also occur after therapeutic doses of ergotamine, especially in those with a history of asthma.[67]
Neurologic signs and symptoms (presenting 4 to 24 hours after ergot use) include headaches, lethargy,
coma, seizures, or psychiatric disturbances. Unfortunately, headaches may occur both as a sign of overdose
with ergot alkaloids and as a symptom of withdrawal in patients who chronically take ergotamines.[57]
Neurologic deficits may be either reversible or irreversible. There may be a genetic component to the
response to ergot preparations in both the vasospastic and central nervous system effects.[34]
Gastrointestinal symptoms may be limited to vomiting with abdominal cramps and diarrhea. However,
mesenteric ischemia, ischemic pancreatitis, hepatitis,[13] and portal hypertension[18] have all been reported
as complications of ergotamine ingestion. Rectal stenosis has also been reported in association with the use
of ergotamine suppositories for chronic periods of time.[28] Anorectal ergotism has occurred, often with
subsequent fistula formation.[28]
Both early and late fetal mortality and hypoxic-type anomalies (occurring during first-trimester gestation)
have been observed in animals. Hypoxic-type anomalies may also occur in humans ingesting therapeutic
doses of ergotamine preparations in the first trimesters of pregnancy.
Marked uterine stimulation is known to occur and has been associated with abortion and fetal death in
humans.[7]
Less common reports of ergot toxicity involve ischemia of the tongue after a single dose of
ergotamine.[26][69] Even brachial artery thrombosis has been reported after chronic high-dose ingestion of
ergotamine.[25] Apparent rare complications of ergot use—pericardial fibrosis as well as pleural
fibrosis—have been described.[52] Chronic ergot use has been associated with the development of valvular
heart disease.[1][24][52][60][61] Seizures have been reported in neonates, and confusion or focal neurologic
deficits have been seen in the elderly.[14][65] Ocular toxicity including transient monocular blindness and
bilateral papillitis has been noted.[22][48] Ergotism may be difficult to determine if systemic hypertension is not
present and only a single end organ is affected.


Given the variable nature of the signs and symptoms that may occur with ergot intoxication, the differential
diagnosis is broad and includes numerous medications. All physiologic and pharmaceutical entities that may
cause headache, nausea, vomiting, hypertension, bradycardia, peripheral cyanosis, arterial insufficiency,
and uterine spasm, as well as acute psychiatric disturbances or blindness, should be considered.[51] Other
medical conditions must be entertained when treating these patients, and the workup would include
appropriate diagnostic studies ( Table 54–4 ).
Table 54-4 -- Differential Diagnosis of Ergot Toxicity

Cerebral aneurysm
Peripheral embolism
Mesenteric ischemia
Arterial insufficiency
Migraine headache
Intrauterine fetal demise
Hypertensive crisis


LABORATORY STUDIES
No specific blood or urine specimens can establish the diagnosis of ergotism. Although assays for ergot
alkaloids in plasma exist, they have no clinical significance.[71] Any laboratory workup should be made within
the confines of the patient’s symptoms. A patient on ergot preparations who presents with anginal-type chest
discomfort should have an electrocardiogram and enzyme markers of myocardial cell necrosis to rule out
myocardial ischemia. Patients with evidence of ischemic end-organ damage from mesenteric
vasoconstriction should have appropriate laboratory studies done to help ascertain the extent of organ
damage. This may include tests of renal and liver function, or d-lactate levels as well as an arterial blood
gas, if gut ischemia is suspected. Patients with evidence of ischemia should have angiography to ascertain
pure vasospasm versus vasospasm and thrombosis. Treatment should not be withheld pending these
diagnostic studies.


TREATMENT
General treatment for any ischemic episode includes oxygen and isotonic fluid administration to maximize
perfusion. Oral or transdermal vasodilators (nitropaste) may be used for less significant cases, but
intravenous and possibly intra-arterial medications are frequently required. Further therapy must be dictated
by the response to treatment and other specific symptoms.
Treatment of end-organ ischemia, whether in the extremities, central nervous system, intra-abdominal
organs, or heart, should include medications for vasodilation and prevention of further thrombus formation.
Therapy should be initiated before angiography. Intravenous treatment should include vasodilators that are
easily titratable. Although sodium nitroprusside is useful, it may be difficult to achieve appropriate
vasodilation of the affected vascular bed without severe systemic hypotension. It is for this reason that intra-
arterial infusions of specific vasodilating agents may be needed. Tolazoline[56][63][66] in an initial intra-arterial
bolus of 25 to 100 mg has been reported effective by some authors. This bolus may be repeated if
necessary and it may be infused at 1 to 10 mg/kg/hr.
Phentolamine may be administered intra-arterially in a 5- to 25-mg bolus and continued as a constant intra-
arterial infusion. This should be titrated to achieve adequate perfusion to the affected vascular bed without
severe systemic effect. Similarly, nitroprusside in standard intravenous dosages may be infused intra-
arterially and titrated to good perfusion of the affected vascular bed. The limiting feature of all these
medications is systemic hypotension. No rigorous scientific studies have been performed using any of the
agents in this section, and they may not be effective in every case.
Heparin in therapeutic doses[59] (bolus with 80 IU/kg, followed by a constant infusion of 18 IU/kg/hr), or the
equivalent low-molecular-weight fractionated heparin, is suggested until verification that there is no
associated thrombosis. Even then, these agents (heparin or enoxaparin) may be continued to prevent
thrombus formation during continued periods of vascular spasm. Antiplatelet agents should also be used as
part of standard, first-line therapy. Aspirin (325 mg) should be administered. Newer glycoprotein platelet
inhibitors (abciximab, tirofiban, or eptifibatide) have not been studied in patients with ergot toxicity. Given
ergot’s known effects on the vascular endothelium, these platelet inhibitors may be useful as second-line
agents.[17]
Other agents such as angiotensin-converting enzyme inhibitors (captopril) are effective when given orally to
patients with evidence of moderate peripheral ischemia.[46][70] Calcium channel blockers like nifedipine have
also been described with success.[29] Neither of these agents are easily titratable, and side effects of
systemic hypotension may limit their effectiveness. Prostaglandins have been described as effective and
safe when given as intravenous or intra-arterial infusions.[16] Alprostadil (prostaglandin E1) at doses of 1 to
20 ng/kg/min[35] and epoprostenol (prostacyclin I2) at 20 ng/kg/min[50] have been effective.[46][70]
Table 54–5 lists those agents that have been reported as useful and may be considered as first-line agents
for treatment of vasoconstriction caused by ergot alkaloids. Diazoxide, niacin, papaverine,
phenoxybenzamine, and reserpine are now considered ineffective. Finally, because of the serotonergic
effect of ergots, all patients with evidence of concomitant serotonin toxicity should be treated with
cyproheptadine (initial oral dose of 8 mg). Hyperbaric oxygen has been reported to be successful for
peripheral ischemia nonresponsive to medical intervention in one case series. Considering its safety profile it
may prove to be a useful therapy.[49]
Table 54-5 -- Treatment of Ergotism

Oral activated charcoal/sorbitol
Intravenous fluids
Supplemental O2
Nitropaste or oral vasodilators
Aspirin, 325 mg PO
Heparin, 80 IU/kg bolus, then 18 IU/kg/hr intravenously
Sodium nitroprusside, 0.5–10 µg/kg/min intravenously or intra-arterially or phentolamine (titrate to effect)
Prostaglandin E1, 1–20 ng/kg/min intravenously or intra-arterially (titrate to effect)
Prostacyclin I2, 20 ng/kg/min intravenously or intra-arterially (titrate to effect)
Hyperbaric oxygen


DISPOSITION
Any patient with evidence of ergotism on initial evaluation needs inpatient admission because the effects
may continue for 24 to 48 hours. Asymptomatic patients who present after a known overdose are
problematic. Nausea and vomiting are common, and a large portion of the ingestant may be expelled before
arrival. However, the systemic effects of vasospasm may not be noted for up to 24 hours, and any patient
who presents after the ingestion of an ergot alkaloid should be observed for a 24-hour period to assess for
late severe vasospastic effects.
In patients with evidence of vasospastic ergotism, intra-arterial medications should be continued for at least
24 hours before attempting to titrate the dosage downward. During intra-arterial infusions of vasodilating
agents, patients should be maintained with a partial thromboplastin time of 70 to 90 seconds if they are on
heparin.


SEQUELAE
The immediate sequelae of severe ergot poisoning is anoxic cell death caused by ischemia to the affected
organ system, whether this is a distal extremity, the intestines, kidneys, heart, or brain. Patients may have
permanent distal extremity ischemia or gangrene, ischemic bowel, stroke, myocardial infarction, or uterine
contractions and fetal demise secondary to their ergotism.
Other rare but well-known complications of methysergide are pleuropulmonary, endocardial, pericardial,
retroperitoneal, and/or vascular fibrosis. No studies have demonstrated any consistent evidence of
mutagenic potential for ergot alkaloids.


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Chapter 55 – Heparin
HAROLD H. OSBORN
Essentials
• Known treatment with heparin or access to heparin
• Prolonged or unexpected bleeding from minor trauma
• Spontaneous bleeding (hematemesis, hematuria, petechiae) or an unexplained decrease in hematocrit
• Markedly elevated activated partial thromboplastin time (APTT) with a normal or slightly elevated
prothrombin time (PT)
• Thrombocytopenia
• Severe effects: sudden neurologic deficit, arterial thrombosis, and thrombocytopenia
INTRODUCTION
Heparin, a potent anticoagulant, was discovered in 1916 by a medical student who was studying coagulants.
It derives its name from its abundance in the liver.[25] It is widely used in medicine today in the prophylaxis
and treatment of venous thromboses, pulmonary emboli, arterial occlusions, mural thrombi and cardiac
emboli, unstable angina, transient ischemic attacks, and disseminated intravascular coagulation (DIC). It is
also used in the prevention of coagulation in patients undergoing bypass surgery and hemodialysis and as
an adjunct to coronary thrombolysis.[18]
Heparin has a significant side effect profile and is frequently associated with iatrogenic deaths in
hospitalized patients. Although surreptitious use of heparin has been reported,[24] most cases of overdose
involve hospitalized patients, especially infants. [10][13][27] Knowledge of the mechanism of action of heparin,
proper dosing, administration, and monitoring, as well as early recognition of side effects, may help to
prevent the most serious reactions to heparin.


Pharmacology
Heparin is a complex linear anionic polyelectrolyte with a molecular weight of 60,000 to 100,000 daltons. Its
carbohydrate components include uronic acids and amino sugars in polysaccharide chains, and these, in
turn, are bound to a core protein found in the secretory granules of mast cells.
Heparin is commercially available as the calcium or sodium salt and is derived from porcine intestinal or
bovine lung tissue. During isolation the core protein is removed and the glycosaminoglycan chains are
degraded to yield a mixture of fragments with a mean molecular weight of 12,000 daltons. It is dispensed in
units based on an international standard (1 mg heparin 120 IU).
Low molecular weight heparins (LMWHs) are fragments of heparin with a mean molecular weight less than
7000 daltons. They are isolated by gel filtration chromatography, differential precipitation with alcohol, or
depolymerization with nitrous acid.[9][17] Heparinoids, such as dermatan, heparan, and chrondroitin, are, like
heparin, naturally occurring glycosaminoglycans with anticoagulant properties.
Heparin’s anticoagulant effect occurs immediately after intravenous injection and within 20 to 30 minutes of
subcutaneous administration. Heparin is eliminated by a complex mechanism: Small amounts are
metabolized by liver heparinases or excreted unchanged in the urine, whereas the majority is taken up by
macrophages and endothelial cells, where it is depolymerized and desulfated. One consequence of these
mixed kinetics is that heparin levels can rise steeply at higher doses (>24,000 units/d). The half-life of
heparin is 30 to 60 minutes at doses of 25 to 100 units/kg and 60 to 80 minutes at doses greater than 100
units/kg. The half-life is increased in patients with renal failure and cirrhosis and decreased in patients with
pulmonary emboli.
Pathophysiology
Heparin exerts its anticoagulant action through its effect on antithrombin III (AT III) and, at higher
concentrations, through heparin cofactor II.[23] Heparin induces a conformational change in the structure of
AT III, making its reactive site (an arginine-serine peptide bond) more accessible and increasing its binding
to thrombin by a thousandfold. In the presence of heparin, AT III inhibits activated coagulation factors,
especially thrombin and factor Xa, in both the intrinsic and the common pathways. This results in an
elevation of the activated partial thromboplastin time (APTT) and, to a lesser extent, the prothrombin time
(PT). Once thrombin/AT III binding is complete, the heparin molecule is released and regains its activity.
Heparinoids and LMWHs (<4000 daltons) have less ability to catalyze the thrombin/AT III reaction. Rather,
they exert their main anticoagulant effect by facilitating the inhibition of factor Xa by AT III.
In addition to its anticoagulant action, heparin both inhibits and enhances platelet aggregation, increases
vascular permeability, and regulates angiogenesis. Heparin inhibits its own anticoagulant effect by binding to
platelet factor 4, a protein released during platelet aggregation.


Acute Effects
The toxicity of heparin can be categorized into acute, subacute, and chronic effects ( Table 55–1 ). The
acute administration of heparin has been reported to result in hypotension in neonates,[32] cardiovascular
collapse,[3] pulmonary edema,[1] and cardiac arrest. Immediate, type I allergic reactions, including asthma,
urticaria, and anaphylaxis, have also been described.
Table 55-1 -- Clinical Presentation

Acute (1–3 days) Subacute (3–14 days) Chronic (>14 days)
Bleeding Thrombocytopenia Osteoporosis/spontaneous fractures
Hypotension Vasospasm/thrombosis Alopecia
Asthma/urticaria Skin necrosis/panniculitis Eczema
Anaphylaxis/cardiovascular collapse Elevated hepatic transaminases Hyperlipemia
Pulmonary edema Hallucinations/altered perception Hypoaldosteronism/hyperkalemia
Prematurity/fetal death
Risk of Hemorrhage
The primary adverse effect of heparin is hemorrhage. In a study of 2656 patients, Walker and Jick
determined the cumulative risk of bleeding, irrespective of dose, mode, and frequency of heparin
administration, to be 9.2 per cent.[34] Bleeding occurs most commonly in the gastrointestinal and
genitourinary tracts, in skin, and at the site of recent surgery. Epistaxis and intracranial and pulmonary
hemorrhages occur in less than 1 per cent of patients given heparin. Bleeding complications appear to be
more closely related to the dose and the duration of therapy than to the route of administration, with an
incidence of 17.2 per cent at doses exceeding 100 units/kg.[34] Pooled analysis of several trials reveals a 6.8
per cent incidence of major bleeding in patients receiving heparin by continuous infusion, compared with
14.2 per cent in patients given intermittent intravenous bolus injections (odds ratio 0.42, p = .01).[18]
However, this comparison is confounded by the fact that total doses of heparin were higher in the
intermittent bolus group. Table 55–2 lists various patient characteristics and medications that have been
associated with a higher risk of bleeding during heparin treatment.
Table 55-2 -- Risk Factors for Heparin-Induced Bleeding

Patient Characteristics
Female sex
Elderly
Alcoholism
Renal failure
Malignancies
Recent surgery, trauma, or cerebrovascular accident
Bleeding disorders
Malnourishment and vitamin K deficiency
Medications
Aspirin
Nonsteroidal anti-inflammatory agents
Other anticoagulants or thrombolytics
Other antiplatelet agents
Surreptitious intramuscular self-administration of 700 mg (84,000 units) of heparin by a nurse resulted in

bleeding from puncture sites, a PT of 29 seconds, an APTT of 380 seconds (control, 31 seconds), and a
normal platelet count.[24] Several cases of inadvertent administration of excessive doses of heparin leading
to bleeding and respiratory distress have been reported in neonates.[10][13] Hemorrhage has also been
reported after the use of “heparin flushes” (<500 units/day) to maintain patency of intravenous and arterial
lines.[14][28]
Subacute Effects
Subacute effects include a mild, reversible elevation of hepatic transaminase levels without increases in
bilirubin or alkaline phosphatase concentrations. The incidence of this adverse effect is lower when LMWHs
are used.[26] Skin necrosis and tender erythematous nodules (panniculitis) have been described 6 to 14
days after both the subcutaneous and the intravenous administration of heparin and are more commonly
associated with the bovine than the porcine preparation.[2][16][36]
Thrombocytopenia
Heparin causes thrombocytopenia in up to 11.6 per cent of patients when a platelet count of 150,000/mL is
used as the cutoff.[4][6] Heparin-induced thrombocytopenia is not dose related and occurs in two forms. A
mild form (platelet counts 50–100,000/mL) occurs within 2 to 14 days of the initiation of therapy and usually
does not lead to bleeding problems or necessitate termination of heparin. This form of thrombocytopenia
may be due to a direct effect of heparin on platelet aggregation. A less common but more severe form
occurs within 7 to 14 days and is reversible, provided that heparin is stopped promptly. The apparent
mechanism of the more severe form of thrombocytopenia is a heparin-dependent antiplatelet IgG antibody
that fixes complement to the platelet membrane and causes platelet aggregation.[6] This immune-mediated
reaction is more common in patients receiving bovine heparin and occurs earlier in patients with a prior
exposure. The severe form of thrombocytopenia can lead to the heparin-induced thrombosis-
thrombocytopenia syndrome (HITTS), a paradoxical hypercoagulable state characterized by low platelet
counts, arterial and venous thromboses, and bleeding complications.[35] HITTS is rare, occurring in 0.2 per
cent of patients on heparin therapy. The risk of thrombocytopenia requires that platelet counts be obtained at
regular (3-day) intervals during treatment and that heparin be stopped if counts fall below 50,000.[29]
Chronic Effects
Chronic use of heparin in doses greater than 15,000 units/d for 3 to 6 months has been reported to result in
osteoporosis and spontaneous fractures, especially in pregnant women.[33] Other side effects associated
with chronic use include alopecia, eczema, and a suppression of aldosterone secretion leading to
hyperkalemia, especially in diabetics and patients with renal failure. Heparin does not cross the placenta or
get into breast milk and is not associated with fetal anticoagulation or congenital abnormality.[12] However,
prematurity, fetal loss, and neonatal death occur commonly with heparin therapy and are thought to be due
primarily to the underlying maternal disease.[11]


The differential diagnosis of heparin toxicity includes those other agents and conditions that affect platelets
or result in bleeding complications ( Table 55–3 ). Congenital deficiency of coagulation factors such as VIII
(hemophilia), IX (Christmas disease), XI, and XII can result in an elevated APTT and bleeding. Liver disease
results in deficiency of factors II, V, VII, and X and is distinguished by elevation of both the PT and APTT.
Vitamin K deficiency results in impairment of the postsynthetic activation of factors II, VII, IX, and X and a
coagulopathy that is also associated with an elevated PT and APTT. DIC due to a variety of conditions such
as sepsis, burns, hyperthermia, and hypothermia can mimic heparin toxicity by causing thrombosis and
bleeding. DIC can be distinguished by its tendency to depress levels of fibrinogen and raise levels of fibrin
degradation products. Finally, the use of other anticoagulants, thrombolytic agents, and antiplatelet drugs
has to be considered in the differential diagnosis of heparin-induced bleeding. Conditions such as marrow
suppression, hypersplenism, autoimmune reactions to various medications, idiopathic thrombocytopenic
purpura, and thrombotic thrombocytopenic purpura can, like heparin, cause thrombocytopenia, although
these conditions do not usually result in an elevation of the PT and APTT.

Bleeding
Congential or acquired deficiency of clotting factors
Vitamin K deficiency
Crotalid snake envenomations
Use of other anticoagulants, thrombolytic agents, or antiplatelet drugs
Thrombocytopenia
Marrow dysfunction
Megaloblastic anemias
Autoimmune disorders
Hemolytic-uremic syndrome
Hypersplenism
Massive transfusion
Idiopathic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Crotalid envenomation


LABORATORY STUDIES
In the appropriate clinical setting, the diagnosis of heparin toxicity can be confirmed by the demonstration of
a markedly elevated APTT and a normal or slightly prolonged PT, with or without bleeding. Heparin itself is
difficult to assay. In cases in which surreptitious use is suspected, protamine sulfate titration and
non–clotting-based colorimetric and fluorometric methods may be used to measure heparin levels.[8] The
aca heparin assay, an older chromogenic assay for heparin that measures activated factor X activity, may be
altered in the presence of protamine.[7]
Heparin-induced thrombocytopenia can be confirmed with a serotonin release assay or the finding of platelet
aggregation in the presence of heparin. Thrombocytopenia accompanied by vague low back, leg, or
abdominal pain or absent pulses should suggest HITTS. Doppler testing, angiography, platelet aggregation
assays, and AT III levels may assist in confirming the diagnosis.


TREATMENT
The appearance of bleeding, thrombosis, and emboli or the finding of a markedly elevated APTT, even in
the absence of complications, requires an immediate cessation of heparin and other agents that could
potentiate its effect ( Table 55–4 ).

General
Stop heparin.
Stop all medications that potentiate heparin.
Support ABCs—airway, breathing, circulation.
Administer crystalloid, blood, and platelets as needed.
Specific
Bleeding
Heparin reversal: Administer protamine sulfate slowly intravenously over 5 minutes (1 mg will neutralize ~100
units of heparin). Follow the clotting parameters for 24 hours. Repeat if necessary.
HITTS Syndrome
Consider antiplatelet agents such as aspirin or persantine and thrombolytic agents such as streptokinase or
tissue plasminogen activator.
Hematology consult
Attention to airway, breathing, and circulation takes precedence, and intravenous access should be secured
with a large-bore line. Bleeding, if present, should be controlled, and severe hemorrhage may necessitate a
transfusion of O-negative or type-specific blood. A platelet count, hematocrit, PT, and APTT should be
obtained immediately and should be performed periodically to monitor the patient’s condition until stable.
Thrombotic and embolic complications associated with HITTS require consultation with a hematologist and
vascular surgeon.
Toxin Specific
Because of heparin’s relatively short half-life, patients without complications or with only mild insignificant
bleeding can be observed, with rapid improvement expected. Patients who are bleeding from heparin-
induced thrombocytopenia, and not its anticoagulant effect, may follow a more protracted course and may
require platelet transfusion. Exchange transfusion to enhance elimination has been attempted in neonates
overdosed with heparin.[32] Dialysis has been demonstrated to be ineffective in the management of heparin
overdose.[22]
Heparin Inhibition (Protamine)
If necessary, heparin’s anticoagulant effect can be reversed with a heparin inhibitor. The best-known heparin
inhibitor, protamine, is commercially prepared from salmon milt, the secretion-laden male gonads of salmon.
The milt is ground, filtered, defatted by heating with alcohol, and then precipitated. The final product is
available as a powder or a solution.[15] Protamine is a highly alkaline polycationic compound containing a
large amount of arginine. Because of its many positive charges, it forms a stable complex with heparin.
Protamine’s affinity for heparin is greater than that of AT III, and protamine can force dissociation of the
heparin/ATIII complex.[19]
Approximately 1 mg of protamine sulfate will neutralize 100 units (about 1 mg) of heparin. In the setting of a
heparin overdose, the amount of protamine to be administered should be based on the estimated amount of
heparin remaining in the patient based on heparin’s elimination half-life of 60 to 80 minutes. Because
protamine, in high doses, can act as an anticoagulant, the dose should always be based on a conservative
estimate.
A “heparin rebound” effect has been noted after administration of protamine to reverse the anticoagulant
effect of heparin used in cardiopulmonary bypass.[30] In most studies, the heparin rebound occurs within 8
hours of protamine use, but it has been reported to occur as late as 18 hours.[21] The incidence of heparin
rebound and the need for additional protamine vary, depending on the neutralization protocol used after
surgery. The reappearance of circulating heparin is apparently due to its return from the extravascular
compartment through lymphatics and the thoracic duct,[31] and possibly to the dissociation of the
protamine/heparin complex. Although described principally after bypass surgery, heparin rebound is a
possibility after the use of protamine as an antidote for heparin overdose. Therefore, coagulation tests and
heparin levels (if available) should be monitored for a full 24 hours after reversal with protamine.
Protamine has been associated with a number of adverse effects: hypotension, pulmonary edema,
anaphylactoid reactions, anaphylaxis, bradycardia, thrombocytopenia, leukopenia, and anticoagulant
activity.[15] Risk factors for a reaction to protamine include prior use of other protamine-containing
medications such as NPH (neutral protamine Hagedorn) insulin, allergy to fish, and prior exposure to
protamine. Some of these effects are dose and rate related and may be mediated by formation of
arachidonic acid or endothelium-derived relaxing factor (nitric oxide).[20] Pretreatment with indomethacin
may minimize some of these effects. To avoid the rate-related hypotension and anaphylactoid reactions,
protamine should be administered slowly over at least 5 minutes.
Alternative Inhibitors
Other heparin inhibitors such as protamine chloride, hexadimethrine, and toluidine blue have been
developed for the treatment of heparin toxicity. Protamine chloride may have an advantage over protamine
sulfate by maintaining a stronger bond to heparin with less dissociation over time.
HITTS
Treatment of HITTS includes cessation of heparin and, if necessary, the substitution of another
anticoagulant. Because this syndrome is antibody-mediated, protamine is not particularly helpful in this
setting. Corticosteroids have not proved beneficial,[5] and antiplatelet agents, although theoretically
reasonable, remain untested. In cases of thromboses or emboli, treatment with a thrombolytic agent such as
streptokinase or tissue plasminogen activator may be necessary.
Alternative Anticoagulants
If the patient’s underlying medical condition requires continued anticoagulation, there are other suitable
alternatives. Warfarin compounds can be administered but take 3 to 5 days to achieve anticoagulant activity
and are less effective than heparin in the treatment of acute thromboembolic events. LMWHs are effective
and may have a lower incidence of heparin-induced thrombocytopenia and bleeding than does heparin.
Ancrod, an extract of venom from the Malayan pit viper, is not yet approved in the United States but is
available in Canada and Europe. Finally, concentrates of AT III are available and can be used to enhance
the anticoagulant effect of AT III. Doses of 2000 to 3000 units will increase circulating levels of AT III by 50
per cent without increasing the risk of bleeding.[29]


DISPOSITION
Most patients receiving heparin for anticoagulation are inpatients who are significantly ill from an underlying
disease. Those patients who become toxic while receiving heparin as outpatients and those rare patients
using heparin surreptitiously who present to the emergency department should be admitted to the hospital.
Patients with bleeding problems and those with thromboembolic complications of heparin therapy should be
admitted to a monitored setting. All patients should be monitored closely until their clotting parameters return
to normal or to clinically appropriate levels.


SEQUELAE
Sequelae of heparin toxicity include complications of bleeding and thrombosis and vary depending on the
organ system involved. Increased fetal wastage and prematurity have been described but may be due more
to the underlying maternal disease than to heparin itself. Chronic use may result in osteoporosis, eczema,
alopecia, and hyperlipemia.


REFERENCES
1. Ahmed SS, Nussbaum M: Development of pulmonary edema related to heparin administration. J Clin
Pharmacol 1981; 21:126-128.
2. Amerena J, Mashford ML, Wallace S: Adverse effects of anticoagulants. Adverse Drug React Acute
Poisoning Rev 1990; 9:1-36.
3. Ansell JE, Clark Jr WP, Compton CC: Fatal reactions associated with intravenous heparin [letter]. Drug
Intell Clin Pharm 1986; 20:74-75.
4. Ansell JE, Price JM, Shah S, et al: Heparin-induced thrombocytopenia: What is its real frequency?.
Chest 1985; 88:878-882.
5. Arthur CK, Isbister JP, Aspery EM: The heparin-induced thrombosis–thrombocytopenia syndrome: A
review. Pathology 1985; 17:82-86.
6. Becker PS, Miller VT: Heparin-induced thrombocytopenia. Stroke 1989; 20:1449-1459.
7. Castellani WJ, Hodges ED, Bode AP: Effect of protamine sulfate on the aca heparin assay. Clin
Chem 1991; 37:1119.
8. Chen W, Yang VC: Versatile, non-clotting based heparin assay requiring no instrumentation. Clin
Chem 1991; 37:832-837.
9. Enoxaparin—a low molecular weight heparin. Med Lett 1993; 35:75-76.
10. Galant SP: Accidental heparinzation of a newborn infant. Am J Dis Child 1967; 114:313-319.
11. Ginsberg JS, Hirsh J: Anticoagulants during pregnancy. Am Rev Med 1989; 40:79-86.
12. Ginsberg JS, Kowalchuk G, Hirsh J, et al: Heparin therapy during pregnancy. Arch Intern
Med 1989; 149:2233-2236.
13. Glueck HI, Light IJ, Flessa H, et al: Sodium heparin administration to a newborn infant.
JAMA 1965; 191:159-160.
14. Harrington L, Hufnagel JM: Heparin-induced thrombocytopenia and thrombosis syndrome: A case
study. Heart Lung 1990; 19:93-99.
15. Horrow JC: Protamine: A review of its toxicity. Anesth Analg 1985; 64:348-361.
16. Hartman AR, Hood RM, Anagnostopoulos E: Phenomenon of heparin-induced thrombocytopenia

associated with skin necrosis. J Vasc Surg 1988; 7:781-784.
17. Hirsh J, Levine MN: Low molecular weight heparin. Blood 1992; 79:1-13.
18. Hirsh J: Heparin. N Engl J Med 1991; 324:1565-1574.

19. Holland CL, Singh AK, McMaster PRB, et al: Adverse reactions to protamine sulfate following cardiac
surgery. Clin Cardiol 1984; 7:157-162.
20. Howland MA: Protamine. In: Goldfrank LR, Flomenbaum NE, Levin NA, et al ed. Toxicologic
Emergencies, 5th ed. New York: Appleton & Lange; 1994:624-625.
21. Hyun BH, Ponce RE, Davila JC, et al: Heparin rebound phenomenon in extracorporeal circulation.
Surg Gynecol Obstet 1962; 115:191-198.
22. Maner JR: Pharmacological aspects of renal failure and dialysis.

In: Drukkes W, Parsons FM, Maher JF, ed. Replacement of Renal Function by Dialysis, 2nd ed.
Amsterdam: Martinus Nyhoff; 1983:781.
23. Majerus PW, Broze GJ, Miletich JP, et al: Heparin. In: Gilman AG, Rall TW, New AS, et
al ed. Goodman and Gilman’s The Pharmocological Basis of Therapeutics, 8th ed. New York: Pergomon
Press; 1990:1313-1317.
24. Martin CMM, Engstrom PF, Barett O: Surreptitious self-administration of heparin.

JAMA 1970; 212:475-476.
25. McLean J: The thromboplastic action of cephalin. Am J Physiol 1916; 41:250-257.
26. Monreal M, Lafoz E, Salvador R, et al: Adverse effects of three different forms of heparin therapy:
Thrombocytopenia, increased transaminases, and hyperkalemia. Eur J Clin Pharmacol 1989; 37:415-418.
27. Pachman DJ: Accidental heparin poisoning in an infant. Am J Dis Child 1965; 110:210-212.
28. Passannante A, Macik BG: Case report: The heparin flush syndrome: A cause of iatrogenic
hemorrhage. Am J Med Sci 1988; 296:71-73.
29. Penner JA: Managing the hemorrhagic complications of heparin therapy. Hematol Oncol Clin North
Am 1993; 7:1281-1289.
30. Raul TK, Crow MJ, Rajah SM, et al: Heparin administration during extracorporeal circulation: Heparin
rebound and postoperative bleeding. J Thorac Cardiovasc Surg 1979; 78:95-102.
31. Schreiner R: Our experience in regional heparinization. Trans Am Soc Artif Intern Organs 1958; 4:36-
41.
32. Schreiner RL, Wynn RJ, McNulty C: Accidental heparin toxicity in the newborn intensive care unit. J
Pediatr 1978; 92:115-116.
33. Silber M, Olund A: Successful outcome of pregnancy complicated by giant myoma and severe heparin-
induced osteopenia. Gynecol Obstet Invest 1989; 28:51-52.
34. Walker AM, Jick H: Predictors of bleeding during heparin therapy. JAMA 1980; 244:1209-1212.
35. Weismann R, Tobin R: Arterial embolism occurring during systemic heparin therapy. Arch
Surg 1958; 76:219-225.
36. Winsor HM, Freeman M: An investigation of routes of administration of heparin other than injection. Am
J Med 1964; 37:408-416.


Chapter 56 – Anticholinergics and Antihistamines (H1 Antagonists)
KATHLEEN A. DELANEY
Essentials
• Altered mental status, from delirium to coma
• Amnesia
• Peripheral antimuscarinic effects (some or all may be present):
° Dry flushed skin
° Dry mucous membranes
° Hyperthermia
° Tachycardia
° Dilated pupils
° Decreased bowel sounds
° Urinary retention
• Normalization with physostigmine (contraindicated with electrocardiographic [EKG] conduction

abnormalities or if cyclic antidepressant toxicity is suspected)
INTRODUCTION
Drugs with prominent anticholinergic effects include the belladonna alkaloids, antihistamines (H1
antagonists), and chemically related antiparkinsonian drugs such as benztropine mesylate (Cogentin) and
trihexyphenidyl hydrochloride (Artane). Some cyclic antidepressants and some phenothiazines also have
anticholinergic effects. Most of the toxicity of the first-generation antihistamines, the antiparkinsonian drugs,
and the belladonna alkaloids in the overdose setting is a consequence of their anticholinergic effects. The
phenothiazine promethazine (Phenergan) and the cyclic cyclobenzaprine (Flexeril) also exhibit
predominantly anticholinergic toxicity in the overdose setting ( Table 56–1 ).[7][28][49] The cyclic
antidepressants and phenothiazines have toxic cardiac, hemodynamic, and central nervous system (CNS)
effects that overshadow the effects of anticholinergic toxicity. Two of the second-generation nonsedating
antihistamines, terfenadine (Seldane) and astemizole (Hismanal), have limited anticholinergic effects but
may have significant cardiac toxicity, both in the overdose setting and when combined with drugs such as
ketoconazole or erythromycin that impair their metabolism. [40][43][57] Terfenadine production was
discontinued by the manufacturer on February 1, 1998, and astemizole production was halted in June 1999
in the United States. Although levels of loratadine, another second-generation H1 antagonist, are raised by
concomitant administration of erythromycin, they do not result in cardiotoxicity.[4] Cardiotoxicity has also not
been reported with the use of fexofenadine (Allegra), cetirizine (Zyrtec), or azelastine (Astelin).
Table 56-1 -- Drugs (and Plants) Exhibiting Predominantly Anticholinergic Toxicity in the Overdose
Setting
Belladonna Alkaloids and Representative Synthetic Cogeners
Atropine
Scopolamine
Homatropine
Cyclopentolate
Tropicamide
Propantheline (Pro-Banthine)
Ipatropium bromide
Antiparkinsonian Drugs
Benztropine mesylate (Cogentin)
Trihexyphenidyl hydrochloride (Artane)
Procyclidine hydrochloride (Kemadrin)
Biperiden lactate (Akineton)
Ethopropazine hydrochloride (Parsidol)
H1 Histamine Receptor Antagonists
Diphenhydramine (Benadryl)
Chlorpheniramine (Chlor-Trimeton)
Brompheniramine (Dimetane)
Cyclizine (Marezine)
Meclizine (Antivert)
Promethazine (Phenergan)
Hydroxyzine (Atarax, Vistaril)
Dimenhydrinate (Dramamine)
Doxylamine
Cyclics
Cyclobenzaprine (Flexeril)
Plants Containing Significant Amounts of Belladonna Alkaloids (Solanaceae Family)
Atropa belladonna (deadly nightshade)
Hyocyamus niger (black henbane)
Datura stramonium (Jimsonweed)
Brugmansia x candida (Angel’s trumpet)
Solandra species (Chalice vine, cup-of-gold)
Naturally occurring belladonna alkaloids, including atropine, scopolamine, and hyoscine, are found in many
members of the Solanaceae plant family.[6][26] Scopolamine, which has significant CNS toxicity, is the
predominant alkaloid in jimsonweed (Datura stramonium). Jimsonweed grows hardily in most climates and is
a frequent cause of plant-related poisonings.[17][20][32][50]“Recreational” poisonings have been commonly
reported in groups of adolescents who smoke or ingest parts of the jimsonweed plant to get “high.” [20][39][50]
Inadvertent poisonings have resulted from herbal cigarettes and teas contaminated with belladonna
alkaloids and from self medication with stramonium powder for the treatment of asthma.[5][17][46][51]
Accidental and suicidal overdoses occur with nonprescription antihistamines such as pyrilamine,
diphenhydramine (Nytol, Benadryl, Sominex), and cyclizine (Marezine). Common prescription drugs
implicated in serious overdoses include benztropine (Cogentin), cyproheptadine (Periactin), hydroxyzine
(Atarax), cyclobenzaprine (Flexeril), and promethazine (Phenergan). A series of intentional poisonings
occurred in New York City when tasteless scopolamine was added to the drinks of bar patrons to facilitate
robbery.[5] Inadvertent poisoning has resulted from systemic absorption of topical ophthalmic preparations of
homatropine.[44]
The American Association of Poison Control Centers reported a 1 per cent incidence of serious effects or
fatalities related to antihistamine and anticholinergic overdoses, in contrast to 8 per cent for a similar number
of antidepressant overdoses.[29] Poisoning with drugs whose toxicity is limited to anticholinergic effects
rarely results in death when adequate supportive care is provided. However, the thermoregulatory
dysfunction caused by impairment of sweating may result in fatal hyperthermia in the agitated or seizing
patient with an anticholinergic overdose. Heatstroke fatalities have also occurred in heat-exposed or
exercising patients on therapeutic doses of anticholinergic agents. [56][60]


Pharmacology
Absorption of antihistamines from the gastrointestinal tract is usually rapid. After a therapeutic dose, the
peak drug effect is usually seen in 1 hour. However, with large ingestions evidence of significant toxicity may
not occur for several hours.[19][25][28] Anticholinergic toxicity may be prolonged, possibly due to decreased
gut motility.[11][53][59] Symptoms of poisoning rapidly follow the ingestion of teas or inhalation of burning plant
material. The onset of symptoms may be delayed for many hours after the ingestion of seeds.[14][20][32]
Dermal absorption of topical antihistamine preparations has resulted in anticholinergic poisoning in
children.[49]
The H1 antagonists are metabolized by liver microsomal enzymes, some with active metabolites that
prolong the duration of action of the drugs. Little parent drug appears unchanged in the urine. The duration
of action for therapeutic doses ranges from 4 to 6 hours for pyrilamine, chlorpheniramine, or tripelennamine
to 24 hours for meclizine, terfenadine, or astemizole.[2] In the overdose setting, toxicity may last for many
days [53][59]; anticholinergic signs and symptoms persisted for 9 days in a 38-year-old man who overdosed on
benztropine mesylate.[11]
Pathophysiology
Anticholinergic Effects
The toxic (and many therapeutic) effects of anticholinergic drugs are related to their inhibitory effects on both
central and peripheral muscarinic cholinergic receptors. Nicotinic cholinergic receptors at the neuromuscular
junction are not affected. Peripheral muscarinic receptors mediate the end-organ effects of the
parasympathetic nervous system, which stimulate sweating, secretion from mucosal and salivary glands,
pupillary constriction, intestinal motility, and bladder contraction. Parasympathetic fibers in the vagus nerve
slow heart rate and atrioventricular nodal conduction. Central muscarinic receptors are involved in recent
memory, cognition and perception, and some aspects of motor coordination. [10][23][48][53][54] Blockade of
these receptors produces the familiar signs and symptoms of anticholinergic toxicity, discussed below.
Cardiac Toxicity of the Nonsedating Antihistamines
Some patients taking terfenadine or astemizole develop very high drug levels that result in spontaneous
torsades de pointes tachycardia. This has been associated with taking extra doses of the drug and with the
concomitant use of ketoconazole or erythromycin, both of which block the cytochrome P-450 3A4 enzyme
that is responsible for the metabolism of terfenadine and astemizole.[40][57][58] Other inhibitors of this enzyme
include clarithromycin, fluconazole, miconazole, itraconazole, fluoxetine, nefazadone, omeprazole,
cimetidine, diltiazem, quinidine, and grapefruit juice (flavonoids). Ventricular tachycardia has also been seen
after overdose.[43] These dysrhythmias occur secondary to prolongation of the QT c by potassium channel
blockade.[8][58] In cases of cardiotoxicity related to astemizole, a metabolite, desmethylastemizole, may be
the etiologic agent. [58]


Symptoms occur within a few hours of a serious ingestion in most cases. Delays in the onset of symptoms
have been associated with ingestion of seeds of Datura stramonium[32] and after cyclobenzaprine (Flexeril)
ingestions.[28] Inhibition of peripheral muscarinic receptors results in tachycardia, pupillary dilatation, loss of
accommodation, inability to sweat, drying of mucosal surfaces, gastrointestinal paresis, and urinary
retention. These physical signs (mydriasis; dry mouth and dry, flushed skin; ileus; and bladder distention)
constitute the anticholinergic “toxidrome” and suggest the diagnosis of poisoning with an anticholinergic
agent ( Table 56–2 ).[1][15][22] The absence of axillary sweat is a more sensitive finding. Occasionally, only a
few of these signs will be evident, especially in chronic poisonings.[16][30][34] Inhibition of CNS muscarinic
receptors causes visual hallucinations, amnesia, delirium, seizures, and coma. Myoclonus and
choreoathetosis are also commonly observed. [10][23][42][48][53][54][55] Examination of case series of
anticholinergic poisoning suggests that seizures occur less commonly in adults than in children.[17][19][45][59]
Seizures occur in patients poisoned with cyclic antidepressants.[3] Acute dystonia and dyskinesia have
occurred with use of diphenhydramine and benztropine mesylate.[4a][19a]
Table 56-2 -- Clinical Presentation of First Generation H1 Antagonist Overdose

Antimuscarinic Effects CNS Effects ECG Effects
Dry, flushed skin Seizures Sinus tachycardia
Dry mucous membranes Delirium
Dilated pupils Coma
Decreased bowel sounds or ileus
Urinary retention
As a rule, EKG abnormalities (except sinus tachycardia) are unusual in overdoses of predominantly
anticholinergic agents. Their presence suggests a very large exposure[13][19][25] or poisoning with a more
cardiotoxic agent with anticholinergic side effects such as a cyclic antidepressant or a neuroleptic agent.
Diphenhydramine toxicity resulting in a wide complex tachycardia responsive to intravenous sodium
bicarbonate has been reported. [6a] Patients with toxic effects related to the second-generation antihistamines
terfenadine and astemizole may have QTc prolongation with runs of torsades de pointes tachycardia.
Overdose of doxylamine or diphenhydramine in patients who were febrile and seizing or agitated has been
associated with rhabdomyolysis and myoglobinuric renal failure.[10a][12][52] Agitated, delirious patients with
peripheral anticholinergic signs may develop markedly elevated temperatures that result in the classic
manifestations of heat stroke: liver injury, rhabdomyolysis and myoglobinuric renal failure, cerebral edema,
and disseminated intravascular coagulation.[9]


The differential diagnosis of the patient who presents with an altered mental state is of course extensive and
includes metabolic and endocrine abnormalities, structural brain lesions, CNS infection, sedative hypnotic
withdrawal, and effects of toxins. Subarachnoid hemorrhage may cause changes in the mental state that are
difficult to distinguish from a toxic delirium ( Table 56–3 ) [31](see Chapter 17 ).
Table 56-3 -- Differential Diagnosis of Delirium

Toxic Etiologies
Glucocorticoids
Lithium
Salicylates
Anticholinergics
Sympathomimetics (cocaine, amphetamines)
Phencyclidine
Mushrooms with muscimol and ibotenic acid: Amanita pantherina, Amanita muscaria
Solvents
Carbon monoxide
Sedative hypnotic withdrawal
Metabolic Etiologies
Addison’s disease
Hyponatremia
Hypoglycemia
Hypercarbia
Hypoxia
Hypercalcemia
Uremia
Thyrotoxicosis
Shock
Sepsis
Infectious and Inflammatory Etiologies
Meningoencephalitis
Meningitis
Vasculitis
Human immunodeficiency virus–related central nervous system infections
Neurologic and Neurosurgical Abnormalities
Cerebrovascular accident
Subdural and epidural hematoma
Frontal contusion
Postictal state
Temporal lobe seizures
When poisoning with a pure anticholinergic agent is suspected by the history and the presence of a
toxidrome, the complete normalization of the mental status following the administration of physostigmine is a
useful diagnostic test confirmatory of anticholinergic poisoning. Physostigmine itself may cause seizures and
has been associated with asystole in patients with EKG conduction disturbances[41](see Treatment later).
Patients with excessive sympathetic stimulation from toxins, psychosis, or sedative hypnotic withdrawal also
have elevated temperature, tachycardia, and dilated pupils. Although they are usually diaphoretic, the skin
may be dry in the setting of dehydration and they may appear to be anticholinergic. Tremor, rather than
myoclonus, is noted in the sympathetic state; and bowel sounds are more likely to be present. Nystagmus is
commonly seen in patients with sedative hypnotic withdrawal, cocaine, and phencyclidine poisoning.
Patients with lithium poisoning have significant hyperreflexia and clonus. Other toxins that can cause
agitated delirium include salicylates, monoamine oxidase inhibitors, phencyclidine, cocaine, and
amphetamines. Over 200 medications have been associated with delirium in the elderly.[33]


LABORATORY STUDIES
Metabolic and EKG Evaluation
Routine laboratory investigation should include determination of blood urea nitrogen, calcium, glucose, and
electrolyte levels. This will detect disorders of sodium, calcium, and glucose and also uremia, which may be
associated with an altered mental state. Elevation of the serum creatine kinase levels and a urine dipstick
test that indicates myoglobinuria (positive for blood in the absence of significant red cells) suggest the
presence of rhabdomyolysis. Elevation of the anion gap is not specific because many agitated patients have
lactic acidosis, although it may suggest the presence of another toxin, such as salicylate or a toxic alcohol or
glycol or an infectious or metabolic disturbance, such as sepsis or diabetic ketoacidosis. Further testing to
evaluate for the presence of serious infection, including blood cultures, chest radiograph, and lumbar
puncture should be dictated by the clinical setting and physical examination.
The EKG is a critical test in suspected anticholinergic poisoning. Many drugs that have anticholinergic
toxicity also have significant cardiac effects. The finding of conduction disturbances such as QRS complex
widening or QTc prolongation suggests the presence of a cyclic antidepressant or neuroleptic agent such as
mesoridazine or thioridazine. QTc prolongation also occurs with terfenadine and astemizole. A rightward
deviation of the terminal 40 msec of the electrical axis, which results in an S wave in lead I and an R wave in
lead AVR, also suggests the presence of a cyclic antidepressant.[38] The demonstration of EKG conduction
disturbances helps in the diagnosis of the toxic agent involved and contraindicates the administration of
physostigmine.
Toxicologic Screening
Toxicologic screening is rarely useful in the diagnosis of the patient with anticholinergic poisoning. The
belladonna alkaloids are not detected on routine screens, and few laboratories measure antihistamines. The
qualitative demonstration of the presence of cocaine, phencyclidine, amphetamines, a cyclic antidepressant,
or a neuroleptic agent may be useful. Quantitative tests for salicylates and lithium are helpful if those agents
are suspected. Quantitative levels of anticholinergic drugs have been correlated with mental status
impairment in postoperative patients, although such levels are not available in most institutions.[54][55] Many
patients with significant infectious or neurosurgical problems will have evidence of a toxin that is incidental or
has precipitated a more serious traumatic or infectious problem. Head computed tomography and lumbar
puncture should be used liberally to exclude structural abnormalities or CNS infection in patients in whom
the cause of the mental status deterioration is not clear.


TREATMENT
Many patients with anticholinergic poisoning who present to an emergency department have no clear history
of exposure. The diagnosis is suspected on the basis of the physical examination and evaluation is guided
by consideration of the broader differential diagnosis of the acutely agitated and febrile or comatose patient
(see Table 56–3 ).
Most patients with anticholinergic overdoses do well with sedation, temperature control, hydration, activated
charcoal, and observation in an intensive care environment. Some caveats and additional therapies are
described here ( Table 56–4 ).
Table 56-4 -- Treatment of Antihistamine Overdose

Decontamination:
Activated charcoal
Consider gastric lavage in severe cases
Agitation:
Intravenous benzodiazepines
Consider physostigmine IV over 5 minutes
Adult: 1–2 mg
Pediatric: 0.02 mg/kg (maximum, 2 mg)
Hyperthermia:
Ice water immersion or tepid water/fans
Seizures:
Intravenous benzodiazepines
Consider physostigmine for refractory seizures
Supraventricular tachycardia:
Supportive care
Consider physostigmine
Torsades de pointes:
Cardioversion
Magnesium sulfate IV over 10–30 minutes
Adult: 2–6 grams
Pediatric: 25–50 mg/kg
Overdrive pacing
Rhabdomyolysis:
Maintain 1–2 mL/kg/hr urine output
Laboratory evaluation:
Electrocardiography
Serum creatinine, creatine kinase, electrolytes
Exclude hypoglycemia
Hyperthermia
Hyperthermia in the agitated patient with anticholinergic poisoning may be more life threatening than the
overdose itself. Aggressive cooling with an ice water bath or evaporative techniques should be the first
priority in managing the severely hyperthermic patient (see Chapter 27 ).[9][24] Cooling should be initiated in
any patient whose temperature is 104°F (40°C) or more. Heat production caused by intense muscle activity
is best controlled by sedation with an intravenous benzodiazepine, such as diazepam 5 to 10 mg every 5 to
10 minutes or lorazepam 2 to 4 mg every 20 to 30 minutes, with dose titrated to effect. Antipyretic agents
and simple cooling blankets are not effective.[56] A brisk urine output of 1 to 2 mL/kg/hr should be maintained
to avoid injury to the renal tubules by myoglobin.
Agitation
Intravenous benzodiazepines titrated to sedation are the drugs of choice to treat agitation in the patient with
suspected anticholinergic overdose. They protect against seizures, lack anticholinergic effects, are least
likely to cause hypotension, and are the agents of choice for the patient whose actual diagnosis is sedative
hypnotic withdrawal or cocaine poisoning. The major indications for chemical control with benzodiazepines
are to reduce the incidence of hyperthermia and the risks of rhabdomyolysis and myoglobinuric renal failure.
Future prospective studies may indicate a role for physostigmine. A retrospective study evaluated the
efficacy of physostigmine alone, benzodiazepines alone, or the two drugs combined in treating 52 patients
with anticholinergic poisoning. Physostigmine as sole therapy controlled agitation and reversed delirium in
96 percent and 87 percent of patients, respectively, whereas benzodiazepines controlled agitation in only 24
percent and did not reverse delirium.[5a]
Decontamination
In the majority of cases, the administration of a single dose of activated charcoal is sufficient for
decontamination. Activated charcoal mixed in water has been shown to effectively bind diphenhydramine,[18]
cyclic antidepressants, and phenothiazines.[35] There is little evidence to support the use of repetitive dose
charcoal in anticholinergic poisoning. Abdominal distention due to ileus is a common problem in patients
with significant anticholinergic toxicity. Repetitive dosing of cathartics may contribute to abdominal distention
and the risk of aspiration. Magnesium toxicity has been described as a complication of repeated
administration of magnesium citrate in a patient with anticholinergic poisoning.[21]
Gastric lavage should be considered in patients who present within 1 to 2 hours when a life-threatening
ingestion is suspected by history. Anticholinergic effects delay gastric emptying so that lavage may be
helpful regardless of the time of ingestion in very seriously poisoned patients. Significant agitation is a
contraindication to the institution of gastric lavage because the risk of injury or aspiration during lavage is
high relative to the anticipated benefit.
Physostigmine
The observation by British ophthalmologists that the effects of physostigmine on the eye were opposite to
the effects of atropine led, in 1864, to the first use of physostigmine to treat atropine poisoning.[37]
Physostigmine is a naturally occurring acetylcholinesterase inhibitor similar to neostigmine, pyridostigmine,
and edrophonium. However, because it is a tertiary amine it is the only cholinesterase inhibitor that crosses
the blood-brain barrier. It blocks the enzymatic hydrolysis of acetylcholine and causes it to accumulate in the
synaptic space, antagonizing the affects of acetylcholine receptor blockade at both central and peripheral
muscarinic sites. Its routine use as an antidote in the patient with anticholinergic poisoning is
controversial.[27] In the absence of anticholinergic blockade, physostigmine has the potential for significant
toxicity related to its ability to stimulate acetylcholine receptors. This stimulation can cause seizures, muscle
weakness, bradycardia, lacrimation, salivation, bronchorrhea, diarrhea, and may exacerbate asthma. Even
in cases in which there is documented anticholinergic effect, seizures have been reported after the rapid
administration of physostigmine.[36] Asystole has been reported after administration of physostigmine to
patients with cyclic antidepressant overdose, and the demonstration of a conduction abnormality on the EKG
is a contraindication to its use. [41]
Despite its potential toxicity physostigmine can be helpful in the management of some patients with pure
anticholinergic overdose. It is indicated in the management of intractable seizures, coma, severe agitation,
and symptomatic narrow-complex supraventricular tachycardia.[22][30][47] It is also useful to confirm the
suspected clinical diagnosis of anticholinergic toxicity. Complete reversal of coma or severe agitation with
normalization of the mental status confirms the diagnosis and obviates the need for further studies such as
computed tomography and lumbar puncture. The initial dose is 1 to 2 mg in the adult or 0.02 mg/kg
(maximum 2 mg) in the child, which should be infused intravenously over 5 minutes. It may be repeated if
the response is inadequate and signs of cholinergic excess do not appear.[6] Physostigmine should not be
given as a constant infusion. The effects of a single dose begin to wear off in approximately 1 hour. After
that time, with the diagnosis confirmed, the patient may be managed supportively. Repeat dosing is rarely
indicated unless there is recurrence of a life-threatening condition that responded to the initial therapy, in
which case the dose may be repeated as needed. It should not be used in patients with conduction
abnormalities or known cyclic antidepressant ingestions. Its toxicity precludes its use as an empirical “coma”
therapy, as is recommended in many older publications.


DISPOSITION
Patients with moderate to severe signs of anticholinergic poisoning or with known or suspected torsades de
pointes should be admitted to an intensive care unit for monitoring, observation for seizures, and control of
agitation and temperature. Some of these patients may have prolonged clinical courses, requiring days of
intensive care before the anticholinergic effects resolve.[11][53][59] Patients with milder symptoms that resolve
during observation in the emergency department do not require medical admission. Because the onset of
symptoms after antihistamine ingestion occurs within several hours, a 4-hour period of observation is
adequate to exclude significant toxicity in an asymptomatic patient. Patients who have ingested the seeds of
Datura stramonium and patients with cyclobenzaprine ingestion should be observed for 8 hours before
discharge. Psychiatric assessment, documentation of a nontoxic acetaminophen level, and assessment of
the pediatric patient’s home situation should be accomplished before discharge.


SEQUELAE
Permanent injury to the central nervous system may result from severe hyperthermia. Most patients who
survive the poisoning do not have permanent sequelae. Deaths have been reported.[14a][18a][58a]


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35. Neuvonen PJ, Olkkola KT: Oral activated charcoal in the treatment of intoxications: Role of single and
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36. Newton RW: Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage.
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37. Nickalls RWD, Nickalls EA: The first use of physostigmine in the treatment of atropine poisoning: A
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38. Niemann JT, Bessen HA, Rothstein RJ, et al: Electrocardiographic criteria for tricyclic antidepressant
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40. Peck CC, Temple R, Collins JM: Understanding consequences of concurrent therapies.
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41. Pentel P, Peterson CD: Asystole complication physostigmine treatment of tricyclic antidepressant
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43. Rao KA, Adlakha A, Verma-Ansil B, et al: Torsades de pointes ventricular tachycardia associated with
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44. Reilly KM, Chan L, Mehta NJ, Salluzzo RF: Systemic toxicity from ocular homatropine. Acad Emerg
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46. Rhoads PM, Tong TG, Banner Jr W, Anderson R: Anticholinergic poisonings associated with
commercial burdock root tea. J Toxicol Clin Toxicol 1984–1985; 22:581-583.
47. Rumack B: Anticholinergic poisoning: Treatment with physostigmine. Pediatrics 1972; 52:449-451.
48. Safer DJ, Allen RP: The central effects of scopolamine in man. Biol Psychiatry 1971; 3:347-355.
49. Shawn DH, McGuigan MA: Poisoning from dermal absorption of promethazine. Can Med Assoc
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50. Shervette RE, et al: Jimson “Loco” weed abuse in adolescents. Pediatrics 1979; 63:520-524.
51. Siegel RK: Herbal intoxication: Psychoactive effects from herbal cigarettes, tea, and capsules.
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52. Soto LF, Miller CH, Ognibere AJ: Severe rhabdomyolysis after doxylamine overdose. Postgrad
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58. Vorperian VR, Zhou Z, Mohammad S, et al: Torsades de pointes with an antihistamine metabolite:
Potassium channel blockade with desmethylastemizole. J Am Coll Cardiol 1996; 28:1556-1561.
58a. Winn RE, McDonnell KP: Fatality secondary to massive overdose of dimenhydrinate. Ann Emerg
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Psychiatry 1970; 126:1787.


Chapter 57 – Carbamazepine
PATRICK E. McKINNEY KATHLEEN BIRNBAUM
Essentials[15][19][54]
• Central nervous system (CNS) depression, ataxia, nystagmus, slurred speech, coma
• Respiratory depression/apnea
• Other effects: paradoxical seizures, anticholinergic effects, dyskinesias
• Elevated serum carbamazepine concentrations
INTRODUCTION
Carbamazepine is an iminostilbene derivative with structural and pharmacologic similarity to tricyclic

antidepressants such as imipramine. It has been prescribed in the United States since the 1960s for
approved indications, including trigeminal neuralgia, partial seizures, and generalized tonic-clonic
seizures.[1] It has also been used in the treatment of bipolar-affective disorder, dyscontrol syndrome, alcohol
withdrawal syndrome, resistant schizophrenia, pain syndromes, and restless legs syndrome. Although
overdose may cause apnea, seizures, and coma, fatalities are relatively uncommon. [15][19] In 1995, there
were 6602 exposures to carbamazepine reported to the American Association of Poison Control Centers. [25]
Sixty-six per cent of these patients were treated in health care facilities, and six fatalities were reported, but
only one fatality was identified in which carbamazepine was the primary causative agent. [25]


Pharmacokinetics
Carbamazepine (sometimes referred to as CBZ) is available as 100-mg chewable tablets, 200-mg tablets,
and a 100-mg/5 mL oral suspension. Gastrointestinal absorption is slow and erratic because carbamazepine
is a lipophilic compound that is relatively insoluble in aqueous media. Food has no consistent effect on
absorption. Doses larger than 20 mg/kg are not as efficiently absorbed as smaller doses, and an inverse
relationship occurs between absorption and doses >20 to 25 mg/kg.[33] Peak concentrations are generally
reached 4 to 8 hours after a single dose in adults, but they may occur as late as 72 hours after
overdose.[11][33] The apparent volume of distribution ranges from 0.8 to 2.0 L/kg in adults on therapeutic
doses.[33] Wide interindividual variation occurs in the time to peak plasma concentrations and volume of
distribution.[33] Carbamazepine is 75 to 78 per cent bound to plasma protein in adults.[33] Pharmacokinetic
and dosing parameters are summarized in Table 57–1 .
Table 57-1 -- Pharmacokinetic and Therapeutic Parameters of Carbamazepine

100-mg chewable tablets
Available Forms 200-mg tablets
100-mg/5mL suspension
Maximum Recommended Dose [1]
Younger than 6 years 20 mg/kg/d *
6 to 15 years 1 g/d †
Older than 15 years 1.2 g/d †
Therapeutic Plasma Level (Trough) 4–12 µg/mL
Plasma Protein Binding[33]
Neonate (32–42 weeks) 65–70%
Infants, children, adults 75–78%
Volume of Distribution (L/kg) [33]
Neonate 1.1–2.5
Children 1.2–3.5
Adult 0.8–2.0
Plasma Half-Life (hr)[33]
Neonate (32–42 weeks, chronic) 8–37
Children (acute, chronic) 3–32
Adult (initial) 18–55
Adult (chronic) 5–26
Time to Peak (hr)[33]
Neonate 2–6
Children 4–8
Adult ‡ 4–8
Carbamazepine Epoxide[33][46][49] §
Plasma protein binding 48–53%
Volume of distribution (L/kg) 0.59–1.50
Plasma half-life (hrs) 3–23
Time to peak (hrs) 1–2
* Some patients require more than 20 mg/kg/d.
† Some patients require 1.6–2.4 g/d.
‡ Peaks have been reported as late as 26 hours after overdose ingestion.
§ Studies administered carbamazepine epoxide to adults.
Carbamazepine is extensively metabolized by the liver. More than seven carbamazepine metabolites have
been identified, but the primary metabolite is carbamazepine-10,11-epoxide (CBZ-E), the only metabolite
shown to possess anticonvulsant activity.[5][24][33][39] Thirty to 60 per cent of carbamazepine is metabolized
to CBZ-E in epileptic patients. The clearance of CBZ-E is at least three times as rapid as the clearance for
carbamazepine.[33] Seventy-two per cent of carbamazepine is excreted in the urine, with only 1 to 2 per cent
of the parent drug excreted unchanged.[6][33][34] Twenty-eight per cent is excreted in the feces. The presence
of the drug in the feces may be due to incomplete absorption or biliary excretion of metabolites.[33][34] In rats
and monkeys, measurable amounts of carbamazepine have been detected in the feces after intravenous
administration. These data indicate that the drug undergoes enterohepatic recirculation.[33]
Carbamazepine follows first-order elimination kinetics after therapeutic doses. It can autoinduce liver
enzymes, so concentrations of the drug and drug half-life may decrease after initiation of drug therapy. Liver
enzyme induction usually occurs after 2 to 4 days, but carbamazepine concentrations may not plateau for 20
to 30 days after initiation of therapy. Estimations of plasma half-life in adults range from 18 to 55 hours, but
with chronic dosing the half-life may be shortened to 5 to 26 hours.[33] In overdose, the half-life of
carbamazepine may be prolonged and a plateau in plasma concentrations may occur as a result of delayed
absorption and possibly saturation kinetics in epoxidation with large doses.[51][54]
The initial dosage for seizure control in adults is 200 mg twice a day with meals, with weekly increases of
200 mg/d as needed, with a few patients requiring 1.6 to 2.4 g/d.[1] Infants and young children often require
more frequent dosing and relatively larger daily doses than adults because they have more rapid clearance
rates.[33] Adult therapeutic carbamazepine plasma levels range between 4 and 12 µg/mL. There is no
established relationship between the dose of carbamazepine and the plasma concentrations of
carbamazepine or its active metabolite, CBZ-E. [32][33]
Multiple drug interactions may occur with carbamazepine secondary to its ability to induce hepatic
microsomal mono-oxygenase enzymes. Carbamazepine may reduce concentrations of primidone,
phenytoin, benzodiazepines, cyclic antidepressants, ethosuximide, phenobarbital, valproate, haloperidol,
warfarin, theophylline, cyclosporine, oral contraceptives, corticosteroids, and doxycycline.[3][21][22][30]
Carbamazepine concentrations may be decreased or increased by the addition of drugs that are enzyme
inducers or inhibitors ( Table 57–2 ). Concomitant use with clozapine increases the risk of bone marrow
suppression and is contraindicated. Patients on lithium and carbamazepine have developed neurotoxicity
despite therapeutic levels of both drugs, and patients with underlying neurologic or metabolic disorders or
those with a previous history of lithium-induced neurotoxicity may be at increased risk.[42]
Table 57-2 -- Carbamazepine Drug Interactions

Drugs Increasing Carbamazepine Concentrations Drugs Decreasing Carbamazepine Concentrations
Cimetidine Phenytoin
Danazol Phenobarbital
Diltiazem Primidone
Erythromycin Carbamazepine
Isoniazid Succinimides
Nicotinamide Valproic acid
Propoxyphene
Verapamil
Troleandomycin
Pathophysiology
Although the mechanism of action is not fully understood, carbamazepine and CBZ-E appear to limit
sustained, high-frequency, repetitive firing of sodium-dependent action potentials.[33] In vitro studies indicate
that carbamazepine, like phenytoin, blocks sodium channels at therapeutic doses. [32] Carbamazepine has
also demonstrated sedative, anticholinergic, antidepressant, antidiuretic, muscle relaxant, and
antidysrhythmic activity.[1][12] These properties account for the clinical picture seen in overdose.


Acute Toxicity
In most cases of overdose patients develop varying levels of CNS depression with or without concomitant
respiratory depression. Common clinical effects include drowsiness, ataxia, nystagmus, slurred speech,
dyskinesias, vomiting, and tachycardia.[19] Life-threatening effects include coma, seizures, and respiratory
arrest.[19] CNS effects are a major component of the clinical picture and are common at concentrations
greater than 9 µg/mL.[6] Nystagmus, tremor, and dysarthria may also be seen at therapeutic concentrations.
Agitation and hallucinations may occur, followed by mental status depression and coma. Cyclic coma has
been reported and may be due to delayed drug absorption secondary to decreased gastric motility, erratic
drug absorption, bezoar formation, and enterohepatic recirculation or to a combination of these
factors.[11][45][51][54] Prolonged coma may result in bullous skin lesions, rhabdomyolysis, and renal failure.
Cerebellar dysfunction and abnormal movements, including opisthotonus, dyskinesias, and ataxia, may be
seen. Reflexes may be hyperactive, and clonus may be present. Pupillary effects are not consistent, and
both mydriasis and miosis as well as a variable response to light have been reported.
Paradoxical seizures may occur after overdose in up to 34 per cent of patients.[40] Seizures may occur both
in patients with and without a history of convulsions. In many reported cases, other possible causes of
seizures such as co-ingestion of other drugs, hypoxia, or electrolyte disturbances are not adequately
described, making the causal relationship difficult to establish. Seizures associated with carbamazepine
overdose are associated with increased mortality. [40]
Because the drug is structurally similar to the tricyclic antidepressants, similar toxic effects may be seen.
Anticholinergic effects are common, and components of the anticholinergic syndrome such as tachycardia,
mydriasis, confusion, decreased bowel activity, and dry, flushed skin are often seen. However, the full
constellation of findings of the classic anticholinergic syndrome does not commonly develop. In two series of
carbamazepine-poisoned patients, findings such as tachycardia, urinary retention, and mydriasis were seen
in less than 50 per cent of patients.[19][41] Cyclic antidepressant membrane depressant effects such as
hypotension and prolongation of QRS complex and QT interval are less common.[2] Sinus bradycardia,
supraventricular tachycardia, wide QRS tachycardia, ventricular fibrillation, and prolongation of all EKG
intervals have been reported,[19][47] but significant cardiovascular effects are uncommon.[2] Pre-existing
cardiovascular disease may be a risk factor for carbamazepine-induced dysrhythmias, though cardiotoxicity
can also be seen in patients with no history of cardiac history. [4][19]
Respiratory effects include respiratory depression and apnea. Pulmonary edema is uncommon but has been
reported.[47] Vomiting is common, and decreased gastric transit time and ileus may be present. Hepatic
toxicity may range from asymptomatic elevation of transaminases to hepatitis and pancreatitis. [28][50]
Significant elevations of temperature may represent a clinical picture similar to neuroleptic malignant
syndrome.[36] Clinical effects in overdose are summarized in Table 57–3 .
Table 57-3 -- Clinical Presentation of Carbamazepine Toxicity

Neurologic
Coma (may be cyclic)
Seizures
Ataxia
Vertigo
Dysarthria
Plantar reflex extensor/flexor
Tremor
Opisthotonus
Dyskinesia
Decerebrate posturing
Clonus
Hyperreflexia
Combative
Visual hallucinations
Respiratory
Pulmonary edema
Apnea
Cardiovascular
Sinus tachycardia
Atrioventricular block
Long PR segment
Long QRS complex
Long QT segment
Supraventricular tachycardia
Bradycardia
Hypotension
Hypertension
Wide QRS tachycardia
Ventricular fibrillation
Ophthalmologic
Miosis
Mydriasis
Nystagmus
Diplopia
Pupillary light response: normal/diminished/absent
Ophthalmoplegia
Temperature
Hypothermia
Hyperthermia
Gastrointestinal
Vomiting
Pancreatitis
Hepatitis
Hyperammonemia
Urinary retention
Skin/Musculoskeletal
Bullae
Rhabdomyolysis
Hematologic
Leukopenia
Thrombocytopenia
Aplastic anemia
Agranulocytosis
Chronic Toxicity
The adverse effects observed with acute toxicity may also be seen during chronic therapy. Hematologic,
hepatic, and renal effects are unique to chronic toxicity. In addition, a hypersensitivity syndrome and SIADH
may be seen.[13] Agranulocytosis and aplastic anemia occur very rarely in 1/50,000 cases.[18] Severe
thrombocytopenia is unusual; however, a transient thrombocytopenia on initiation of therapy has been more
commonly reported.[18][37][48] Mild, transient leukopenia occurs in about 10 per cent of patients and usually
resolves despite continued drug administration. [37] Clinically significant hepatotoxicity (cholestatic and
hepatocellular jaundice, hepatitis) is very rarely reported.[37] Elevation of alkaline phosphatase occurs in up
to 5 to 10 per cent of patients and usually does not require discontinuation of treatment. Transaminase
elevations may be caused by hepatic enzyme induction.[37] Because hepatic and hematologic toxicity
usually occurs during the first few months of therapy, a complete blood cell count and liver function studies
should be obtained at least monthly during the first few months and periodically thereafter.[18][38][48] Chronic
carbamazepine therapy has been associated with hypersensitivity reactions such as eosinophilia, Stevens-
Johnson syndrome, photosensitivity, rashes, systemic lupus erythematosus, and renal toxicity. [27][33] These
adverse reactions may require discontinuation of therapy. Although some anticonvulsants such as phenytoin
have been associated with suppression of cellular immune function, in vitro evidence does not implicate
carbamazepine as an immunosuppressive agent.[31]
The teratogenic potential of carbamazepine is not well defined. Animal models of anticonvulsant
teratogenicity do not typically find a strong association between carbamazepine or CBZ-E and
developmental malformations.[14] Human case reports have implicated carbamazepine overdose during the
early first trimester with neural tube defects, but this link is not firmly established.[26] Carbamazepine-related
decreases in serum folate have been postulated as a mechanism to explain neural tube defects[26];
however, rat studies indicate that carbamazepine treatment may actually increase serum folate
concentrations.[8]
Pediatric
Pediatric carbamazepine intoxication generally produces a picture similar to that seen in the adult.[29] In
preverbal or nonambulatory children, toxicity may manifest as nonspecific signs and symptoms such as
lethargy, poor feeding, or behavioral changes. Clinically significant symptoms such as coma and apnea
appear to be more frequent at higher carbamazepine concentrations. However, cases of severe toxicity have
been reported with minimally elevated carbamazepine concentrations.[43] The likelihood of seizures may not
correlate with serum concentrations.[44]


The differential diagnosis of carbamazepine poisoning is shown in Table 57–4 . Drugs with similar structure
or function may produce a similar clinical picture in overdose. Therefore, drugs that have anticholinergic
properties, cause CNS depression or movement disorders, or affect cardiac conduction may mimic
carbamazepine. The anticonvulsants, especially phenytoin, produce a picture similar to carbamazepine
overdose or may be present as co-ingestants. Although anticonvulsants are not detected by most urine
toxicology screens, specific serum assays can determine concentrations of many anticonvulsants.
Carbamazepine is structurally similar to the tricyclic antidepressants and may produce similar signs and
symptoms. Another tricyclic compound, cyclobenzaprine (also sometimes referred to as “CBZ”) can produce
similar anticholinergic and cardiac findings. Sedative-hypnotic agents such as benzodiazepines,
barbiturates, and older-generation agents such as meprobamate and ethchlorvynol should be considered in
patients with CNS and respiratory depression. Other medical conditions such as Wernicke’s
encephalopathy, hypoglycemia, cerebellar tumors, infarction, infection, or bleeding are included in the
differential diagnosis.
Table 57-4 -- Differential Diagnosis of Carbamazepine Toxicity

Drugs
Amantidine
Antihistamine/anticholinergic agents
Baclofen
Benzodiazepines
Carbon monoxide
Carisoprodol
Chloral hydrate
Cocaine
Cyclobenzaprine
Ethanol
Ethchlorvynol
Ethosuccimide
Ethylene glycol
Felbamate
Gabapentin
Glutethimide
Ketamine
L-Dopa
Lamotrigine
Lithium
Meprobamate
Methaqualone
Methyprylon
Neuroleptic agents
Pemoline
Phencyclidine
Phenobarbital
Phenytoin
Primidone
Valproic acid/derivatives
Other Causes
Wernicke’s encephalopathy
Cerebellar pathology
Hemorrhage
Infarct
Mass
Infection
Hypoglycemia
Hypoxia


LABORATORY STUDIES
Carbamazepine Levels
Carbamazepine can be assayed by high-performance liquid chromatography, gas-liquid chromatography,

fluorescence polarization immunoassay, or enzyme multiplied immunoassay. The therapeutic level usually
ranges from 4 to 12 µg/mL. Some patients may experience side effects at lower plasma concentrations,
whereas others may tolerate and require higher concentrations for the desired therapeutic effect.
Carbamazepine is highly protein bound, and both free and total drug concentrations may be measured. Free
drug therapeutic levels range from 1.6 to 2.4 µg/mL.[23] CBZ-E concentrations have a reference range of 0.8
to 3.2 µg/mL.
The correlation between total carbamazepine concentrations and symptomatology is not exact. With
increasing concentrations, a greater percentage of patients is likely to be symptomatic. In one case series,
serum levels of 40 µg/mL or more were significantly associated with the development of seizures, coma,
respiratory depression, and cardiac conduction delays.[19] However, patients may be relatively symptom free
with carbamazepine levels over 30 µg/mL. Conversely, severe toxicity has been reported despite
“therapeutic” levels.[43] Because absorption of carbamazepine is slow and peak levels may not be seen for
up to 72 hours, serial drug concentrations are recommended to detect the peak plasma concentration.[11]
Other Tests
Electrolytes should be measured because carbamazepine is associated with the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) and hyponatremia.[13] Acidosis is uncommon unless seizures or
hypotension are present. Mild hyperglycemia has been reported.[41] Hypokalemia can occur and may be
related to high peak carbamazepine concentrations.[41] Mild and transient elevations of gamma glutamyl
transferase and alkaline phosphatase have been reported[41]; therefore, liver function studies may be
indicated. A complete blood cell count should be obtained because of the potential for transient leukopenia,
thrombocytopenia, and agranulocytosis. Pancytopenia and aplastic anemia rarely occur during therapeutic
use.[18][37][48]
Patients with significant intoxication merit measurement of oxygen saturation. Arterial blood gases may be
indicated to assess acid-base status and ventilation. An electrocardiogram should be obtained to identify
atrioventricular block or interval prolongation. Radiographic studies such as computed tomography or
magnetic resonance imaging of the head may be indicated to rule out CNS pathology if serum
carbamazepine concentrations do not support the clinical findings.


TREATMENT
The initial treatment of carbamazepine poisoning should be directed toward assessment, stabilization, and
general supportive care ( Table 57–5 ). Tachycardia (usually sinus) can occur but typically does not require
therapy. Because of the structural similarity of carbamazepine to the tricyclic antidepressants, wide complex
tachycardia from carbamazepine toxicity may, theoretically, respond to intravenous sodium bicarbonate
bolus therapy. Hypotension not responsive to crystalloid infusion or vasopressor agents may also,
theoretically, respond to sodium bicarbonate intravenous bolus therapy.
Table 57-5 -- Treatment of Carbamazepine Toxicity

Supportive care with attention to ABCs—airway, breathing, circulation
Consider the “coma cocktail”
Thiamine hydrochloride, 100 mg IV/IM
Naloxone, 2–20 mg IV/IM
Rapid glucose determination or empirical dextrose administration
Oxygen administration
Bed rest until ataxia resolves
Cardiac monitoring is not required in most cases, although intensive care or subacute care may be required for
appropriate level of care
Gastric decontamination
Consider gastric lavage for early presentation, large amounts, continued drug absorption, and intubated
patients
Activated charcoal 1 g/kg PO
Consider repeat dose activated charcoal, 0.25–0.5 g/kg PO every 2–6 hours until toxicity is resolving and drug
levels falling
Consider a single dose of cathartic:
Sorbitol
Adult: 1–3 mL/kg (1–2 g/kg) PO of a 70% solution
Pediatric: (> 1 yr) 1–3 mL/kg (0.5–1.0 g/kg to a maximum of 50 g) PO of a 35% solution
Magnesium citrate 6% solution, 4 mL/kg to a maximum 300 mL
Magnesium sulfate 10% solution, 250 mg/kg to a maximum 30 g
Seizures *
Diazepam: 5–10 mg IV in adults; 0.2–0.5 mg/kg IV in children. Repeat as necessary.
Lorazepam: 2–4 mg IV in adults, 0.05–0.1 mg/kg IV in children. Repeat as necessary.
Phenobarbital: 10–20 mg/kg IV in adults, 10 mg/kg IV in children. Repeat as necessary.
Hypotension:
Crystalloid infusion
Dopamine, 1–20 µg/kg/min
* Be prepared to treat respiratory depression.
Decontamination
Gastric lavage may be considered in patients with significant ingestions, even hours after ingestion. Because
of its anticholinergic properties and poor solubility in aqueous media, carbamazepine in the form of tablets or
pharmacobezoars may remain in the gastrointestinal tract for an extended period of time.[11][53] Several
cases of ileus and prolonged drug absorption have been reported. [11][53]
Carbamazepine is well adsorbed to activated charcoal,[35] which should be administered 1 g/kg orally. A
cathartic is recommended in view of the anticholinergic effects of carbamazepine on bowel motility. Multiple
doses of activated charcoal may be indicated in cases of large ingestions, especially if there is evidence of
ongoing absorption.[53] Although multiple doses will theoretically not significantly increase clearance, limited
clinical data suggest that half-life may decrease with increasing charcoal doses. [7][52] However, even in
cases in which the apparent half-life of carbamazepine is shortened by activated charcoal, a clinical benefit
is difficult to detect.[52]
The patient who continues to absorb drug after gastric lavage and activated charcoal presents a special
problem. Most clinicians believe this occurs due to continued dissolution of a clump of poorly soluble pills or
slowed movement of pill clumps through the gastrointestinal tract due to anticholinergic drug effects. In
theory, maximizing activated charcoal therapy would seem to be attractive, thus surrounding the remaining
pills and pill fragments with charcoal. However, an ileus may make this difficult. Whole-bowel irrigation with
polyethylene glycol electrolyte solution theoretically might be useful. A case report links clinical improvement
with the resumption of bowel motility, but the cause-and-effect relationship has not been established. [53]
Seizures
Seizures should be treated with a benzodiazepine such as intravenous diazepam or lorazepam. The second
drug of choice is phenobarbital. Care must be given after the use of these agents because of the risk of
additive respiratory depression and the possible need for intubation. Some cases describe the use of
phenytoin, but this has not been experimentally validated.[15][54]
Antidotes
There are no specific antidotes for carbamazepine intoxication. Although transient movement disorders seen
in overdose appear to be secondary to anticholinergic effects and have responded to physostigmine, the risk
of serious side effects from physostigmine precludes its use for these benign disorders. Flumazenil has
reportedly reversed carbamazepine-induced CNS and electroencephalographic abnormalities.[55] Because
of the potential for exacerbation of a pre-existing seizure disorder and the structural similarity of
carbamazepine to tricyclic antidepressants, use of flumazenil with carbamazepine toxicity is not
recommended.
Extracorporeal drug removal in the setting of carbamazepine toxicity is controversial. Pharmacokinetic

parameters including high protein binding make hemodialysis and peritoneal dialysis ineffective.[16][17]
Several reported cases describe clinical improvement and transient decrease in drug half-life coincident with
the institution of charcoal hemoperfusion; however, the amount of drug removed by this procedure is usually
small. [9][10] Hemoperfusion may be considered in patients with significantly elevated plasma drug
concentrations and serious clinical effects such as hypotension and seizures unresponsive to conservative
therapy. Plasmapheresis has not been successful in removing clinically significant amounts of drug and
cannot be recommended.[20] Manipulation of urinary pH or flow rate does not significantly affect drug
clearance, which is primarily dependent on hepatic metabolism. Medications that inhibit carbamazepine
metabolism such as erythromycin and cimetidine should be avoided.


DISPOSITION
Because of the risk of delayed drug absorption and toxicity, a reasonable observation time for patients with a
significant ingestion would be at least 6 to 8 hours, with documentation of at least two declining plasma drug
concentrations. Asymptomatic patients who meet these criteria and are discharged should have adequate
support systems so that they can be observed for potential deterioration at home. Resumption of therapeutic
use of carbamazepine should occur with the assistance of the patient’s physician.
Patients who exhibit significant CNS depression, movement disorders, cardiac effects such as widened
QRS, or rising carbamazepine levels should be admitted to a monitored bed in a critical care setting.
Adequate observation is needed because of the potential for continued deterioration and deterioration after
apparent recovery. Some clinicians recommend a 24-hour observation period after recovery, but this has not
been experimentally validated. Evidence of passage of activated charcoal in the stool would be desirable.


SEQUELAE
No acute sequelae are expected after recovery from carbamazepine overdose provided there has not been
secondary injury from hypoxia or hypotension.


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30. MacNab AJ, Robinson JL, Adderly RJ, et al: Heart block secondary to erythromycin-induced
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natural killer cell activity and genotoxicity in vitro. Toxicol Appl Pharmacol 1987; 87:10-17.
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194.
40. Schmidt S, Schmitz-Buhl : Signs and symptoms of carbamazepine overdose. J Neurol 1995; 242:169-
173.
41. Seymour JF: Carbamazepine overdose. Drug Safety 1993; 8:81-88.
42. Shukla S, Godwin CD, Long LEB, et al: Lithium-carbamazepine neurotoxicity and risk factors. Am J
Psychiatry 1984; 141:1604-1606.
43. Spiller HA, Krenzelok EP, Cookson E: Carbamazepine overdose: A prospective study of serum levels
and toxicity. Clin Toxicol 1990; 28:445-458.
44. Stremski ES, Brady WB, Prasad K, et al: Pediatric carbamazepine intoxication. Ann Emerg
Med 1995; 25:624-630.
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Neurology 1981; 1:621-624.
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humans. J Pharmacobiodyn 1987; 10:652-661.
47. Tibballs J: Acute toxic reaction to carbamazepine: Clinical effects and serum concentrations. J
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(Tegretol). Eur Neurol 1988; 28:161-163.


Chapter 58 – Phenytoin
PATRICK E. McKINNEY
Essentials
• Nystagmus
• Ataxia
• Nausea and vomiting
• Elevated total or free plasma phenytoin concentration
INTRODUCTION
Phenytoin (5,5-diphenyl-2,4-imidazolidinedione) is one of the most widely prescribed anticonvulsants in the

United States. Labeled indications for phenytoin include tonic-clonic and psychomotor seizures. It is also
used for other seizure disorders, such as simple partial and partial complex seizures, as well as for seizure
prophylaxis after head trauma and before neurosurgery. Additionally it has been used as an antidysrhythmic
agent in cases of digoxin and cyclic antidepressant toxicity and in the treatment of disorders as diverse as tic
douloureux, pre-eclampsia, epidermolysis bullosa, migraine headaches, and chronic, nonhealing wounds.
Also known as diphenylhydantoin (DPH), phenytoin was first synthesized in 1908 by Blitz. Its anticonvulsant
properties were first discovered by Merritt and Putnam during a systematic evaluation of potential
anticonvulsant drugs.[38] Phenytoin was the first drug found to possess potent anticonvulsant activity free
from the sedative properties present in the antiseizure drugs clinically available at the time.
Phenytoin (MW 252.26) is a hydantoin derivative that is structurally related to the barbiturates. It is a bitter,
odorless, white powder that is practically insoluble in water. Phenytoin sodium injection solutions contain
propylene glycol 40 per cent and ethanol 10 per cent for stability and are adjusted to pH 12 with sodium
hydroxide to maintain solubility. Fosphenytoin is a phosphate ester prodrug of phenytoin that is newly
available in the United States. Fosphenytoin injection solutions are freely soluble in water and do not contain
propylene glycol. The pH is adjusted to 6 to 9; and, because of this, intravenous and intramuscular injections
of fosphenytoin appear to be free of local tissue corrosive effects.[10] Phenytoin is available as phenytoin
chewable tablets (50 mg) and phenytoin oral suspension (30 mg/5 mL or 125 mg/5 mL). The phenytoin
sodium salt is available as phenytoin sodium prompt (30 and 100 mg capsules), phenytoin sodium extended
(30 and 100 mg capsules), and phenytoin sodium injection (50 mg/mL). Combination products are also
available containing phenytoin and phenobarbital.[3]


Pharmacology
Absorption
The absorption of phenytoin is slow even at therapeutic doses and may be highly dependent on formulation.
The drug is poorly soluble in the acidic environment of the stomach and is primarily absorbed in the small
intestine. Peak serum concentrations after a single 400-mg dose occur 8.4 hours after oral administration.[23]
The time to maximal concentration increases to over 13 hours with increasing doses within the therapeutic
range and can be expected to be prolonged even further in overdose.
The bioavailability may range from 57.7 to 85.6 per cent after a single oral dose and varies among different
oral formulations because of differences in surface area, excipient, dissolution, and absorption.[19][41] Thus,
a switch in phenytoin formulations may result in altered bioavailability without a change in dose. Phenytoin
may be administered as an intramuscular injection, although this is not recommended because of the
potential for tissue injury. The injectable solution pH is 12, which causes tissue irritation. Also, crystallization
of the drug may occur, causing tissue damage, decreased bioavailability, and delayed, erratic absorption.
Therefore, if oral administration is not feasible or desired, phenytoin should be given by intravenous infusion.
Fosphenytoin may be given by either the intravenous or intramuscular route without concern for local tissue
damage.
Distribution
Phenytoin rapidly diffuses into tissues. After intravenous administration, the distribution half-life is 0.63 ±
0.14 hour.[19] The apparent volume of distribution ranges from 0.4 to 0.63 L/kg in adults and may increase in
overdose.[41] Phenytoin is highly protein bound, with approximately 90 per cent bound to plasma proteins
(principally albumin in adults).[41] Only the free fraction is active; therefore, anything that alters plasma
protein binding or decreases plasma protein concentration may alter free phenytoin concentrations.
Increased free phenytoin concentrations may produce toxicity but may also lead to a shorter effective half-
life as more free phenytoin is available for metabolism. Plasma protein binding may be decreased in
overdose, uremia, and liver disease, with displacement by other drugs, and in patients with chronic disease
and/or malnourishment. Pharmacokinetic parameters for fosphenytoin are similar to those of phenytoin.[10]
The apparent volume of distribution of fosphenytoin is approximately 0.13 L/kg, and protein binding
approaches 95 per cent. Bioavailability is comparable to an equivalent dose of phenytoin. Fosphenytoin is
rapidly converted to phenytoin by phosphatases found in many tissues, primarily the liver and red blood
cells. The conversion half-life to phenytoin is 8 to 15 minutes, but it may be decreased in patients with
decreased protein binding.[10] Therapeutic phenytoin concentrations are attained within 10 minutes of
intravenous administration of fosphenytoin at a rate greater than or equal to 100 mg/min. Therapeutic
concentrations are attained within 30 minutes if slower infusion rates are used or if the drug is given by
intramuscular injection.[10]
Metabolism
Phenytoin is predominantly metabolized in the liver to inactive metabolites, primarily 5-(p-hydroxyphenyl)-5-
phenylhydantoin (p-HPPH), which is conjugated to glucuronide and excreted in the urine. Less than 5 per
cent of a daily dose is excreted unchanged.[41] Slow para-hydroxylation has been identified in some families
and may be a risk factor for slow phenytoin metabolism and toxicity.[51] In pregnancy, phenytoin clearance
increases, often more than doubling, causing decreases in plasma phenytoin concentrations and changes in
dose requirements.
The metabolism of phenytoin is best described by Michaelis-Menten kinetics. At low concentrations (0–10
µg/mL), metabolism is a first-order process and a fixed percentage of drug is metabolized in a given time.
The effective half-life at these concentrations is 16 to 19 hours.[19] At higher doses, often in the high
therapeutic range, metabolic pathways become saturated; and small increases in dose may lead to large
increases in plasma concentrations. At this point, a fixed amount of drug is metabolized for a given unit of
time (zero-order kinetics); therefore, “half-life” is not a strictly correct term in these circumstances. The
Michaelis-Menten kinetics may in part account for the large reported range of “half-lives” of 7 to 60 hours.[5]
Pathophysiology
The mechanism of action of phenytoin is not completely clear. Phenytoin appears to inhibit neuronal high-
frequency firing by reducing the ability of sodium (Na+) channels to recover from inactivation.[36] Thus, at
high-frequency firing rates, the neuron becomes refractory to reactivation. Phenytoin may also inhibit
calcium (Ca2+ ) fluxes, modify Na+ and potassium (K+) transport, increase brain -aminobutyric acid (GABA)
levels, and potentiate GABAA-mediated postsynaptic inhibition.[12] The exact role each of these mechanisms
may play in seizure suppression is not clear.
Phenytoin also affects cardiac conduction, decreasing the automaticity of the sinoatrial node and ventricular
pacemakers, prolonging the effective refractory period, and increasing the atrioventricular conduction. These
properties place it with lidocaine as a type 1b antidysrhythmic agent. [18] Along with most other
anticonvulsants, it induces hepatic cytochrome P-450 mixed function oxidases. Phenytoin may also inhibit
insulin release, leading to hyperglycemia in rare instances.


Acute Toxicity
Acute phenytoin toxicity usually results from intentional medication overdose. Occasionally, acute toxicity
may be iatrogenically produced with an excessive loading dose of phenytoin or a loading dose in the face of
therapeutic or toxic phenytoin concentrations. Occasional case reports also describe acute intoxication when
phenytoin is mixed with crack cocaine or marijuana and smoked in an attempt to produce a superior
“high.”[24][54] As serum phenytoin concentrations rise, patients usually experience a continuum of symptoms
( Table 58–1 ). At lower concentrations, ocular and vestibulocerebellar abnormalities are prominent,
including nystagmus, dizziness, and ataxia. At higher phenytoin concentrations, the CNS is increasingly
affected and coma may occur after large ingestions. Death rarely results from isolated oral phenytoin
toxicity. In a review of fatal case reports, death usually appears to result from respiratory complications and
typically involves co-ingestion of other substances. [37]
Table 58-1 -- Clinical Presentation of Phenytoin Toxicity

Vital Signs
Bradycardia
Tachycardia
Fever
Decreased respirations
Hypotension
Ataxia
Confusion
Weakness
Hypotonia
Tremor
Babinski reflex
Slurred speech
Choreoathetosis
Nystagmus
Diplopia
Hypo/hyperreflexia
Lethargy
Coma
Gastrointestinal
Nausea
Vomiting
Cardiovascular
Bradycardia
Tachycardia
Hypotension
Dermatologic
Hypertrichosis
Morbilliform/scarlatiniform rash
Bullous/exfoliative/purpuric dermatitis
Stevens-Johnson syndrome
Psychiatric
Hallucinations
Euphoria
Irritability
Developmental/Carcinogenic
Fetal hydantoin syndrome
Neurologic Findings
Nystagmus is the most common ocular finding in phenytoin toxicity and may occur at therapeutic doses,[37]
although absence of this finding does not rule out toxicity.[42] Nystagmus is usually elicited during lateral
horizontal gaze; however, spontaneous horizontal or vertical nystagmus may be seen in more severely
intoxicated patients. Other ocular findings may include diplopia and blurred vision. Pupils may be large,
small, or midposition, and pupillary light reflexes may also be variable. Absent corneal, oculocephalic, and
oculovestibular reflexes may be seen in severely poisoned patients.[37]
In more significantly intoxicated patients, other neurologic findings such as truncal and peripheral ataxia may
develop and may be accompanied by dizziness, vertigo, and dysarthria. Progressive CNS depression may
occur; however, fluctuating agitation and lethargy have also been described. [37] In severe cases, coma may
develop. Deep tendon reflexes may be increased, decreased, or variable. Clonus has been described and
an abnormal Babinski response may be seen. Movement disorders, including choreoathetosis, dystonia,
ballismus, and intermittent opisthotonus, occur rarely.[1] Psychiatric symptoms associated with phenytoin
intoxication may include confusion, depression, and visual, tactile, and auditory hallucinations.[6] Some
patients may develop a fine tremor that may or may not have an intention component.
The concept of paradoxical seizures after phenytoin overdose remains controversial.[16] Most reported cases
describe an increased frequency of seizure activity over several days to weeks associated with elevated
serum phenytoin concentrations. However, other variables that could potentially contribute to increased
seizure frequency are incompletely described.[47][49] Seizure activity in the face of acute phenytoin overdose
is not commonly reported.[37] Seizures should prompt a search for co-ingestants or physiologic variables
such as hypoxia or electrolyte imbalance that may contribute to the picture.
Gastrointestinal Findings
Gastrointestinal findings commonly include nausea and vomiting. Therapeutic doses as low as 1 g (oral
loading dose) are commonly associated with vomiting. Hepatitis is usually not seen in acute intoxication,
although transient elevations in lactate dehydrogenase and aspartate aminotransferase have been noted.[37]
Cardiovascular Findings
The cardiovascular effects of intravenous and oral phenytoin preparations must be considered separately.
Oral phenytoin therapeutic use, toxicity, and overdose are rarely associated with cardiovascular effects of
clinical significance. A variable effect on atrioventricular conduction, sometimes manifested by PR segment
prolongation, has been described.[56] Bradycardia and rare reports of supraventricular tachycardia exist, but
the majority of the existing data suggests that oral phenytoin toxicity is not accompanied by significant
hypotension, cardiac conduction disturbances, or dysrhythmias.[56] Consequently, patients who require
admission for isolated phenytoin toxicity do not require a cardiac monitored bed.
The concern over cardiotoxicity results from reports of apnea, hypotension, bradycardia, dysrhythmias, high-
degree atrioventricular block, and death associated with intravenous phenytoin use.[45][52] These early
reports were substantiated by confirming this toxicity in animal models.[40] More recent data have implicated
the diluent, propylene glycol, as the cause of these significant cardiovascular effects. Intravenous infusion of
propylene glycol in cats caused hypotension, apnea, bradycardia, ST segment and T wave changes,
atrioventricular block, and asystole.[30] The cardiac rhythm disturbances of propylene glycol appeared to be
attenuated by pretreatment with phenytoin in this model. However, infusion of phenytoin without propylene
glycol also caused mild hypotension and bradycardia. The consensus is that the severe cardiac toxicity from
intravenous phenytoin is secondary to the propylene glycol diluent and is probably related to rate and
concentration of infusion and possibly to total dose as well. Current recommendations suggest infusion rates
no faster than 50 mg/min, although rates from 25 to 40 mg/min have been recommended, especially for the
elderly and those with preexisting cardiac disease.[17][50] It has also been recommended that the
concentration of phenytoin for infusion not exceed 6.7 mg/mL.[17] These caveats may no longer apply if
parenteral preparations of phenytoin are replaced by fosphenytoin. Because fosphenytoin does not contain
the propylene glycol excipient, it is expected to lack the significant cardiovascular toxicity of intravenous
phenytoin. However, this remains to be confirmed by more extensive clinical experience.
Other Effects
Endocrine and metabolic effects are occasionally attributed to phenytoin. Phenytoin use and toxicity have
been associated with hyperglycemia in both diabetic and nondiabetic patients.[9][25] Hypernatremic coma
presumed secondary to phenytoin intoxication has been reported.[31]
Chronic Toxicity
Chronic phenytoin intoxication may develop when maintenance doses are increased because enzyme
systems are saturated at serum concentrations within the therapeutic range. Therefore, a small increase in
dose may be accompanied by a large increase in plasma concentration. Because the effective “half-life” is
so long when enzymes are saturated, the steady state may not occur for 1 to 2 weeks. Thus, toxicity may
occur many days after the dose is increased, making the diagnosis more difficult.
Toxicity may also develop when protein binding of the drug is decreased, thus increasing the free, active
fraction of the drug in the serum. Increased free phenytoin fraction may occur from hypoalbuminemia or
displacement from albumin by other drugs. Chronic toxicity may also occur from altered hepatic drug
metabolism, usually drug induced. A large number of potential drug-drug interactions must be considered in
the patient receiving phenytoin therapy ( Table 58–2 ). Phenytoin induction of the cytochrome P-450 system
may lead to decreased plasma concentrations of some medications. Conversely, other medications that
induce the cytochrome P-450 system may lead to decreased phenytoin concentrations. Drugs that inhibit the
cytochrome P-450 system may lead to phenytoin toxicity. Some drugs, such as phenobarbital, may induce
the microsomal system but also inhibit phenytoin inactivation, leading to variable and unpredictable results
regarding phenytoin metabolism.
Table 58-2 -- Phenytoin Drug Interactions

Reported to Decrease Concentrations
Concentrations
Reported to Increase Phenytoin Increased by
Decreased by Phenytoin
Phenytoin Concentrations Concentrations Phenytoin
Co-trimoxazole Ethanol Phenobarbital Digitoxin
Sodium valproate Phenobarbital Dexamethasone
Cimetidine Carbamazepine 25-Hydroxycholecalciferol
Isoniazid Theophylline Carbamazepine
Disulfiram Theophylline
Warfarin Furosemide
Ibuprofen Levodopa
Amiodarone Doxycycline
Salicylic acid (increases free
fraction by displacing from Cortisol
plasma protein)
Phenylbutazone (increases free
fraction by displacing from Oral contraceptives
plasma protein)
Chloramphenicol Methadone
Methylphenidate Quinine
Chlordiazepoxide
Diazepam
Reported to Decrease Concentrations
Concentrations
Reported to Increase Phenytoin Increased by
Decreased by Phenytoin
Phenytoin Concentrations Concentrations Phenytoin
Sulfamethizole
Ethosuximide
Chlorpromazine
Prochlorperazine
Propoxyphene
Phenobarbital
Ethanol
Dicoumarol
Imipramine
Miconazole
Thioridazine
Patients with chronic phenytoin intoxication usually present with many of the same signs and symptoms as
those with acute intoxication. CNS and psychiatric findings may be more prominent, especially in the elderly
and in patients with underlying CNS pathology. The insidious development of symptoms in chronic
intoxication may make the diagnosis of phenytoin toxicity more difficult in these circumstances. Populations
particularly at risk include institutionalized, developmentally delayed patients, or others who may be difficult
to assess for confusion or lethargy. Elevated phenytoin concentrations and/or signs of toxicity have been
detected in 14.8 to 55 per cent of institutionalized mentally retarded patients receiving phenytoin.[2]
Serious Adverse Effects
A rare, acute pulmonary hypersensitivity angiitis secondary to phenytoin may occur but appears to be
reversible when treated with corticosteroids.[39] A rash may occur in 5 to 54 per cent of patients and appears
to be more common in children.[55] These rashes may range in severity from simple exanthems to Stevens-
Johnson-type fatal illnesses. A constellation of findings including rash, fever, lymphadenopathy, and
hepatitis has been described and named the “phenytoin syndrome.”[48] Most reported cases involve African-
American patients and are temporally associated with at least several weeks of phenytoin therapy without
toxic plasma concentrations. The causal relationship has not been persuasively established.
Fetal Hydantoin Syndrome
Phenytoin use during pregnancy has been associated with the fetal hydantoin syndrome, which is
characterized by prenatal and postnatal growth insufficiency, microcephaly, and mental retardation.[20]
Specific abnormalities include midfacial hypoplasia, hypertelorism, flattened philtrum, and shortened nose[53]
(see Fig. 12–1 ). It has been estimated that 11 per cent of infants exposed to phenytoin in utero will develop
the full syndrome but another 30 per cent may develop minor findings.[20][46] The relationship between these
abnormalities and phenytoin use continues to be debated. It is hypothesized that the mechanism of
maldevelopment may involve anticonvulsant-mediated reduction in folic acid.[7] Animal data suggest that
phenytoin therapy during pregnancy may also be responsible for learning disabilities.[53] Because of the
potential adverse effects of maternal seizure activity during pregnancy, phenytoin is not contraindicated.
Rather, a careful risk and benefit assessment should be made by the neurologist and obstetrician. It has
been suggested that phenytoin is associated with prenatal development of neuroblastoma, but
epidemiologic studies have produced conflicting results.[26]
Pediatric
Phenytoin intoxication in the pediatric population closely resembles that seen in the adult patient. However,
the findings of ataxia and nystagmus may be difficult to test in an infant or preambulatory child. Phenytoin
intoxication in this age group may be manifested by lethargy, hypotonia, poor feeding, and delay in achieving
developmental milestones.[29] Similar diagnostic difficulties arise in the developmentally delayed child
receiving phenytoin. In these cases, neurologic complaints and vague systemic complaints such as
weakness, fatigue, or feeding problems merit measuring serum phenytoin concentrations. In school-age
children, ataxia, headache, blurred vision, and poor school performance may indicate phenytoin toxicity.
Phenytoin is excreted in breast milk, and methemoglobinemia, drowsiness, and decreased sucking activity
have been reported.[18]


The differential diagnosis of phenytoin intoxication includes substances and disease entities that might
produce the typical picture of nystagmus, ataxia, slurred speech, and mental status changes ( Table 58–3 ).
Most of the other anticonvulsants will produce these signs and symptoms and, because they are often
available to the seizure patient, intoxication with these agents should be suspected and drug levels assayed
when feasible. Other sedative/hypnotic agents including benzodiazepines, ethanol and the other alcohols,
chloral hydrate, glutethimide, and meprobamate may produce similar symptoms. Muscle relaxants, including
carisoprodol, baclofen, and methocarbamol, and psychiatric medications, such as the cyclic antidepressants
and the selective serotonin reuptake inhibitors, may also produce lethargy, nystagmus, and ataxia. Cyclic
antidepressants, however, are often accompanied by tachycardia, other anticholinergic findings, and
electrocardiographic abnormalities that should make the clinical diagnosis possible. Ketamine and
phencyclidine may cause this symptom-complex, but it may also be accompanied by significant behavioral
abnormalities and miosis. Carbon monoxide poisoning should also be suspected, especially if accompanied
by a suggestive exposure history. Cerebellar pathology, including hemorrhage, infarction, and tumor, should
be ruled out. Wernicke encephalopathy is classically described as ataxia, ophthalmoplegia, and mental
status changes. It should be suspected in anyone at risk for thiamine depletion, including alcoholics or
chronically ill patients at risk for malnourishment. Hypoglycemia may present as any constellation of
neurologic findings.
Table 58-3 -- Differential Diagnosis of Phenytoin Toxicity

Other Medications
Carbamazepine
Phenobarbital
Gabapentin
Lamotrigine
Valproic acid/derivatives
Primidone
Felbamate
Ethosuximide
Benzodiazepines
Ethanol
Ketamine
Phencyclidine
Baclofen
Carbon monoxide
Ethylene glycol
Glutethimide
Methyprylon
Methaqualone
Carisoprodol
Chloral hydrate
Lithium
Other Pathologic Processes
Wernicke encephalopathy
Cerebellar pathology
Hemorrhage
Infarct
Mass
Infection
Hypoglycemia


LABORATORY STUDIES
Serum phenytoin concentrations should be obtained in any case of suspected phenytoin overdose or in
patients on chronic therapy who present with signs and symptoms of toxicity. In acute overdose, because of
the potential for delayed absorption, serial phenytoin concentrations are recommended. In some cases,
absorption has continued for days after ingestion.[11] Phenytoin concentrations obtained before absorption
may lead to erroneously concluding that a nontoxic dose has been ingested. If phenytoin concentrations are
nondetectable or very low, screening for other available or suspected anticonvulsants such as phenobarbital,
carbamazepine, and valproic acid may be useful if signs of toxicity are present. In cases of chronic toxicity, if
continued absorption is unlikely, serial levels during the initial evaluation are not necessary. Toxicity has also
been described in patients with therapeutic total phenytoin concentrations but elevated free phenytoin
concentrations.[28] Hypoalbuminemic patients or patients receiving medications that displace phenytoin from
albumin should have free phenytoin concentrations measured if the clinical picture suggests toxicity but
does not correlate with total phenytoin concentrations.[28] Phenytoin concentrations in hair and saliva appear
to correlate with plasma concentrations but have a limited role in the management of intoxication.[2]


TREATMENT
General
Supportive care comprises the initial treatment of a patient with acute or chronic phenytoin toxicity ( Table
58–4 ). Because of the possibility of co-ingestants, patients with acute overdose should be placed on a
cardiac monitor during the initial evaluation. The rare cases of death from acute phenytoin intoxication are
due to respiratory depression, so careful attention should be paid to airway management. If opioid
intoxication is suspected, naloxone, 1–2 mg, should be given intravenously and known or suspected
hypoglycemia should be assessed with rapid glucose determination or treated empirically with intravenous
dextrose. Because Wernicke encephalopathy can mimic acute or chronic phenytoin toxicity, 100 mg of
thiamine should be administered either intravenously or intramuscularly. Because many patients with
possible phenytoin intoxication have a seizure disorder, the diagnostic or therapeutic use of flumazenil is
contraindicated because of the risk of precipitating seizures. Ataxia is a common finding, so patients should
be confined to bed or allowed up only with assistance to prevent potential falls and subsequent trauma.
Table 58-4 -- Treatment of Phenytoin Toxicity

Supportive care with attention to ABCs—airway, breathing, circulation
Bed rest and supervised activity until ataxia resolves
Cardiac monitoring is not required
Gastric decontamination
Consider gastric lavage for early presentation with very large amounts and intubated patients
Activated charcoal, 1 g/kg (maximum, 50–100 g/dose) PO
Consider repeat dose activated charcoal, 25–50 g PO every 2–6 hours, until toxicity is resolving and levels are
falling
Consider a single dose of cathartic
Seizures:
Diazepam, 5–10 mg IV in adults, 0.2–0.5 mg/kg IV in children
Lorazepam, 0.5–2 mg IV in adults, 0.05 mg/kg IV in children
Phenobarbital, 10–20 mg/kg IV in adults and children
In massive ingestions, or ingestions accompanied by severe signs of intoxication, gastric lavage can be
considered. Activated charcoal is the mainstay of gastrointestinal decontamination after phenytoin overdose
and may theoretically be effective even hours after ingestion. An initial dose of cathartic may be
administered. The time interval after which gastric lavage is no longer likely to be effective after phenytoin
ingestion remains to be determined. Because of the potential of ingestion of delayed-release forms as well
as the slow dissolution and absorption of phenytoin, lavage several hours after ingestion may result in drug
recovery, but its effect on outcome has not been conclusively determined.
The efficacy of multiple doses of activated charcoal has not been established. The delayed absorption
characteristics of phenytoin suggest that multiple-dose activated charcoal might prevent further absorption.
The low apparent volume of distribution of phenytoin suggests a role for multiple-dose activated charcoal in
enhancing clearance of absorbed drug, because significant amounts of drug might be found in the plasma.
However, the high protein binding of phenytoin suggests that multidose charcoal would not be effective.
Multiple doses of activated charcoal increased phenytoin clearance in volunteers receiving therapeutic
doses of intravenous phenytoin.[34][43] However, no studies have evaluated whether this increase in
clearance will result in a clinically significant shortening of duration of toxicity. The risks of ileus and
pulmonary aspiration after multiple doses of charcoal must be weighed against the expected benefits when
considering multidose charcoal therapy.
Neurologic/Cardiovascular Complications
Seizures should be treated with benzodiazepines or barbiturates. Significant cardiovascular toxicity

secondary to propylene glycol may occur during intravenous phenytoin infusion, including bradycardia and
first-degree heart block, and should be treated by slowing or stopping the infusion. Symptomatic bradycardia
may be treated with atropine sulfate, 0.5–2.0 mg intravenously, and hypotension may be treated with
crystalloid infusion. If the hypotension is unresponsive to crystalloid infusion, vasopressors such as
dopamine or norepinephrine should be added; however, they are rarely required. Cardiac arrest is treated
according to advanced cardiac life support protocol for the specific dysrhythmia. Nystagmus, dizziness,
ataxia, and somnolence may require slowing or stopping the infusion. Fosphenytoin has not been
associated with clinically significant hypotension or cardiac conduction defects in healthy volunteers at
infusion rates up to 150 mg/min.[10] Adverse effects seen with fosphenytoin include paresthesias,
nystagmus, dizziness, headache, and drowsiness and are believed to be due to subsequent metabolism to
phenytoin.
Other Methods
There is no proven role for extracorporeal drug removal in the therapy for phenytoin toxicity. Cases
describing the use of peritoneal dialysis, plasmapheresis, hemodialysis, and charcoal hemoperfusion all
report minimal drug clearance.[4][14][27][44] There are no specific antidotes for phenytoin toxicity.


DISPOSITION
Discharge
Because of the delayed absorption of phenytoin, an abbreviated observation period is not suitable. If there is
no evidence of developing clinical toxicity and serial serum phenytoin concentrations are not elevated or
increasing after acute overdose, the patient can be considered for discharge after 6 to 8 hours of
observation. The major risks of mild phenytoin intoxication are ataxia and falling, with subsequent injury. If
the support services and social situation are adequate to ensure observation and assistance with
ambulation, mild toxicity can be managed on an outpatient basis with careful follow-up.[13] Candidates for
outpatient management should be carefully screened. Many patients receiving phenytoin also have
developmental abnormalities that might make detection of signs of increasing toxicity difficult and may place
them at higher risk for falling and injury. Patients and caregivers should be informed of the possibility of
delayed intoxication, the signs and symptoms of toxicity, and the possible need for re-evaluation.
Patients with mild chronic intoxication can be discharged home after phenytoin concentrations have been
measured as long as there is no concern about rising plasma concentrations. The patient should be able to
ambulate without difficulty or, if minimally ataxic, have adequate assistance at home. Phenytoin should be
withheld until signs and symptoms of intoxication have resolved and plasma concentrations are therapeutic.
Measuring a phenytoin concentration in 24 to 48 hours may be helpful in deciding when to restart therapy.
Many patients with chronic toxicity will require a dosage adjustment. This should be done in conjunction with
a primary care provider because close follow-up and repeat phenytoin levels will be required.
Admission
Hospitalization should be considered for patients with significant ataxia, seizures, CNS depression, or a
significant potential to develop these symptoms over the next 24 to 48 hours. Mildly intoxicated patients with
a potentially significant ingestion and the possibility of deterioration should also be admitted. Mild to
moderately intoxicated patients may be admitted to a nonmonitored ward if there are no confounding
medical or psychiatric issues that would merit more intensive monitoring. More severely intoxicated patients
may require admission to an intensive care unit for observation and supportive care. Patients who are toxic
from oral phenytoin do not require admission specifically for cardiac monitoring. Patients who present with
seizures and phenytoin toxicity should be admitted while alternative anticonvulsant medications are given as
needed. Suicidal patients should undergo psychiatric evaluation.


SEQUELAE
Acute
Most cases of acute phenytoin intoxication will completely resolve if no significant hypotension, hypoxia, or
seizure activity occurs. Neurologic manifestations of phenytoin intoxication may require several months to
resolve and in some cases may persist even after phenytoin concentrations are no longer detectable.[1] It
has been suggested that acute intoxication may produce cerebellar degeneration, but this phenomenon
appears to be primarily associated with chronic use.[32][33]
Long-Term
Long-term phenytoin use is associated with a variety of adverse reactions. Perhaps the most widely
recognized side effect is gingival hypertrophy. It is estimated that between 40 and 50 per cent of patients
treated with phenytoin develop cosmetically significant gingival hypertrophy[22] attributed to overgrowth of
gingival fibroblasts.[21] Gingival hypertrophy may be minimized by meticulous dental hygiene.
Long-term therapy has been associated with several persistent neurologic syndromes, including peripheral
neuropathy and cerebellar degeneration. Most case series reporting the cerebellar degeneration syndrome
describe seizure patients who develop dysarthria, ataxia, nystagmus, and cerebellar atrophy on computed
tomography or magnetic resonance imaging after long-term therapy with phenytoin. However, other causes
of cerebellar degeneration such as concomitant medications, ethanol, and seizure-induced hypoxia could
not be ruled out.[35] It is controversial whether phenytoin causes direct toxicity and loss of Purkinje cells.[15]


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30. Louis S, Kutt H, McDowell F: The cardiocirculatory changes caused by intravenous dilantin and its
solvent. Am Heart J 1967; 74:523-529.
31. Luscher TF, Siegenthaler-Zuber G, Kuhlmann U: Severe hypernatremic coma due to DPH intoxication.
Clin Nephrol 1983; 20:268-269.
32. Masur H, Fahrendorf G, Oberwittler C, et al: Cerebellar atrophy following acute intoxication with
phenytoin. Neurology 1990; 40:1800.
33. Masur H, Elger CE, Ludolph AC, et al: Cerebellar atrophy following acute intoxication with phenytoin.
Neurology 1989; 39:432-433.
34. Mauro LS, Mauro VF, Brown DL, et al: Enhancement of phenytoin elimination by multiple-dose activated
charcoal. Ann Emerg Med 1987; 16:1132-1135.
35. McLain LW, Marin JT, Allen JH: Cerebellar degeneration due to chronic phenytoin therapy. Ann
Neurol 1980; 7:18-23.
36. McNamara JO: Drugs effective in the therapy of epilepsies.
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38. Merritt HH, Putnam TJ: Sodium diphenyl hydantoinate in the treatment of convulsive disorders.
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39. Michael JR, Rudin ML: Acute pulmonary disease caused by phenytoin. Ann Intern Med 1981; 95:452-
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40. Mixter CG, Moran JM, Austen WG: Cardiac and peripheral vascular effects of diphenylhydantoin
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41. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979; 4:153-169.
42. Riker WK, Downes H, Olsen GD, et al: Conjugate lateral gaze nystagmus and free phenytoin
concentrations in plasma: Lack of correlation. Epilepsia 1978; 19:93-98.
43. Rowden AM, Spoor JE, Bertino Jr JS: The effect of activated charcoal on phenytoin pharmacokinetics.
Ann Emerg Med 1990; 19:1144-1147.
44. Rubinger D, Levy M, Roll D, et al: Inefficiency of haemodialysis in acute phenytoin intoxication. Br J
Clin Pharmacol 1979; 7:405-407.
45. Russell M, Bousvaros G: Fatal results from diphenylhydantoin administered intravenously.

JAMA 1968; 206:2118-2119.
46. Seeler RA, Israel JN, Royal JE, et al: Ganglioneuroblastoma and the fetal hydantoin-alcohol sydrome.
Pediatrics 1979; 63:524-527.
47. Stilman N, Masdeu JC: Incidence of seizures with phenytoin toxicity. Neurology 1985; 35:1769-1772.
48. Tomsick RS: The phenytoin syndrome. Cutis 1983; 32:535-541.
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Epilepsia 1975; 16:753-758.
50. United States Pharmacopeia Dispensing Information 1999, 19th ed, vol 1. Drug Information for the
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51. Vasko MR, Bell RD, Daly DD: Inheritance of phenytoin hypometabolism: A kinetic study of one family.
52. Voigt GC: Death following intravenous sodium diphenylhydantoin. Johns Hopkins Med
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Uncited reference
Boucher BA: Fosphenytoin: A novel phenytoin prodrug. Pharmacotherapy 1996; 16:777-791.


Chapter 59 – Valproate and Selected Newer Anticonvulsants
SVEN A. NORMANN VINCENT C. SPERANZA GREGORY G. GAAR
Essentials
• Decreased level of consciousness
• Paradoxical seizures
• Nausea, vomiting, diarrhea
• Stable cardiovascular status
• Liver function abnormalities
VALPROIC ACID
Valproic acid, sodium valproate, and divalproex sodium are anticonvulsants that are structurally related.
These compounds are used either as monotherapy or with other anticonvulsants for treatment of
generalized tonic-clonic, absence, and myoclonic seizures.[32] They are approved for the treatment of the
manic phase of bipolar illness as well as for migraine headache. In the United States, oral forms include
capsules (250 mg valproic acid), a syrup (250 mg valproic acid/5 mL), a “sprinkle” capsule (125 mg
divalproex sodium), and a delayed-release tablet (125, 250, or 500 mg divalproex sodium delayed release).
An intravenous formulation of sodium valproate is available.
Pharmacology
The mechanism of action of valproic acid is not clearly established, and it may have multiple effects. It works
by increasing central nervous system (CNS) concentrations of -aminobutyric acid (GABA), either by
inhibiting the enzymes that catabolize GABA or by blocking the postsynaptic diffusion of GABA from
synaptic clefts.[28] It also prolongs the recovery of inactivated voltage-dependent sodium channels in a
manner similar to phenytoin and carbamazepine.
Oral absorption of valproic acid is rapid; peak plasma concentration occurs within 1 to 4 hours of a single
oral dose. Food in the gastrointestinal tract may slow the rate of absorption but does not affect the total
amount absorbed.[25] Divalproex sodium must dissociate in the jejunum for valproate to be absorbed. Thus,
the peak plasma level occurs 3 to 5 hours after a single oral dose[14]; it was delayed for 17 hours in one
overdose case.[24] At plasma concentrations of 80 µg/mL, 90 per cent of valproic acid is protein bound.[14][38]
Saturation of plasma proteins occurs at levels of 100 µg/mL or greater, thus increasing the “free” drug
fraction as the level increases.[25] The volume of distribution is 0.13 to 0.23 L/kg. The drug is extensively
metabolized, and some of the metabolites are biologically active and accumulate in plasma and CNS tissue.
Elimination follows first-order kinetics. The elimination half-life is normally 7 to 15 hours,[25][38] but it was
prolonged to 19 and 20 hours in two overdose cases.[4] It can also be prolonged in infants, the elderly, and
patients with hepatic dysfunction.[8][38]
Pathophysiology
Increased levels of GABA due to decreased or delayed metabolism may be responsible for the general CNS
depression seen after overdose. Valproate use can also elevate ammonia levels. This hyperammonemia
results from valproate-induced increases in propionic acid that inhibit carbamyl phosphate synthetase I, the
enzyme that catalyzes the initial reaction in the urea cycle.[12][13]
Toxicity may occur after acute ingestion of toxic amounts, during chronic therapy with appropriate doses, or,
as a rare, idiosyncratic reaction ( Table 59–1 ).
Table 59-1 -- Valproate Toxicity: Clinical Presentation

Central and Peripheral Nervous System Features
CNS depression
Decreased reflexes
Coma
Paradoxical seizures
Gastrointestinal Features
Nausea, vomiting
Diarrhea
Rare Findings
Pancreatitis
Hyperammonemia
Hepatic transaminase elevation
Hypernatremia, hyperkalemia, hypocalcemia
Acute Ingestion of Toxic Amounts
The clinical course after acute ingestion is variable and cannot be predicted solely from the amount
ingested. Symptoms of CNS depression, ranging from drowsiness to coma,[11] occur primarily. Respiratory
depression has been reported in comatose patients.[42] Loss of deep tendon reflexes has been seen,[17][23]
and pinpoint pupils may mimic opioid toxicity.[2] Paradoxical seizures may occur in patients with underlying
seizure disorders.[18][23] Other reported complications include cerebral edema[30] and fever.
Nausea, vomiting, and diarrhea can occur after acute intoxication. Although liver function test results may be
elevated with chronic use, hepatotoxicity is not associated with acute toxic ingestion. Acute pancreatitis
occurs rarely.[4]
Electrolyte abnormalities, including hypernatremia, hyperkalemia, and hypocalcemia,[4] have been rarely
reported. Acute changes in renal function are probably not a direct effect of valproic acid toxicity.[41]
Chronic Therapy with Appropriate Dosages
Patients receiving appropriate dosages may present with alterations in mental status such as drowsiness
and confusion. These alterations are associated with valproate serum levels greater than 100 µg/mL.
Seizure disorders may also worsen with higher levels.
Hyperammonemia without other liver function abnormalities has been associated with lethargy, ataxia,
stupor, and coma.[13][31] Nausea, abdominal pain, and vomiting have been noted.
Hematologic abnormalities have occurred with long-term single-agent therapy. Thrombocytopenia and
macrocytosis resolved after dosages were slightly reduced.[33] Pancytopenia is fortunately very rare.[39]
Rare, Idiosyncratic Reactions
Hepatotoxicity has been well documented in association with valproic acid therapy.[7] The mechanism of the
injury is unclear; liver damage is not often associated with the usual fever and rash that accompany
hypersensitivity reactions. In one of the most extensive reviews,[7] those at greatest risk appear to be
children younger than age 2 who are receiving multiple drugs including valproate. Those with metabolic
disorders or developmental delays also are at higher risk.[7] The reaction most often occurs during the initial
months of therapy. Changes in mental status, jaundice, emesis, and increased frequency of seizures are
seen in relation to the liver failure.
Pancreatitis is a serious complication that is not dose related. It has occurred early after institution of
therapy, after years of drug use, or rarely with overdose. Patients most often present with vomiting and
abdominal pain.[46]
Differential diagnoses are summarized in Table 59–2 .
Table 59-2 -- Valproate Toxicity: Differential Diagnosis

Hypoxia
Intracranial tumors
Metabolic disorders
Hypoglycemia
Diabetic ketoacidosis
Reye syndrome
Other drugs
Opioids
Barbiturates
Central a2-receptor agonists (e.g., clonidine)
Ethanol
Sedative-hypnotics
Postictal state
Laboratory Studies
An elevated quantitative serum valproate level helps confirm the diagnosis after other possible causes have
been excluded. In patients with seizure disorders using multiple medications, other quantitative
anticonvulsant levels can be useful. For patients ingesting divalproex sodium, serial levels are
recommended as the time to peak absorption is delayed.
Therapeutic serum levels are in the range of 50 to 100 µg/mL, although seizure control in some patients
requires higher levels. Plasma concentrations after acute overdose do not strictly correlate with clinical
outcome. After acute overdose, toxic effects have occurred at therapeutic concentrations.[45]
If valproate levels are not available, therapy should be based on the clinical presentation.
Patients exhibiting signs and symptoms consistent with valproate poisoning should have a complete blood
cell count; a basic metabolic panel to include determination of electrolyte, blood urea nitrogen, creatinine,
and glucose levels; and liver function tests. In cases of unexplained or persistent confusion, stupor, or coma,
a serum ammonia level should be checked. Serum amylase and lipase levels are indicated for signs and
symptoms of pancreatitis. Pulse oximetry and arterial blood gases should be done as clinically indicated.
Treatment
Acute Toxic Ingestion

Supportive therapy is the first priority ( Table 59–3 ). Patients who present with coma should have
appropriate interventions: airway management, administration of oxygen, circulatory assessment, bedside
glucose determination (and treatment if indicated), and intravenous access. As opioids paint a similar clinical
picture, naloxone, 0.4 to 2.0 mg, should be administered intravenously. Alberto and associates reported a
response to naloxone in a 22-year-old man,[2] and Steiman and colleagues reported similar results in a 19-
month-old child.[43] Naloxone may work by antagonizing GABA effects[15]; however, this has not been
consistently observed. [4]
Table 59-3 -- Valproate Toxicity: Treatment Essentials

Supportive care with attention to airway and ventilation
Activated charcoal
1 g/kg orally. Multiple doses may increase elimination
Syrup of ipecac not indicated
Gastric lavage
May be considered if can be done within 60 minutes of ingestion of tablets, capsules, or delayed/sustained-
release preparation
Whole-bowel irrigation
Theoretically useful if compound is sustained-release or enteric-coated
Naloxone trial, 0.4–2 µg IV
Gastrointestinal decontamination is the next logical consideration. Activated charcoal adsorbs valproate in
vitro,[36] and 1 g/kg should be given soon after the ingestion. [3] If the patient’s weight is unknown, 50 to 100 g
is given to adults and 25 to 50 g is given to children, either orally or instilled through a nasogastric or
orogastric tube. Syrup of ipecac is contraindicated, owing to the expected development of decreased levels
of consciousness. Because the absorption of valproic acid and valproate sodium is rapid, gastric lavage will
have limited usefulness. It may be efficacious if undertaken within 60 minutes of ingestion, or if divalproex
was ingested. Whole-bowel irrigation has been suggested for sustained-release or enteric-coated
compounds and may be considered with divalproex sodium delayed-release tablets or coated particles in
capsules.[3]
High valproate concentrations have been measured in bile, and repeat doses of activated charcoal may
decrease enterohepatic recirculation of the drug. Continuous nasogastric infusion of activated charcoal, 0.25
to 0.50 g/kg/hr, decreased the elimination half-life of valproic acid in one overdosed patient.[19]
Hemodialysis and charcoal hemoperfusion have reportedly enhanced elimination in certain patients
refractory to other therapies.[20][24][29][34][41][44] Serum protein binding of valproic acid decreases as the
serum drug level increases above 100 µg/mL. [19] The resulting increase in free drug coupled with a low
volume of distribution and low molecular weight (144.21 g/Mol) of valproate enhance the effectiveness of
extracorporeal removal. These treatment modalities are rarely used but might prove useful in patients with
renal failure, persistent coma, or severe metabolic abnormalities. However, no controlled trials demonstrate
that clinical outcome is improved by using any of these measures for decreasing absorption or enhancing
elimination.
Other Measures
There is no specific antidote available for poisoning due to valproate. Valproate and other medications that
might cause hepatotoxicity or CNS depression should be discontinued. In patients with underlying seizure
disorders, care should be taken not to overshoot drug elimination and produce a subtherapeutic drug level.
Seizures might occur and can be treated with appropriate doses of benzodiazepines such as lorazepam or
diazepam.
Chronic Therapy with Appropriate Dosages
For patients taking usual dosages who develop alterations in mental status, valproate levels should be
obtained, the drug held, and lower dosages considered. Hematologic or hepatic toxicity should be
monitored, supportive care provided, and other anticonvulsants considered.
Disposition
Patients who ingest preparations that are rapidly absorbed should be monitored for neurologic depression
and observed for at least 6 hours after ingestion. They can be discharged from the hospital if they remain
asymptomatic, have responsible caregivers, and can reaccess medical care later if necessary. Patients
ingesting delayed-release or enteric-coated preparations should have an initial blood level drawn and should
be monitored for a minimum of 12 hours. If a second level is decreasing and there are no clinical signs or
symptoms of toxicity, the patient can be discharged for home observation with the same precautions.
Patients with ingestions of multiple drugs should be treated as clinically indicated by the combination of
agents. Patients who have or develop altered levels of consciousness or other signs and symptoms of
toxicity should be admitted into an intensive care unit for observation and good supportive care. Patients
with intentional ingestions should have psychiatric evaluation before their release from the health care
facility.
Sequelae
The morbidity and mortality associated with acute overdosage of valproate is primarily related to hypoxia
and metabolic derangements. Visual disturbances were reported in one patient who had a prolonged
comatose state.[5]


NEWER ANTICONVULSANT AGENTS
Experience with toxicity due to acute overdose of the new anticonvulsant medications is limited. The kinetics
of these drugs are summarized in Table 59–4 , and the clinical signs and symptoms of these overdoses are
given in Table 59–5 .
Table 59-4 -- Pharmacokinetics of Newer Anticonvulsants

Volume of Peak Half- Therapeutic
Oral Distribution Protein Levels Life Serum
Dosing (day) Absorption (L/kg) Binding (hr) (hr) Elimination Levels
1200–3600 0.80 24% 1–4 20–24 Renal 50% 20–100 µg/L
Felbamate mg divided in
3–4 doses
Hepatic
50%
900–1800
Gabapentin mg divided in 0.70 0% 1–3 5–6 Renal 80% 2 µg/mL
3 doses 50–60%
50–400 mg in Hepatic
Lamotrigine 98% 1.10 55% 1–4 24 2–4 µg/mL
one dose 50%
200–400 mg
Topiramate divided in 2 0.7 15% 2–4 20 Renal 60% 30 µg/mL
doses 85%
Table 59-5 -- Newer Anticonvulsants: Clinical Presentation

Lethargy, dizziness
Generally safe and non–life-threatening
Status epilepticus after topiramate
Felbamate
Felbamate (Felbatol) was introduced in 1993 for use in adults with partial seizures or in children with
Lennox-Gastaut syndrome. Approximately 1 year later, 10 cases of aplastic anemia had been reported in the
approximately 100,000 patients who had used the drug; the U.S. Food and Drug Administration strongly
urged physicians to suspend its use.[1] It has now been associated with hepatic toxicity as well[37] and is only
recommended in patients whose condition is refractory to treatment with other anticonvulsants.
Two cases of acute overdose have been reported in the literature. Both patients were being treated with
felbamate for seizure control. Symptoms manifested as CNS changes ranging from somnolence to agitation,
ataxia, and downbeat nystagmus. [27][35] The patients were treated supportively and recovered.
Gabapentin
Gabapentin (Neurontin) is used in partial seizures with or without secondary generalization. It has been well
tolerated; choreoathetotic movements and facial dyskinesias were reported during therapy.[10] After acute
overdose, lethargy, dizziness, slurred speech, and diplopia are described in the relatively limited case
reviews. Patients did not have life-threatening complications. Treatment was supportive and symptoms
resolved over periods of 12 to 18 hours. No sequelae have been noted.[21][22]
Lamotrigine
Lamotrigine (Lamictal) has been used as adjunctive therapy in the treatment of partial seizures. Rash has
been often reported as an adverse effect, similar to many other anticonvulsants.[16][40] Headache, ataxia,
and dizziness were reported in the initial clinical trials.
Few cases of toxic ingestion are reported; most are suicide attempts with dosages up to 3 g. Drowsiness,
dizziness, nystagmus, and ataxia were reported. Loss of deep tendon reflexes has been observed.
Gastrointestinal effects included nausea and vomiting. No respiratory depression was seen. Symptoms
resolved over 24 to 48 hours with drug withdrawal and symptomatic, supportive therapy.[6][9][26]
Topiramate
Topiramate (Topimax) is used as adjunctive therapy for partial seizures. In five overdose cases with
ingestions ranging from 1.8 to 100 g, all of the patients had confusion, ataxia, lethargy, and memory lapse.
One patient was unresponsive, and the patient with the largest overdose had status epilepticus. All patients
received supportive care and recovered without sequelae (manufacturer’s information).
Treatment
The limited information available regarding poisoning with the newer agents suggests that symptomatic and
supportive care has been successful in those cases reported. Careful attention to appropriate
gastrointestinal decontamination and support of vital functions is indicated. Disposition of patients depends
on the intent of the poisoning as well as on the clinical circumstances.


REFERENCES
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responsive to naloxone. Ann Emerg Med 1989; 18:889-891.
3. American Academy of Clinical Toxicology and European Association of Poison Centres and Clinical
Toxicologists: Position Statements on Gastrointestinal Decontamination. J Toxicol Clin
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4. Anderson GO, Ritland S: Life threatening intoxication with sodium valproate. J Toxicol Clin
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5. Biegler D: Neurological sequelae after intoxication with sodium valproate. Acta Neurol
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6. Blankenhorn V, Hoffman HG, Polatschek B: Acute intoxication with the new antiepileptic drug lamotrigine
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7. Bryant AE, Dreifuss FE: Valproic acid hepatic fatalities: III. US experience since 1986.
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8. Bryson SM, Verma N, Scott PJW, et al: Pharmacokinetics of valproic acid in young and elderly subjects.
Br J Clin Pharmacol 1983; 16:104-105.
9. Buckley NA, Whyte IM, Dawson AH: Self-poisoning with lamotrigine. Lancet 1993; 342:1552-1553.
10. Buetefisch CM, Guiterrez A, Gutmann L: Choreoathetotic movements: A possible side effect of
gabapentin. Neurology 1996; 46:851-852.
11. Chadwick DW, Cumming WJK, Livingston MB, et al: Acute intoxication with sodium valproate. Ann
Neurol 1979; 6:552-553.
12. Coulter DL, Allen RJ: Secondary hyperammonemia: A possible mechanism of valproate
encephalopathy. Lancet 1980; 1:1310.
13. Coulter DL, Allen RJ: Hyperammonemia with valproic acid therapy. J Pediatr 1981; 99:317-319.
14. Davis R, Peters DH, McTavish D: Valproic acid: A reappraisal of its pharmacological properties and
clinical efficacy in epilepsy. Drugs 1994; 47:332-372.
15. Dingledine R, Iversen LL, Breuker E: Naloxone as a GABA antagonist: Evidence from iontophoretic,
receptor binding and convulsant studies. Eur J Pharmacol 1978; 47:19-27.
16. Dooley J, Camfield P, Gordon K, et al: Lamotrigine-induced rash in children. Neurology 1996; 46:210-
242.
17. Dupuis RE, Lichtman SN, Pollack GM: Acute valproic acid overdose: Clinical course and
pharmacokinetic disposition of valproic acid metabolites. Drug Safety 1990; 5:65-71.
18. Eeg-Olofsson O, Lindskog U: Acute intoxication with valproate. Lancet 1982; 1:1306.
19. Farrar HC, Herold DA, Reed MD: Acute valproic acid intoxication: Enhanced drug clearance with oral
activated charcoal. Crit Care Med 1993; 21:299-301.
20. Fernandez MC, Kloster JC, O’Brien SM, et al: Hemodialysis and hemoperfusion for treatment of valproic
acid and gabapentin poisoning. Vet Hum Toxicol 1996; 38:438-442.
21. Fischer JH, Barr AN, Rogers L, et al: Lack of serious toxicity following gabapentin overdose.
Neurology 1994; 4:982-983.
22. Garafalo E, Koto E, Feuerstein T: Experience with gabapentin overdose: Five case studies.
Epilepsia 1993; 34:157.
23. Garnier R, Boudignat O, Fournier PE: Valproate poisoning. Lancet 1982; 2:97.
24. Graudins A, Aaron CK: Delayed peak serum valproic acid in massive divalproex overdose: Treatment
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25. Gugler R, von Unruh GE: Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet 1980; 5:50-
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26. Harchelroad F, Lang D, Valeriano J: Lamotrigine overdose. Vet Hum Toxicol 1994; 36:372.
27. Hwang TL, Still CN, Jones JE: Reversible downbeat nystagmus and ataxia in felbamate intoxication.
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28. Hyden H, Cupello A, Palm A: Naloxone reverses the inhibition by sodium valproate of GABA transport
across the Deiters’ neuronal plasma membrane. Ann Neurol 1987; 21:416-417.
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30. Khoo SH, Leyland MJ: Cerebral edema following acute sodium valproate overdose. J Toxicol Clin
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31. Kulick SK, Kramer DA: Hyperammonemia secondary to valproic acid as a cause of lethargy in a
postictal patient. Ann Emerg Med 1993; 22:610-612.
32. Mattson RH, Cramer JA, Colllins JF, et al: A comparison of valproate with carbamazepine for the
treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. N Engl J
Med 1992; 327:765-771.
33. May RB, Sunder TR: Hematologic manifestations of long-term valproate therapy.
Epilepsia 1993; 34:1098-1101.
34. Mortensen PB, Hansen HE, Pedersen B, et al: Acute valproate intoxication: Biochemical investigations
and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol 1983; 21:64-68.
35. Nagel TR, Schunk JE: Felbamate overdose: A case report and discussion of a new antiepileptic drug.
36. Neuvonen PJ, Kannisto H, Hirvisalo EL: Effect of activated charcoal on absorption of tolbutamide and
valproate in man. Eur J Clin Pharmacol 1983; 24:243-246.
37. O’Neill MG, Perdun CS, Wilson MB, et al: Felbamate associated fatal hepatic necrosis.
Neurology 1996; 46:1457-1459.
38. Pinder RM, Brogden RN, Speight TM, et al: Soldium valproate: A review of its pharmacological
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40. Richens A: Safety of lamotrigine. Epilepsia 1994; 35(Suppl):537-540.
41. Roodhooft AM, Van Dam K, Haentjens D, et al: Acute sodium valproate intoxication: Occurrence of
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42. Schnabel R, Rambeck B, Janssen F: Fatal intoxication with sodium valproate. Lancet 1984; 1:221-
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44. Tank JE, Palmer BF: Simultaneous “in series” hemodialysis and hemoperfusion in the management of
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Chapter 60 – Antivirals
RACHEL L. CHIN
Overdoses of antiviral agents are uncommon, and cases have been reported in the literature only rarely.
Most antivirals are relatively benign, and overdoses generally reflect an exaggeration of their usual adverse
effects ( Table 60–1 ). Pharmacokinetic profiles of these drugs are found in Table 60–2 , and these agents
are classified according to clinical toxic effects in Table 60–3 .
Table 60-1 -- Antivirals: Uses, Clinical Effects, and Treatment

Class Therapeutic Use Adverse Effects Overdose Effects Treatment
Antiherpesvirus
Nephrotoxicity and
Ophthalmic herpes
Crystalline nephropathy, neurotoxocity (altered
zoster, herpes
gastrointestinal sensorium, tremor, Hydration,
Acyclovir simplex virus (HSV),
symptoms, rash, myoclonus, delirium, hemodialysis
varicella-zoster virus
headache seizures, extrapyramidal
(VZV) infection
signs)
Hemolytic-uremic
Primary and syndrome/thrombotic
Valacyclovir NR Supportive
recurrent HSV thrombocytopenic
purpura
Headache,
Uncomplicated
Famciclovir gastrointestinal NR Supportive
herpes zoster
symptoms
Severe
Granulocyte colony-
myelosuppression,
stimulating factor
Cytomegalovirus retinal detachment,
(G-CSF) or
(CMV) retinitis and hepatotoxicity, central
Ganciclovir NR granulocyte
other life-threatening nervous system
macrophage colony-
CMV infections symptoms (headache,
stimulating factor
behavior changes,
(GM-CSF)
seizures, coma)
Nephrotoxicity, hypo- or
hypercalcemia, hypo- or
hyperphosphatemia, Supportive; correct
CMV, VZV, and HSV
Foscarnet genital ulcerations, NR electrolyte
resistant to acyclovir
central nervous system imbalances
symptoms (headache,
irritability, seizures)
Irreversible
CMV resistant to
nephrotoxicity, Hydration,
Cidofovir ganciclovir and NR
neutropenia, metabolic supportive
foscarnet
acidosis, uveitis, iritis
Antiretrovirals
Myelosuppression,
headache, nausea,
Seizures, ataxia,
Human asthenia, abdominal
Zidovudine nystagmus,
immunodeficiency pain, rash, fever, Supportive
(AZT) myelosuppression,
virus (HIV) infection diarrhea, anorexia,
fatigue, lethargy
malaise, myalgia, toxic
myopathy
Painful peripheral
HIV strains resistant neuropathy, pancreatitis,
or intolerant to AZT headache, insomnia,
and also used gastrointestinal
Didanosine
concurrently with symptoms, rash, NR Supportive
(ddl)
AZT in patients with hyperuricemia,
advanced HIV thrombocytopenia,
disease hypokalemia, and
hepatotoxicity
HIV-infected patients Peripheral neuropathy,
intolerant to AZT and pancreatitis, rash,
Zalcitabine
also used hepatotoxicity, stomatitis, NR Supportive
(ddC)
concurrently with esophageal ulceration,
AZT fever, neutropenia
Treatment of
advanced HIV Painful peripheral
Stavudine
infection in patients neuropathy, anemia, NR Supportive
(d4T)
who are intolerant of arthralgia, fever, rash
AZT
Combination therapy Neutropenia, headache,
Lamivudine NR Supportive
for HIV, hepatitis B nausea
Hypersensitivity reaction
(fever, rash,
Combination therapy bronchospasm,
Abacavir NR Supportive
for HIV lymphadenopathy,
hypotension),
pancreatitis
Rash, Stevens-Johnson
Combination therapy
Delavirdine syndrome, erythema NR Supportive
for HIV
multiforme (rare)
Neutropenia, elevated
Combination therapy transaminases, hepatitis, Supportive, G-CSF
Nevirapine NR
for HIV rash, Stevens-Johnson for neutropenia
syndrome (rare)
CNS effects
(hallucinations, euphoria,
Combination therapy
Efavirenz impaired cognition, NR Supportive
for HIV
agitation, drowsiness),
rash
Anti-influenza Drugs
Neurotoxic reactions
including delirium,
Prophylaxis and Hydration; lidocaine
hallucinations, seizures,
treatment of for complex
and coma; cardiovascular
influenza A. Also ventricular ectopy;
effects including cardiac
used to treat Anticholinergic benzodiazepines for
Amantadine arrest, hypotension,
parkinsonism and symptoms seizures;
bradycardia, cardiac
neuroleptic-induced magnesium and
conduction disturbances,
extrapyramidal overdrive pacing for
malignant ventricular
symptoms torsades
dysrhythmias, torsades
de pointes
Prophylaxis and
Rimantadine treatment of Same as above NR Supportive
influenza A
Treatment of
condyloma
Acute febrile influenza-
acuminatum, chronic
like syndrome,
Interferon hepatitis B and C, NR Supportive
myelosuppression, and
Kaposi’s sarcoma,
neurotoxicity
and multiple
sclerosis
Mild conjunctival
irritation, rash, wheezing,
Treatment of
reversible deterioration in
respiratory syncytial
pulmonary function,
Ribavirin virus infections and NR Supportive
gastrointestinal
certain viral
symptoms, neurotoxicity,
hemorrhagic fevers
and bone marrow
suppression
Bronchospasm,
Uncomplicated
Zanamivir oropharyngeal edema, NR Supportive
influenza
rash
Uncomplicated
Oseltamivir Nausea, vomiting NR Supportive
influenza
Protease Inhibitors
Gastrointestinal
Treatment of HIV
Saquinavir symptoms, mild NR Supportive
disease
neutropenia, rash
Gastrointestinal
symptoms, anorexia,
altered taste, circumoral
and peripheral
Retonavir Same as above NR Supportive
paresthesias; increased
liver function tests,
creatine kinase, and
triglycerides
Gastrointestinal
Drowsiness, dizziness,
Indinavir Same as above symptoms, Supportive
nausea, paresthesias †
nephrolithiasis
Combination therapy Diarrhea, flatulence, LFT
Nelfinavir NR Supportive
for HIV abnormalities
Paresthesias, nausea,
Combination therapy
Amprenavir diarrhea, acute hemolytic NR Supportive
for HIV
anemia, hyperglycemia
NR, not reported.
† Other drugs co-ingested; see text.
Table 60-2 -- Antiviral Drugs: Pharmacokinetics

Time to Peak Elimination Half-
Drug Levels (hr) Metabolism Excretion Life (hr)
Antiherpesvirus agents
Renal: majority drug
Acyclovir 1.5–2.5 Hepatic: <15% 2–3
unchanged
RI+:20
Hepatic: to active drug,
Famciclovir <1 Penciclovir 2–3
penciclovir
Renal: 73%
Fecal: 27%
Ganciclovir Hepatic: minimal Renal: 94–99% 1.7–5.8
Unchanged RI+:9.3–29
Foscarnet None Renal Plasma: 3–6
Hepatic to active drug,
Valacyclovir 0.5 Renal: 45.6% 2–3
acyclovir
Fecal: 47.12%
Cidofivir NA Intracellular Renal 2.5
Antiretrovirals
Hepatic + renal Renal: metabolites +
Zidovudine 0.5–2 1–1.1
glucuronidation unchanged
Didanosine 0.5–1 Unknown Renal 0.8–2.7
DdATp = active
metabolite
Zalcitabine 1–2 Intracellular Renal: majority unchanged 1–3
Hepatic: minimal
Stavudine 0.5–1.5 Intracellular Renal 1–1.6
Other: unknown
Lamivudine 1–1.5 Hepatic: minimal Renal: majority unchanged 2–7
Abacavir 0.7–2 Hepatic Renal: 82% 1.5
Delavirdine 1 Hepatic Renal: 51% 5.8
Fecal: 44%
Nevirapine 4 Hepatic Renal: 80% 25–30
Fecal: 10%
Efavirenz 3–5 Hepatic Renal: 14–34% 40–55
Fecal: 16–61%
Lamivudine 0.5–2 None Renal 3–6
Anti-influenza drugs
Renal: majority drug
Amantadine 1–4 Hepatic: minimal Young: 10–31
unchanged
Elderly: 23–45
RI+:7–10 days
Rimantadine 2–6 Hepatic: extensive Renal: metabolites 20–37
RI+:48–72
Zanamivir 1–2 None Renal 2.5–5.1
Oseltamivir 1–4 Hepatic Renal 1–3
Renal, with tubular
Interferon IM: 3–6 Hepatic: minimal 2.3–5.5
proteolytic degradation
SQ: 6–8
Ribavirin 1–1.5 Intracellular Renal Adult: 24–35.5
Hepatic Child: 6.5–11
Protease inhibitors
Saquinavir 3 Hepatic Fecal 13
Ritonavir 2–4 Hepatic Fecal: 86.4% 3–3.5
Renal: 11.3%
Indinavir 0.8 Hepatic Fecal: 83% 1.8
Nelfinavir 2–4 Hepatic Fecal: 87% 3.5–5
Amprenavir 1–2 Hepatic Fecal: 75% 7.1–10.6
Renal: 14%
RI+, renal insufficiency/renal failure.
Table 60-3 -- Antiviral Drugs: Classification By Toxic Effects

Nausea, Vomiting Anemia
Acyclovir Acyclovir
Amantadine Ganciclovir
Amprenavir Lamivudine
Didanosine Ribavirin
Famciclovir Stavudine
Foscarnet Zidovudine
Ganciclovir Neutropenia
Indinavir Cidofovir
Interferon Didanosine
Lamivudine Ganciclovir
Oseltamivir Interferon
Ribavirin Nevirapine
Ritonavir Lamivudine
Saquinavir Saquinavir
Zalcitabine Stavudine
Zidovudine Zalcitabine
Cardiotoxicity Zidovudine
Amantadine Thrombocytopenia
Interferon Acyclovir
Hepatotoxicity Didanosine
Acyclovir Ganciclovir
Didanosine Interferon
Ganciclovir Valacyclovir
Nevirapine Zalcitabine
Nelfinavir Zidovudine
Ritonavir Pancreatitis
Zalcitabine Abacavir
Zidovudine Didanosine
Nephropathy Zalcitabine
Acyclovir Altered Mental Status
Cidofovir Acyclovir
Foscarnet Amandadine
Ganciclovir Efavirenz
Indinavir Ganciclovir
Neuropathy Interferon
Amprenavir Ribavirin
Didanosine Rimantadine
Lamivudine Rash
Stavudine Abacavir
Zalcitabine Acyclovir
Seizures Delavirdine
Acyclovir Didanosine
Foscarnet Efavirenz
Ganciclovir Foscarnet
Zidovudine Ganciclovir
Nevirapine
Saquinavir
Zalcitabine
Zanamivir
ANTIHERPESVIRUS AGENTS
Essentials
• Anemia, neutropenia, thrombocytopenia
• Crystalluria
• Hypocalcemia or hypercalcemia
• Hypophosphatemia or hyperphosphatemia
• Retinal detachment
Introduction
Acyclovir is used orally to treat localized or ophthalmic herpes zoster and intravenously to treat serious
herpes simplex virus (HSV) or varicella-zoster virus (VZV) infections.[14] Acyclovir may also be given as
chronic suppressive therapy to decrease the frequency of recurrent genital HSV disease. Valacyclovir, the l-
valyl ester of acyclovir, is used to treat primary and recurrent HSV; it is also approved for use as suppressive
therapy. Famciclovir is used orally to treat acute uncomplicated herpes zoster (shingles). Ganciclovir is given
intravenously to treat cytomegalovirus (CMV) retinitis and other life-threatening CMV infections in
immunocompromised patients.[18] CMV retinitis occurs in up to 30 per cent of patients with the acquired
immunodeficiency syndrome (AIDS) and often causes blindness.[55][57] Foscarnet is used to treat CMV
infection, as well as VZV and HSV infections resistant to acyclovir. Cidofovir is used to treat CMV in patients
who have failed ganciclovir and foscarnet.
Pathophysiology
Acyclovir, famciclovir, and ganciclovir are nucleoside analogs of guanine. Valacyclovir is an oral prodrug that
is metabolized to acyclovir within minutes of absorption from the gastrointestinal tract. To become active,
acyclovir and famciclovir require phosphorylation by a virus-specific thymidine kinase to their
monophosphate derivatives. They are then phosphorylated by cellular enzymes to a triphosphate
compound, the active moiety that inhibits viral DNA polymerase. Only certain herpesviruses produce the
thymidine kinase necessary for activation. Cytomegalovirus does not produce thymidine kinase. In contrast
to acyclovir and famciclovir, ganciclovir can be activated not only by thymidine kinase but also by a
phosphotransferase that is produced by CMV, which explains its distinctive activity against CMV. Foscarnet
is an inorganic pyrophosphate analog that inhibits DNA polymerase in herpesviruses and reverse
transcriptase in human immunodeficiency virus (HIV).[3] Foscarnet and cidofovir, an acyclic phosphonate
nucleotide analog that inhibits viral DNA polymerase, do not require intracellular activation.
Acyclovir
Acyclovir is generally tolerated well, with infrequent side effects being nausea, diarrhea, rash, and
headache. It is eliminated mainly by the kidney. After being given intravenously, and especially if given
rapidly, acyclovir induces crystalline nephropathy, leading to reversible renal dysfunction in 5 per cent of
patients. The intravenous form also leads to neurotoxicity in 1–4 per cent of patients, resulting in altered
sensorium, tremor, myoclonus, delirium, seizures, or extrapyramidal signs. [22][60] Neurotoxicity may be
worsened when acyclovir is given with zidovudine, resulting in severe somnolence.[9] Headache is common,
occurring in 13 per cent of patients receiving acyclovir as chronic suppressive therapy. Patients with
underlying renal insufficiency may have unexpectedly high plasma concentrations of acyclovir, resulting in
acute renal failure, coma, or both. [15][47]
Overdoses of acyclovir are relatively uncommon. In one report, two neonates were inadvertently given
excessive doses of intravenous acyclovir, resulting in serum concentrations of 100 µg/mL and 26 µg/mL
(normal range of trough levels: 0.14–1.2 µg/mL). One infant was treated with exchange transfusion and the
other with oral activated charcoal. Both infants were asymptomatic and showed normal development at 10
months of age. The authors observed that renal excretion, enhanced with intravenous hydration, appeared
to eliminate acyclovir adequately and that exchange transfusion was unnecessary and probably
ineffective.[38] However, inother cases of acyclovir overdose that involved acute or chronic renal dysfunction,
patients were symptomatic with visual hallucinations, nausea, vomiting, lethargy, confusion, dizziness,
myoclonus, and seizures.[15][34] In the presence of renal insufficiency, hemodialysis appears to be the most
effective treatment modality for reducing acyclovir levels.[34]
Valacyclovir
As valacyclovir is an acyclovir prodrug, the side effects are similar to those of acyclovir. However, the
manufacturer reports that a thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome has occurred
in patients receiving more than 8 g daily with advanced HIV or who are post–renal transplant[48a] (Product
information, Valtrex, GlaxoWellcome, USA, 1999). No overdoses have been reported with valacyclovir.
Famciclovir
Oral famciclovir is also generally well tolerated but may be associated with headache, diarrhea, and nausea.
In clinical trials, adverse effects with famciclovir were no more frequent than with placebo.[51] No cases of
famciclovir overdose have been reported.
Ganciclovir
The principal dose-limiting toxicity of ganciclovir is myelosuppression, with neutropenia occurring in 40 per
cent of patients, thrombocytopenia in 20 per cent, and anemia in 2 per cent. Severe myelosuppression may
occur when the drug is given concurrently with zidovudine. The neutropenia occurs typically during the
second week of treatment and usually is reversible within 1 week of drug cessation. CNS side effects have
been reported in 5 per cent of patients and have included confusion, seizure, coma, psychosis,
hallucinations, mental status changes, anxiety, and ataxia.[18][42] A distinctive side effect can occur in
patients with CMV retinitis, namely, ganciclovir-induced retinal detachment. This complication has been
reported in up to 30 per cent of ganciclovir-treated patients with CMV retinitis but is seen rarely in patients
without CMV retinitis. Retinal detachment appears to result from successful treatment of the retinal CMV
infection, resulting in necrosis and thinning of the retinal tissue. This complication occurs more frequently in
AIDS patients than in other immunosuppressed patients, perhaps because of the impaired ability of AIDS
patients to form firm scar tissue.[18][20] Overdoses of ganciclovir have not been reported in the literature.
Cidofovir
The toxicity associated with cidofovir that concerns physicians most is irreversible proximal tubule cell injury
resulting in renal tubular necrosis. Acute renal failure necessitating dialysis has occurred. Cidofovir has been
reported to cause decreased serum bicarbonate, metabolic acidosis, and Fanconi’s syndrome. Neutropenia
and anemia have occurred in patients treated with cidofovir. Iritis and uveitis have developed, predominantly
in patients who have underlying diabetes mellitus, who are on concurrent protease inhibitor therapy, or who
have received previous therapy from CMV retinitis.
Foscarnet
The major toxicities of foscarnet are nephrotoxicity and alterations in serum calcium and phosphate levels.
Increases in serum creatinine occur in one half of patients but reverse on cessation of the drug in most
patients. The mechanism of nephrotoxicity has been attributed to acute tubular necrosis, crystalluria, and
interstitial nephritis. Foscarnet is highly ionized at physiologic pH and commonly increases or decreases
serum levels of calcium and phosphate.[28][36] Hypocalcemia may produce symptoms of paresthesias,
dysrhythmias, tetany, and seizures. The risk of symptomatic hypocalcemia is increased with concomitant
administration of intravenous pentamidine.[68] Nausea and CNS symptoms, including headache, irritability,
and seizures, have been attributed to foscarnet administration. Genital ulcers have also been associated
with foscarnet therapy. These ulcerations appear to result from retention of or repeated exposure to
concentrations of unchanged foscarnet in the urine.[28] There are no reported cases of acute foscarnet
intoxication.
The differential diagnosis includes other causes of nephrotoxicity, crystalluria, neurotoxicity,

myelosuppression, hypocalcemia or hypercalcemia, hypophosphatemia or hyperphosphatemia, and retinal
detachment.
Laboratory Studies
Patients receiving acyclovir, valacyclovir, or cidofovir should have their blood urea nitrogen and creatinine
levels monitored. The maximal renal concentration of acyclovir occurs during the first 2 hours after
intravenous infusion, and increased blood urea nitrogen and creatinine levels may be observed during this
period. A urine specimen should be checked for the presence of crystals. In cases of acute toxicity, the
plasma concentration of acyclovir may be measured; normal trough levels are 0.14–1.2 µg/mL.[15] Patients
receiving ganciclovir or cidofovir should have their blood cell counts monitored. Patients receiving foscarnet
should have measurements of renal function, electrolyte, calcium, and phosphate levels.
Treatment
Most cases of acute toxicity due to antiherpesvirus agents have been iatrogenic after intravenous
administration of excessive doses and typically occur in the setting of renal insufficiency. Nephrotoxicity due
to acyclovir may be prevented by adequate hydration to maintain urine output. If a patient is symptomatic or
has inadequate renal clearance, acyclovir may be removed by hemodialysis with approximately 45 per cent
drug removal with concomitant improvement of symptoms.[34] Myelosuppression due to ganciclovir or
cidofovir may be treated by discontinuing the drug and giving granulocyte colony-stimulating factor (G-CSF)
or granulocyte-macrophage colony-stimulating factor (GM-CSF) for severe neutropenia or platelet infusions
for thrombocytopenia.[18][23][42] Patients receiving foscarnet should be hydrated before medication.
Electrolyte levels should be checked and any abnormalities treated accordingly.
Disposition
Decisions regarding admission should be made on the basis of the severity of side effects, specifically
crystalluria, electrolyte imbalance, neurotoxicity, and severe neutropenia. Patients with acute acyclovir
intoxication and evidence of renal insufficiency may require intravenous hydration, monitoring of renal
function, and possibly hemodialysis.


ANTIRETROVIRAL AGENTS
Essentials
• Anemia
• Myopathy
• Neutropenia
• Pancreatitis
• Peripheral neuropathy
Introduction
The number of antiretroviral drugs has increased dramatically with the emergence of HIV. Antiretroviral
therapy is considered first-line therapy for infection with this virus.
Treatment of HIV and AIDS is changing rapidly (current information on federal treatment guidelines for HIV
and AIDS can be found on the HIV/AIDS Treatment Information Service web site, www.hivatis.org ).
Current therapy recommendations require a minimum of three agents—the goals being sustained
suppression of HIV plasma RNA, sustained increase in CD4+ count, and improved clinical outcome.
Monotherapy is never recommended. Most initial regimens include two nucleoside analogs plus a non-
nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor. Zidovudine (azidothymidine [AZT])
was the first antiretroviral introduced.[52] Oral zidovudine decreases the frequency of opportunistic infections
and prolongs survival in patients with AIDS or AIDS-related complex.[17] In patients with few or no symptoms
and CD4 lymphocyte counts less than 500 cells/mm3, zidovudine delays progression of HIV infection.[64]
Didanosine (dideoxyinosine [ddI]), zalcitabine (dideoxycytidine [ddC]), stavudine (d4T), and lamivudine
(3TC) result in virologic and immunologic improvements in some patients with AIDS.[4][16][19][65] They are
active against most HIV strains that are resistant to zidovudine.[1][26]
Nevirapine, delavirdine, and efavirenz all are active against HIV-1, but not HIV-2 or any other human viruses.
The development of rapid resistance to all agents and intolerable side effects have led to the current
rationale of using “cocktails” of various agents.
Pathophysiology
The first antiretroviral agents available were 2',3'-dideoxynucleoside analogs. Specifically, zidovudine and
stavudine are analogs of thymidine, didanosine is an analog of the purine inosine, and zalcitabine is an
analog of cytosine. These agents inhibit the RNA-dependent DNA polymerase (reverse transcriptase) of
HIV. In addition, antiretroviral agents can serve as substrates of reverse transcriptase. When they are
incorporated during viral DNA synthesis, they terminate DNA chain elongation. The non-nucleoside reverse
transcriptase inhibitors (NNRTIs) nevirapine, delavirdine, and efavirenz inhibit viral replication by binding to
reverse transcriptase and interfere with viral RNA- and DNA-directed polymerase activities. The NNRTIs do
not require intracellular conversion to an active metabolite. Because antiretroviral agents act against reverse
transcriptase, they block acute infection of cells but are minimally active in cells that are infected chronically.
Resistance of HIV to antiretroviral agents is due primarily to mutations of the viral reverse transcriptase.
Clinical Presentations
Zidovudine
Adverse effects of zidovudine include headache, nausea, asthenia, abdominal pain, rash, fever, diarrhea,
anorexia, malaise, and myalgia. These side effects typically improve with continued use of the drug. The
major toxicities of zidovudine are anemia and neutropenia, and these increase with lower CD4 counts and
more advanced disease. [39][48] Severe anemia or neutropenia occurs in 30–40 per cent of patients with
symptomatic AIDS.[50] Long-term zidovudine therapy is associated with a toxic myopathy that presents as
weakness, pain, and increased creatine phosphokinase levels. [45] This myopathy resolves slowly with
discontinuation of the drug. Combined use of zidovudine and acyclovir may result in severe somnolence.[9]
Several cases of zidovudine overdose have been reported in the literature. Large ingestions of zidovudine
have generally resulted in no adverse effects, even with doses as large as 20,000 mg and measured serum
levels of 339 µmol/L (normal peak level < 5).[43][62] Myelosuppression, which is a feature of chronic
administration, has been observed after acute overdose in only one reported case, and in that case blood
cell counts normalized within 20 days.[33] Reported cases of large zidovudine overdoses have resulted in
nystagmus, ataxia, and grand mal seizure.[49][58] In all reported cases, patients recovered from acute
zidovudine intoxication with no long-term sequelae.
Didanosine
Toxicities associated with didanosine are painful peripheral neuropathy and pancreatitis. Neuropathy
typically causes paresthesia, numbness, and pain in the lower extremities.[40] The risk of pancreatitis
increases with advanced HIV disease and when didanosine is given concomitantly with intravenous
pentamidine.[19][65] Other adverse effects include headache, insomnia, nausea, emesis, abdominal pain,
fever, rash, hyperuricemia, thrombocytopenia, increased aminotransferase activity, and, rarely, fulminant
hepatic failure, which may be fatal.[32][67] Available preparations of didanosine contain moderate amounts of
sodium, which may exacerbate congestive heart failure in some patients. [66] Didanosine can also cause
hypokalemia, which may necessitate discontinuation of the drug, although it is unclear whether the
hypokalemia is due to the drug or existing formulations.[30] Overdoses of didanosine have not been reported.
Zalcitabine
Zalcitabine shares with didanosine the adverse effect of peripheral neuropathy, which occurs in up to 30 per
cent of patients at currently recommended doses.[35] The symptoms include pain, paresthesia, and
hypesthesia in the lower extremities and resolve after the medication is discontinued.[65] Other symptoms
include rash, stomatitis, esophageal ulceration, fever, and a neutropenia that occurs in up to 10 per cent of
patients.[50] Cases of acute intoxication with zalcitabine have not yet been reported.
Stavudine
The major reversible dose-limiting toxicity of stavudine is peripheral neuropathy. Other adverse effects are
anemia, neutropenia, and elevated transaminases.[45][54][59][65] Because of the potential for peripheral
neuropathy, stavudine should be avoided in patients taking other agents associated with neuropathy, such
as didanosine or zalcitabine. There are no reported cases of stavudine overdose.
Lamivudine
The side effects are similar to those caused by zidovudine, such as gastrointestinal effects (usually nausea),
malaise, headache, and neutropenia. Cases of pancreatitis have been reported, especially in children.[16][59]
Overdoses of lamivudine have not been reported yet in the literature.
Abacavir
The most severe reaction reported with abacavir is a hypersensitivity reaction consisting of fever, rash,
nausea, vomiting, malaise, and anorexia. Other symptoms include bronchospasm, lymphadenopathy, and
abdominal pain. Abacavir should be discontinued and should not be restarted if hypersensitivity is suspected
because rechallenge may cause recurrence of symptoms, progressing to hypotension and death.
Pancreatitis and increased GGT have also occurred with abacavir.
Delavirdine
Eighteen per cent of patients taking delavirdine in clinical trials experienced a diffuse, maculopapular rash
that was often pruritic. Stevens-Johnson syndrome and erythema multiforme have been reported rarely, and
have resolved after cessation of therapy. There are no published reports of delavirdine overdose.
Nevirapine
A maculopapular, erythematous rash was reported in 7 per cent of patients receiving nevirapine in clinical
trials. Stevens-Johnson syndrome has occurred with nevirapine. Neutropenia, elevated levels of
transaminases, and hepatitis can occur within the first few weeks of therapy. Reports of nevirapine overdose
were not found in the literature.
Efavirenz
Central nervous system effects, including hallucinations, euphoria, impaired cognition, agitation, and
drowsiness, are fairly common with efavirenz. Patients with a history of substance abuse or mental illness
are more likely to experience these symptoms. Bedtime dosing of efavirenz is thought to improve tolerability
of the central nervous system effects. Skin rashes have also been reported with efavirenz. In clinical trials,
children experienced more frequent and severe rashes than those of adults.
Diagnosis of side effects due to antiretroviral agents is often difficult because HIV infection itself and
associated opportunistic infections may cause many of the same adverse effects. Discontinuation of the
medication may assist with determining the etiology.
Laboratory Studies
Electrolytes, creatine kinase, liver function, and amylase should be monitored depending on the drug
involved and the patient’s condition. Serial blood cell counts should be followed in overdoses of zidovudine,
although acute myelosuppression is rare.
Treatment
The treatment of adverse effects is supportive. Painful neuropathy and pancreatitis can be treated by
lowering the dosages or discontinuing the agents.
Disposition
Because overdoses of these drugs are generally benign, ingestions rarely require admission. However, large
overdoses of zidovudine have been associated with seizures and these patients should be admitted.
Patients with abnormal results of neurologic examinations may require observation.


ANTI-INFLUENZA DRUGS
Essentials
• Anticholinergic symptoms
• Bronchospasm
• Cardiac dysrhythmias, including torsades de pointes
• Neurologic symptoms
Introduction
Amantadine is used for the prophylaxis and treatment of infections caused by various strains of influenza A
virus.[6] It is also used in the treatment of parkinsonism and neuroleptic-induced extrapyramidal
symptoms.[2][13] Oseltamivir and zanamivir are newer agents approved for use in uncomplicated influenza
infection in patients who have been symptomatic for less than 2 days.
Pathophysiology
Amantadine and its methyl derivative rimantadine are tricyclic amines. They specifically inhibit the replication
of influenza A viruses. The primary effect of these drugs is to interfere with the viral M2 protein, a membrane
protein that serves as an ion channel. Both amantadine and rimantadine share similar susceptibility and
resistance profiles.[25] Rimantadine is 4–10 times more active than amantadine.[24] In addition to its antiviral
effects, amantadine affects the neurologic system. At the cellular level amantadine inhibits the presynaptic
reuptake of catecholamines, thereby increasing the activation of postsynaptic dopaminergic and
noradrenergic receptors. This dopaminergic effect accounts for the activity of amantadine in
parkinsonism.[53]
Oseltamivir phosphate is an ethyl ester prodrug that is hydrolyzed to its active form, oseltamivir carboxylate.
The exact mechanism of action of oseltamivir and the inhalation-only zanamivir is unknown, but they are
thought to inhibit influenza virus neuraminidase. Resistance to both agents has been reported.
The most common side effects of amantadine and rimantadine are minor gastrointestinal and central
nervous system (CNS) complaints. Toxicity is related to the anticholinergic properties of the drug.[44] CNS
side effects include nervousness, depression, anxiety, confusion, dizziness, vertigo, tremors, and
ataxia.[24][47] These effects usually diminish after the first week of treatment and rapidly disappear when the
drug is discontinued. For a given dosage, plasma drug concentrations in the elderly are twice as high as for
younger adults, owing to decreased renal excretion. Thus, the dosage of amantadine should be reduced in
the elderly.
Overdoses of amantadine are associated with serious neurotoxic reactions, including delirium,
hallucinations, seizures, and coma. The risk for neurotoxicity is increased by concomitant ingestion of
antihistamines, anticholinergic drugs, and psychotropic drugs.[56] Overdoses of amantadine have also been
associated with cardiovascular effects, including cardiac arrest, hypotension, bradycardia, cardiac
conduction disturbances, and malignant ventricular dysrhythmias with prolongation of the Q-Tc interval and
torsades de pointes. Noncardiogenic pulmonary edema can occur. Fatalities due to amantadine overdose
have been reported.[8] The risk of torsades is increased greatly if the patient is taking a class I
antidysrhythmic.[53]
Oseltamivir seems to be a relatively benign agent, as nausea and vomiting are the most frequently reported
adverse effects. In contrast, zanamivir has been reported to cause bronchospasm in patients with underlying
asthma or obstructive airway disease. Anaphylactoid reactions, including oropharyngeal edema and serious
skin rashes, have also occurred. Anticholinergic symptoms are not seen with these agents.
The differential diagnosis for amantadine and rimantidine includes other causes of anticholinergic symptoms
and ventricular dysrhythmias.
Laboratory Studies
Electrocardiographic and cardiac monitoring should be performed in all cases of suspected overdose. Other
tests are dictated by the patient’s clinical condition and diagnoses considered in the differential diagnosis.
Treatment
Treatment should be directed at maintaining cardiovascular function and reducing CNS stimulation.
Because a high percentage of amantadine is excreted unchanged in the urine, maintaining an adequate
urine output is important.[56] The electrocardiographic changes are similar to those seen in cyclic
antidepressant overdoses. Physostigmine has been used in amantadine toxicity but is generally not
recommended, because physostigmine has been strongly associated with asystolic arrest in cyclic
antidepressant overdoses.[61] Torsades should be treated in standard fashion with magnesium and overdrive
pacing. Inotropic agents such as isoproterenol may be contraindicated in cases of amantadine overdose.[53]
Lidocaine has been successfully used to suppress complex ventricular ectopy.[44] Class IA and III
antidysrhythmic drugs are contraindicated due to potential potentiation of prolonged Q-Tc and torsades.
Temporary cardiac pacing may also be indicated. Seizures are treated in the usual manner with
benzodiazepines, followed by barbiturates if necessary.
Disposition
Most patients with amantadine toxicity require admission, observation, and supportive care. Because
malignant tachydysrhythmias and noncardiogenic pulmonary edema can appear up to 48 hours after
ingestion of large quantities of amantadine,[53] patients may require continuous electrocardiographic
monitoring. In addition, patients with mental status changes, confusion, or anticholinergic symptoms should
be admitted.


INTERFERON
Essentials
• Granulocytopenia
• Neurotoxicity
• Thrombocytopenia
Introduction
Interferons (IFNs) are cytokines that are synthesized by cells in response to various stimuli, including
viruses. IFNs are classified as a, ß, and . IFN-a and IFN-ß are produced by nearly all cells in response to
viral infection and other stimuli, whereas IFN- is produced by T lymphocytes and natural killer cells in
response to various antigens and cytokines. IFN- serves important immunoregulatory functions but has less
antiviral activity than IFN-a or IFN-ß. The class of IFN-a contains over 24 individual species, and
preparations have been developed from natural sources and recombinant techniques.[24] Preparations of
natural and recombinant IFN-a available for clinical use are referred to as interferons alfa. Interferons alfa
are currently approved for treatment of condyloma acuminatum, chronic hepatitis B and C, Kaposi’s
sarcoma, and multiple sclerosis.[5][12]
Pathophysiology
Interferons achieve their antiviral effects indirectly. They induce neighboring cells to synthesize several
proteins that inhibit viral infection by various mechanisms. The primary mechanism involves a 2',5'-
oligoadenylate synthetase and a protein kinase, which inhibit viral protein synthesis.[12]
Intramuscular or subcutaneous injection of IFN is commonly associated with an acute febrile influenza-like
syndrome beginning several hours after injection. High-dose or chronic therapy is limited by
myelosuppression and neurotoxicity. Bone marrow suppression is manifested by neutropenia and
thrombocytopenia. Neurotoxicity is manifested by somnolence, confusion, behavioral disturbance, and,
rarely, seizures.[46] Overdoses of IFN have not been reported in the literature.
The differential diagnosis includes other causes of bone marrow suppression with granulocytopenia and
thrombocytopenia, neurotoxicity including seizures, thyroid dysfunction, and cardiotoxicity. Because IFNs
are administered parenterally, acute intoxication is likely to be iatrogenic.
Laboratory Studies
Patients on high-dose or chronic therapy with IFNs should have their blood cell counts monitored.
Treatment
Treatment of side effects of IFNs is supportive.
Disposition
There is little clinical experience with IFN overdose, and decisions regarding admission should be based on
clinical assessment of the patient.


RIBAVIRIN (VIRAZOLE)
Essentials
• Anemia
• Bronchospasm
• Lymphopenia
• Neurologic symptoms
Introduction
Ribavirin is a nucleoside analog with a broad spectrum of antiviral activity against RNA viruses. It is used as
an aerosol for respiratory syncytial virus infections and certain viral hemorrhagic fevers.[21][27]
Pathophysiology
The antiviral mechanism of action of ribavirin is not fully understood. It appears to inhibit the replication of
RNA viruses by inhibiting viral RNA-dependent RNA polymerase, by depleting intracellular guanine pools,
and by interfering with the “capping” of viral RNAs.[41]
Aerosolized ribavirin is tolerated well but may cause mild conjunctival irritation, rash, wheezing, and
reversible deterioration in pulmonary function.[29] Ribavirin has been associated with deterioration of
respiratory function in patients with reactive airway disease. Although systemic ribavirin has not been
approved by the U.S. Food and Drug Administration, experience with ribavirin in clinical trials reveals various
side effects. In HIV-infected patients, chronic oral therapy is associated with dose-related lymphopenia and
gastrointestinal and CNS complaints, including headache, lethargy, insomnia, and mood alterations.
Reversible increases in serum bilirubin, iron, and uric acid levels occur during short-term oral
administration.[24] Intravenous ribavirin causes dose-related anemia due to extravascular hemolysis and
suppression of bone marrow. [27] Overdoses of ribavirin have not been reported in the literature.
The differential diagnosis includes other causes of bronchospasm, anemia, lymphopenia, gastrointestinal,
and neurologic complaints. The appearance of these signs and symptoms in the context of administration of
ribavirin suggests the diagnosis.
Laboratory Studies
In patients using oral or intravenous ribavirin, a complete blood cell count should be done and serum
bilirubin, iron, and uric acid levels should be monitored.
Treatment
Treatment should be directed at maintaining supportive respiratory therapy in patients receiving aerosolized
ribavirin. Oral and intravenous ribavirin are associated with dose-related signs and symptoms, and treatment
for these is supportive.
Disposition
Patients with mental status changes, bone marrow suppression, and severe GI symptoms should be
admitted.


PROTEASE INHIBITORS
Essentials
• Hepatic transaminase elevations
• Hypertriglyceridemia
• Nephrolithiasis
Introduction
Protease inhibitors are inhibitors of the HIV protease. They are used in combination with nucleoside analogs
or as monotherapy for the treatment of HIV infection. Details on newer agents are found in Tables 60–1 and
60–2 .
Pathophysiology
Protease inhibitors are specific substrate analogs of HIV protease. They inhibit both HIV-1 and HIV-2
proteases, preventing cleavage and processing of the protein precursor. This inhibition results in the
formation of immature noninfectious viral particles.[31][63]
Saquinavir (Invirase)
Saquinavir is generally tolerated well. The most common side effects are mild headache, diarrhea, nausea,
and abdominal pain.[7] No serious toxicities have been reported.
Ritonavir (Norvir)
Adverse effects are common with ritonavir use. They include diarrhea, nausea, headache, circumoral and
peripheral paresthesias, altered taste, and elevated serum concentrations of triglycerides, cholesterol,
creatine kinase, and transaminases.[10][37] Severity of symptoms appears directly related to plasma
concentrations of the drug.[11]
Indinavir (Crixivan)
Indinavir is generally well tolerated. The most important adverse effect is nephrolithiasis, which occurs in
approximately 5 per cent of patients over the first year of treatment. Indinavir has also been associated with
mild gastrointestinal symptoms, including abdominal pain, nausea, vomiting, and gastroesophageal
reflux.[11] An HIV-infected patient who ingested 6000 mg of indinavir, ethanol, and 10 double-strength
trimethoprim-sulfamethoxazole tablets developed drowsiness, dizziness, nausea, and paresthesias of the
extremities. The patient was treated with one dose of oral activated charcoal and crystalloid hydration for 18
hours. His symptoms resolved after 4 hours, and no nephrolithiasis developed.[4a]
The differential diagnosis of protease inhibitor toxicity includes other causes of gastroenteritis, hepatitis, and
nephrolithiasis.
Laboratory Studies
Renal function tests, liver function tests, triglycerides, and cholesterol levels may be monitored, depending
on the agent involved.
Treatment
Treatment of side effects is supportive. Indinavir-induced nephrolithiasis is treated with aggressive hydration
and pain management. Overdoses of protease inhibitors have not been reported in the literature.
Disposition
Patients intolerant of outpatient management for dehydration and nephrolithiasis should be admitted for
hydration and pain control.


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Chapter 61 – Antimalarials
SUZANNE DOYON
Essentials
• Risk of exposure: recent travel, country of origin, known prescription for patient or family member.
• Cardiovascular: electrocardiogram (EKG) conduction disturbances, ventricular dysrhythmias,
hypotension.
• Ophthalmologic: tunnel vision, blurred vision, blindness; pale fundus, cherry red spot, dilated pupils.
• Otic: tinnitus, high-frequency hearing loss.
• Central nervous system: coma, seizures.
• Blood levels of quinine and chloroquine correlate with severity of symptoms.
INTRODUCTION
Malaria is a common infectious cause of death and illness in many tropical areas of the world. Utilization of
antimalarial drugs is widespread for both prophylaxis of infection in travelers and treatment of acute
infection. The quinoline derivatives quinine, chloroquine, and mefloquine are the most widely used
antimalarial drugs. Antimicrobials such as sulfadoxine, dapsone, trimethoprim, pyrimethamine, and
tetracyclines also have some efficacy as antimalarials. Artemisinin is a new antimalarial agent currently
being tested in Viet Nam and the People’s Republic of China. The emergence of many strains of
Plasmodium falciparum that are resistant to chloroquine necessitates the continued use of quinine, which is
both less potent and more toxic.[48] The combination of mefloquine and artemisinin has also emerged as an
effective treatment for resistant strains.[31] In addition to therapeutic exposures to antimalarial agents, both
accidental and suicidal overdoses also commonly occur, particularly in Africa and in France, where a
popular 1982 publication endorsed chloroquine as a preferred agent for committing suicide.[26] This chapter
will focus primarily on the quinolines, which are the most toxic of the antimalarial agents and are most often
involved in serious overdoses.


Pharmacology
Quinolines
The mechanism of action of the quinolines remains obscure. Possible therapeutic mechanisms include
inhibition of protozoal DNA and RNA synthesis and precipitation of membrane-toxic heme compounds.
Some of their toxicity in mammals is believed to be related to inhibition of DNA synthesis.[48]
Chloroquine, a synthetic 4-aminoquinoline, is the drug of choice for the treatment of susceptible forms of
malaria. It is also used to treat rheumatoid arthritis and discoid lupus erythematosus.[48] It has a large
volume of distribution owing to extensive binding to tissues. Renal clearance of the unchanged drug and its
major hepatic metabolite account for 75 per cent of its elimination.[48] Chloroquine is available in phosphate
and sulfate preparations (Plaquenil Sulfate 200 mg, equivalent to 155 mg of base; Aralen Phosphate 500
mg, equivalent to 300 mg of base). Dosages expressed in this chapter refer to the chloroquine base.
Quinine, a naturally occurring plant alkaloid obtained from cinchona bark, was used for 350 years to treat
malaria and is still used to treat infections with chloroquine-resistant strains of P. falciparum. Quinine sulfate
has also been prescribed for the treatment of painful leg cramps, although the U.S. Food and Drug
Administration has withdrawn its approval for this indication. It has also been used clandestinely as an
ineffective abortifacient, a heroin adulterant, and finally, in minuscule amounts as a bittering agent in soft
drinks. Quinine has a volume of distribution of 1.5 L/kg with a half-life of elimination of 11 hours. It is
extensively bound to a1-glycoproteins. Sick patients appear to tolerate much higher levels of quinine with
less toxicity than is seen in healthy patients following an overdose. This has been attributed to higher levels
of a1-glycoproteins in patients with malaria that bind quinine and decrease its free fraction.[46] Quinine is
extensively metabolized in the liver, with only 20 per cent excreted in the urine.[48]
Mefloquine is a synthetic 4-quinoline methanol derivative. It has an extensive hepatobiliary recirculation that
results in peak plasma levels at 17 hours after ingestion and a half-life of elimination of 2–3 weeks. It is also
highly protein-bound and eliminated almost exclusively by biliary excretion into feces.[48] It is active against
both sensitive and multidrug resistant strains of P. falciparum.[31]
Artemisinin
Artemisinin is a naturally occurring lactone derived from the Chinese medicinal herb qing hao, also called
qinghaosu or sweet wormwood. Extracts of this plant are available in oral, parenteral, and suppository forms
and are used in China and Southeast Asia for the treatment of malaria.[30][31] Extensive pharmacokinetic and
toxicologic data are not yet available. Artemisinin is concentrated in parasitized erythrocytes. It decomposes
in an iron-mediated reaction to free radical products that cause oxygen-dependent damage to parasite
proteins and lipid membranes. [12][30]
Pathophysiology
Quinine
Quinine, like its optical isomer quinidine, is a negative inotrope. It slows myocardial depolarization and
conduction, increasing the action potential duration and effective refractory period. However, severe
cardiotoxicity secondary to quinine intoxication is less common than with quinidine.[32]
The widely reported auditory and ocular toxicities of quinine appear to be related to a direct toxic effect of the
drug on the acoustic nerve and the retina. Quinine predictably induces high-tone hearing loss at therapeutic
plasma concentrations.[15][44] In guinea pigs, high-dose quinine causes degeneration of the organ of
Corti.[1][44] Multiple human studies have documented ocular toxicity manifested as alteration in color
perception, blurred vision, or decreased acuity. Animal studies of quinine toxicity show morphologic changes
in the retina, referred to as bony spicule formations, and histologic changes in the photoreceptor and
ganglionic cells.[10][23] Historically, the ocular toxicity of quinine was attributed to ischemia induced by
vasoconstriction, resulting in the use of stellate ganglion block to relieve vasoconstriction.[3][13] However,
angiographies performed in patients with quinine amblyopia demonstrate preservation of normal arteriolar
caliber, obviating any theoretical indication for this procedure.[10][23][29]
Quinine also causes altered levels of consciousness and seizures. It is unclear whether the central nervous
system disturbances are due to direct neurotoxicity or are secondary to the myocardial depressant effect of
quinine with subsequent hypoperfusion of the central nervous system. Hypoglycemia has been observed in
patients with severe malaria treated with intravenous quinine. It has been attributed to the potentiation of
insulin release from pancreatic cells.[29][40]
Chloroquine
Chloroquine is a potent negative inotrope that reduces cardiac excitability, slows repolarization along the
conduction system, and has a membrane-stabilizing effect.[22] Diazepam appears to have a cardioprotective
effect in chloroquine poisoning, an unusual observation that has been pharmacologically difficult to
rationalize.[14][19][35][42][43][47] It has been proposed that a pharmacokinetic interaction between chloroquine
and diazepam leads to a washout of chloroquine from cells or decreases the myocardial concentration of
chloroquine.[35][43] Alternatively, diazepam may increase chloroquine excretion from the central
compartment.[14] The discovery of myocardial benzodiazepine receptors has led to a proposed competition
between diazepam and chloroquine at a common binding site.[14] Hypotension is a prominent feature of
acute choloroquine intoxication and is believed to be secondary to the cardiodepressant effect of the drug
rather than to direct peripheral vasodilation. Hypokalemia has been associated with chloroquine intoxication,
possibly owing to impairment of cellular membrane potassium transport mechanisms.[2][16][38]
Mefloquine
The precise mechanisms for mefloquine toxicity remain unknown.[7][9][44][50]


Quinine
Quinine is the most toxic of the antimalarial drugs. Mild toxicity, often referred to as cinchonism, is seen
during therapeutic dosing.[4] Symptoms of cinchonism are nausea, vomiting, dizziness, headache, tinnitus,
and visual disturbances. In one study of therapeutic dosing in volunteers, audiometrically detectable
reversible hearing loss occurred in 9 of 12 subjects at a mean plasma level of 2 mg/L.[15] Clinically
insignificant Q-Tc prolongation also occurs during therapeutic dosing.[15] The acute ingestion of 2–8 g of
quinine is potentially fatal in an adult. Large doses of quinine cause EKG conduction disturbances and
cardiac dysrhythmias that are similar to the effects of quinidine. The EKG manifestations of quinine toxicity
include ST segment depression, T-wave inversion, and prolongation of the P-R, Q-T, and QRS intervals.
Ventricular tachycardia and idioventricular rhythms also occur. Reported central nervous system effects
include depressed level of consciousness, delirium, seizures, and coma.[4][5] Visual disturbances are
common. The most frequent visual disturbance is constriction of the visual field, followed by alteration of
color perception, diplopia, and blindness. At some time before the onset of blindness the pupils become
fixed and dilated. Retinal examination shows progressive edema and pallor with a cherry red spot visible at
the macula.[3][10][11][13][23][27] Less predictable idiosyncratic toxicity associated with quinine therapy includes
immune thrombocytopenic purpura (ITP) caused by quinine-dependent antibodies that react with platelets.
The more recently described quinine-induced hemolytic-uremia syndrome has been reported to occur in
association with quinine-dependent antibody-mediated endothelial cell activation.[25][37] Acute hepatic injury
that recurred with rechallenge has also been reported during treatment with quinine.[24]
Table 61-1 -- Clinical Presentation of Antimicrobial Toxicity

Quinine
Cinchonism—nausea, vomiting, dizziness, headache, tinnitus, hearing loss, visual disturbances
Cardiovascular—prolonged conduction, ventricular dysrhythmias
CNS—decreased level of consciousness, delirium, coma, seizures
Chloroquine
CNS—headache, dizziness, lethargy, coma, seizures
Cardiovascular—prolonged conduction, bradycardia, ventricular tachycardia/fibrillation, torsades de pointes,
hypotension, shock
Respiratory—dyspnea, sudden apnea
Other—nausea, vomiting, deafness, visual disturbances
Mefloquine
CNS—decreased level of consciousness, seizures
Cardiovascular—hypotension, sinus tachycardia, prolonged QTc
Chloroquine
Chloroquine is a safe drug when recommended therapeutic doses are used. Most serious toxicity occurs
following accidental or intentional overdose. The acute ingestion of 1–1.5 g (20 mg/kg) will result in toxicity in
an adult, and ingestion of 5 g is potentially lethal.[42] One 300-mg tablet resulted in the death of a 3-year-
old, [33] and 750 mg caused ventricular fibrillation in a 13-year-old.[18] The mortality rate from the deliberate
suicidal ingestion of chloroquine is 10–20 per cent in most case series.[17][37]
Hypotension, defined as systolic blood pressure of 80 mmHg or less, and sinus bradycardia commonly
occur, as do more life-threatening dysrythmias such as torsades de pointes, ventricular tachycardia, and
ventricular fibrillation.[17][18][38][42][47] Dyspnea may be followed by sudden apnea. Nausea and vomiting have
been described but are not universal symptoms. Deafness has rarely been observed. Visual disturbances
such as blurred vision, diplopia, impaired color perception, and even blindness have also been associated
with acute chloroquine intoxications. Central nervous system symptoms range from headache and dizziness
to seizures, lethargy, and coma.[17][38][42] Very large ingestions of chloroquine result in the rapid onset of
coma, QRS widening with dysrhythmias, and shock.[17][38][39][42]
Mefloquine
Very few cases of mefloquine toxicity are reported in the literature. Mefloquine has been reported to cause
hypotension, rhythm disturbances, hepatotoxicity, and central nervous system depression following acute
ingestions.[7] The incidence of toxicity during therapeutic dosing is 60 times higher with mefloquine treatment
than with mefloquine prophylaxis.[9][50] Mild hepatotoxicity (transaminases 50–100 IU/L) with mild
hypotension and tachycardia has been documented. Central nervous system abnormalities that include
seizures and psychiatric abnormalities have been associated with the chronic therapeutic use of
mefloquine.[45][50] A case series of five patients who developed seizures while being treated with mefloquine
has spawned the term “mefloquine acute brain syndrome.”[45] It cannot be discerned from the data given in
this paper if the convulsive agent is the parent compound or the metabolites or whether these syndromes
simply represent atypical cases of cerebral malaria. One study showed mild lowering of blood sugar
associated with hyperinsulinemia and transient prolongation of the Q-Tc interval in healthy volunteers taking
prophylactic doses of mefloquine. No neurologic symptoms were detected in this study.[21]
Artemisinin
The qinghaosu compounds appear to have significantly less toxicity than the quinoline agents during
therapeutic dosing. Q-Tc prolongation has been noted in humans during therapeutic dosing. Very large
doses in dogs cause tremors, restlessness, seizures, and progressive brainstem injury, resulting in death.
Large doses in rats cause cerebral edema, mucosal ulceration, and bone marrow suppression.[30]


The differential diagnosis of acute poisoning with antimalarials must include disorders that affect cardiac
rhythm, myocardial contractility, and the auditory and visual systems. The toxic differential diagnosis
includes salicylates, furosemide, and methanol and myriad cardiotoxic agents such as type 1a agents,
tricyclic antidepressants, thioridazine, mesoridazine, terfenadine, astemizole, and propoxyphene ( Table
61–2 ).
Table 61-2 -- Differential Diagnosis of Antimicrobial Toxicity

Cardiac effects
Type 1a dysrhythmics: quinidine, procainamide, disopyramide
Tricyclic antidepressants
Thioridazine, mesoridazine
Terfenadine, astemizole
Propoxyphene
Auditory/ocular effects
Salicylates
Methanol
Furosemide


LABORATORY STUDIES
Quinine and Chloroquine
Blood glucose levels should be closely monitored, as hypoglycemia has been frequently observed in
patients treated with quinine.[29][40]
The EKG remains the best diagnositc tool in evaluating quinine or chloroquine poisoning. A QRS duration
above 0.14 seconds indicates severe toxicity.
Like many membrane active drugs, the toxicity of chloroquine and quinine is closely related to their plasma
concentrations. Both drugs have a narrow therapeutic index. Unfortunately, these levels are rarely available
to the clinician.
Quinine-induced cinchonism appears at concentrations of 8–15 mg/L. Visual disturbances are rare at
plasma concentrations that are less than 10 mg/L. Ototoxicity has been reported at levels as low as 2
mg/L.[15] Cardiotoxicity develops as plasma concentrations approach 16 mg/L.[5][6] There is no proven
association between quinine toxicity and serum potassium levels, although some authors believe that such
an association exists.[8][32]
Chloroquine concentrations of 0.8 mg/L or greater are only occasionally associated with side effects.
Concentrations of less than 2.5 mg/L cause mild symptoms without EKG changes. Concentrations greater
than 5 mg/L are associated with neurologic disturbances, hypotension, and EKG abnormalities.[17][32]
Published data suggest that hypokalemia (3±0.8 mEq/L) correlates directly with the blood chloroquine
concentration, the degree of hypotension, and the prolongation of the QRS complex and Q-T interval.[2][16]
However, the hypokalemia could result from a number of confounding variables, especially prehospital use
of vasopressors, and further research is required in this area.[16]
In acute poisonings, serum levels of quinine and chloroquine correlate relatively well with the severity of the
intoxication. Levels of quinine over 12 mg/L and of chloroquine over 5 mg/L are especially worrisome.[32][41]
Mefloquine
Serum concentrations have rarely been documented following prophylactic mefloquine therapy. In one
patient treated with antimalarial doses of mefloquine, central nervous system toxicity was observed at a level
of 6719 ng/mL.[45] In cases of acute ingestion, sinus tachycardia with ventricular ectopic beats, hypotension,
and elevated hepatic transaminases has been observed at concentrations of 3200 ng/mL.[7]


Decontamination
Resuscitation of the airway and cardiovascular status should precede any attempts at decontamination. The
decision to institute gastric emptying should be made based on the severity and the timing of the ingestion.
Early gastric lavage may be beneficial in serious ingestions. Activated charcoal is indicated for any
potentially serious ingestion. Multiple dose activated charcoal has been recommended for management of
quinine poisoning.[34][41] The following sections discuss clinical interventions that may be useful and fall
outside the standard approaches to cardiac resuscitation.
Table 61-3 -- Treatment of Antimicrobial Toxicity

Quinine
Hypotension
• Volume resuscitation
• Epinephrine 0.25 µg/kg/min IV, increasing by 0.25 µg/kg/min every minute until BP>100 mmHg.
QRS duration > 0.14 sec
• Hypertonic sodium bicarbonate 0.5–2 mEq/kg IV followed by an infusion at 0.5 mEq/kg/hr until the EKG
changes resolve.
Torsades de pointes
• Lidocaine
• Magnesium
• Overdrive pacing
Chloroquine
Hypotension
• Same dosages as for quinine
QRS duration > 0.14 sec
• Diazepam 0.5–2 mg/kg IV over 30 min, followed by an infusion at 1–2 mg/kg/d for 48 hr
• Hypertonic sodium bicarbonate, same dosages as for quinine
Mefloquine
Activated charcoal
Supportive care
No data available regarding more specific therapies
Quinine
Cardiovascular Toxicity
Hypotension initially should be managed with a trial of normal saline or lactated Ringer’s solution.
Epinephrine, a potent direct-acting vasopressor, is the vasopressor of choice when volume resuscitation
fails. The starting dose of epinephrine is 0.25 µg/kg/min, to be increased by 0.25 µg/kg/min every minute
until a systolic pressure of 100 mmHg is obtained.[32][42] The placement of a transaortic balloon pump should
be considered if hypotension is intractable and life-threatening.
Based on experience with other membrane-stabilizing drugs it is recommended that sodium bicarbonate be
administered in an attempt to reverse the effects of quinine on myocardial conduction. An intravenous bolus
of 0.5–2 mEq/kg of hypertonic sodium bicarbonate is indicated if the QRS duration is at or above 0.14
second. This should be followed by an infusion at 0.5 mEq/kg/hr. These dosages are based on experience
with the treatment of cardiotoxicity secondary to poisoning with other type 1a agents, particularly tricyclic
antidepressants. All antidysrhythmic drugs with membrane-stabilizing properties (e.g., types 1a and 1c and
sotalol) are contraindicated, as they may worsen the disturbance. Torsades de pointes tachycardia may
respond to infusion of lidocaine or magnesium; however, overdrive pacing is often required.[32]
Bradycardia and atrioventricular block initially should be treated with standard therapies that include the
administration of atropine and pacemaker placement. When these problems persist, an infusion of
epinephrine may be effective. Highly depressed myocardial tissue may respond poorly to pacemaker
placement.
Ocular Toxicity
There is no proven therapy for the ocular toxicity of quinine. The induction of vasodilation by stellate
ganglion block has been advocated in anecdotal reports; however, controlled studies using unilateral blocks
have conclusively demonstrated the futility of this intervention.[3][11][13][23][27]
Drug Removal
Although published studies indicate that the elimination of quinine is increased when the urine is acidified,
this may worsen cardiotoxicity and is therefore contraindicated. No studies demonstrate a benefit from either
extracorporeal drug removal or plasma exchange.[5][32][36]
Chloroquine
The treatment of chloroquine poisoning resembles that of quinine toxicity with the following additions.
Hypertonic sodium bicarbonate was shown in one study in rats to partially reverse the QRS prolongation
induced by chloroquine.[20] The administration of sodium bicarbonate, in the same dosages as cited above,
is recommended if the QRS duration is at or above 0.14 second. Because sodium bicarbonate may
exacerbate chloroquine-induced hypokalemia, close monitoring of serum electrolytes is recommended. The
administration of epinephrine apears to have a cardioprotective effect in chloroquine poisoning, [43][47] as
does the administration of diazepam.[14][19][35][42][43][47] For the chloroquine-poisoned patient with severe
conduction disturbances (QRS duration over 0.14 second), in addition to administration of sodium
bicarbonate, the patient should be treated with diazepam. The recommended dose is 0.5–2 mg/kg given
intravenously over 30 minutes followed by an infusion of 1–2 mg/kg/hr for 48 hours.[14][19][35][42] All
antidysrhythmic drugs with membrane-stabilizing properties are contraindicated.
Hypokalemia
Hypokalemia is proposed to have a cardioprotective effect in patients poisoned with chloroquine so that
potassium correction is not recommended during the first 8 hours of treatment. [16][32]
Drug Removal
There is no evidence that forced diuresis, acidification of the urine, or extracorporeal drug removal is
effective in the treatment of chloroquine toxicity.[28][49]
Mefloquine
There are no data documenting the treatment of mefloquine toxicity. Although not studied, it is reasonable to
use multidose activated charcoal in mefloquine poisoning in which there is a significant enterohepatic
recirculation of drug.


DISPOSITION
All patients with deliberate ingestions should be admitted for observation and treatment.[32] Patients with
visual disturbances need ophthalmologic referral and close follow-up. The vast majority of patients blinded
by quinine show some form of improvement in 1–50 days. The improvement in visual acuity can continue for
several months.[27]
Patients with quinine-induced auditory disturbances need follow-up audiograms. The effect of quinine on
hearing loss is generally considered to be reversible.[1][44] Similarly, improvement in auditory acuity can
continue for several months.


SEQUELAE
Recovery from total blindness due to quinine poisoning is uncertain.[23] Permanent visual loss has been
documented, especially if plasma concentrations of quinine exceed 15 µg/mL. Permanent hearing loss is
rare. Persistently abnormal audiograms have been documented.[44]


REFERENCES
1. Alvan G, Karlsson KK, Villen T: Reversible hearing impairment related to quinine blood concentrations in
guinea pigs. Life Sci 1989; 45:751.
2. Angel G, Guerre BP, Rogier C: Hypokaelemia related to acute chloroquine poisoning. [Letter].
Lancet 1995; 346:1625.
3. Bankes JLK, Hayward JA, Jones MBS: Quinine amblyopia treated with stellate ganglion block. Br Med
J 1972; 4:85.
4. Bateman DN, Dyson EH: Quinine toxicity. Adv Drug Reactions 1986; 4:215.
5. Bateman DN, Blain PG, Woodhouse KW, et al: Pharmacokinetics and clinical toxicity of quinine
overdosage: Lack of efficacy of techniques intended to enhance elimination. Q J Med 1985; 54:125.
6. Boland ME, Roper SMB, Henry JA: Complications of quinine poisoning. Lancet 1985;384.
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Med 1990; 19:1903.
8. Brandfonbrener M, Kronholm J, Jones HR: The effect of serum potassium concentration and quinidine
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9. Brem JL, Kerr L, Stuerchler D: Mefloquine prophylaxis: An overview of spontaneous reports of severe
psychiatric reactions and convulsions. J Trop Med Hyg 1992; 95:167.
10. Brinton GS, Norton EWD, Zahn JR, Knighton RW: Ocular quinine toxicity. Am J
11. Brust JCM, Richter RW: Quinine amblyoplia related to heroin addiction. Ann Intern Med 1971; 74:84.
12. Butler AR, Gilbert BC, Hulme P, et al: EPR evidence for the involvement of free radicals in the iron-
catalyzed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some
polycyclic endoperoxides. Free Radic Res 1998; 28:471.
13. Canning CR, Hague S: Ocular quinine toxicity. Br J Ophthalmol 1988; 72:23.
14. Charbonneau P, Lacotte J, Lemarchand C, et al: Effet antiarhythmique du diazepam lors des
intoxications à la chloroquine. Réanimation Soins Intensifs, Médecine d’Urgence 1986; 2:265.
15. Claessen FA, van Boxtel CJ, Perenboom RM, et al: Quinine pharmacokinetics: Ototoxic and cardiotoxic
effects in healthy Caucasian subjects and in patients with falciparum malaria. Trop Med Int
Health 1998; 3:482.
16. Clemessy JL, Favier C, Borron SW, et al: Hypokalemia related to acute chloroquine ingestion.
Lancet 1995; 346:877.
17. Clemessy JL, Taboulet P, Hoffmann JR, et al: Treatment of acute chloroquine poisoning: A 5 year
experience. Crit Care Med 1996; 24(7):1189.
18. Collee GG, Samra GS, Hanson GC: Chloroquine poisoning: Ventricular fibrillation following “trivial”
overdose in a child. Intensive Care Med 1992; 18:170.
19. Corvette J, Victual E, Aplomb S, et al: Experimental assessment of the prospective activity of diazepam
on the acute toxicity of chloroquine. J Toxicol Clin Toxicol 1983; 20:271.
20. Curry SC, Connor DA, Clark RF, et al: The effect of hypertonic sodium bicarbonate on QRS duration in
rats poisoned with chloroquine. J Toxicol Clin Toxicol 1996; 34(1):73.
21. Davis TM, Demo LG, Aye-Eddie SA, et al: Neurological, cardiovascular and metabolic effects of
mefloquine in healthy volunteers: A double-blind, placebo-controlled trial [see comments]. Br J Clin
Pharm 1996; 42:415.
22. Don Michael TA, Aiwazzadeh S: The effects of acute chloroquine poisoning with special reference to the
heart. Am Heart J 1970; 79:831.
23. Dyson EH, Proudfoot AT, Prescott LF, et al: Death and blindness due to overdose of quinine. Br Med
J 1985; 291:31.
24. Farver DK, Lavin MN: Quinine-induced hepatotoxicity. Ann Pharmacother 1999; 33:32.
25. Glynne P, Salama A, Chaudhry A, et al: Quinine-induced immune thrombocytopenic purpura followed
by hemolytic uremic syndrome. Am J Kidney Dis 1999; 33:133.
26. Guillon C, Le Bonniec Y: Suicide mode d’emploi: Historique, technique, actualite, Paris, Moreau
Editions, 1982.
27. Guly U, Driscoll P: The management of quinine induced blindness. Arch Emerg Med 1992; 9:317.
28. Heath A, Ahlmen J, Mellstrand T, Wickstrom I: Resin hemoperfusion in chloroquine poisoning. J

29. Henquin J: Quinine and the stimulus secretion coupling in pancreatic B cells: Glucose like effect on
potassium permeability and insulin release. Endocrinology 1982; 110:1325.
30. Hien TT, White NJ: Qinghuaso (Drug Profiles). Lancet 1993; 341:603.
31. Hien TT, Vinh Chau NV, Vinh NN, et al: Management of multiple drug-resistant malaria in Vet Am Ann
Acad Med Singapore 1997; 26:659.
32. Jaeger A, Sauder P, Kopferschmitt J, Flesch F: Clinical features and management of poisoning due to
antimalarial drugs. Med Toxicol 1987; 2:242.
33. Kelly JC, Wasserman GS, Bernard WD, et al: Chloroquine poisoning in a child. Ann Emerg
Med 1990; 19:47.
34. Kivisto KT, Neuvonen PJ: Activated charcoal for chloroquine poisoning. [Letter].
BMJ 1993; 307(2):1068.
35. Koudogbo B, Asselo MC, Ngemby Mbena C, et al: Mode d’action antidotique du diazepam dans le
traitement des intoxications a la chloroquine. J Toxicol Clin Exp 1986; 6:307.
36. Markham TN, Dodson VN, Eckberg DL: Peritoneal dialysis in quinine sulfate intoxication.
JAMA 1967; 202:1102.
37. McDonald SP, Shanahan EM, Thomas AC, et al: Quinine-induced hemolytic uremic syndrome. Clin
Nephrol 1997; 47:397.
38. McKenzie AG: Intensive therapy for chloroquine poisoning. A review of 29 cases. S Afr Med
J 1996; 86:597.
39. Obafunwa JO, Al-Ogleh AM, Busuttil A: Suicidal chloroquine poisoning: Report of two cases. Med Sci
Law Oct 1994; 34(4):334.
40. Okitolonda W, Delacollette C, Malengreau M, et al: High incidence of hypoglycemia in African patients
treated with intravenous quinine for severe malaria. Br Med J 1987; 295:716.
41. Prescott LF, Hamilton AR, Heyworth R: Treatment of quinine overdose with repeated oral charcoal. Br
J Clin Pharmacol 1989; 27:95.
42. Riou B, Barriot P, Rimailho A, et al: Treatment of severe chloroquine poisoning. N Engl J
Med 1988; 318:1.
43. Riou B, Rimailho A, Galliot M, et al: Protective cardiovascular effects of diazepam in experimental acute
chloroquine poisoning. Intensive Care Med 1988; 14:610.
44. Roche RJ, Silamut K, Pukrittayakamee S, et al: Quinine induces reversible high tone hearing loss. Br J
Clin Pharmacol 1990; 29:780.
45. Rouviex B, Bricaire F, Michon C, et al: Mefloquine and an acute brain syndrome. Ann Intern
Med 1989; 110:577.
46. Silamut K, Molunto P, Ho M, et al: Alpha-1-acid glycoprotein and plasma protein binding of quinine in
falciparum malaria. Br J Clin Pharmacol 1991; 32:311.
47. Sofola OA: The effects of chloroquine on the electrocardiogram and heart rate in anesthetized dogs.
Clin Physiol 1983; 3:75.
48. Tracy JW, Webster LT: Drugs used in the chemotherapy of protozoal infections. Malaria.
In: Hardman JG, Limbird LE, Moninoff PB, et al ed. Goodman & Gilmans’ The Pharmacological Basis of
Therapeutics, 9th ed. New York: McGraw-Hill; 1996.
49. Van Stone JC: Hemodialysis and chloroquine poisoning. J Clin Med 1976; 88:87.
50. Weinke T, Trautmann M, Held T, et al: Neuropsychiatric effects after the use of mefloquine. Am J Trop
Med Hyg 1991; 45(1):86.


Uncited reference
van Agtmael MA, Eggelte TA, van Boxtel CJ: Artemisinin drugs in the treatment of malaria: From medicinal
herb to registered medication. Trends Pharmacol Sci 1999; 20:199-205.


Chapter 62 – Cyclic Antidepressants
PAUL R. PENTEL DANIEL E. KEYLER
Essentials
• The onset and progression of symptoms after overdose are often quite rapid.
• The most common presenting signs are a decreased level of consciousness, sinus tachycardia, and
QRS prolongation.
• QRS prolongation is the most distinctive diagnostic feature and identifies patients at highest risk of
complications.
• Potentially fatal complications include hypotension, ventricular dysrhythmias, seizures, and
hyperthermia.
INTRODUCTION
Antidepressant overdose is common because these drugs are often available to depressed patients who
have a high suicide risk. Of the various types of antidepressants, the selective serotonin reuptake inhibitors
produce a relatively benign overdose and rarely result in fatalities. In contrast, the cyclic antidepressants
(CAs) and monoamine oxidase inhibitors are much more toxic and fatalities may result from their misuse.
This chapter considers CA toxicity; monoamine oxidase inhibitors are discussed in Chapter 66 , and
selective serotonin reuptake inhibitors are discussed in Chapter 63 .


Pharmacology
CAs are well absorbed from the gastrointestinal tract and are eliminated primarily by hepatic metabolism.
There is little biliary secretion of active drug. Metabolism of CAs is by means of various cytochrome P-450
(CYP) enzymes. Hydroxylation of desipramine and imipramine is by the CYP2D6 isoenzyme. In genetically
slow metabolizers (5 per cent of the population in the United States) or patients taking other drugs that
inhibit or compete for this enzyme (e.g., fluoxetine, cimetidine, many antipsychotics), much longer half-lives
can occur and patients can become toxic on usual doses or recover from overdose more slowly.[33] Most
CAs have active metabolites; the tertiary amines (e.g., imipramine, amitriptyline) are demethylated to active
secondary amines (desipramine, nortriptyline), and most CAs also undergo ring hydroxylation to active
metabolites. In overdose, levels of metabolites are low and toxicity is principally due to the parent
compound.[12] Distribution half-lives even with overdose are short (1–2 hr). As a result (provided that
activated charcoal has been administered to terminate drug absorption), serum CA levels typically decline
rapidly during the first 6 to 12 hours after presentation. The subsequent decline in serum CA levels is slower,
owing to elimination half-lives for most CAs of 10 to 20 hours (50–100 hr for protriptyline).[8][30] The
elimination half-life may be prolonged with massive ingestions, owing to saturable metabolism. [21]
Pathophysiology
Physiologic effects of the CAs that contribute to their toxicity include blockade of cardiac sodium and
potassium channels; blockade of a-adrenergic, cholinergic muscarinic, and histaminic receptors; and
inhibition of neuronal catecholamine reuptake. Effects of these drugs on cardiac calcium channels and
neuronal N-methyl- D-aspartate (NMDA) receptors are of less certain importance.
The most important toxic effect of the CAs is sodium channel blockade.[35] The cardiac sodium channel is
responsible for cardiac cell depolarization (action potential phase 0, Fig. 62–1 ); its inhibition leads to slowed
depolarization of individual cardiac cells. This, in turn, leads to slowing of the wave of depolarization across
the myocardium. The electrocardiographic manifestation of slowed depolarization is prolongation of the QRS
complex, the hallmark of CA overdose.[25] Sodium channel blockade in vitro or in animals can be partly
reversed by increasing the ambient pH or sodium concentration, providing the basis for the use of hypertonic
sodium bicarbonate (NaHCO3) to treat some of the cardiac effects of this overdose. Conversely, QRS
prolongation is aggravated by decreasing the ambient pH.[24] The mechanism of this effect is not
established; but by analogy with the antidysrhythmic agent flecainide, displacement of the CA from its
binding site on the sodium channel is a possibility.[28]
Figure 62-1 Effects of CA toxicity on cardiac cell action potentials and the EKG. Depolarization of cardiac cells (phase 0 of the action
potential) is due to an inward sodium current mediated by opening of the fast sodium channel. CAs in toxic doses inhibit the inward
sodium current and thereby slow phase 0 depolarization of cardiac cells within the bundle branches, Purkinje fibers, and ventricular
myocardium. This slowing of phase 0 depolarization is difficult to appreciate from tracings of the individual action potentials because of
the rapidity of depolarization, but the net effect of slowed depolarization of individual cells is slowed conduction of the wave of
depolarization from cell to cell through the His-Purkinje system and ventricular myocardium. As a result, the electrocardiographic QRS
complex, which represents the wave of ventricular depolarization, is prolonged. (Redrawn and modified from Plate 11 from The Ciba
Collection of Medical Illustrations, Volume 5, Section II, by Frank H. Netter, M.D.)
QRS prolongation serves as a marker for CA ingestion and the risk of adverse cardiac or central nervous
system (CNS) events such as ventricular tachycardia or seizures.[3] This is true not just because QRS
prolongation identifies patients who have ingested a substantial overdose, but also because slowed cardiac
conduction is the proximate cause of much of the cardiovascular toxicity of these drugs. Slowed conduction
affects the entire ventricular myocardium and conducting system but may occur nonuniformly. Greater
degrees of slowing in one area relative to another provide the substrate for re-entrant dysrhythmias and is
the likely mechanism by which the CAs produce ventricular tachycardia.[38] Sodium channel inhibition is also
important because it is linked to myocardial contraction (excitation-contraction coupling), perhaps by
regulating the intracellular sodium concentration at membrane sodium-calcium exchange sites. Agents that
interfere with sodium channel opening and sodium entry into cells may therefore reduce the intracellular
calcium concentration, resulting in impaired cardiac contractility and hypotension.
The CAs also block the potassium channel of cardiac cells, inhibiting the outward potassium current that
contributes to repolarization.[35] This results in QT interval prolongation. Prolonged repolarization can
predispose to development of torsades de pointes, but this is uncommon with CA overdose, possibly
because torsades is less likely in the presence of an increased heart rate, and most patients with CA
overdose have a sinus tachycardia.
Alpha-adrenergic blockade causes systemic vasodilation, which is an important contributor to

hypotension.[16] Cholinergic muscarinic receptor blockade may cause an anticholinergic syndrome, including
sinus tachycardia, delirium, coma, mydriasis, impaired gut motility, urinary retention, impaired sweating, and
dry mucosa. Although anticholinergic potencies of therapeutic doses of CAs differ, any of these drugs may
produce an anticholinergic syndrome with overdose. Histamine receptor blockade is of unclear importance,
but it may contribute to coma. Seizures have been attributed to cholinergic or histaminic receptor blockade,
but their mechanism is in fact unclear, and neuronal sodium channel inhibition could also contribute.
Inhibition of neuronal neurotransmitter (norepinephrine, dopamine, and serotonin) reuptake is probably

important in mediating the therapeutic effects of CAs but is less relevant in overdose. The initial
hypertension occasionally seen after overdose could be due to slowed norepinephrine turnover, and
excessive norepinephrine could possibly also contribute to dysrhythmias, but supportive data are lacking.[15]
Hyperthermia may develop due to excessive heat production from agitation, myoclonus, or seizures, along
with reduced heat dissipation from impaired sweating.[29]


CLINICAL PRESENTATION (Table 62–1)
Toxic Dose
Serious toxicity in adults is uncommon with ingestions of less than 1 g of CA, although toxicity may still be
life threatening if other drugs have been co-ingested. Ingestions of more than 2 g may be fatal.
Table 62-1 -- Clinical Presentation of Cyclic Antidepressant Toxicity

Delirium
Coma
Myoclonus
Seizures
Cardiovascular
QRS prolongation
Sinus tachycardia
First degree atrioventricular block
Rightward shift of QRS axis
Ventricular tachycardia
Hypotension
Autonomic
Decreased bowel sounds and motility
Urinary retention
Impaired sweating
Pupil size variable
Other
Hyperthermia
Acidosis or rhabdomyolysis from severe agitation or seizures
General Features
Rapid deterioration in clinical status is common with CA overdose, not because of rapid CA absorption but
rather due to the high doses ingested, so that absorption of even a fraction of the dose is often sufficient to
produce severe toxicity.[5] Most CAs produce similar signs and symptoms with overdose ( Table 62–2 ).
Amoxapine is more likely to produce CNS toxicity, notably seizures, and very little cardiovascular toxicity.[18]
Maprotiline is also more likely to produce seizures, but it may produce some cardiovascular toxicity as well.
Lofepramine is a prodrug that is slowly metabolized to desipramine. Because the parent compound is not
toxic, overdose tends to be relatively benign. Death from CA overdose in hospitalized patients is usually due
to hypotension or ventricular dysrhythmias, because CNS toxicity is more readily managed.[2][13] Prehospital,
CNS toxicity assumes increased importance because airway compromise, impaired ventilation, or seizures
may prove fatal in unattended patients.
Table 62-2 -- Principal Overdose Toxicity of Some Cyclic Antidepressants *

Drug Cardiovascular Seizures
Amitriptyline +++ +++
Nortriptyline +++ +++
Imipramine +++ +++
Desipramine +++ +++
Doxepin +++ +++
Clomipramine +++ +++
Dothiepin +++ +++
Protriptyline +++ +++
Trimipramine +++ +++
Maprotiline ++ ++++
Amoxapine + ++++
Lofepramine † + +
* All of the drugs listed may produce coma and anticholinergic effects with overdose.
† Lofepramine is a prodrug that is slowly metabolized to desipramine, thereby limiting its overdose toxicity.
Central Nervous System Effects
Modest doses of CAs may produce an agitated delirium. More often, the presentation is characterized by a
decreased level of consciousness, often requiring airway protection and assisted ventilation.[2][13] If seizures
occur, they typically develop within the first few hours after ingestion and are generalized and brief. In
patients with coexisting cardiovascular toxicity, particularly if severe, seizures may lead to rapid and marked
worsening of hypotension or dysrhythmias, perhaps due to the accompanying acidosis.[10] Myoclonus is less
common than seizures.
Cardiovascular Effects
The most common cardiovascular manifestations of CA overdose are sinus tachycardia and QRS
prolongation; the most important and most frequently fatal are hypotension and ventricular tachycardia. First-
degree atrioventricular block is common, but higher degrees of atrioventricular block are rare.
QRS Prolongation
QRS prolongation usually takes the form of a nonspecific intraventricular conduction delay rather than a
discrete bundle branch block ( Fig. 62–2 ).[2] QRS duration is a valuable marker of risk for complications,
with values of greater than 0.16 second identifying patients at high risk for ventricular dysrhythmias or
seizures.[3] Other manifestations of the conduction delay include a rightward shift of the QRS axis and the
axis of the terminal 40 msec of the QRS complex and increased R wave voltage in lead aVR, but none of
these markers has proven more specific or sensitive than QRS duration.[7][18] Because sodium channel
blockade is rate dependent, a rapid heart rate will exaggerate QRS prolongation.[20] QTc prolongation, often
present even at therapeutic doses, is variable and of no prognostic importance.[7]
Figure 62-2 EKG tracings from a patient who presented 2 hours after ingestion of imipramine. Representative leads demonstrate
marked QRS prolongation (A). P waves are not visible, but the rhythm was demonstrated to be sinus tachycardia with intraventricular
conduction delay by the gradual shortening of the QRS duration and reappearance of P waves over 36 hours (B).
Hypotension
Hypotension often occurs in the absence of QRS prolongation, owing to vasodilation.[16][32] If QRS
prolongation is present, then impaired cardiac contractility is likely contributing as well. Tachydysrhythmias
or hyperthermia may aggravate hypotension.
Dysrhythmias
Sinus tachycardia is present in more than half of patients with CA overdose and is usually of no
consequence. Premature ventricular beats are rare. Ventricular tachycardia is usually monomorphic, and
less commonly torsades de pointes occurs.[3][32] Differentiating ventricular tachycardia (uncommon) from
sinus tachycardia with QRS prolongation (common) may be difficult.
Other Effects
Hyperthermia may develop rapidly in patients with excessive muscular activity from agitation or seizures.
Temperatures above 105°F may be fatal or result in permanent neurologic sequelae.[29] Acidosis may be
caused by the same factors, as well as by hypoventilation. Pulmonary edema is common but is probably due
to aspiration and hypotension rather than to a specific effect of the CAs. [31]
An anticholinergic syndrome often occurs that may include sinus tachycardia, delirium, coma, mydriasis,
impaired gut motility, urinary retention, impaired sweating, and dry mucosa. However, patients need not
have all of these findings, and the absence of anticholinergic effects does not rule out CA overdose.


Because CA overdose is common, it should be considered in all patients presenting with abrupt onset of
delirium, seizures, a decreased level of consciousness, hypotension, or tachycardia. The most useful
diagnostic marker is QRS prolongation because it is produced by relatively few other medications or
conditions ( Table 62–3 ). Detection of CAs in urine is supportive of the diagnosis, but this test is often
positive even with therapeutic doses.
Table 62-3 -- Differential Diagnosis of Cyclic Antidepressant Toxicity: Causes of QRS Prolongation
QRS Prolongation with Therapeutic Doses
Class IC antidysrhythmic agents; encainide, flecainide, propafenone
QRS Prolongation Primarily with Overdose
Cyclic antidepressants (except amoxapine)
Class IA antidysrhythmic agents: quinidine, procainamide, disopyramide
High-dose antipsychotics: thioridazine, chlorpromazine, mesoridazine
Antimalarials: quinine, chloroquine, hydroxychloroquine
Cocaine
Digoxin
Membrane-stabilizing ß-adrenergic receptor antagonists: propranolol
Propoxyphene
Very uncommon even with overdose: diphenhydramine, lithium
Nondrug Causes
Hyperkalemia
Hypocalcemia
Ischemia
Cardiomyopathy


LABORATORY STUDIES
Alternative explanations for the patient’s condition can be sought with routine screening tests, including
serum electrolytes, blood urea nitrogen, glucose, and a complete blood cell count. In patients with significant
cardiovascular toxicity, arterial blood gases should be measured to guide the administration of hypertonic
NaHCO3. Urine toxicology screens may be useful when the diagnosis is in question for detecting the
presence of CAs, other drugs that prolong QRS duration (see Table 62–3 ), or other co-ingested drugs. A
12-lead EKG is essential to look for and follow QRS duration or dysrhythmias. A chest radiograph is useful if
pulmonary edema is in question or aspiration is suspected.
Serum CA levels are not generally available in real time. Therapeutic serum levels of CAs, although
established for only a few, are 50 to 250 ng/mL (of parent compound), and levels of more than 1000 ng/mL
(corresponding to ingestion of more than 1 g) usually produce toxicity. Serum CA levels are not as useful as
clinical markers such as QRS duration for predicting complications of CA overdose and are not usually
monitored.[2][3][13]


TREATMENT (Table 62–4)
Because rapid deterioration is common, patients with suspected CA overdose should be closely observed
with intravenous access, continuous cardiac monitoring, and frequent measurement of blood pressure and
core temperature (particularly in patients who are agitated or seizing). The most important aspect of initial
management is the prompt administration of activated charcoal, 1 g/kg (maximum 50 g). There is no
evidence that prior gastric lavage is beneficial, and it delays the administration of activated charcoal.[4] If
used, gastric lavage should probably be limited to patients seen within 1 hour of CA ingestion. Induction of
emesis is contraindicated because of the risk of aspiration due to seizures or a deteriorating level of
consciousness. Because the CAs have a large volume of distribution, repeated doses of activated charcoal,
hemodialysis, and hemoperfusion all remove very little drug and are not clinically useful.
Table 62-4 -- Treatment Essentials of Cyclic Antidepressant Toxicity *

General
Activated charcoal, 1 g/kg PO (maximum: 50 g) with sorbitol
Avoid syrup of ipecac
Coma
Protect airway, ventilate if necessary
Delirium
Diazepam, 5–10 mg, or lorazepam, 1–2 mg, intravenously if severely agitated; monitor for hyperthermia
Seizures
Diazepam, 10 mg, or lorazepam, 1–2 mg intravenously; repeat as needed
Prevent acidosis; ventilate, administer hypertonic NaHCO3 † intravenously, 50 mEq, if seizure prolonged
Hyperthermia
Rapid cooling; evaporation, ice water gastric lavage
Paralysis if patient persistently agitated or seizing
Monitor for acidosis, hypertonic NaHCO3 intravenously, 50 mEq, if arterial pH <7.4
QRS Prolongation
<0.014 sec; observe
=0.14 sec, or 0.11–0.14 sec and increasing or accompanied by hypotension; hypertonic NaHCO3 intravenously,
50 mEq; repeat as needed until arterial pH = 7.5
Ventricular Tachycardia
Hypertonic NaHCO3 intravenously, 50 mEq, as needed until arterial pH = 7.5
Lidocaine 1 mg/kg (maximum: 75 mg) over no less than 1 minute, followed by infusion of 1–3 mg/min
Overdrive pacing
Hypotension
Volume challenge; 500 mL 0.9% NaCl
If QRS is prolonged: hypertonic NaHCO3 intravenously, 50 mEq; repeat as needed until arterial pH = 7.5
Dopamine, 5 µg/kg/min intravenously; increase as needed
or
Norepinephrine, 8 µg/min intravenously; increase as needed
Treat aggravating factors (ventricular tachycardia, hyperthermia, seizures) if present
Mechanical support (aortic balloon pump, cardiac bypass) for refractory hypotension
Drugs to Avoid
Class IA and IC antidysrhythmics
Physostigmine
Flumazenil
* For children younger than 12 years old, see Addendum E for pediatric drug doses.
† 1 molar (mEq/mL)
The most effective intervention for the cardiovascular toxicity of CA overdose is hypertonic (1 molar, or 1
mEq/mL) NaHCO3. In animals, NaHCO3 is effective in reducing CA-induced QRS prolongation, reversing
hypotension, and treating ventricular dysrhythmias.[24][25] Human data are anecdotal but similar. NaHCO3 is
generally administered as intravenous boluses of 50 mEq of a 1 mEq/mL solution as needed to correct
acidosis and, if toxicity persists, to raise the arterial blood pH to 7.5. It is not known if a higher pH would
confer additional benefit. Hypertonic NaHCO3 should not be diluted in crystalloid and administered as a
continuous infusion because it will no longer be effective in raising the plasma sodium concentration.[25]
Because NaHCO3 is hypertonic, administration of intravenous boluses of hypertonic NaHCO3 increases both
the plasma pH and the plasma sodium concentration. Some animal studies suggest that increasing pH is
more important, whereas others suggest that increasing the sodium concentration is the critical factor.[24][28]
In vitro studies of Purkinje fibers suggest that both are important.[35] There are no human data to address
this question.
Hypertonic NaHCO3 administration is indicated for patients with ventricular dysrhythmias or hypotension that
has not responded to crystalloid. It is not clear whether hypertonic NaHCO3 is beneficial for patients with
normal blood pressure and cardiac rhythm whose only manifestation of cardiac toxicity is QRS prolongation.
A common approach is to administer hypertonic NaHCO3 to such patients if QRS prolongation is marked
(0.14 sec or more) because of their higher risk of ventricular dysrhythmias, or if QRS duration is increasing.
Routine administration of hypertonic NaHCO3 is not indicated because it may lead to fluid overload,
hypernatremia, or excessive alkalosis. [39]
Hyperventilation to raise blood pH has been used in patients with anecdotal benefit, and the use of
hypertonic NaCl has been suggested, but clinical experience and animal data for hypertonic NaHCO3 are far
more extensive. Phenytoin has been used to reduce QRS duration, but proof of efficacy is lacking, and
phenytoin aggravated dysrhythmias in one animal study.[6]
Hypotension
CA-induced hypotension often responds to crystalloid administration (e.g., 500 mL of 0.9 per cent saline
over 15 minutes).[16][32] If the QRS duration is prolonged, hypertonic NaHCO3 can also be administered. If
hypotension persists, catecholamines may be added. In animals, many catecholamines are effective and it
is not clear if any one is superior.[15] Common choices are norepinephrine or dopamine.[36] Very high doses
of vasopressors may be needed to overcome CA-induced a-adrenergic blockade. If time permits, the use of
a pulmonary artery catheter to measure the relative contribution of vasodilation and impaired cardiac output
may be useful in selecting the appropriate drug and dose.
Dysrhythmias
Sinus tachycardia rarely requires treatment. Ventricular tachycardia in animals responds to hypertonic
NaHCO3 or to lidocaine.[14][24] Hypertonic NaHCO 3 is preferred because of its safety. If lidocaine is used, it
should be infused slowly to reduce the risk of precipitating seizures. Class IA or IC antidysrhythmic agents
(e.g., quinidine, procainamide, flecainide, encainide) may aggravate toxicity and should not be used.
Overdrive pacing has been used anecdotally to terminate ventricular tachycardia.[27]
Central Nervous System Toxicity
Coma is treated by supportive care, including endotracheal intubation for airway protection and assisted
ventilation. Delirium can usually be managed with restraints and reassurance. Benzodiazepines may be
used for agitation but can aggravate CNS depression. Seizures, if prolonged or repeated, may respond to a
benzodiazepine.[11] Phenytoin has been used as a second-line drug, but efficacy data are lacking.
Barbiturates were effective in an animal model (in which phenytoin was not)[1] but may aggravate
hypotension. Propofol has been used in one patient.[19] Because seizures may cause acidosis, adequate
ventilation should be ensured and administration of hypertonic NaHCO3 considered if seizures are
prolonged. Neuromuscular blockade may be considered for refractory seizures if refractory acidosis or
hyperthermia occur, but it should be brief because it may mask ongoing cerebral seizure activity.
Physostigmine has been used in the past for CA-induced CNS toxicity, but it is contraindicated because it
may produce bradycardia or asystole even at usual therapeutic doses.[23]
Other Factors
Hyperthermia may be controlled with rapid cooling through evaporation or ice water gastric lavage. If
agitation or seizures persist during hyperthermia, temporary neuromuscular blockade may be useful.
Flumazenil should not be administered to patients with overdoses involving CAs because it may precipitate
seizures.[34]
Because CA toxicity is reversible, heroic measures may be justified in patients who remain viable but whose
blood pressure cannot be supported pharmacologically. Such measures may be useful if they can help to
support the patient while CA plasma levels fall due to tissue distribution. Survival after prolonged (3 hr)
cardiopulmonary resuscitation or the use of an intra-aortic balloon pump has been reported.[37] Cardiac
bypass has been of benefit in animals.[37]


DISPOSITION
Asymptomatic patients who receive activated charcoal may be observed in the emergency department with
cardiac monitoring and an intravenous access for 6 hours. Those who remain free of signs or symptoms of
toxicity need no further medical monitoring, and psychiatric evaluation can be obtained.[13] Patients with any
signs or symptoms of CA overdose, including persistent sinus tachycardia, should be admitted. Cardiac
monitoring in an intensive care unit should be continued until all signs and symptoms have resolved. If the
patient’s baseline QRS duration is not known, monitoring should continue until it is less than 0.10 second. If
QRS duration stabilizes at more than 0.10 second, measuring the serum CA level may be helpful. Levels
exceeding the therapeutic range suggest that QRS prolongation is due to residual CA toxicity, whereas
levels that are therapeutic or subtherapeutic suggest that QRS prolongation simply represents the patient’s
baseline cardiac conduction.


SEQUELAE
Barring secondary complications such as anoxic brain damage, the acute effects of CA overdose are all
reversible.


REFERENCES
1. Beaubien AR, Carpenter DC, Mathieu LF, et al: Antagonism of imipramine poisoning by anticonvulsants
in the rat. Toxicol Appl Pharmacol 1976; 38:1.
2. Biggs JT, Spiker DG, Petit JM, et al: Tricyclic antidepressant overdose: Incidence of symptoms.
JAMA 1977; 238:135.
3. Boehnert MT, Lovejoy FH: Value of the QRS duration versus the serum drug level in predicting seizures
and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J
Med 1985; 323:474.
4. Bosse GM, Barefoot JA, Pfeifer MP, et al: Comparison of three methods of decontamination in tricyclic
antidepressant overdose. J Emerg Med 1995; 13:203-209.
5. Callaham M, Kassel D: Epidemiology of fatal tricyclic antidepressant ingestion: Implications for

management. Ann Emerg Med 1985; 14:1.
6. Callaham M, Schumaker H, Pentel P: Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline

poisoning. J Pharmacol Exp Ther 1988; 245:216.
7. Caravati EM, Bossart PJ: Demographic and electrocardiographic factors associated with severe tricyclic
antidepressant toxicity. Clin Toxicol 1991; 29:31-43.
8. Crome P: Poisoning due to tricyclic antidepressant overdosage: Clinical presentation and treatment.
Med Toxicol 1986; 1:261-285.
10. Ellison DW, Pentel PR: Clinical features and consequences of seizures due to cyclic antidepressant
11. Follmer CH, Lum BK: Protective action of diazepam and of sympathomimetic amines against
amitriptyline induced toxicity. J Pharmacol Exp Ther 1982; 222:424.
12. Gram LF, Bjerre N, Kragh-Sorenson P, et al: Imipramine metabolites in blood of patients during therapy
and after overdose. Clin Pharmacol Ther 1983; 33:335.
13. Hulten BA, Heath A: Clinical aspects of tricyclic antidepressant poisoning. Acta Med
Scand 1982; 213:275.
14. Javid IJ, Davis JM, Maiorano M: Uptake and/or binding of tricyclic antidepressants in human red cells.
Life Sci 1985; 26:1761-1769.
15. Knudsen K, Abrahamsson J: Effects of epinephrine and norepinephrine on hemodynamic parameters

and arrhythmias during a continuous infusion of amitriptyline in rats. Clin Toxicol 1993; 31:461-471.
16. Langou RA, Van Dyke C, Tahan SR, et al: Cardiovascular manifestations of tricyclic antidepressant
overdose. Am Heart J 1980; 100:458-463.
18. Litovitz TL, Troutman WH: Amoxapine overdose—seizures and fatalities. JAMA 1983; 250:1069.
19. Merigian KS, Browning RG, Leeper KV: Successful treatment of amoxapine-induced refractory status
epilepticus with propofol (Diprivan). Acad Emerg Med 1995; 2:128-133.
20. Nattel S: Frequency-dependent effects of amitriptyline on ventricular conduction and cardiac rhythm in
dogs. Circulation 1985; 72:896-906.
21. Nelson JC, Jatlow PI: Nonlinear desipramine kinetics: Prevalence and importance. Clin Pharmacol
Ther 1987; 41:666.
23. Pentel P, Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant
overdose. Ann Emerg Med 1980; 9:588.
24. Pentel PR, Benowitz NL: Efficacy and mechanism of action of sodium bicarbonate in the treatment of
desipramine toxicity in rats. J Pharmacol Exp Ther 1984; 230:12-19.
25. Pentel PR, Benowitz NL: Tricyclic antidepressant poisoning: Management of arrhythmias. Med
Toxicol 1986; 1:101-121.
27. Peters RW, Buser GA, Kim HJ, et al: Tricyclic overdose causing sustained monomorphic ventricular
tachycardia. Am J Cardiol 1992; 70:1226-1228.
28. Ranger S, Sheldon R, Fermini B, et al: Modulation of flecainide’s cardiac sodium channel blocking
actions by extracellular sodium: A possible cellular mechanism for the action of sodium salts in flecainide
cardiotoxicity. J Pharmacol Exp Ther 1993; 264:1160-1167.
29. Rosenberg J, Pentel PR, Pond S, et al: Hyperthermia associated with drug intoxication. Vet Hum
Toxicol 1984; 26:413.
30. Schultz P, Turner-Tamiysay K, Smith G, et al: Amitriptyline disposition in young and elderly normal men.
Clin Pharmacol Ther 1983; 33:360.
31. Shannon M, Lovejoy FH: Pulmonary consequences of severe tricyclic antidepressant ingestion. Clin
Toxicol 1987; 25:443.
32. Shannon M, Merola J, Lovejoy FH: Hypotension in severe tricyclic antidepressant overdose. Am J
Emerg Med 1988; 6:439.
33. Spina E, Henthorm TK, Eleborg L, et al: Desmethylimipramine overdose: Nonlinear kinetics in a slow
hydroxylator. Ther Drug Monit 1985; 7:239.
35. Tamargo J, Rodriguez S, Garcia de Jalon P: Electrophysiological effects of desipramine on guinea pig
papillary muscles. Eur J Pharmacol 1979; 55:171.
36. Teba L, Schiebel F, Dedhia HV, et al: Beneficial effect of norepinephrine in the treatment of circulatory
shock caused by tricyclic antidepressant overdose. Am J Emerg Med 1988; 6:566.
37. Williams JM, Hollingshed MJ, Vasilakis A, et al: Extracorporeal circulation in the management of severe
tricyclic antidepressant overdose. Am J Emerg Med 1994; 12:456-458.
38. Wit AL, Cranefield PF, Hoffman BF: Slow conduction and re-entry in the ventricular conducting system.
Circ Res 1972; 30:11.
39. Wrenn K, Smith B, Slovis C: Profound alkalemia during treatment of tricyclic antidepressant overdose: A
potential hazard of combined hyperventilation and intravenous bicarbonate. Am J Emerg
Med 1992; 10:553-555.


Uncited references
Dawling S, Crome P, Graithwaite R: Pharmacokinetics of single oral doses of nortriptyline in depressed

elderly hospital patients and young healthy volunteers. Clin Pharmacokinet 1980; 5:394.
Liebelt EL, Francis PD, Woolf AD: ECG lead aVR versus QRS interval in predicting seizures and
arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med 1995; 26:195-201.
Ngao M, Takatori T, Wu B, et al: Immunotherapy for the treatment of acute paraquat poisoning. Hum
Toxicol 1989; 8:121-123.
Pentel PR, Bullock ML, DeVane CL: Hemoperfusion for imipramine overdose: Elimination of active
metabolites. J Toxicol Clin Toxicol 1982; 19:239.


Chapter 63 – Serotonin Reuptake Inhibitors, Newer Antidepressants, and the Serotonin
Syndrome
JEFFREY BRENT
Essentials
• These drugs have a large therapeutic index with little toxicity after an overdose. The most common
clinical finding in overdose, when there is one, is lethargy.
• Seizures, electrocardiogram (EKG) disturbances, and significant mental status depression can occur
with very large ingestions. Always consider alternative causes.
• In combination with other serotonergic agents these drugs predispose to the potentially serious
serotonin syndrome, characterized by mental status and neuromotor and autonomic disturbances.
INTRODUCTION
After the synthesis of tricyclic compounds in the 1940s their efficacy as antidepressants became apparent.
The initial enthusiastic use of tricyclic antidepressants was tempered by the frequent occurrence of sedative
and anticholinergic side effects. Their narrow therapeutic index was of even greater concern, especially in
the setting of overdose, when life-threatening cardiac dysrhythmias, central nervous system (CNS)
depression, and seizures commonly occur.[26] A search for safer compounds led to the discovery of the
importance of the neurotransmitter serotonin (5-hydroxytryptamine [5HT]) in the pathophysiology of
depression and the development of a new class of antidepressants that inhibit the reuptake of serotonin.
These new agents fall into two categories based on their pharmacologic mechanisms of action. Selective
serotonin reuptake inhibitors (SSRIs) act exclusively through selective inhibition of serotonin reuptake,
whereas serotonin reuptake inhibitors (SRIs) have variable effects on synaptic levels of epinephrine,
norepinephrine, and dopamine in addition to inhibiting serotonin reuptake.[23] The available SSRIs and SRIs
are listed in Table 63–1 . SRIs include newer antidepressants such as venlafaxine (Effexor), nefazodone
(Serzone), and mirtazapine (Remeron). Although these new agents have not demonstrated greater
therapeutic efficacy than the cyclic antidepressants in the treatment of depression, they are markedly freer of
both the adverse side effects noted with therapeutic use of the cyclics as well as the profound life-
threatening toxicity associated with overdose.[3][9][16][41][45][58][62][97] However, the advent of the SRIs and RIs
has demonstrated the potential consequence of accumulation of excess serotonin at neurosynapses, which
results in the serotonin syndrome. This syndrome typically has occurred during the use of two or more
agents that enhance synaptic serotonin by different mechanisms, although it has been reported with
overdose of a single drug.[43]
Table 63-1 -- Selective Serotonin Reuptake Inhibitors

Generic Name Type Trade Name Therapeutic Dose Other Effects
Fluoxetine SSRI Prozac 20–80 mg/d
Generic Name Type Trade Name Therapeutic Dose Other Effects
Fluvoxamine SSRI Luvox 100–300 mg/d
Paroxetine SSRI Paxil 20–60 mg/d
Sertraline SSRI Zoloft 50–200 mg/d
Citalopram SSRI Celexa 20–40 mg/d
200–600 mg/d Norepinephrine reuptake inhibitor
5HT2 receptor antagonist
Nefazodone SRI Serzone
Alpha-adrenergic receptor antagonist
5HT reuptake inhibitor
Norepinephrine reuptake inhibitor
Venlafaxine SRI Effexor 75–375 mg/d
Mirtazapine SRI Remeron 15–45 mg/d
Bupropion SRI Wellbutrin 100–450 mg/d
Dopamine reuptake inhibitor


SSRIs/SRIs
Pharmacology
SSRIs
Serotonin is synthesized from the amino acid tryptophan and stored in intracellular vesicles by an ion-
trapping mechanism. Intracellular serotonin that is not sequestered in vesicles is vulnerable to degradation
by the cytoplasmic enzyme monoamine oxidase type A (MAOA). Neuronal stimulation results in release of
stored serotonin into the synapse. All of the SSRI antidepressants raise synaptic serotonin by inhibiting its
reuptake into presynaptic nerve terminals after depolarization of the neuron ( Fig. 63–1 ). The effects of
serotonin depend on specific interactions with receptors that are found in a variety of locations. There are
seven families of 5HT receptors (5HT1–7) that are the products of a family of genetic loci. These include the
clinically defined receptors 5HT 1A, 5HT1D, and 5HT2 for which specific agonists or antagonists have been
identified. Activation of these receptors produces a variety of effects, such as inhibition or activation of
adenyl cyclase and activation of phospholipase. They are also linked to gated ion channels. Some of the
receptor mechanisms are unknown.[55][82][100]
Figure 63-1 Normal serotonin neurochemistry. (1) The amino acid l-tryptophan enters the neuron via a carrier protein and is
converted to 5-hydroxytryptamine (5-HT or serotonin). (2) Serotonin is stored in vesicles prior to synaptic release. (3) Serotonin is
released upon presynaptic nerve depolarization. (4) Once serotonin is released it can bind to presynaptic and postsynaptic receptors.
The presynaptic 5-HT1D receptor (heteroreceptor) limits 5-HT release. The presynaptic 5-HT1A receptor is located on the cell body
(somatodendritic) and also limits serotonin release. Many different types of 5-HT receptors are located postsynaptically. (5) Serotonin
is transported (pumped) back into the neuron through protein channels located on the presynaptic membrane. (6) Once inside the
presynaptic neuron 5-HT can be recycled into the storage vesicles for future release. (7) Serotonin is metabolized by the enzyme
monoamine oxidase (MAO) type A, which resides on outer mitochondrial membranes. (8) Hydroxyindoleacetic acid (5-HIAA) is the
main metabolite of serotonin and undergoes elimination from the neuron by a carrier-mediated process. Shaded circle, serotonin.
(From Mills KC: Serotonin syndrome: A clinical update. Crit Care Clin 13:766, 1997.)
The exact relationship between serotonin levels and the roles of specific 5HT receptors in the
pathophysiology of depression has been a focus of considerable scientific investigation. There is little doubt
that SSRIs are mood-enhancing, and evidence suggests that this occurs because of elevation of brain
synaptic 5HT levels.[14][81] The specific mechanisms of serotonin as a modulator of mood remain unclear.
Although all of the SSRIs exert their therapeutic effects through a similar mechanism, they differ significantly
in their metabolism and potential for interactions with other drugs. Elimination half-lives range from 1 day for
sertraline and paroxetine to 7 to 15 days for norfluoxetine, the active metabolite of fluoxetine. [72] All of the
SSRIs, with the exception of fluvoxamine, have active metabolites, although only norfluoxetine exerts a
significant pharmacologic effect. Norfluoxetine appears to be a more potent inhibitor of serotonin reuptake
than fluoxetine, its parent compound. All of the SSRIs undergo oxidative metabolism by hepatic cytochrome
P-450 enzymes before renal elimination. Elimination half-lives are altered by the presence of renal or
hepatic disease and may also be affected by age. Elderly patients have significantly higher levels of
citalopram and paroxetine, for example.
SRIs
Venlafaxine (Effexor) is a bicyclic antidepressant that inhibits the reuptake of serotonin and also less
potently inhibits the reuptake of norepinephrine and dopamine. It is metabolized in the liver to
desmethylvenlafaxine, an active metabolite. The half-life of the parent compound is 4 hours, and that of the
metabolite is 10 hours. Cimetidine decreases the clearance of venlafaxine. The side effect and toxicity
profile is similar to that of the SSRIs.[15]
In addition to its effects on the presynaptic reuptake of serotonin, nefazodone (Serzone) also antagonizes
the 5HT2 receptor. It is metabolized in the liver to two active metabolites. Mild sedation without
cardiovascular effects is the most common effect of overdose.[25]
Mirtazapine is a newer antidepressant with noradrenergic and serotonergic activity. Sedation is the most
common side effect. It also causes agranulocytosis in approximately 1 in 1000 patients that reverses on
discontinuation of the medication. Its toxicity is comparable to that of SSRIs.[9]
Pathophysiology
An excess of serotonin in the CNS gives rise to the clinical syndrome known as the serotonin syndrome (
Fig. 63–2 ). Although the serotonin syndrome has been reported to occur in the setting of overdose with a
single serotonergic agent,[43] it is far more commonly described as a consequence of the administration of
two drugs that increase CNS serotonin by different mechanisms, such as the combination of an SSRI and
an MAOA inhibitor (MAOAI). The serotonin syndrome is likely related to stimulation of 5HT1A and 5HT2
receptors. This would be consistent with the observation that cyproheptadine, a 5HT 1A antagonist, appears
to reverse the symptoms of the serotonin syndrome while the 5HT1D agonist sumatriptan does not cause the
serotonin syndrome. The variety of agents that cause serotonergic effects and their mechanisms are given
in Table 63–2 .
Figure 63-2 Mechanisms of serotonin syndrome. (1) Increased doses of l-tryptophan will proportionally increase 5-hydroxytryptamine
(5-HT or serotonin) formation. (2) Amphetamines and other drugs increase the release of stored serotonin. (3) Inhibition of serotonin
metabolism by monoamine oxidase (MAO) inhibitors will increase presynaptic 5-HT concentration. (4) Impairment of 5-HT transport
into the presynaptic nerve by uptake blockers increase synaptic 5-HT concentration. (5) Direct serotonin agonists can stimulate
postsynaptic 5-HT receptors. (6) Lithium increases postsynaptic receptor responses. Diamond, drug-blocking 5-HT uptake; shaded
circles, 5-HT; star, direct-acting 5-HT agonist. (From Mills KC: Serotonin syndrome: A clinical update. Crit Care Clin 13:769, 1997.)
Table 63-2 -- Common Serotonergic Agents

Common
Agent Trade Name Effects on 5HT Remarks
Amphetamines Dexedrine, Stimulate release Effect seen with various amphetamine-like
Adderall, agents
various
Because of partial agonist properties, tends not
5HT1A partial
Buspirone BuSpar to be a major contributor to the serotonin
agonist
syndrome
5HT4 receptor is not responsible for the
serotonin syndrome so appears to be safe with
Cisapride Propulsid 5HT4 agonist
concomitant administration of other serotonergic
agents
Cocaine Inhibits reuptake
Dextromethorphan Various Inhibits reuptake
Common
Agent Trade Name Effects on 5HT Remarks
Stimulates release
Dexfenfluramine Redux * and inhibits
uptake
Stimulates release
Fenfluramine Pondimin * and inhibits
uptake
Sibutramine Meridia Inhibits reuptake
Levodopa/carbidopa Sinemet Stimulates release
Unclear, but
A direct agonist effect on 5HT receptors has
Lithium Various appears to
been suggested
enhance release
5HT1A and 5HT2
LSD
agonist
Monoamine oxidase
Various Inhibit metabolism Also may decrease reuptake in overdose
inhibitors (MAOIs)
Reported to contribute to the serotonin
Meperidine Demerol Inhibits reuptake
syndrome only in combination with MAOIs
MDMA † Stimulates release Also an MAOI
See Table
SSRIs Inhibit reuptake
63–1
5HT1D receptor does not appear to contribute to
the serotonin syndrome. Appears to be safe with
Sumatriptan Imitrex 5HT1D agonist
the concomitant administration of other
serotonergic agents
Naratriptan Amerge
Rizatriptan Maxalt
Zolmitriptan Zomig
Several case reports document serotonergic
Tramadol Ultram Unclear
syndrome in combination with SSRIs
Metabolic
Tryptophan precursor (see
Fig. 63–1 )
* Withdrawn from the U.S. market 9/15/97.
† MDMA is methylenedioxy methamphetamine, or Ecstasy, a designer amphetamine. Other phenylethylamine class hallucinogens may have
similar serotonergic effects.
Acute Toxicity
Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms after an
overdose.[7][16][17][22][24][31][41][46][51][57][60][61][62][70][79][97] When symptoms do occur, drowsiness is most
common, followed by deeper depression of consciousness with large ingestions.[3][7][22][46][58][79] Other less
frequently reported effects include dizziness,[11][46][79] headaches,[46][79] hypotension,[48] extrapyramidal
signs, [22] flulike symptoms,[44] urticaria, [44] angioedema,[44] nausea and vomiting,[7][11][46][57]
tachycardia,[7][22][46] tremor,[7] myoclonus,[69] and agitation.[11][22][46] The effects of overdose in children are
similar to those in adults.[22][43][60][61]
Rarely, seizures and dysrhythmias occur after overdoses of SRIs and SSRIs.[3][8][69][79][99] A review of 44
cases of pure citalopram overdose in a Swedish data bank showed that a history of ingestion of more than
600 mg (10 times the maximum daily dose) was associated with QRS widening in 6 of 18 patients and
seizures in 6 of 18. All 5 patients with doses reportedly greater than 1900 mg had a wide QRS complex,
seizures, or both. Seizures occurred within the first few hours and did not recur, and EKG abnormalities
resolved within 12 to 14 hours. No malignant dysrhythmias were observed.[69] In a series of forensic cases
the ingestion of 3.9 g of citalopram was suspected as the sole cause of death in 1 patient.[65]
Although it is likely that at least some of the effects of overdose are manifestations of serotonergic excess, it
is uncommon to see evidence of the serotonin syndrome after overdose. The reason for this is unclear and
may be related to the inability of an agent with one serotonergic mechanism acutely to raise brain CNS
serotonin to the necessary toxic levels.
Serotonin Syndrome
The diagnosis of the serotonin syndrome is based on finding a variety of nonpathognomonic neuromotor,
CNS, or autonomic signs in a patient exposed to pharmacologic agents that have serotonergic effects.
Clinical manifestations vary from mild confusion, tachycardia, tremor, or clonus to coma, life-threatening
hyperthermia, and neuromuscular rigidity. Both the severity and speed of onset of symptoms vary widely
among reported cases. Symptoms generally begin a short time after the addition of a second serotonergic
agent or an increase in dosage.[55] The clinical manifestations of the serotonin syndrome are described in
several series of patients with the serotonin syndrome derived from literature reports of individual
cases.[45][54][86][89] Table 63–3 lists the CNS, neuromotor, and autonomic symptoms and their frequency
derived from 100 reported cases in a 1995 review.[54] The most recent diagnostic criteria are given in Table
63–4 .[18][19][40][89]
Table 63-3 -- Signs and Symptoms of Serotonin Syndrome (Review of 100 Cases)[54]
Sign/Symptom Frequency (%)
Cognitive-Behavioral Symptoms
Confusion/disorientation 51
Agitation/irritability 34
Coma/unresponsiveness 29
Anxiety 15
Euphoria/hypomania 14
Headache 13
Drowsiness 13
Seizures 12
Insomnia 11
Hallucinations (visual and auditory) 6
Dizziness 5
Autonomic Nervous System
Hyperthermia 45
Diaphoresis 45
Sinus tachycardia 36
Hypertension 35
Dilated pupils 28
Tachypnea 26
Nausea 23
Unreactive pupils 20
Flushing 16
Hypotension 15
Diarrhea 8
Ventricular tachycardia 6
Cyanosis 5
Abdominal cramps 4
Salivation 2
Neuromuscular
Myoclonus 58
Hyperreflexia 52
Muscle rigidity 51
Restlessness/hyperactivity 48
Tremor 43
Ataxia/incoordination 40
Clonus 23
Babinski’s sign (bilateral) 16
Nystagmus 15
Trismus 7
Teeth chattering 6
Opisthotonus 6
Paresthesias 6
Adapted, with permission, from the October, 1995, volume 52(5) issue of American Family Physician, published
by the American Academy of Family Physicians.
Table 63-4 -- Diagnostic Criteria for the Serotonin Syndrome

Criteria A, B, and C must each be satisfied:
A) Occurs after the addition of a known serotonergic agent to an established medication regimen or an
increase in the dose of a serotonergic agent.
At least three of the following clinical features are present:
Uncontrollable shivering
Incoordination
Restlessness in feet while sitting
Initial involuntary contractions followed by myoclonic-like movements in legs
Hyperreflexia
Frightened diaphoretic hyperarousal state
Agitation
Oculogyric crisis
Diarrhea
Fever
B) Other causes (see Table 63–5 ) ruled out
C) A neuroleptic had not been started or increased in dosage before the onset of the signs and symptoms listed
above.
Based on modifications of the Sternbach criteria[89] by Insel et al[40] and Dursun et al. [18][19]
Patients with mood disorders frequently require treatment with more than one agent to control their
symptoms, a therapeutic approach that has resulted in many of the reported cases of serotonin syndrome.
Although almost any combination of serotonergic agents can produce a serotonin syndrome, the most
commonly reported cases involve combinations of MAOAIs, SSRIs, clomipramine, or moclobemide, and less
often trazodone, buspirone, or cyclic antidepressants.[6][32][54][55][86][89][92] Lithium, which also has
serotonergic effects, is frequently used in combination with an SSRI to treat patients with bipolar disease
manifested by depression. Several published case reports describe the development of serotonin syndrome
in patients treated with this combination.[37][59][63]
Case reports dating back to 1962 have documented severe episodes of hyperthermia, hypotension, coma,
myoclonus, and rigidity that occurred when patients on MAOAIs were treated with meperidine.[12][93][96][101]
Because meperidine inhibits serotonin reuptake these adverse reactions have been attributed
retrospectively to a serotonin syndrome.[55] Although this reaction is idiosyncratic in that it does not occur in
all patients on MAOAIs who receive meperidine,[20] the severity of symptoms in cases where it does occur
requires avoidance of the administration of meperidine to any patient on an MAOAI. Morphine appears to be
a safe alternative to meperidine. There have not been reports of a serotonin syndrome precipitated by the
administration of meperidine to patients treated with other serotonergic agents. Other opioids with
serotonergic effects that have been associated with serotonin syndrome include tramadol in patients on
SSRIs, [21][49][53] dextromethorphan in patients on MAOAIs, [75][78][80][83] and pentazocine in a patient on
fluoxetine.[34] A few cases of serotonin syndrome have also been reported in patients who received
dextromethorphan while taking an SSRI. [36] The reason for this interaction is unclear, because, unlike other
serotonergic drug combinations reported to cause serotonin syndrome, both agents have similar
serotonergic mechanisms and would not be expected to act synergistically. These reported cases involved
patients chronically treated with paroxetine or fluoxetine and may actually represent a metabolic interaction
because both of these agents inhibit cytochrome P-450 2D6, the same enzyme that metabolizes
dextromethorphan. [5][66] Conceivably the administration of dextromethorphan to a patient taking an SSRI
that inhibits the metabolism of dextromethorphan may cause a serotonin syndrome through the added
serotonergic effects of the two drugs in addition to increased toxic effects of accumulated
dextromethorphan. [72][76][85]
The concomitant administration of the amino acid tryptophan with an MAOAI has also been frequently
associated with the serotonin syndrome.[2][6][10][29][33][39][40][47][52][64][71][73][94]
Almost all cases of serious serotonergic drug interactions that involve MAOAIs have occurred in patients
taking drugs that inhibit MAO isoenzyme A. Recently, however, case reports suggesting the possibility of
serotonin syndrome secondary to serotonergic antidepressant interactions with the MAO isoenzyme B
inhibitor deprenyl (Selegiline, Eldepryl) in depressed patients with Parkinson’s disease have appeared.
Because this interaction was previously thought not to occur, its possibility should be carefully noted by
clinicians.[42][56][74][88][90] It is unclear whether these case reports represent a true interaction.
SSRIs/SRIs taken in overdose do not produce a specific toxidrome and most patients will be asymptomatic
or drowsy. Seizures may occur. The differential diagnosis of toxic seizures is extensive and can be found in
Chapter 18 .
The diagnosis of the serotonin syndrome is a more difficult diagnostic challenge, and the differential
diagnoses to be considered are listed in Table 63–5 . Several common medical conditions can be confused
with the serotonin syndrome, although scrupulous attention to the history will usually allow differentiation
between these various states. Hypersympathetic states are seen with overdoses of sympathomimetic agents
such as amphetamines, cocaine, and phencyclidine. Similarly, a sympathomimetic state occurs in
withdrawal syndromes from ethanol, other sedative hypnotics, and barbiturates. All of these withdrawal
states are due to excessive sympathetic output from the locus ceruleus. The neuroleptic malignant
syndrome (NMS) can occur after the use of neuroleptic agents and presents more typically as rigidity rather
than myoclonus or hyperreflexia, although this distinction can be subtle in clinical practice. The NMS can
also occur after abrupt withdrawal of a dopaminergic agonist. As seen in Table 63–4 , either the recent
initiation of neuroleptic therapy, or an increase in dosage, rules out the serotonin syndrome by generally
accepted diagnostic criteria. Table 63–6 highlights the differences between NMS and serotonin syndrome. A
variety of infectious states can be associated with some of the features of the serotonin syndrome, including
meningitis, meningoencephalitis, and sepsis.
Table 63-5 -- Differential Diagnosis of the Serotonin Syndrome

Common
Overdoses and Poisonings
Sympathomimetics
Lithium
Salicylates
Anticholinergics
Withdrawal States
Ethanol
Barbiturates
Sedative-hypnotics
Infections
Central nervous system
Systemic inflammatory response syndrome
Neuroleptic Malignant Syndrome (see Table 63–6 )
Uncommon
Overdoses and Poisonings
Strychnine
2,4-Dichlorophenoxyacetic acid
Dinitrophenol
Pentachlorophenol
Other
Water hemlock
Tetanus
Thyrotoxicosis
Stiff man syndrome
Collagen Vascular Disease
Cerebral Vasculitis
Lupus Cerebritis
Table 63-6 -- Comparison of Serotonin Syndrome (SS) Versus Neuroleptic Malignant Syndrome (NMS)
SS NMS
Etiology
Antagonism of dopamine receptors is believed
Dopamine antagonists
No to be the main pathophysiologic mechanism
(e.g., haloperidol)
producing NMS
Withdrawal of
No Has been reported to produce NMS
dopamine agonists
Dopamine agonists Dopamine agonist may indirectly
No
(e.g., L-dopa) increase CNS serotonin activity
Serotonin agonists
Yes No
(e.g., MAOIs)
Serotonin antagonists
No No
(e.g., cyproheptadine)
Symptoms and Signs
Symptoms frequently begin within Symptom development is usually more
minutes to hours after addition of gradual: occurring over days to weeks, but may
Onset of symptoms
second drug or increase in dose of occur immediately after a single dose of
primary drug medication
Resolution of Often improve or resolve in less than Symptoms are slower to resolve (average of 9
symptoms 24 hours days)
Hyperthermia *
46% >90%
(>38°C)
Altered level of
54% >90%
consciousness *
Autonomic dysfunction
50–90% >90%
*
Muscle rigidity * 49% >90%
Leukocytosis * 13% >90%
Increased creatine
18% >90%
kinase
SS NMS
Elevated hepatic
9% >75%
transaminases *
Metabolic acidosis * 9% Very common
Hyperreflexia * 55% Rare
Myoclonus * 57% Rare
Treatments
No reason to believe they would be of
Dopamine agonists
benefit, and theoretically they may Are commonly believed to improve condition
(e.g., bromocriptine)
exacerbate condition
Serotonin antagonists May improve condition No beneficial effect
Distinguishing between SS and NMS is not always possible without a history of medication use. Rigidity or
myoclonus involving the legs much more than the arms gives weight toward SS if serotonergic agents are
involved.
From Mills KC: Serotonin syndrome: A clinical update. Crit Care Clin 1997; 13:777.
* Percentages are based on case reports and are subject to reporting bias.
The toxidrome engendered by an overdose of MAOIs is multifactorial and complex. Because MAOA is
responsible for 5HT metabolism, it is likely that a serotonin excess state is one component of the toxicity
seen after an overdose of MAOIs. This toxicity is seen most commonly with those MAOIs that inhibit MAO
isoenzyme A. In addition to their effects on adrenergic amine metabolism, MAOIs can increase synaptic
serotonin (see Fig. 63–2 ). Those MAOIs that are hydrazines, such as isocarboxazid and phenelzine, also
antagonize -aminobutyric acid (GABA), which may further predispose to CNS excitation and seizures.
It is difficult to clinically differentiate the effects of lithium toxicity from those of the serotonin syndrome. They
both occur in patients with history of psychiatric illness whose medications may be unknown at the time of
presentation. They both may cause altered mental status, incoordination, restlessness, myoclonus,
hyperreflexia, diaphoresis, agitation, and fever. The differentiation between these two conditions is made on
the basis of elevated lithium levels and the medication history. Because lithium is a serotonergic agent some
components of lithium toxicity are likely manifestations of serotonin excess.
Salicylate toxicity can present as a clinical picture somewhat similar to serotonin syndrome. The presence of
a significant metabolic acidosis should be a clue to the diagnosis, which can be verified with a salicylate
level.
Laboratory Studies
No specific laboratory studies help in the diagnosis and treatment of either SSRI/SRI overdoses or the
serotonin syndrome. Blood levels of the drugs are neither readily available nor useful. Standard laboratory
studies such as an acetaminophen level, electrolytes to rule out toxins that generate a metabolic acidosis,
and an EKG to rule out cardiotoxic agents are indicated in the standard evaluation of all potentially
significant overdoses. Laboratory assessment of indicators of rhabdomyolysis such as serum creatine
kinase and creatinine and a urinalysis should be considered in patients with significant neuromotor rigidity,
hyperthermia, or agitation.
For patients presenting with a suspected serotonin syndrome, laboratory studies should be directed toward
evaluation of the various criteria in Table 63–4 .
Treatment
Overdose
Overdose is treated according to the fundamental principles of decontamination and standard supportive
care ( Table 63–7 ). Administration of activated charcoal may prevent drug absorption, although its efficacy
in the prevention of complications from the ingestion of SSRIs/SRIs has not been documented. Any toxic
manifestations that arise as a direct result of the ingestion of these agents, in the absence of a serotonin
syndrome, should be treated by standard supportive measures, including cardiac monitoring for severe
cases where EKG changes are noted. Seizures, if they occur, should be treated with an intravenous
benzodiazepine or, if persistent, phenobarbital. There are no specific antidotes to SSRI/SRI poisoning.
Table 63-7 -- Treatment of Serotonin Reuptake Inhibitor Toxicity

Acute Overdose
Activated charcoal
Supportive care
Benzodiazepines (IV) seizures, severe agitation
Phenobarbital for recurrent seizures
Intensive care unit monitoring electrocardiographic conduction disturbances
Serotonin Syndrome
Supportive care: airway, fluids, electrolyte correction
Discontinue serotonergic agents
Hyperthermia: aggressive external cooling with ice water, mist, and fans
Rigidity, seizures, agitation: intravenous benzodiazepine—lorazepam, 1–2 mg IV q 15–20 minutes, or
diazepam, 5–10 mg IV q 10 minutes, titrated to desired effect
Severe symptoms: consider cyproheptadine, 4–8 mg PO q 1–4 hours (max 32 mg) or 0.25 mg/kg/day divided q
1–4 hours in a child
Serotonin Syndrome
Activated charcoal has no role in the management of this syndrome. The mainstay of treatment of the
serotonin syndrome is supportive care, including airway management, hydration and correction of electrolyte
abnormalities, sedation with a benzodiazepine, and control of hyperthermia (see Table 63–7 ). Hyperthermia
in this setting does not respond to antipyretics, and external cooling is indicated. The first-line agent for the
management of rigidity is an intravenous benzodiazepine. After the discontinuation of serotoninergic drugs,
most of these patients have significant improvement within 12 to 24 hours.[55]
For patients exhibiting major serotonergic manifestations, anecdotal data suggest some benefit with the use
of serotonin antagonists. A variety of known 5HT antagonists are listed in Table 63–8 . Although some have
been proposed or used for treatment of the serotonin syndrome, no prospective human study has evaluated
the efficacy of any of these agents in the treatment of the serotonin syndrome.
Table 63-8 -- Serotonin Antagonists

Antagonist Receptor Specificity
Cyproheptadine 5HT1A and 5HT2
Methysergide Mostly 5HT2A/2C, although has activity at other 5HT receptors
Phenothiazines 5HT2
Ondansetron 5HT3
Risperidone 5HT2A/2C
Ergot alkaloids Nonspecific
Yohimbine Specificity not determined
Clozapine 5HT2A/2C
Imidazolines Specificity not determined
Ketanserin Mostly 5HT2A
The most consistent clinical experience in treatment of humans with serotonin syndrome has been with
cyproheptadine (Periactin), a serotonin receptor antagonist that exerts its most potent effects at the 5HT2
and 5HT1A receptors.[68] Several patients with serotonin syndrome treated apparently successfully with
cyproheptadine have been reported.[4][30][50][59] Animal studies also support the efficacy of cyproheptadine in
the treatment of serotonin syndrome.[28] In addition to being a 5HT antagonist, cyproheptadine has
anticholinergic side effects that limit its use. Cyproheptadine is only available as an oral preparation. The
recommended dose is 4 to 8 mg every 1 to 4 hours for an adult (maximum, 32 mg/day); for a child, the
maximum dose is 0.25 mg/kg/d divided every 1 to 4 hours.[55]
Methysergide maleate, a nonspecific 5HT antagonist, has some efficacy in preventing the serotonin
syndrome in animal models.[38] It was anecdotally reported to be effective in one patient with serotonin
syndrome caused by therapeutic doses of levodopa and bromocriptine.[77]
Beta-adrenergic receptor antagonists such as propranolol have been shown to block the serotonin syndrome
in animals,[13][38] presumably due to their 5HT 1 receptor antagonist activity.[87] However, responses to use of
propranolol in the treatment of serotonin syndrome in humans have been inconsistent.[33]
Disposition
There is rarely a need for hospitalization in patients who present with pure SSRI/SRI
overdoses.[7][16][17][22][24][31][41][46][51][62] The patient with a potentially large ingestion should be observed for
seizures, CNS depression, or EKG abnormalities before discharge from the emergency department.
Although there have been no clinically evaluated guidelines for admission of patients with a serotonin
syndrome, the potential seriousness of this condition suggests that all symptomatic patients should be
admitted. Once they are asymptomatic, it does not appear that further medical monitoring is indicated.
Patients with ingestions with suicidal intent require psychiatric evaluation.
Sequelae
There are no long-term sequelae once the acute toxic symptoms resolve. The long half-lives of some of
these agents, especially fluoxetine, create a period of risk for development of the serotonin syndrome if
other serotonergic agents are taken during that time. This risk is not greater than that of any patient taking
the drug on a chronic basis.


BUPROPION
Bupropion (Wellbutrin) is a unique monocyclic antidepressant that has no effect on 5HT reuptake. It is
unusual among the antidepressants because it inhibits dopamine reuptake. Bupropion may also have some
minor effect on norepinephrine reuptake.[76] Peak plasma levels are reached 2 and 3 hours after a dose of
regular- or sustained-release preparations, respectively. It undergoes considerable first-pass metabolism in
the liver. Three active metabolites have been identified, but their potencies and toxicity are unclear.
A retrospective analysis of 58 cases of bupropion overdose reported to five regional poison control centers
demonstrated sinus tachycardia, lethargy, tremors, and seizures as manifestations of toxicity. [84] A fatality
that occurred after ingestion of 23 g of bupropion was associated with seizures, cardiac arrest, and death.[35]
Another massive overdose resulted in significant conduction delays on the EKG.[67] Seizures also occur
during standard therapeutic dosing of bupropion.[95]


SPECIAL CIRCUMSTANCES: DRUG-DRUG INTERACTIONS
Because different SSRIs/SRIs are metabolized by different cytochrome P-450 enzymes, there is a potential
for drug-drug interactions specific to each SSRI/SRI. Fluvoxamine inhibits cytochrome P-450 1A and 2C,
potentially decreasing the clearance of drugs metabolized by those enzymes, such as amitriptyline,
phenytoin, propranolol, or warfarin. Paroxetine, fluoxetine, and their metabolites strongly inhibit cytochrome
P-450 2D6, whereas nefazodone and sertraline have milder effects.[1][62][66][72] In addition to metabolizing
paroxetine, fluoxetine, sertraline, and nefazodone, cytochrome P-450 2D6 also metabolizes potentially toxic
agents such as encainide, flecainide, and propafenone, cyclic antidepressants, and metoprolol. [62][72] The
clinical significance of these effects are unclear and difficult to predict because the levels of these enzymes
vary greatly among individuals in the population. Fluoxetine has been reported to precipitate cyclic
antidepressant toxicity, presumably related to impairment of metabolism.[98] Fluoxetine, norfluoxetine,
fluvoxamine, and nefazodone have mild to moderate inhibitory effects on cytochrome P-450 3A, which
metabolizes many important therapeutic drugs, including carbamazepine, antihistamines, and calcium
channel blockers.[72] Clinically significant interactions have been reported to occur between fluoxetine and
terfenadine,[91] fluvoxamine and carbamazepine,[91] and nefazodone and carbamazepine.[27]


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Chapter 64 – Lithium
HAROLD H. OSBORN DAVID MALKEVICH
Essentials
• History of lithium therapy or ingestion
• Mild/moderate toxic symptoms: tremor, hyperreflexia, drowsiness, clonus
• Major toxic symptoms: confusion, ataxia, stupor, coma, seizures
• Lithium level greater than 1.2 mEq/L
INTRODUCTION
Lithium was discovered in 1818 by Arfwedson working in the laboratory of Berzelius. It is a monovalent
cation and, with an atomic number of 3, is the lightest metal known. It is a member of the alkali metal group
(which also includes sodium, potassium, rubidium, and cesium). Because of its high reactivity the pure metal
in elemental form is never found in nature. Lithium was first used medicinally in the 1800s as a treatment for
gout. Its use in the early 1900s as a salt substitute for patients with hypertension and congestive heart failure
resulted in several fatalities and was quickly abandoned.[16][26] While searching for a humoral factor in
mania, Cade accidentally discovered that lithium had a calming effect and, in 1949, was the first to use it in
the treatment of psychiatric patients.[13] Sustained-release lithium preparations were introduced in the United
States in 1979.
Lithium is now commonly used in the treatment of manic-depressive illness. It is particularly efficacious in
the treatment of acute mania (in combination with a neuroleptic) and in the prophylaxis of bipolar disorder. It
is less effective for unipolar states but is often used as adjuvant therapy in the treatment of resistant
depression. It is also employed as a prophylactic agent for patients with cluster headaches and as a stimulus
to white blood cell production in neutropenic patients.[37][48] It is estimated that at least 1 in every 1000
people living in the United States takes lithium on a regular basis.[54][55]
Lithium has a narrow toxic:therapeutic ratio, and its use in depressed patients lacking good judgment or
predisposed to suicidal acts increases the risk of toxicity. It is one of the few commonly prescribed
medications capable of precipitating its own toxicity. The polyuria and resistance to antidiuretic hormone
often found with lithium can lead to volume depletion and increased renal reabsorption of lithium.
Available forms include (1) syrup (8 mEq lithium as citrate/5 mL); (2) capsules containing regular-release
lithium carbonate in 150-mg, 300-mg, and 600-mg doses; (3) regular-release tablets containing 300 mg of
lithium carbonate; and (4) sustained-release tablets designed to more slowly release lithium carbonate:
controlled-release (450 mg), film-coated (300 mg), and slow-release (300 mg).


Pharmacology
The mechanism or mechanisms of action of lithium are complex, and those actions responsible for its
therapeutic effects remain uncertain. Lithium inhibits agonist adenylate cyclases; the inhibition of human
brain noradrenaline-stimulated adenylate cyclase may play an important role in its therapeutic effect. It also
inhibits G proteins involved in the opening of some ion channels. Lithium depletes brain inositol, the
precursor of the phosphatidylinositol system that transduces signals from many neurotransmitter and
hormonal systems. However, the role of inositol depletion in lithium’s therapeutic effects has been
criticized.[72] It also enhances the effect of serotonin and increases the neuroendocrine response to
serotonin agonists. [46]
After oral ingestion regular release lithium in normal doses is rapidly and completely absorbed in the
stomach and small intestine, with peak serum levels occurring in 2 to 3 hours and gastrointestinal absorption
complete within 8 hours. Sustained-release preparations in normal doses undergo more gradual
gastrointestinal absorption, with peak serum levels at 2.0 to 5.5 hours. For both preparations, absorption and
peak levels can be delayed in overdose, because toxicokinetics do not mirror pharmacokinetics. Delays of 4
to 12 hours have been reported in several overdose cases,[11][67][52] and a delay of 3 days was recorded in
one case of a regular release lithium overdose.[72] Lithium crosses all cellular membranes slowly, which
accounts for its slow body distribution and delayed onset of action. Six to 10 days are required for complete
distribution, which follows a complex multicompartment model.[2] At equilibrium, lithium is variably distributed
throughout the body. For example, cerebrospinal fluid lithium concentrations are 40 to 60 per cent of plasma
concentrations, whether or not toxicity is present.[76] Lithium is not protein bound and has a volume of
distribution of 0.6 to 1.0 L/kg, making it amenable to dialysis. The elimination half-life of lithium is 12 hours
initially and 22 hours after several weeks of treatment. This half-life may be somewhat longer in the elderly
owing to impaired renal function. In acute overdoses the elimination half-life has been reported to be 20.9 ±
1.3 hours, whereas patients chronically toxic from therapeutic doses have a longer elimination half-life of
32.2 ± 3.5 hours.[21]
Lithium does not undergo metabolism, and elimination is almost entirely renal. Lithium excretion is
dependent on both glomerular filtration rate and renal tubular reabsorption, with 70 per cent of filtered lithium
reabsorbed in the proximal convoluted tubule and 10 to 15 per cent in the descending loop. Renal excretion
is biphasic, with up to two thirds of an acute dose excreted in 6 to 12 hours and the remainder eliminated
slowly over 10 to 14 days. The kinetics of elimination can be markedly altered by changes in diet (salt
intake), renal function, cardiac output, hydration status, overdose, and co-administration of other
medications such as diuretics.
Pathophysiology
Lithium exerts its harmful effects on the body in a variety of ways. As a monovalent cation, lithium shares
properties with both extracellular sodium and intracellular potassium, although it has a more uniform bodily
distribution. By partially substituting for these cations lithium influences ion distribution and transfer; and
these effects may be responsible, in part, for its toxicity.[72] It may also alter the cellular microenvironment
and affect responses to hormones, coupling of energy processes, or genetic expression. Lithium interacts
with the catalytic units of various adenylate cyclases coupled to various receptors such as ß-adrenergic
receptors and dopamine, and these adenylate cyclase interactions may be responsible for some side
effects.[72] In the kidney, interference with the vasopressin-mediated stimulation of adenylate cyclase
prevents generation of cyclic adenosine monophosphate in the medullary collecting system, producing renal
concentrating defects.[29] Lithium also blocks the receptor-mediated activation of adenylate cyclase in other
tissues such as the thyroid. Lithium’s inhibition of inositol phosphate metabolism alters organ development in
the embryo.[10] Lithium affects the metabolism of monoamines and has been demonstrated to accelerate the
presynaptic destruction of norepinephrine, inhibit the release of norepinephrine, and increase neuronal
uptake of norepinephrine.[46] Finally, lithium influences nerve excitation, synaptic transmission, and neuronal
metabolism. The neurotoxic effects seen with lithium are presumed to be due to changes in cell membrane
conductivity and synaptic transmission.[14]
Multiple factors can contribute to the development of lithium toxicity. Because lithium is handled like sodium
in the proximal tubules of the kidney, anything that causes sodium depletion can enhance lithium
reabsorption and precipitate toxicity. Volume depletion due to febrile illnesses, gastrointestinal losses,
diuretics, or excessive laxative use can also elevate lithium levels. Similarly, lithium itself can impair renal
concentrating ability and cause a nephrogenic diabetes insipidus with long-term use. Renal insufficiency and
impaired renal perfusion, as seen with congestive heart failure, can decrease lithium clearance, whereas
nonsteroidal anti-inflammatory drugs such as phenylbutazone, indomethacin, and piroxicam increase lithium
reabsorption in the proximal tubules. Elevated lithium levels have also been associated with phenytoin,
angiotensin-converting enzyme inhibitors, metronidazole, tetracycline, and spectinomycin. [66][23]


The toxic and adverse effects of lithium can be divided into four distinct groups: (1) chronic toxicity in
patients taking therapeutic doses; (2) acute toxicity as seen with an acute or acute-on-chronic overdose; (3)
transient adverse effects seen with the initiation of lithium therapy; and (4) persistent adverse effects that
continue during therapeutic lithium administration ( Table 64–1 ).
Table 64-1 -- Clinical Presentation of Lithium Toxicity

Minor Persistent
Chronic Toxicity
Effects Acute Overdose
Nausea and
vomiting, diarrhea, Nausea and vomiting,
Gastrointestinal Anorexia, nausea and vomiting
abdominal diarrhea
discomfort
Neurologic Fine tremor, muscle May be asymptomatic. Can Muscle weakness, tremor, apathy,
weakness, fatigue develop tremors, rigidity, dysarthria, muscle rigidity,
clonus, fasciculations, fasciculations, choreoathetosis, vertigo,
hyperreflexia, lethargy, pseudotumor cerebri, tinnitus, ataxia,
confusion, coma, seizures blurred vision, confusion, seizures,
coma
Sinus node Hypotension, sinus node dysfunction, T
Cardiovascular dysfunction, T wave Hypotension wave changes, prolonged QTc,
changes, U waves myocarditis, dysrhythmias
Nephrogenic diabetes insipidus,
Renal Polyuria, mild thirst interstitial nephritis, distal tubular
acidosis, acute renal failure (rare)
Thyroid goiter, hypothyroidism,
Thyroid goiter, hyperthyroidism, hypercalcemia,
Endocrine
hypothyroidism hyperglycemia, weight gain, sexual
dysfunction
Hematologic Leukocytosis Leukocytosis, aplastic anemia
Dermal Psoriasis, angioedema, acne
Chronic Toxicity
Chronic toxicity occurs in patients taking therapeutic doses who develop toxic serum lithium levels through
various mechanisms: (1) increase in lithium dose, either prescribed or accidental by an unsupervised
patient; (2) adverse drug interaction or effect that decreases lithium clearance; and (3) decreased sodium
intake and decreased effective circulatory volume from various causes, including “renal vicious circles”
whereby lithium-induced acute and subacute renal failure leads to a declining glomerular filtration rate with
subsequent renal tubular reabsorption of lithium.[3]
Severe cases of lithium poisoning are usually due to chronic intoxication, and the manifestations are
protean. Muscular weakness, drowsiness, tremor, hyperreflexia, and incoordination are early signs of lithium
intoxication. Diarrhea and vomiting can occur. However, neurologic signs and symptoms predominate and
indicate the severity of toxicity. Initially, patients may present with decreased alertness, apathy, and anorexia
and may manifest tremor, dysarthria, mild muscle rigidity, and fasciculations. With worsening toxicity,
patients may develop clonus, ataxia, tinnitus, parkinsonian signs, and blurred vision. If unrecognized, chronic
toxicity can result in coma, seizures, and death. The severity of toxicity with chronic lithium poisoning is
determined by both the degree and the duration of elevation of the total body burden of lithium.
The neurotoxic effects of lithium tend to develop gradually, and clinical findings are usually a better guide to
toxicity than serum levels.[44] In the acute overdose setting, lithium levels as high as 8.3 mEq/L have been
tolerated and managed without hemodialysis.[42][52] Disturbingly, several reports of chronic intoxication have
documented severe neurotoxicity despite lithium levels in the “therapeutic” range.[1][6][57][62] Possible
explanations for this phenomenon include concomitant use of other medications (especially neuroleptics),
tissue retention of lithium (acutely manic patients retain more lithium intracellularly than controls and tolerate
higher levels), use of lithium in schizophrenic patients, and the presence of an intercurrent medical
illness.[6][62] Because brain lithium levels correlate better with red blood cell lithium levels than with plasma
levels, an elevated red blood cell lithium level may be a more reliable predictor of impending neurotoxicity
but is seldom available in standard hospital laboratories.[45] Cardiovascular deterioration is rare with lithium
poisoning and, when seen, is usually associated with underlying cardiac disease or severe
neurotoxicity.[58][75]
Acute Toxicity
Acute overdoses are generally less common and less serious than chronically intoxicated cases. Acute
gastrointestinal effects (nausea and vomiting and diarrhea) are most common. Numerous case reports have
documented a relatively milder course after an acute overdose despite significantly elevated levels and only
supportive care.[11][28][30][32][36] Presumably, this lack of correlation between symptoms and lithium levels is
due to the long time needed for lithium to distribute intracellularly. In contrast to chronically intoxicated
patients, acutely poisoned patients have less risk of developing neurologic findings and manifest little, if any,
change in the electrocardiogram.[56]
Transient Adverse Effects
Transient adverse effects often appear during the first 2 to 3 weeks after initiation of lithium therapy and
include fine resting hand tremor; polyuria and mild thirst (due to inhibition of antidiuretic hormone);
gastrointestinal discomfort, nausea, vomiting, and loose stools; and muscle weakness and fatigue. These
effects are self-limited and usually subside with continued treatment.[51]
Persistent Adverse Effects
Persistent adverse effects include polyuria, polydipsia, leukocytosis, euthyroid goiter, hyperthyroidism or
hypothyroidism, weight gain, mild resting tremor (often responsive to ß-adrenergic receptor antagonists), T
wave changes on the electrocardiogram (secondary to displacement of intracellular potassium by lithium),
and sinus node dysfunction. [15][58][75] Rare but reported effects found with chronic administration include
nystagmus, extrapyramidal signs, choreoathetosis, memory loss, facial paralysis, glucosuria,
polyneuropathy, psoriasis, hypercalcemia, and pseudotumor cerebri.[3][27]
Renal
A majority of patients maintained on lithium carbonate develop some abnormality in urinary concentrating
ability. Up to 40 per cent of patients will develop polyuria (>3 L urine/24 hr) or polydipsia, whereas 5 to 20
per cent will develop a nephrogenic diabetes insipidus.[5][8][9][70] The impairment in urinary concentration
correlates with duration of therapy, serum lithium level, and total dose.[8] In general, the nephrogenic
diabetes insipidus disappears weeks after discontinuation of therapy, but cases of persistent diabetes
associated with interstitial nephritis have been described.[58][73] Finally, lithium produces a reversible defect
in urinary acidification characteristic of a distal renal tubular acidosis. However, this is categorized as an
incomplete renal tubular acidosis because patients are not acidemic under normal circumstances.[47] Renal
failure rarely occurs, if at all.
Hematologic
An increase in mature neutrophil forms occurs most commonly and may be due to a lithium-induced
increase in granulocyte macrophage stem cells. Lithium has been used therapeutically to raise neutrophil
counts in cancer patients treated with chemotherapeutic agents and in patients with the acquired
immunodeficiency disorder treated with antiretroviral agents.[48] Lithium may also raise eosinophil and
platelet counts.
Endocrine
Chronic lithium therapy can induce several thyroid disorders, including euthyroid goiter, hypothyroidism, and
hyperthyroidism.[15][58] A carefully controlled study using ultrasound to determine thyroid gland size found a
44 per cent prevalence of goiter in patients treated for 5 years and a 50 per cent prevalence in those treated
for 10 or more years. Subclinical or overt hypothyroidism was found in 4 per cent and 21 per cent of those
treated for 5 and 10 or more years, respectively.[45] The mechanism of this effect is unclear because serum
thyrotropin levels were normal in the patients with goiter and few of the hypothyroid patients had evidence of
autoimmunity. The association between hypercalcemia, hyperparathyroidism, and lithium therapy has been
well documented,[61] and patients taking lithium can become hypercalcemic. In vitro studies indicate that
lithium reduces parathyroid cell sensitivity to calcium, resulting in increased parathyroid hormone
secretion.[12] In humans, it is unclear whether lithium is primarily responsible for initiating
hyperparathyroidism. Moreover, the long-term effects and the clinical significance of lithium-induced
hypercalcemia are uncertain.
Fetal Effect
Recent well-designed cohort studies indicate lithium is less of a teratogenic risk than previously
thought.[17][31] Older biased studies and case reports had linked lithium with fetal cardiac anomalies,
especially Ebstein’s anomaly.[34][58][74] Despite these recent findings, maternal lithium therapy should be
tapered and withheld during the first trimester of pregnancy unless deemed clinically essential. [17]
Lithium and the Neuroleptic Malignant Syndrome
Patients maintained on lithium have presented with altered mental status, rigidity, and fever, and some have
been diagnosed with neuroleptic malignant syndrome (NMS).[18][60][63] However, lithium has never been
solely implicated in causing NMS, and all cases reported have been associated with simultaneous
neuroleptic use. Lithium has been shown in animals to block striatal dopamine synthesis.[25] Lithium can
cause hyperreflexia and increased muscle tone and may increase susceptibility to NMS in patients
maintained on both lithium and neuroleptics.


Lithium’s diverse effects can mimic a variety of other conditions ( Table 64–2 ). Altered mental status,
tremor, seizures, and gastrointestinal effects must be distinguished from hypoglycemia, cyclic
antidepressant overdose, thyrotoxicosis, metal and metalloid poisoning, and sedative hypnotic/ethanol
withdrawal. Polyuria, thirst, and nephrogenic diabetes insipidus associated with lithium toxicity can also be
seen with uncontrolled diabetes mellitus, renal salt wasting, and diabetes insipidus due to pituitary
insufficiency. Muscular rigidity, generalized weakness, and ataxia seen with lithium poisoning can also occur
with other neurologic disorders, including parkinsonism, brain tumors, and the side effects of neuroleptic
medication.
Table 64-2 -- Differential Diagnosis of Lithium Intoxication

Hypoglycemia
Psychosis
Sedative/hypnotic, ethanol, barbiturate withdrawal
Thyrotoxicosis/hypothyroidism/myxedema
Nephrogenic diabetes insipidus, other causes
CNS: meningitis/encephalitis/tumor
Metal and metalloid poisoning
Neuroleptic extrapyramidal effects, including neuroleptic malignant syndrome
Drug toxicity:
Theophylline
Phenothiazines
Monoamine oxidase inhibitors (drug and food interactions)
Phenytoin
Valproic acid
Fortunately, most of lithium’s toxic manifestations are associated with chronic use and occur in patients with
diagnosed psychiatric conditions who are known to be on lithium therapy.
.


LABORATORY STUDIES
Therapeutic Lithium Monitoring
The therapeutic range of lithium is 0.6 to 1.2 mEq/L; however, in the elderly it can range from 0.4 to 1.0
mEq/L. Levels above 1.4 mEq/L are no more effective than lower levels but carry a greater risk of toxicity.[19]
Lithium has an extremely low therapeutic-to-toxic ratio. Therapy must be initiated at a low dose with gradual
increments and frequent monitoring of plasma concentrations. Patients requiring more frequent monitoring
include the elderly, those with impaired renal function, and those taking other medications known to raise
lithium levels, such as thiazide and potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs.
Lithium Toxicity
In cases of suspected toxicity, serum lithium, electrolytes, blood urea nitrogen, and creatinine levels should
be obtained, along with an electrocardiogram. Because lithium is an unmeasured cation, an elevated lithium
level can result in a decreased or absent anion gap.[35] Red blood cell lithium levels are preferable to serum
levels, because they correlate better with neurotoxicity but are usually not available in hospital
laboratories.[43][51] One lithium level is never sufficient in a toxic patient, and repeat serum lithium levels are
indicated.
In patients treated chronically with lithium, complete blood cell counts, electrolytes, and renal function and
thyroid function tests should be monitored. Serum ß2-microglobulin has been found to be a more sensitive
indicator of renal function than blood urea nitrogen and creatinine.[50]


TREATMENT
Gastric Decontamination
Gastrointestinal decontamination is performed for acute ingestions ( Table 64–3 ). Gastric lavage with a
large-bore orogastric tube may be efficacious if performed within 1 to 2 hours after ingestion. A single dose
of activated charcoal should be administered for possible co-ingestants. Activated charcoal will not adsorb
lithium, a cation, or prevent its absorption. In vitro experiments and in vivo studies in mice failed to
demonstrate significant adsorption of lithium to charcoal or a decrease in serum lithium levels.[22][41]
Table 64-3 -- Essentials of Treatment of Lithium Toxicity

I. Gastrointestinal Decontamination *
A. Lavage with a large-bore tube (adults: 36–42 Fr; children: 24–32 Fr) for ingestions within 1 to 2 hours of
presentation
B. Whole-bowel irrigation with PEG solution (adults: 500 mL–2 L/hr; children 20 mL/kg/hr) for ingestions of
sustained-release preparations
II. General Support
A. Intravenous isotonic crystalloid to correct dehydration and maintain urinary output of 1–2 mL/kg/hr
B. Dopamine, 2 µg/kg/min, intravenously for enhanced diuresis (if necessary) after adequate hydration
III. Enhanced Elimination
A. Hemodialysis
1. If presence of severe neurologic findings: altered mental status, ataxia, seizures, coma
2. If presence of elevated lithium levels and renal failure
3. If development of any symptoms in acute or acute-on-chronic overdose
B. CAVHD and CVVHD (can be considered in hemodynamically unstable patients)
* Routine use of sodium polystyrene sulfonate is not currently recommended.
Whole-bowel irrigation with polyethylene glycol electrolyte solution may be a safe and effective means of
gastrointestinal decontamination after acute ingestions of sustained-release lithium formulations. A two-
phase crossover study in a small number of healthy volunteers demonstrated a significantly reduced area
under the concentration-versus-time curve when whole-body irrigation was performed 1 hour after ingestion
of sustained-release lithium carbonate.[59]
Because lithium has a structure similar to sodium and potassium the concept of therapy with an exchange
resin such as sodium polystyrene sulfonate (SPS) has been proposed. SPS is normally used in
hyperkalemic patients, and potassium is exchanged for sodium to lower serum potassium levels. In lithium-
toxic patients either lithium or potassium would be exchanged for the sodium. Linakis and coworkers
demonstrated effective reduction of elevated serum lithium concentrations by SPS in a murine model, even
when the lithium was administered intravenously.[39][40] However, the serum potassium levels in the
poisoned mice were lowered by both lithium and the SPS treatment.[40] In a crossover study with a small
number of healthy volunteers using a relatively small dose of lithium, single-dose SPS administration
lowered lithium levels significantly without affecting serum sodium or potassium levels.[69] Repetitive dose
SPS (total dose: 150 g) has been used in one case of acute-on-chronic lithium overdose.[49] The use of SPS
lowered the calculated serum elimination half-life of lithium, and the only adverse effect was diarrhea during
the course of therapy. Serum sodium and potassium levels were unchanged, although the patient received
potassium supplementation. The effect of SPS in lowering tissue levels of lithium remains unknown, and
therefore its therapeutic role is uncertain. It should not be considered a replacement for dialysis, and it is
relatively contraindicated in patients with volume overload states such as congestive heart failure.
Lithium carbonate, the least soluble of the lithium salts, can form bezoars within the gastrointestinal tract
after large overdoses, which may require endoscopic removal.[68] A report of two cases of delayed toxicity
(up to 5 days after ingestion) after a sustained-release overdose demonstrates the need for aggressive
decontamination and careful follow-up of these patients.[24]
Intravenous Crystalloids
Intravenous crystalloids are administered to correct dehydration and to maintain urinary output at 1 to 2
mL/kg per hour in euvolemic patients. Correction of volume deficits with isotonic crystalloid is recommended
in dehydrated lithium-toxic patients. Volume expansion in these patients will result in improved glomerular
filtration rates and renal lithium excretion. Forced saline diuresis is not advocated for the routine treatment of
lithium poisoning. A study of intoxicated symptomatic patients treated with normal saline infusion found no
enhancement of the fractional excretion of lithium, and some patients developed hypernatremia.[27] Although
sodium bicarbonate decreases the absorption of lithium in the proximal tubules, it offers no advantage over
normal saline and should not be used.
Hemodialysis
Because it is a water soluble, poorly protein bound, small ion that has a relatively small volume of
distribution, lithium can be eliminated by hemodialysis at a rate more rapid than renal elimination. Kinetics
were studied in a series of 14 patients with lithium poisoning, three of whom underwent hemodialysis. During
toxicity, the apparent mean serum half-life was 23.16 ± 9 hours, and the mean renal clearance was 17.2 ±
5.4 mL/min with a mean total clearance of 26.5 ± 13.3 mL/min. During hemodialysis the clearance was 63.2
to 114.4 mL/min, with a serum half-life ranging from 3.6 to 5.7 hours.[33] Precise indications for dialysis have
never been established or validated and hence vary considerably. In general, hemodialysis will be used
more often in patients with chronic toxicity rather than in those with acute overdose. Patients presenting with
serious manifestations of toxicity such as altered mental status, ataxia, seizures, or coma are more likely to
suffer permanent neurologic sequelae and should be dialyzed early to decrease the lithium burden of the
central nervous system. Patients with underlying renal disease and elevated lithium levels are at greater risk
and should be dialyzed for any signs of toxicity. Patients who are drowsy but oriented can be initially
managed with intravenous administration of crystalloids, with hemodialysis initiated for deterioration in
mental status. In acute overdose patients, hemodialysis should be reserved for those patients who develop
symptoms, however mild.
A single hemodialysis treatment should continue until the serum lithium level measures less than 1.0 mEq/L.
The need for further hemodialysis treatments will be determined by the degree of “rebound” in the serum
lithium level. This “rebound effect” on the serum lithium level occurs due to continuing equilibration of the
intracellular and extracellular compartments.[33] A repeat lithium level should be obtained 6 to 8 hours after
dialysis is completed. If the level exceeds 1 mEq/L, repeat hemodialysis is indicated. The endpoint of
dialysis is a lithium level that remains less than l.0 mEq/L.[27]
A single case report suggests dialysis with a bicarbonate dialysate (35 mMol/L) is more effective than an
acetate dialysate.[65] One retrospective study of all published reports of lithium-toxic patients with sequelae
of cognitive dysfunction suggested that those dialyzed suffered greater deterioration in the hospital and more
sequelae than those not dialyzed. [64] Multiple potential sources of bias make this study difficult to interpret,
and these findings require further study in a prospective trial.
Peritoneal Dialysis
This technique is less effective than hemodialysis and may be no better than normal urinary excretion. It
should only be considered if hemodialysis is unavailable.
Continuous Arteriovenous Hemodiafiltration
Continuous arteriovenous hemodiafiltration (CAVHDF) and continuous venovenous hemodiafiltration

(CVVHDF) have enhanced lithium removal in a small number of reported patients.[7][38] With flow rates of 4
L/hr (CAVHDF) and 1 to 2 L/hr (CVVHDF), mean lithium clearance was 41.4 ± 4.6 mL/min (CAVHDF) and
48.4 ± 1.4 to 61.9 ± 2.3 mL/min (CVVHDF) in seven patients. Duration of hemodiafiltration ranged from 18 to
44 hours, and clinically significant rebound in the serum lithium levels did not occur.[38] Compared with
hemodialysis, these modalities are better tolerated in hemodynamically unstable patients and avoid massive
solute shifts. Further research is needed to establish advantages, indications, and complications.
Diuretics
Diuretics are not recommended in the treatment of lithium intoxication. Diuretics acting on the loop of Henle
or the distal tubule do not alter lithium elimination, whereas diuretics such as mannitol and aminophylline
that do influence lithium excretion may have significant side effects. In general, the sequelae of diuretic
therapy (dehydration and retention of sodium and lithium) negate the benefits.


DISPOSITION
All asymptomatic patients with acute and acute-on-chronic lithium overdoses should be hydrated and
observed in the hospital for signs of toxicity. Patients with signs or symptoms of lithium toxicity, whether
acute, acute-on-chronic, or chronic, should be admitted to the hospital for further evaluation and treatment.
Patients with severe toxicity will require intensive care admission.
Patients who have overdosed (acute, acute-on-chronic) on sustained-release lithium preparations should
have serial blood levels drawn and be observed at least 24 hours before discharge. Patients who remain
asymptomatic with lithium levels less than 2.0 mEq/L after 24 hours may be discharged after a psychiatric
evaluation and referral to their primary care physician.


SEQUELAE
Neurotoxic effects after chronic poisoning normally last days to weeks but may result in permanent
sequelae.[4][20][53][64] Dysarthria, muscular rigidity, hyperreflexia, hypertonia, and short-term memory deficits
have been described.[4][20] Persistent choreoathetosis, nystagmus, and ataxia reflect damage to the basal
ganglia and/or cerebellum.[4][71] Many of the case reports documenting these sequelae are complicated by
the concomitant administration of neuroleptics and other medications. However, persistent sequelae have
been described in patients not exposed to ethanol or other agents.


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Chapter 65 – Neuroleptics
FRANCIS J. DE ROOS
Essentials
• History of schizophrenia or psychiatric disease
• Orthostatic hypotension with phenothiazines
• Anticholinergic effects
• Dystonia
INTRODUCTION
The term neuroleptic is a general categorization of structurally diverse medications traditionally used in the
treatment of psychoses. Also termed major tranquilizers or antipsychotics, these drugs have been classically
divided into several structural classes, including phenothiazines, butyrophenones, thioxanthines,
dibenzoxazepines, indoles, benzisoxazoles, dibenzothiazepines, and dibenzodiazepines ( Table 65–1 ).
Phenothiazines, which are the most common and best studied of the neuroleptics, have a core ring structure
and are subdivided into three classes: (1) aliphatics, including chlorpromazine; (2) piperidines, including
thioridazine and mesoridazine; and (3) piperazines, which include prochlorperazine, fluphenazine, and
perphenazine.[4] Over the past decade several new antipsychotic agents, all structurally dissimilar, have
been marketed in the United States, including clozapine, risperidone, olanzapine, and quetiapine. With
numerous and diverse groups it becomes much more practical to discuss and classify antipsychotics in
terms of their mechanisms of action, namely the degree of dopamine (D2) and serotonin receptor
antagonism ( Table 65–2 ). The degree of D 2 antagonism is described relative to the potency of the
traditional agent and varies from the high potency of haloperidol and thiothixene to the lower potencies of
chlorpromazine and loxapine. In general, the serotonin and dopamine antagonists such as clozapine and
olanzapine are extremely potent serotonin (5HT2A) antagonists and mild D2 antagonists. In contrast, the D2
antagonism of risperidone is on the order of a moderate- or high-potency traditional neuroleptic.[27]
Table 65-1 -- Classification of Antipsychotics Based on Structure

Phenothiazines
Aliphatics
Chlorpromazine (Thorazine)
Promethazine (Phenergan)
Piperidines
Mesoridazine (Serentil)
Thioridazine (Mellaril)
Piperazines
Prochlorperazine (Compazine)
Fluphenazine (Prolixin)
Perphenazine (Trilafon)
Trifluoperazine (Stelazine)
Butyrophenones
Haloperidol (Haldol)
Droperidol (Inapsine)
Thioxanthenes
Chlorprothixene (Taractan)
Thiothixene (Navane)
Indoles
Molindone (Moban)
Dibenzoxazepines
Loxapine (Loxitane)
Dibenzodiazepines
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Dibenzothiazepines
Quetiapine (Seroquel)
Benzisoxazoles
Risperidone (Risperidal)
Table 65-2 -- Classification of Antipsychotics Based on Mechanism of Action

D2 Receptor Antagonists
Low potency
Chlorpromazine (Thorazine)
Chlorprothixene (Taractan)
Mesoridazine (Serentil)
Thioridazine (Mellaril)
Medium potency
Droperidol (Inapsine)
Loxapine (Loxitane)
Molindone (Moban)
Perphenazine (Trilafon)
High potency
Fluphenazine (Prolixin)
Haloperidol (Haldol)
Trifluoperazine (Stelazine)
Thiothixene (Navane)
D2 Serotonin Receptor
Antagonists
Clozapine (Clozaril)
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Neuroleptics are widely used to treat many ailments, including psychosis due to schizophrenia,
schizoaffective disorder, mania, abnormal movement disorders as seen in Huntington chorea and Tourette
syndrome, vomiting, headaches, and hiccups. Despite their widespread use, which has resulted in over
11,000 annual exposures reported to poison control centers, very few deaths occur.[34] In 1997, 11 deaths
involving phenothiazines were reported and over 75 per cent of these involved mixed ingestions.
Unfortunately, the American Association of Poison Control Centers does not report newer antipsychotic
exposures separately, and thus their exposure data are unknown.


Pharmacology
Despite structural differences, most of these drugs share similar pharmacokinetics. They are orally
absorbed, are highly protein bound (< 95 per cent), have large volumes of distribution (15–30 L/kg), and
accumulate in fatty tissue.[12] They undergo complex hepatic metabolism, which results in multiple active
compounds.[35] This accounts for their long and unpredictable duration of effect and the lack of correlation
with dose, serum levels, and clinical efficacy.[11][38] Central nervous system (CNS) depression and
extrapyramidal symptoms have been noted in neonates born to mothers chronically on neuroleptics, which
suggest that these agents cross the placenta.
Pathophysiology
Although the etiology of schizophrenia is complex and our understanding of this disorder is still in its infancy,
several lesions in neurotransmitter and receptor physiology have been identified and have become the
primary targets of pharmacologic therapy. The most well-established abnormality is an increase in dopamine
activity in the mesolimbic system.[54] This region of the brain involves our emotions and perceptions. The
hallucinations, delusions, hostility, grandiosity, and paranoid thinking, often termed the positive symptoms of
schizophrenia, appear to involve this dopamine excess. Traditional antipsychotics target this lesion by
antagonizing dopamine at the postsynaptic dopamine subtype 2 (D2) receptor.[47][54] There are, however, six
distinct dopamine receptor subtypes (D1, D2A, D2B, D3, D4, and D5); and, depending on the antipsychotic
agent, none or several of these may also be antagonized.[53] The clinical consequences of this variable
dopamine antagonism are unclear at this time.
Although the positive symptoms of schizophrenia have been the traditional target of pharmacotherapy, a
significant number of schizophrenics suffer from completely different problems, often termed negative
symptoms. These include a blunted affect, poor abstract thinking, apathy, and social withdrawal. These
manifestations appear to be related to an inability to “activate” or use the dorsolateral prefrontal cortex. In
addition, there are greater quantities of serotonin in this region. It is postulated that this increase in
serotonin, an inhibitory neurotransmitter, is responsible for the decreased activity in this region.[44][54] All of
the newer antipsychotics are potent serotonin (5HT2) antagonists as well as D 2 antagonists, and have been
effective in treating the negative symptoms as well as treating schizophrenics who have been resistant to
traditional agents. [24][25]
Unfortunately, the D 2 antagonism occurs not only in the mesolimbic tract but also in the other regions of the
brain where D2 receptors are prominent, including the mesocortical and nigrostriatal tracts. This results in
undesired consequences, including worsening of negative symptoms and a multitude of extrapyramidal
effects, such as dystonia, akathisia, and parkinsonian-like movement disorders. There is a direct correlation
between the degree of D2 antagonism and an agent’s propensity to induce these extrapyramidal effects.[8]
Most of the newer antipsychotic agents have little D2 antagonism in these areas and thus do not induce
these movement disorders.
In addition to D2 and serotonin receptors, most of these agents antagonize, to varying degrees, a multitude
of other receptors, including a-adrenergic, muscarinic, histaminic, and other dopaminergic receptors. These
antagonisms produce many of the undesired effects associated with these agents, including orthostatic
hypotension, reflex tachycardia, priapism (a-adrenergic), dry mouth, blurry vision, constipation, urinary
retention (muscarinic), sedation, weight gain (histaminic), and gynecomastia (dopaminergic).[7][46]


Acute Toxicity
Although antipsychotics are a diverse group of agents, there is significant overlap in their clinical effects in
overdose ( Table 65–3 ). Throughout this general discussion, specific situations and agents will be
highlighted.

Overdose
Slurred speech, sedation, confusion, obtundation, loss of deep tendon or brainstem reflexes, miosis, seizures
(loxitane, clozapine), respiratory depression (uncommon)
Cardiovascular
Hypotension, QT segment prolongation, ventricular dysrhythmias including torsades de pointes (esp.
thioridazine, mezoridazine)
Anticholinergic effects
Adverse Effects
Extrapyramidal symptoms
Increased incidence with greater dopamine antagonistic effects
Dystonia: briefly sustained or fixed abnormal postures, including torticollis, oculogyric crisis, facial grimacing,
opisthotonos, laryngeal spasm
Sense of panic, anxiety, fearfulness
Onset: within days of initiating or increasing dosing
Akathisia: a state of motor restlessness including pacing, rocking, shifting from foot to foot, “restless legs”
syndrome
Feelings of restlessness, irritability, discontent
Onset: within days to weeks of initiating or increasing dosing (can develop within minutes to hours)
Parkinsonism: bradykinesia with mask-like facies, shuffling gait, resting tremor, rigidity
Apathy, anhedonia, slow mentation
Onset: typically within weeks of initiating therapy
Tardive dyskinesia
Involuntary buccolingualomasticatory movements including lip smacking, tongue protrusion, grimacing, and
chewing
Onset: develops after years of therapy
Hyperthermia, rigidity, altered mental status, autonomic instability, metabolic acidosis, rhabdomyolysis
Onset: within days to weeks of initiating or increasing dosing
CNS effects dominate the clinical presentation of acute neuroleptic overdose. Depending on the degree of
intoxication, the CNS depression may manifest as slurred speech, mild sedation, confusion, lethargy, or
obtundation with loss of brain stem and deep tendon reflexes. Although phenothiazines lower the seizure
threshold, they rarely induce seizures in overdose.[16] Exceptions to that include loxapine and clozapine.[45]
These agents both induce seizures in a dose-related manner, with approximately 5 per cent of patients on
clozapine developing seizures with high-dose regimens (600 to 900 mg/d).[14] Respiratory depression is
uncommon and occurs primarily when other CNS depressants are involved and in infants. [20] Miosis,
possibly due to central a-adrenergic blockade, has been associated with many of these agents, most notably
the lower potency D2 antagonists, including chlorpromazine and thioridazine.[39]
Vital sign abnormalities such as temperature dysregulation may result in either mild hypothermia, due to
hypothalamic dysfunction or exposure associated with CNS depressants, or mild hyperthermia, due to the
anticholinergic effects. Orthostatic hypotension is primarily due to a-adrenergic blockade, which results in
vasodilation. Tachycardia may occur, owing in part either to the baroreceptor reflex in response to the
vasodilation or to a direct anticholinergic effect. Other signs of anticholinergic antagonism include dry
mucous membranes, skin flushing, and urinary retention. These anticholinergic effects are most prominent
when low-potency D2 antagonists are involved.[46][47]
A serious but rare complication of the acute overdose is dysrhythmias. Although the piperidine
phenothiazines, thioridazine and mesoridazine, are considered the most cardiotoxic, other agents, such as
chlorpromazine and haloperidol, have also been implicated. The electrocardiographic (EKG) effects are
similar to those of the type I antidysrhythmics and include an initial QTc interval prolongation that is often
accompanied by inconsequential T wave widening and blunting.[18] This may progress to PR and QRS
interval widening and T wave inversions. Disturbances in intraventricular conduction are manifested as a
prolongation and a rightward shift, particularly of the terminal portion, of the QRS interval.[41] Both
supraventricular tachydysrhythmias and ventricular tachydysrhythmias, including torsades de pointes, have
been associated with acute overdose.[3][15][37][41] Although the mechanism is still unclear, some animal data
demonstrate a decreased cardiac excitability, contractility, and conduction velocity and suggest an alteration
in potassium efflux, presumably during phase 3 of repolarization.[23][41] This is similar to other membrane-
stabilizing agents or membrane depressants such as the type IA antidysrhythmics, propranolol,
propoxyphene, and cyclic antidepressants and should be approached similarly.[31][41][60]
Haloperidol, both therapeutically and in overdose, has also been implicated in inducing torsades de pointes.
However, this association is based solely on a few case reports. The animal data, in contrast to thioridazine
where causation is well established, are limited to one study that was unable to demonstrate QTc interval
prolongation with intravenous haloperidol.[22][58][59]
Although there is still limited overdose experience with the newer antipsychotics, such as clozapine,
risperidone, and olanzapine, some generalizations are evident. They all appear to cause dose-dependent
CNS depression. In addition, risperidone and clozapine can produce orthostatic hypotension and reflex
tachycardia.[36] No significant EKG abnormalities have been reported. Sialorrhea, which is seen during
therapeutic dosing of clozapine, has been noted as a prominent finding in poisoned patients.
Extrapyramidal Syndromes
Extrapyramidal syndromes (EPS) may be seen after overdose as well as with therapeutic dosing of
neuroleptics. They are produced by excessive dopamine blockade within the nigrostriatal tissues. They may
manifest either acutely (within hours or days after initiation or an increase in dosing) as with dystonias or
akathisia, or chronically (in weeks to months) as with parkinsonism.[57] There is a high correlation between a
drug’s D2 affinity and its propensity to induce these effects.[7][8] In fact, the newer antipsychotics, such as
clozapine and olanzapine, have such limited D2 antagonism that they rarely induce extrapyramidal
effects.[24][44] Risperidone is the exception. Risperidone is both a potent serotonin and D 2 antagonist, and a
dose-dependent association with extrapyramidal effects is noted. [27][36]
Dystonia is an idiosyncratic syndrome that develops within 4 to 5 days after initiation or rapid escalation of
therapeutic dosing or after overdose of a neuroleptic agent. Dystonic reactions involve involuntary, painful
muscular contractions, and spasm most commonly of the head and neck and can include torticollis (neck
twisting), oculogyric crisis (persistent upward gaze produced by external ocular muscle spasm), tongue
protrusion, and trismus (masseter spasm).[2][33][56] Isolated laryngeal spasm, also termed laryngeal dystonia,
resulting in airway compromise and potentially death, may also occur.[42] Involvement of the trunk may
manifest with opisthotonic, kyphotic, or tortipelvic crises.[2][33] Acute dystonic reactions occur more frequently
in young males and are uncommon in the elderly. Clues in the history may include underlying psychiatric
illness or recent ingestion of a “sleeping pill,” “street Valium,” or an antiemetic.[13]
Akathisia is a syndrome of subjective distress and objective motor restlessness. It typically presents days to
weeks after initiation or increase in therapeutic dosing, but it can occur within minutes to hours. Patients
complain of feeling “on edge” or tense, are unable to sit or stand in one position, and often manifest
repetitive, purposeless movements such as “restless legs” syndrome.[5] Treatment involves lowering the
dosage or adding either antiparkinsonian agents, propranolol, or a benzodiazepine.[8] Unfortunately, this
diagnosis is often missed because the repetitive movements and restlessness are misinterpreted as
worsening psychotic behavior and agitation. [5] Often the patient’s neuroleptic dosing is increased, and the
akathisia is exacerbated.
A parkinsonian-like syndrome may develop within weeks of therapy and manifest with shuffling gait, masked
facial expressions, pill-rolling, rhythmic tremor, and cogwheel rigidity. [2] Perioral tremor (“rabbit” syndrome) is
characterized by abnormal oral-buccal movements that develop after prolonged therapy; it may be a
parkinsonian variant.[4]
Tardive Dyskinesia
Tardive dyskinesia is a chronic, dose-related movement disorder that can be quite devastating. It manifests
with persistent lip smacking, and rhythmic tongue and chewing movements known as buccolingual
masticatory syndrome.[57] The incidence is approximately 30 per cent after a year of cumulative neuroleptic
use and is much higher in the elderly.[52] There is also an association between developing extrapyramidal
signs early in therapy and ultimately developing tardive dyskinesia.[52] The etiology appears to be the result
of chronic dopamine receptor antagonism with resultant increase in the rate of firing of dopaminergic fibers
in the nigrostriatal neurons due to either receptor up-regulation or hypersensitization.[47][57] Prevention
includes using low-potency traditional agents or any of the newer antipsychotics and ceasing therapy of
high-potency agents for periods of time known as drug holidays. Once present, it is not readily reversible
and multiple treatments have been tried with little efficacy.[29] Tardive dyskinesia may be suppressed by the
newer antipsychotic agents.


The differential diagnosis of an acute antipsychotic overdose is broad and includes a wide range of other
poisonings, such as those from anticholinergics, clonidine, cyclic antidepressants, carbamazepine, opioids,
and sedative-hypnotics including benzodiazepines and barbiturates. In addition, if torsades de pointes
develops, one should consider antidysrhythmics (IA, II C, III), quinidine and chloroquine, pentamidine,
amantadine, chloral hydrate, and cyclic antidepressants. Metabolic and CNS maladies include
hypoglycemia, hypercalcemia, hyponatremia or hypernatremia, hepatic or hypertensive encephalopathy,
worsening psychosis or catatonia, depression, encephalitis, and intracranial hemorrhage ( Table 65–4 ).
Table 65-4 -- Differential Diagnosis of Neuroleptic Overdose

Poisonings
Anticholinergics
Carbamazepine, phenytoin
Clonidine
Lithium
Opioids
Sedative-hypnotics (e.g., barbiturates, benzodiazepines, chloral hydrate, methaqualone)
Other Diagnoses
Acute psychosis/catatonia
Depression
Hypoglycemia
Hyponatremia or hypernatremia
Hypomagnesemia
Hypercalcemia
QT Prolongation/Torsades de pointes
Amantadine
Type IA, II C, III antidysrhythmics
Arsenic
Astemizole, terfenadine (selective antihistamines)
Hypocalcemia, hypomagnesemia, hypokalemia
Hypothyroidism
Pentamidine
Quinine/quinidine


LABORATORY STUDIES
As in the evaluation of any patient with altered sensorium, patients with antipsychotic overdoses should have
a rapid glucose determination, pulse oximetry, and an EKG obtained. In general, plasma levels correlate
poorly with both therapeutic and toxic effects of neuroleptics.[8] This is due to the large number of active
metabolites and high lipid solubility.[50] Whereas qualitative assays may confirm an ingestion, all treatment
decisions should be individualized based on each patient’s clinical presentation.
Abdominal radiographs should not be routinely obtained in neuroleptic poisoning. Previously, some
phenothiazines were demonstrated to be radiopaque in vitro, and this led to the use of abdominal
radiographs to confirm ingestion.[43] Unfortunately, when used clinically, the abdominal radiograph rarely
visualizes neuroleptic tablets or alters patient management.
Screening for rhabdomyolysis with urinary hemoglobin (myoglobin cross reacts) or serum creatine kinase
should be performed in patients with severe CNS depression who are found lying on hard surfaces for
hours, who have seizures, or who have rigidity involving large muscle groups either secondary to severe
dystonia or neuroleptic malignant syndrome (NMS). In addition, patients with possible NMS should have
renal function, electrolytes, and coagulation studies sent.
Any patient in the emergency department who is taking clozapine therapeutically should have a white blood
cell count checked to screen for bone marrow suppression.


Acute Toxicity
Supportive care is fundamental therapy for neuroleptic overdose, and there are no specific antidotes. The
patient should be placed on a cardiac monitor, intravenous access obtained, and a physical examination
performed with specific attention to the presence of toxidromes. Any patient with altered mental status
should quickly have a glucose value determined or have empirical glucose administered. Hypotension,
caused by a blockade and peripheral vasodilation, typically responds well to crystalloid resuscitation. If the
hypotension is refractory, vasopressors with predominant a-agonistic effects, such as norepinephrine or
phenylephrine, are preferred to avoid unopposed ß effects.[6] Treat seizures initially with intravenous
benzodiazepines and, if refractory, add phenobarbital.
Table 65-5 -- Treatment of Neuroleptic Overdose

Overdose
Orogastric lavage: consider only in large ingestions, in ingestions involving thioridazine or mezoridazine, or in
critically ill patients
Activated charcoal, 1 g/kg (50 g in adults)
Altered mental status
Empirical dextrose/glucose check, thiamine, oxygen
Hypotension
Crystalloids
If pressors needed, then potent a agonists: norepinephrine or phenylephrine
Ventricular dysrhythmias
Lidocaine, cardioversion/defibrillation: consider sodium bicarbonate bolus therapy
Torsades de pointes
Magnesium, isoproterenol, overdrive pacing
Extrapyramidal Symptoms
Dystonia
Parenteral diphenhydramine, benzotropine, or benzodiazepine
Akathisia
Decrease dosing, benzodiazepines, antiparkinsonian drugs, propranolol
Parkinsonism
Decrease dosing, antiparkinsonian drugs, anticholinergics
Tardive Dyskinesia
Once present difficult to treat
Drug holidays (prevention), switching to lower potency or newer antipsychotic drug
Aggressive supportive care with cooling, crystalloids, muscular relaxation: benzodiazepines, neuromuscular
blockade with nondepolarizing neuroparalytics
Other: bromocriptine, amantadine, dantrolene (efficacy not well proven)
In general, gastric emptying with either syrup of ipecac–induced emesis or orogastric lavage has no role in
typical antipsychotic overdoses. Orogastric lavage may be beneficial in specific situations (e.g., patients who
have ingested large amounts of agents such as thioridazine with its significant cardiac toxicity, patients
manifesting ventricular dysrhythmias, and severely obtunded and intubated patients). Activated charcoal
administered orally or through a nasogastric tube is usually adequate decontamination. Hemodialysis and
hemoperfusion are ineffective, owing to the high protein binding and large volumes of distribution of
neuroleptics.
Ventricular tachydysrhythmias should be treated with lidocaine and cardioversion or defibrillation. Torsades
de pointes may not respond to initial therapy, but isoproterenol, magnesium, or overdrive pacing have all
been effective in managing refractory cases.[28][30][32] Because these agents affect the effective refractory
period and conduction similar to type IA antidysrhythmics and cyclic antidepressants, one may see typical
EKG changes of QRS prolongation and a rightward shift of the terminal portion of the QRS complex.[41][60] If
these EKG findings are present, therapy should include alkalinization with boluses of sodium bicarbonate
and/or hyperventilation. Type IA and IIC antidysrhythmics should be avoided.
Extrapyramidal Syndromes
In patients with acute dystonias, the treatment of choice is parenteral administration of an anticholinergic
agent such as benztropine mesylate (Cogentin), 1 to 2 mg (0.02–0.05 mg/kg in children), or
diphenhydramine, 50 to 100 mg (1–2 mg/kg in children). Oral agents should not be used, owing to delay in
absorption and variable clinical response. Benzodiazepines such as diazepam, 5 to 10 mg intravenously (0.1
mg/kg in children), or lorazepam, 2 mg (0.05 mg/kg in children), may be used in patients in whom
anticholinergics were ineffective.
In patients who develop akathisia or parkinsonism, therapy involves reducing the therapeutic dose, adding
an antiparkinsonian agent, or changing to an antipsychotic with less D2 antagonism.[8]


DISPOSITION
Any patient with severe intoxication, including CNS or respiratory depression, seizures, dysrhythmias, or
hypotension, or a life-threatening adverse effect, including NMS or laryngeal dystonia, should be admitted to
an intensive care unit. After adequate gastrointestinal decontamination with activated charcoal,
asymptomatic patients with normal vital signs and a normal EKG after 4 to 6 hours of monitoring can be
medically cleared for psychiatric evaluation and disposition. Patients successfully treated for acute dystonic
reactions should be discharged with a 2- to 3-day course of the effective therapeutic drug, such as
diphenhydramine, 25 to 50 mg three times a day, to prevent recurrence.[33]


SEQUELAE
Permanent sequelae do not result directly from neuroleptic overdose but can be due to complications such
as prolonged seizures. Tardive dyskinesia is a usually permanent complication of neuroleptic use.


SPECIFIC SITUATIONS
Clozapine-Induced Agranulocytosis
An idiosyncratic effect unique to clozapine is agranulocytosis.[1] This rare but potentially fatal adverse effect
was identified during the 1970s when clozapine was introduced in Europe. It occurs in approximately 1 per
cent of patients, and over 80 per cent of cases present within the first 6 months of therapy.[30] It has limited
the use of clozapine to patients with resistant schizophrenia or those with severe extrapyramidal effects from
traditional neuroleptics.[17] Clozapine must be prescribed in limited quantities with regular follow-up for
complete blood cell count monitoring. If identified early and the drug is discontinued, the bone marrow
suppression is reversible. If there is either a relative drop of greater than 3000/mm3 or an absolute drop
below 3000/mm3 in the white blood cell count, clozapine and other drugs that may also be bone marrow
suppressants should be withheld, the patient should be admitted, and the use of granulocyte colony-
stimulating factor strongly considered.[1] Although the mechanism of this toxicity is not clearly delineated,
one of the metabolites, N-desmethylclozapine, has been demonstrated to suppress hematopoiesis and is
probably involved.[19]
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal idiosyncratic reaction associated with
neuroleptic use as well as discontinuation of antiparkinsonian agents. It occurs in 0.02 to 0.2 per cent of
patients treated with neuroleptics. Risk factors include use of agents with high D2 antagonism such as
haloperidol, recent drug initiation or rapid escalation of dosage, high therapeutic dosing, and any prior
history of NMS.[26] In addition, NMS may develop after cessation of antiparkinsonian drugs or after treatment
with dopamine-depleting drugs such as methyltyrosine (used to treat Huntington chorea).[26] Actual
pathogenesis is unclear, but severe central dopaminergic blockade, particularly in the hypothalamus and
basal ganglia, is critical.[49] Therefore, the newer antipsychotics, because of their limited D2 antagonism in
these areas of the brain, have rarely been involved in producing NMS. In addition, NMS has never been
associated with an acute neuroleptic overdose.
The diagnosis of NMS is primarily clinical and based on a history of neuroleptic exposure or
antiparkinsonian agent withdrawal and the presence of altered mental status, hyperthermia, muscle rigidity,
and autonomic instability.[9] Mental status changes are insidious and often constitute the presenting
symptoms. As with akathisia, these symptoms may be misinterpreted as worsening schizophrenia and
antipsychotic dosing may actually be increased, exacerbating the NMS. These changes may fluctuate from
mutism to agitation to obtundation within hours. The temperature elevation, resulting from both intense
muscular activity and hypothalamic dysfunction, may be life-threatening. The muscular hyperactivity is best
described as a “lead pipe” increase in tone and can be so severe as to result in severe rhabdomyolysis with
subsequent precipitation of myoglobin in renal tubules and renal failure. Other features may include
sialorrhea, diaphoresis, tremor, and incontinence. Nonspecific laboratory abnormalities include elevated
creatine kinase, leukocytosis, and metabolic acidosis.[49]
The diagnosis of NMS is often elusive because the clinical symptoms may initially be subtle and
subsequently develop into a life-threatening event that mimics many other clinical syndromes. These include
lethal catatonia, heat stroke, intracranial hemorrhage, severe sympathomimetic or anticholinergic overdose,
strychnine poisoning, delirium tremens, tetanus, status epilepticus, encephalitis, malignant hyperthermia
associated with general anesthesia, a monoamine oxidase inhibitor interaction or overdose, or serotonin
syndrome.[21]
Treatment
After evaluation of the airway, ventilation, and hemodynamics, treatment should focus on muscular
relaxation and rapid cooling if severe hyperthermia is present. Benzodiazepines should be aggressively
used, such as 1 to 2 mg lorazepam every 2 to 3 minutes. If significant muscle stiffness remains after 15 to
20 minutes, neuromuscular blockade and orotracheal intubation are indicated. Use of succinylcholine may
not be ideal in these patients because of the potential for rhabdomyolysis and possibly hyperkalemia.
Other therapeutic agents are less effective and should not supplant the use of benzodiazepines and
nondepolarizing neuroparalytics to control severe muscle rigidity. Dantrolene inhibits the release of calcium
from the sarcoplasmic reticulum in skeletal muscle and is the drug of choice in malignant hyperthermia. It
has also been recommended and used anecdotally in patients with NMS. However, because the muscular
rigidity of NMS is mediated by central mechanisms rather than at the motor endplate, as in malignant
hyperthermia, there is no physiologic reason why dantrolene should be more efficacious than
benzodiazepines and neuromuscular blockade.[48][49][51] In addition, the data suggesting the benefit of
dopamine agonists, such as bromocriptine and amantadine, are scarce and conflicting.[10][40][48][55] Also,
patients require 24 hours on average before exhibiting a response to these drugs.[49]
Urinary output in patients should be aggressively supported to minimize the potential for rhabdomyolysis-
induced renal failure. Serum creatine kinase levels, electrolytes, renal function, and acid-base status should
be closely monitored. In addition, a complete blood cell count, hepatic enzymes, and coagulation studies
should be closely monitored for the complications of severe hyperthermia, including thrombocytopenia,
hemolysis, coagulopathy, and hepatitis.
The duration of this syndrome is 7 to 10 days. The mortality of patients afflicted with NMS has decreased to
less than 10 per cent with improvements in intensive supportive care. However, many patients suffer
significant complications, including primary pulmonary injury, aspiration, pulmonary embolism, and renal
failure secondary to rhabdomyolysis.[55]


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29. Kobayashi RM: Drug therapy of tardive dyskinesia. N Engl J Med 1977; 296:257-259.
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46. Richelson E: Preclinical pharmacology of neuroleptics: Focus on new generation compounds. J Clin
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47. Reynolds GP: Antipsychotic drug mechanisms and neurotransmitter systems in schizophrenia. Acta
Psychiatr Scand 1994; 89(suppl 380):36-40.
48. Rosebush PI, Stewart T, Mazurek MF: The treatment of neuroleptic malignant syndrome: Are dantrolene
and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry 1991; 159:709-712.
49. Rosenberg MR, Green M: Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern
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50. Sakais G, Curry SH, Mould GP, et al: Physiologic and clinical effects of chlorpromazine and their
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properties. Am J Cardiol 1979; 43:1155-1158.


Chapter 66 – Monoamine Oxidase Inhibitors
M. JOHN MENDELSOHN
Essentials
• Clinical features of overdose are typically delayed 6 to 12 hours.
• Common presenting symptoms include hyperthermia, hypertension, psychomotor agitation, dilated
pupils, abnormal movements, and muscular rigidity.
• Autonomic instability is a hallmark of toxicity.
• Initial stimulatory phase is followed by profound central nervous system (CNS) and cardiovascular
collapse.
• Food or drug interactions may occur weeks after discontinuation of a monoamine oxidase inhibitor
(MAOI).
INTRODUCTION
The antidepressant effect of iproniazid, an antitubercular drug, was first recognized in the early 1950s. This
activity was attributed to the drug’s ability to inhibit the enzyme monoamine oxidase (MAO).[7] MAO-inhibiting
drugs became the popular choice for the treatment of depression until cyclic antidepressants replaced them
2 decades later. Contemporary psychiatrists still note that certain depressive illnesses and recalcitrant
depression may respond favorably to the more potent MAOIs.[3] A resurgence of MAOIs is imminent in
clinical practice because their efficacy in the treatment of Parkinson’s disease,[58][96] post-traumatic stress
disorder,[36] phobias,[67] narcolepsy,[64] chronic pain syndromes,[9] smoking cessation,[13] attention deficit
disorder,[41] and certain otolaryngologic disorders[24] continues to be investigated.[138]


Pharmacology
Monoamine oxidase is an intracellular enzyme that is bound to mitochondrial membranes and is ubiquitous
in all cells except erythrocytes. It degrades endogenous (norepinephrine, epinephrine, dopamine, serotonin)
and exogenous (tyramine, amphetamines, ephedrine) biogenic amines before their reuptake into vesicles.
Two isoenzyme forms of MAO exist, designated MAO-A and MAO-B, which vary by tissue concentration and
substrate activity ( Table 66–1 ).[88] Concentrated in the gastrointestinal tract, placenta, and peripheral
autonomic nervous system, MAO-A has a high specificity for the substrates norepinephrine, epinephrine,
and 5-hydroxytryptamine (serotonin, 5-HT). Found primarily in the central nervous system (brain), and
platelets, MAO-B prefers benzylamine, phenylethylamine, and phenylpropanolamine as substrates.
Dopamine and tyramine are nonselective substrates of both forms. Isoenzyme selectivity is sacrificed in the
setting of high substrate or pharmacologic inhibitor concentration.[43][125] Selective MAO inhibitors such as
moclobemide and selegiline are efficacious antidepressant[4] and anti-Parkinson’s disease agents.[58][96] The
only reported deaths from moclobemide overdose have occurred with co-ingestion of cyclic antidepressants
and/or ethanol.[25][93][97]
Table 66-1 -- Pharmacology of Commercially Available MAO Inhibitors

MAO
Drug Isoenzyme Tissue Specificity Inhibition Primary Usage
Phenylzine A and B All except erythrocytes Irreversible Antidepressant
Tranylcypromine A and B Irreversible Antidepressant
Isocarboxazid A and B Irreversible Antidepressant
Irreversible
Procarbazine A and B Chemotherapeutic
(weak)
Selegiline B* Brain, platelets Irreversible Antiparkinsonian
Pargyline B* Irreversible Antihypertensive
Gastrointestinal, placenta,
Moclobemide A Reversible Antidepressant
peripheral autonomic nerves
St. John’s wort Not Irreversible (in Herbal
Rat brain (experimental)
(Hypericum perforatum) specified vivo) antidepressant
* Predominant isoenzyme, selectivity lost in overdose.
MAOIs are structurally similar to their endogenous and exogenous substrates.[90][115] With the exception of
moclobemide, which is a competitive antagonist, pharmacologic inhibitors of MAO form irreversible covalent
bonds with a flavin adenine dinucleotide moiety on the enzyme.[60] Hence, the reversal of drug effect
depends on de novo enzyme synthesis of MAO, requiring 8 to 12 days to restore 50 per cent of pretreatment
activity.[88]
Inhibition of MAO increases neurotransmitter activity (norepinephrine, serotonin, and dopamine) in the CNS.
Additional MAOI activity includes down-regulation of postsynaptic serotonin (5-HT1, 5-HT2) and adrenergic
(a1, a 2, ß * )receptors, similar to that occurring with chronic cyclic antidepressant therapy.[30][110]
Postsynaptic dopamine receptors remain unaffected. These changes occur sequentially for up to 10 days
once MAOI therapy has been initiated and may persist for weeks after their discontinuation.[30] Because the
pharmacology of MAOIs is related to altered neurotransmitter concentrations and postsynaptic receptor
regulation, toxicity correlates poorly with serum drug levels.
All MAOIs currently available in the United States (see Table 66–1 ) are readily absorbed from the
gastrointestinal tract, undergo extensive first-pass metabolism, and are highly protein bound. After a 20-mg
oral dose of tranylcypromine, the peak plasma concentration is reached in 1 to 3 hours, compared with 2 to
4 hours for 60 mg of phenelzine. Phenelzine and tranylcypromine are metabolized through the hepatic
microsomal system to active sympathomimetic metabolites: phenelzine to phenylethylamine (possesses
weak MAOI activity)[53]; tranylcypromine to phenylethylamine, methamphetamine, and amphetamine;[137]
selegiline to methamphetamine and amphetamine.[22][86][89] Tranylcypromine and selegiline are ultimately
excreted in the urine as 95 to 98 per cent inactive metabolites.[22][89][128]
The plasma elimination half-lives of phenelzine and tranylcypromine are 2 to 3 hours and 1.5 to 4 hours,
respectively.[7][80][81] In a single case report of tranylcypromine overdose, the parent compound’s plasma
half-life is 3.5 hours; no urinary data are reported.[137] The half-life of moclobemide is similar to that of
tranylcypromine and phenylzine.[80][81] Selegiline is metabolized to methamphetamine (half-life, 20.5 hr), but
the overall half-life of the drug and its metabolites is 39 hours.[89] No study reporting the pharmacokinetic
profile of isocarboxazid is available.
* Subtype not identified by experimental assay.

Pathophysiology
Two enzymes, MAO and catecholamine-O-methyl transferase (COMT), are primarily responsible for the
metabolism of biogenic amines in nerve terminals and liver. The latter is an extraneuronal enzyme
responsible for metabolism of circulating catecholamines and is not a pharmacologic substrate for MAOI.
An “autopotentiation” phenomenon occurs as MAOIs both decrease metabolism of and stimulate

neurotransmitter release.[83] Inhibition of MAO increases the pool of bioactive substrates within the
presynaptic neuron and down-regulates postsynaptic catecholamine receptors. On stimulation, supranormal
accumulations of norepinephrine and serotonin, as well as epinephrine, dopamine, and tyramine are
released into the synapse by the presynaptic neuron. In addition to enzyme inhibition, phenelzine and
tranylcypromine structurally resemble amphetamine and exhibit weak indirect-acting sympathomimetic
activity. Once transported into the presynaptic neuron, the MAOI stimulates further release of intraneuronal
catecholamine stores. This explains why fatalities from phenelzine and tranylcypromine overdose are
reported at lower doses than other MAOIs and why “paradoxical” hypertensive reactions are observed with
therapeutic doses of these drugs.[33]
Although the sympathomimetic activity of MAOIs is known, it has been hypothesized that they also possess
intrinsic sympatholytic activity: MAOIs initially stimulate, then inhibit norepinephrine release from
postganglionic sympathetic neurons. This biphasic activity is supported by the finding that cardiac stores of
norepinephrine become depleted in an animal MAOI overdose model,[46] helping to explain the
cardiovascular collapse and CNS depression that occurs in MAOI overdose.[73]
Substances that release stored norepinephrine and other catecholamines from peripheral sympathetic
neurons are referred to as indirect-acting sympathomimetics ( Table 66–2 ). In the setting of nonspecific
irreversible MAO inhibition, such agents liberate an expanded pool of norepinephrine, resulting in a dramatic
hyperadrenergic response. Tyramine, a dietary monoamine present in numerous foodstuffs, acts as an
indirect sympathomimetic and is the primary component of most MAOI-food reactions. Generally, these
food-drug interactions are unpredictable and are not dose dependent.[122] Conversely, direct-acting
sympathomimetics ( Table 66–3 ) bind to postsynaptic receptors where they are primarily inactivated by
COMT. The adrenergic effects of direct-acting agents such as norepinephrine, epinephrine, isoproterenol,
and phenylephrine are not potentiated by MAO inhibition.[16][61][76][126]
Table 66-2 -- Drugs That Interact with MAO Inhibitors

Indirect-Acting Sympathomimetics Serotoninergic Agents Miscellaneous
Amphetamines Amantadine Amantadine
Bretylium Amphetamines Anticholinergics
Cocaine Bupropion Barbiturates (long-acting)
Dexfenfluramine Buspirone Beta-adrenergic
antagonists
Ephedrine Cocaine Codeine
Fenfluramine Codeine Disulfiram
Guanethidine Cyclic antidepressants Ginseng
Ketamine Dexfenfluramine Ketamine
Methamphetamine Dextromethorphan Levodopa
Methyldopa Fenfluramine Oral hypoglycemic agents
Methylenedioxymethamphetamine (MDMA) Levodopa Phenothiazines
Methylphenidate Lithium Methylxanthines
Monoamine oxidase inhibitors L-Tryptophan Aminophylline
Pemoline Lysergic acid diethylamine Caffeine
Phencyclidine MDMA Theophylline
Phenteramine Melatonin
Phenylpropanolamine Meperidine
Pseudoephedrine Mirtazapine
Reserpine Monoamine oxidase inhibitors
Tyramine Pentazocine
Mixed-Acting Sympathomimetics Selective serotonin reuptake
inhibitors
Dopamine Fluoxetine
Ephedrine Fluvoxamine
Mephentermine Nafazodone
Metaraminol Paroxetine
Sertraline
Sibutramine
Trazodone
Tramadol
Venlafexine
Based on case reports and pharmacology. Drugs are listed under multiple headings to illustrate their various
pharmacologic actions or toxicologic profile.
Table 66-3 -- Common Drugs Permitted for Use with MAO Inhibitors
Acetaminophen Direct-acting sympathomimetics Diuretics
Antibiotics Albuterol Fentanyl
Aspirin Clonidine Hydromorphone
Atracurium Dobutamine Lidocaine
Barbiturates (short-acting) Epinephrine Morphine
Benzodiazepines (short-acting) Isoproterenol Nitroglycerin
Calcium channel blockers Methoxamine Nonsteroidal anti-inflammatory drugs
Corticosteroids Norepinephrine Ondansetron
Cyproheptadine Phenylephrine Procainamide
Salbutamol
Terbutaline
All drugs should be used with caution in setting of MAO inhibition. Prolonged and intensified drug effects should
be anticipated. Where clinically relevant, consider using reducing initial drug dosages and titrating to effect.
“Serotonin syndrome” is a potentially fatal interaction that occurs when serotonergic substances such as
meperidine and MAOIs are co-administered (see Table 66–2 ).[17][92][121][132] Circulating (synaptic) 5-HT is
rapidly transported into the presynaptic neuronal cytoplasm, where it is either stored in vesicles or
metabolized by intracellular enzymes. Because 5-HT is a poor substrate for COMT, the primary mechanism
for terminating 5-HT action is uptake from the synapse.[136] In the setting of MAO inhibition where
intracellular stores of 5-HT are expanded, any precipitant that increases the concentration of 5-HT at the
synapse (either directly or by blocking uptake) is potentially catastrophic (see Table 66–2 ). What
distinguishes this phenomenon from indirect-acting sympathomimetic-induced hyperadrenergism is the
preponderance of 5-HT.
Contributing to the narrow toxic-therapeutic ratio of MAOIs is their variable effect on hepatic microsomal
enzymes.[6] This is most likely responsible for the potentiation of many compounds, including certain opiates
and sedative/hypnotics.[42][72][119] Tranylcypromine is a known inhibitor of cytochrome p450 enzymes
CYP2A6 and CYP2C19. These enzymes are involved in the biotransformation of certain barbiturates and
benzodiazepines. Selegiline is a substrate for CYP2D6, an enzyme that biotransforms a large number of
clinically important pharmaceutical drugs.[100]


The clinical effects of MAOI poisoning result from CNS overstimulation and excessive peripheral
sympathetic agonism. Features of an acute overdose may differ from that of a toxic food or drug interaction (
Table 66–4 ). Characteristically, in an acute overdose, symptoms of hyperpyrexia, psychomotor agitation,
and neuromuscular irritability do not present for at least 6 hours. A single report of phenelzine overdose in a
2-year-old describes the symptoms of lethargy and ataxia but does not reveal the time course.[52] Food and
drug reactions typically occur within 30 to 90 minutes after the precipitant is ingested. The resultant
toxicologic profile is consistent with the relative norepinephrine and 5-HT activity of the co-ingested
substance.
Table 66-4 -- MAO Inhibitor Reactions—Clinical Presentation

Reaction Time Course Presentation
Adverse Reaction Onset, rapid Highly variable.
Resolution, 1–2
Modified drug effect days Usually potentiated of drug effects.
Tyramine “Cheese” Onset, rapid Hypertension, tachycardia, bradycardia (ominous), hyperthermia,

Resolution, disorientation, headache, mydriasis, flushing, diaphoresis, stiff
Indirect
6–12 hours neck, seizure, intracranial hemorrhage, death (uncommon)
sympathomimetic NE >>
5-HT
Serotonin Syndrome Onset, rapid Tremor/myoclonus, hyperreflexia, confusion/disorientation,
Resolution, 1–2 muscular rigidity, hyperthermia, diaphoresis, agitation/restlessness,
Excess serotonin activity days hypertension, tachycardia, ataxia, dilated pupils, gastrointestinal
5-HT >> NE symptoms, nystagmus, seizures, death
MAO Inhibitor Onset, delayed Agitation/confusion, tachycardia, hypertension, dilated pupils,
Overdose Resolution, up to gastrointestinal symptoms, hyperthermia, diaphoresis, neuromotor
5 days irritability, autonomic instability (marked), hypotension,
Neurotransmitter pool
obtundation/coma, seizures, cardiovascular collapse, death
expanded NE > 5-HT
(variable)
NE, norepinephrine; 5-HT, 5-hydroxytriptamine.
MAOI Overdose
The presentation of MAOI overdose is highly variable, owing to its multisystem effects, lack of
neurotransmitter specificity, time of presentation after ingestion, and degree of interaction with co-ingested
substances. Perhaps the most important aspect of MAOI overdose is the delayed onset of symptoms.
Conversely, patients on chronic therapy who possess excess catecholamine stores may exhibit sudden
toxicity after a therapeutic dose if an indirect-acting sympathomimetic is also present. The following four-
phase model for acute MAOI poisoning has been proposed.[73] Repeat dosing, co-ingestants, concomitant
therapeutic medications, and underlying medical conditions modify the presentation. Pediatric and adult
overdose presentations are virtually identical except that lethargy and ataxia is more pronounced in young
children.[52][74]
Phase I: Latent Period
Typically, this period is 6 to 12 hours in duration for patients receiving MAOI therapy before overdose. This
latent period may be prolonged 24 to 32 hours for the uninitiated patient not on MAOI therapy. [77]
Phase II: Excitation
Central and peripheral sympathetic stimulation occurs from supranormal neurotransmitter activity
(predominantly norepinephrine and 5-HT). Patients do not exhibit any specific constellation of symptoms, or
“toxidrome,” but 5-HT and its active metabolite tryptamine may be of primary importance.[8][17][86][121] The
initial excitatory phase usually consists of agitation, disorientation, nausea, facial flushing, mydriasis, “ping-
pong” nystagmus[40](periodic alternating gaze),[85] and hyperreflexia/rigidity. Vital sign abnormalities are
often present, reflecting hyperpyrexia, tachycardia, and hypertension, although individual cardiac parameters
may remain within normal limits. Pathologic movements, including facial grimacing, writhing extremities, and
opisthotonus, are almost uniformly described in severe MAOI overdoses. As toxicity increases, the mental
status deteriorates (confusion, hallucinations, lethargy, coma), fever heightens, and diaphoresis, salivation,
muscular rigidity, carpopedal spasm, and myoclonic or tonic-clonic seizure activity may appear. Life-
threatening reactions are marked at this stage by uncontrolled hyperthermia, myocardial ischemia,
cardiogenic pulmonary edema, seizure, and intracranial hemorrhage. Aggressive treatment of hyperthermia,
neuromuscular hyperactivity, violent agitation, and seizures is mandatory at this stage to avoid later
complications, particularly rhabdomyolysis.
Phase III: Depression
Severe MAOI overdoses produce considerable autonomic nervous system instability and can rapidly
progress to CNS and cardiovascular collapse. Twelve to 24 hours after ingestion patients are at risk for an
unpredictable rapid decline in mean arterial pressure. The so-called washout phase, which has been
reported to occur in as little as 8 hours after an isolated MAOI overdose,[87] is often concomitant with a
“spike” in the patient’s core body temperature.[59][73][86][123] This profound alteration in clinical course,
characterized by coma, hypotension, and bradycardia (often progressing into asystole), results from
presynaptic neurotransmitter depletion.[5][85]
Phase IV: Complications
Delayed manifestations of profound autonomic and neuromuscular instability include myoglobinuric renal
failure, the adult respiratory distress syndrome, hemolysis, and disseminated intravascular
coagulation.[18][123] Asystolic cardiac arrest, secondary to either medical complications or depleted
catecholamine stores, usually occurs in this phase of toxicity.
Tyramine Reaction
Tyramine, the first known substrate of MAO,[55] is an indirect-acting sympathomimetic like amphetamine,
dopamine, ephedrine, or phenylpropanolamine. This bioactive amine is abundant in certain foodstuffs (
Table 66–5 ) and is absorbed from the intestine where it is inactivated by gut and, to a lesser extent, hepatic
MAO-A. Therapeutic inhibition of gastrointestinal MAO-A permits excessive amounts of dietary tyramine
(and active by-products of in situ amino acid decarboxylation in the gut) to reach the systemic circulation.[31]
The excess tyramine liberates increased levels of norepinephrine—owing to intraneuronal MAO-A
inhibition—from presynaptic vesicles, creating a hyperadrenergic state.[16] Excess tyramine at the synaptic
cleft also competes for a norepinephrine transporter on the presynaptic membrane. The result in decreased
uptake from the synapse and, as tyramine is carried into the cell, a greater number of inward-facing
transporters available to release cytoplasmic norepinephrine. This model of an indirect sympathomimetic
interaction is distinguished from MAOI overdose by its relative lack of serotonin involvement.
Table 66-5 -- Foods Containing Tyramine

Adapted from Rizack MA: The Medical Letter Handbook of Adverse Drug Interactions. New Rochelle, NY, The
Medical Letter Inc, 1987, pp 301–302; Shulman KI, Walker SE, MacKenzie S, et al: Dietary restriction, tyramine,
and the use of monoamine oxidase inhibitors. J Clin Psychopharmacol 1989; 9:397–402.
Where MAO is therapeutically inhibited, consuming 6 to 10 mg[14][15][31][112] of tyramine can produce a

“cheese reaction,” so-called for its abundance in ripened cheeses. In spite of careful dietary instructions (see
Table 66–5 ) 4 to 8 per cent of patients on MAOIs experience this adverse reaction during therapy.[21] The
onset of symptoms is rapid, usually occurring within 2 hours of food ingestion.[33][111][124] Clinical
presentations of this hyperadrenergic syndrome vary in severity depending on the degree of MAO inhibition
and the amount of exogenous substrate ingested. Typically the heart rate and systolic blood pressure are
markedly elevated (>170 mmHg), whereas patients experience an occipital to generalized headache,
photophobia, neck stiffness (intracranial process absent), palpitations, tachycardia, nausea, vomiting, and
diaphoresis.[33][75][104][115] Seizure activity, cerebral hemorrhage, and myocardial ischemia/infarction are
features of the more severe reactions, which may be fatal.[75][116] Mild to moderate reactions are generally
self-limited, particularly with the reversible MAOIs, where tyramine itself competes with the pharmaceutical
for MAO. In the absence of end-organ damage, symptoms may gradually resolve within 6 hours of onset.
Drug Interactions
Numerous prescription and over-the-counter drugs have been reported to cause complications in patients
receiving chronic MAOI therapy (see Table 66–2 ). These pharmaceutical agents should not be co-
administered with MAOIs. Drug interactions may be loosely categorized into three groups: (1) substances
that predominately induce the liberation of excess norepinephrine (e.g., sympathomimetic drugs such as
reserpine, guanethidine, bretylium, a2-receptor agonists, cocaine, and methylxanthines); (2) those that
predominately affect serotonin (e.g., meperidine, dextromethorphan, cyclic antidepressants, L-tryptophan);
and (3) drugs whose activity is potentiated either synergistically (atropine, insulin) or by inhibition of hepatic
metabolism (morphine, barbiturates).[20][38][45][48][72][122] Even a single dose of any one of these medications
in combination with therapeutic MAO inhibition may precipitate a catastrophic drug reaction. Such reactions
may occur weeks after discontinuation of a MAOI. Conversely, MAOI therapy should not be instituted within
2 weeks of selective serotonin reuptake inhibitor discontinuation and, in particular, within 5 weeks for
fluoxetine.[28][49]
The interaction between MAOIs and indirect-acting sympathomimetics has been extensively reported in
clinical studies and case reports.[11][12][16][31][33][56][63][115][116] This potentially fatal interaction is currently
modeled by the MAOI-tyramine reaction that is mediated primarily by norepinephrine.[16] Fatalities have also
been reported for the MAOI-meperidine interaction,[76] but toxicity is due to excess CNS serotonin instead of
norepinephrine.[41][76] “Serotonin syndrome”[101] is an entity characterized by the combination of mental
status alteration (agitation, confusion, restlessness), motor system changes (myoclonus, hyperreflexia,
rigidity, abnormal movements), and autonomic instability (hyperthermia, flushing, nausea, diarrhea, blood
pressure changes).[17] Meperidine[119] and dextromethorphan[105][109][117] block neuronal serotonin uptake
and are contraindicated in patients on MAOI therapy. Table 66–4 provides the distinguishing features of
MAOI overdose and either tyramine or serotonin-mediated drug interactions.
Miscellaneous drug interactions result from the widespread physiologic activity of MAOIs. They potentiate
the anticholinergic and hypoglycemic properties of co-administered agents such as atropine or
insulin/sulfonylureas.[2][20][32] The pharmacologic effects of certain opioids, barbiturates, chloral hydrate, and
sedative/hypnotic agents metabolized by the liver are enhanced by MAOI inhibition of the mixed-function
oxidase system. Although codeine, morphine, and fentanyl are regarded as safe drugs for patients who
require narcotic therapy, oversedation may occur after standard administration of certain opioids or
barbiturates.[42][113][119][134] Initial doses of these drugs should therefore be adjusted downward and titrated
to effect.
The combination of MAOI and a cyclic antidepressant is still used in selected psychiatric patients [135] in spite
of reported fatalities with this combination. Imipramine, a tricyclic compound whose clinical pharmacology is
not definitely known, has often been reported in these cases. In the absence of a clear etiology for this
interaction, all cyclic antidepressants should be used with extreme caution. Additional drugs with theoretical
contraindications or those demonstrated to be toxic in MAOI-treated animals include theophylline, caffeine,
ß-adrenergic receptor antagonists, phenothiazines, and ketamine. Most nonsteroidal anti-inflammatory drugs
including aspirin, acetaminophen, and ibuprofen may be administered safely to patients on MAOIs (see
Table 66–3 ).


The differential diagnosis of MAOI poisoning is broad, including any condition producing a hyperadrenergic
state that results in sympathetic nervous system overstimulation ( Table 66–6 ). Separating medical and
psychiatric from toxicologic causes, one needs to consider all stimulant, anticholinergic, and hypermetabolic
drugs. Alcohol, barbiturate, sedative-hypnotic, and possibly opioid withdrawal, in addition to dystonic
reactions, the neuroleptic malignant syndrome, and the serotonin syndrome can all produce a clinical picture
similar to MAOI toxicity. Medical conditions that share clinical features with MAOI toxicity include
pheochromocytoma, thyroid storm, hypoglycemia, tetanus, rabies, and heat stroke. In all patients with fever
and altered mental status the possibility of sepsis, meningitis, or encephalitis should be entertained. [99]
Table 66-6 -- Differential Diagnosis of MAO Inhibitor Overdose

Adapted from Mills KC: Monoamine oxidase inhibitor toxicity. Top Emerg Med 1993; 15(3):58–71.


LABORATORY STUDIES
General
The best use of the clinical laboratory in suspected MAOI poisoning is to either identify complications of
toxicity or to “rule out” the possibility of a concomitant disease, such as meningitis. Rapid bedside glucose
evaluation with laboratory serum confirmation should be performed immediately to exclude the possibility of
hypoglycemia. Continuous pulse oximetry, if available, should be used. Early complications (hypoxia,
leukocytosis, hyperglycemia, metabolic acidosis, hyperkalemia, cardiac ischemia, pulmonary edema) are
secondary to the hyperadrenergic state, so initial laboratory studies should include an electrocardiogram,[102]
complete blood cell count, routine electrolytes, blood urea nitrogen, creatinine, urinalysis, and ethanol level.
In the patient with hyperthermia, agitation, or neuromuscular hyperactivity, creatine kinase and urine
myoglobin measurements are necessary to screen for rhabdomyolysis. Women of childbearing age should
have ß-human chorionic gonadotropin testing and, if necessary, appropriate fetal monitoring. Computed
tomography (CT) of the head may be required to exclude intracranial hemorrhage. If co-ingested substances
are in question, salicylate levels, thyroid function tests, and specific drug levels (acetaminophen) should be
ordered. A lumbar puncture may be necessary to obtain cerebrospinal fluid if the diagnosis of either occult
intracranial hemorrhage (CT negative) or meningitis is suspected. Disseminated intravascular coagulation,
hemolysis, rhabdomyolysis, renal failure, and cerebral edema are potential complications that may be
detected by serial laboratory and radiographic studies.
Toxin Specific
Monoamine oxidase inhibitor poisoning or food/drug interaction is entirely a clinical diagnosis. Serum MAOI
levels are not immediately available at most hospitals and correlate poorly with clinical course. Toxicity is
mediated by altered neurotransmitter activity and not based on drug level. Platelet MAO-B levels are used to
determine therapeutic dosing of phenelzine; however, no predictive correlation has been established
between these blood levels and toxicity in an overdose. Commonly used urine and serum drug screens are
unable to detect MAOIs, but adequate quantities of selegiline and tranylcypromine metabolites are identified
as amphetamines on routine screens for drugs of abuse.


General
All patients with a suspected MAOI overdose or adverse reaction require immediate evaluation, stabilization,
and cardiac monitoring with repeated vital sign determinations. Frequent core temperature measurements
are mandatory for early detection of hyperthermia, which should be promptly treated by external cooling
methods. At least one intravenous line should be established and high-flow oxygen readily available in
anticipation of a critical intervention. In the absence of baseline cardiac or renal impairment, urine output
should be maintained at 1 to 2 mL/kg/min. Patients with altered mental status warrant an immediate
investigation of blood glucose concentration and the possible administration of thiamine. The clinician
cannot be complacent about the well-appearing patient, particularly within the first few hours of MAOI
ingestion (see Table 66–4 ).
Table 66-7 -- Treatment of MAO Inhibitor Toxicity

Condition Intervention Dosage (Pediatric)
Suspect MAO inhibitor Charcoal * 1 g/kg
overdose
Gastric lavage for recent
ingestion *
Hypertension Nitroprusside * 0.5 µg/kg/min; titrate to effect
Phentolamine 2–5 mg q10 min (0.1 mg/kg q30 min) or infuse
Hypotension Stop antihypertensive
agents *
Treat dysrhythmias *
Isotonic crystalloid boluses
250–1000 mL (20 mL/kg), may be repeated
*
Norepinephrine 0.1–1.0 µg/kg/min † ; titrate to effect
Phenylephrine 10 µg/min † ; titrate to effect
Epinephrine 0.1–1.0 µg/kg/min † ; titrate to effect
Intra-aortic balloon pump
Cardiac bypass, ECMO
Hyperthermia Water mist, fan, ice,
cooling blanket *
Benzodiazepine *
Diazepam 5–10 mg, q10 min (0.25 mg/kg, q15–30 min)
Lorazepam 1–4 mg (0.05 mg/kg), q20 min
Condition Intervention Dosage (Pediatric)
Neuromuscular blockade
Atracurium 0.4 mg/kg (<2 years old, use 0.3–0.4 mg/kg)
Vecuronium 0.08–0.1 mg/kg (same for pediatrics >1 year old)
Cyproheptadine ‡ 4–8 mg, q1–4 hr to 32 mg/d (0.25 mg/kg/d divided § )
Chlorpromazine 50–100 mg, q6 hr (0.25–0.5 mg/kg, q6–8 hr)
Dantrolene ¶ Not recommended
Seizure Oxygen, cardiac monitor *
Correct hypoglycemia *
Benzodiazepine *
Phenobarbital 20 mg/kg at 100 mg/min load (3 mg/kg load)
Neuromuscular blockade
Atracurium 0.4 mg/kg (<2 years old, use 0.3–0.4 mg/kg)
Vecuronium 0.08–0.1 mg/kg (same for pediatrics >1 year old)
Tachycardia Isotonic crystalloid boluses
250–1000 mL (20 mL/kg); may be repeated
*
Benzodiazepine *
Lidocaine, procainamide As indicated for ventricular dysrhythmia
Bradycardia 0.25–0.5 mg, * q3–5 min up to 4.0 mg (0.02
Atropine *
mg/kg—minimum 0.1 mg, q5–10 min up to 2 mg
Isoproterenol 0.1–1.0 µg/kg/min † to 5 µg/min
Dobutamine 2.5–15 µg/kg/min †
Cardiac pacing
* First-line therapy for given condition.
† Exaggerated response expected; adjust initial dose downward.
‡ Drug of choice when serotonin syndrome evident.
§ 2–6 year old—2 mg, q6–8 hr adjusted to 12 mg; 7–14 year old—4 mg, q6–8 hr adjusted to 16 mg.
Has been used successfully; may produce hypotension or lower seizure threshold.
¶ Used for neuroleptic malignant syndrome; not recommended for known MAO inhibitor overdose.
Decontamination
Activated charcoal is the mainstay of gastric decontamination for MAOI overdoses or potentially toxic drug
interactions ( Table 66–2 ). No data are currently available to support the use of gut decontamination after
ingestion of foods rich in tyramine. This intervention should be considered for patients with adequate airway
protection and intact gastrointestinal tracts whose risk for aspiration (e.g., coincident hydrocarbon ingestion)
is low.[26] There is no proven benefit of giving repeat doses of charcoal because enteric countercurrent
circulation has not been demonstrated. Whole-bowel irrigation with a polyethylene glycol solution may be
employed when co-ingestants include sustained-release preparations or those not readily adsorbed by
activated charcoal such as iron or lithium.
Gastric lavage may be indicated for large ingestions of MAOI or interactive substances. Its judicious use
should be considered up to 4 hours after ingestion if the patient is exhibiting significant toxicity because
MAOIs may delay gastric emptying.[126] Aspiration risks, procedural hazards, and the absence of data
comparing gastric lavage to the known efficacy of activated charcoal argue against the indiscriminate use of
this modality.[129] Syrup of ipecac is contraindicated in the setting of MAOI overdose because of possible
seizure activity.
Hypertension
Autonomic instability is the hallmark of MAOI toxicity. Accurate continuous blood pressure monitoring by
means of an intra-arterial catheter is recommended in symptomatic patients. Nitroprusside, administered as
a continuous infusion starting at a rate of 0.5 µg/kg/min then titrated according to blood-pressure response,
is the first-line antihypertensive agent. Its onset of action is within 30 seconds, and when the drug is
discontinued the effect disappears within 3 minutes.[98] Phentolamine mesylate, a short-acting nonspecific a-
adrenergic receptor blocker, may be administered in 2- to 5-mg aliquots every 10 minutes or as a continuous
infusion until blood pressure is controlled. Successful treatment of MAOI-induced hypertensive emergencies
with nifedipine[29][111] and ß-adrenergic receptor antagonists[1][99] has been reported, but these agents
should be held in lieu of the shorter-acting agents. Beta-adrenergic receptor antagonists should be used with
caution to avoid a paradoxical hypertensive response from unopposed peripheral a-adrenergic agonism.[44]
Central-acting antihypertensives such as a-methyldopa, bretylium, clonidine, guanethidine, and reserpine
are contraindicated in the presence of MAOIs, because of their potential for hypertensive
reactions.[82][98][115]
Hypotension
Hypotension in MAOI overdose may result from overtreatment of previous hypertension or depletion of
endogenous catecholamines. Initial management consists of discontinuing antihypertensive medications
and administering intravenous isotonic crystalloid boluses. For significant hypotension that is refractory to
fluid resuscitation, norepinephrine, a direct-acting a-adrenergic agonist, is the vasopressor of choice.
Indirect-acting vasopressors such as dopamine or ephedrine may precipitate a hypertensive crisis[18] or act
unpredictably when neuronal amine stores and kinetics are altered by MAO inhibition.[16][35][39][61][120]
Epinephrine and isoproterenol are direct-acting sympathomimetics whose effects should not be influenced
by MAO inhibition.[16][39][53][61][127] The ß 1-adrenergic pressor effect of these drugs may be offset by ß2-
adrenergic vasodilation so blood pressure response may be variable. When systemic vascular resistance is
adequate or high, the ß1-adrenergic receptor agonist effect of epinephrine or isoproterenol may be exploited
to increase cardiac output. Because MAOI toxic patients demonstrate increased sensitivity to all
vasopressors, initial doses should be significantly reduced then titrated to effect.
Hyperthermia
One of the major determinants of mortality and morbidity in a MAOI overdose is the presence of severe
hyperpyrexia and neuromuscular hyperactivity.[18][84][86][103][114] Rapid external cooling methods employing
ice baths or water mist and cooling fans are the mainstay of therapy in the hyperthermic patient.
Benzodiazepines are useful adjuncts in controlling neuromuscular hyperactivity and thereby lowering body
temperature. Barbiturates attenuate the pyrexia thought to be triggered centrally by 5-HT.[84] Cyproheptadine
is an effective agent for serotonin-mediated hyperthermia unresponsive to initial cooling
modalities.[10][47][51][71][91][92][95][108]
Marked recalcitrant hyperthermia is an indication for paralysis using a nondepolarizing neuromuscular

blocking agent such as vecuronium or atracurium. Pancuronium bromide may release stored
catecholamines, representing a theoretical hazard.[34][119] Naloxone should not be administered to MAOI-
poisoned patients. One animal study demonstrated that naloxone potentiates the hyperpyrexia in MAOI-
meperidine drug interactions. [70] Because MAOI-induced hyperpyrexia is mediated by catecholamines, not
prostaglandins, antipyretics such as acetaminophen are an ineffective treatment of this response.
There are case reports that support the use of dantrolene sodium in phenelzine-induced
hyperthermia.[19][66][130] Indications of its efficacy in methylenedioxymethamphetamine (MDMA) and cyclic
antidepressant toxicity suggest that dantrolene may attenuate 5-HT–mediated hyperthermia.[37][54][65][79]
This drug should be reserved for the severely poisoned patient who has not responded to aggressive
surface cooling methods, benzodiazepines, barbiturates, cyproheptadine, or muscle paralysis. In the
otherwise-treated patient in whom muscle rigidity is a prominent clinical feature or in whom the neuroleptic
malignant syndrome cannot be ruled out, dantrolene can possibly mitigate rhabdomyolysis and secondary
renal failure.[23]
Seizure
Benzodiazepines such as lorazepam or diazepam are first-line therapy for the absolution of MAOI-induced
seizures. Phenobarbital, up to 20 mg/kg at a rate of 100 mg/min in an adult, until seizure activity terminates,
may be used when high-dose benzodiazepines have failed.[78][124] Respiratory and blood pressure support
must be immediately available because enhanced or prolonged effects of these drugs are expected.
Patients with an epileptic focus or on phenytoin maintenance should be maintained at their therapeutic
antiepileptic drug levels. General anesthesia or neuromuscular blockade is necessary for refractory seizures
to avoid lactic acidosis, hyperthermia, and rhabdomyolysis. Paralysis is best accomplished using a
nondepolarizing neuromuscular agent[113] and bedside electroencephalography to monitor ongoing seizure
activity.
Rhabdomyolysis
Severe hyperthermia, prolonged seizure, or neuromuscular hyperactivity produces rhabdomyolysis and may
result in myoglobinuric renal failure. Associated laboratory abnormalities include hyperkalemia and
hyperphosphatemia. Expectant management of the MAOI-poisoned patient is best to avoid tissue damage
and subsequent leakage of muscle cytoplasmic constituents. In the absence of mitigating conditions such as
intracranial hemorrhage or cardiac insufficiency, the treatment of rhabdomyolysis and myoglobinuria
consists of vigorous diuresis. Normal saline (up to 10 L over 24 hours) with high-dose furosemide and 25 g
of intravenous mannitol are used while carefully paying attention to serum potassium and phosphorus
levels.[68]
Dysrhythmias
The most common dysrhythmia observed in MAOI toxic patients is sinus tachycardia. Little information is
available on the successful treatment of ventricular arrhythmia in MAOI overdose. Correcting intravascular
volume deficits and treating agitation with benzodiazepines should comprise the immediate therapy of
supraventricular tachycardia. Lidocaine, procainamide, and phenytoin are regarded as theoretically safe
treatments of MAOI-induced ventricular tachyarrhythmias.[73] Bretylium, due to its effects on the
intraneuronal metabolism of norepinephrine, may precipitate a surge of catecholamine release followed by
profound hypotension (washout effect).[73][82] Bretylium also possesses intrinsic MAOI activity and should be
avoided.[69]
Beta-adrenergic receptor antagonists pose a theoretical risk of producing hypertension due to the
unopposed a-adrenergic vasoconstriction. Although labetalol and practolol have been safely used to
manage hypertension for an MAOI overdose patient,[1] an ultra-short-acting cardioselective drug such as
esmolol may be preferable for tachydysrhythmias refractory to first-line therapy.[90] To date, esmolol use in
MAOI overdose has not been reported.
Bradycardia is an ominous sign because it represents loss of sympathomimetic activity and may rapidly
deteriorate into asystole. Treatment of bradyarrhythmias may include atropine, isoproterenol, epinephrine,
and cardiac pacing.[73] Extracorporeal membrane oxygenation (ECMO) and cardiac bypass are two
treatment modalities whose use in MAOI poisoning has not been described in the medical literature.
Because cardiovascular collapse occurs rather suddenly in MAOI overdose, ECMO and bypass may
potentially be reserved for organ donor candidates.
Other Measures
The efficacy of extracorporeal decontamination (ECD) in MAOI overdose has yet to be demonstrated. Two
reports of treatment using hemodialysis (tranylcypromine, phenelzine) and one of peritoneal dialysis
(pargyline) have been documented.[74][87][131] Although no dialysate or serial serum drug levels were
reported, eventual improvement was noted in each case. Resolution of toxicity (approximately 24 hours) did
not differ markedly from similar cases where dialysis was not employed. Further studies are required to
support the use of ECD in MAOI poisoning cases.
There is no definitive evidence supporting the use of diuresis to increase MAOI excretion. A single report
outlines the influence of urinary pH on tranylcypromine excretion in four subjects. In alkaline urine (pH 8)
about 1 per cent of a 20-mg tranylcypromine sulfate dose appeared unchanged in the urine at 16 hours. This
increased to 8 per cent when the urine is acidified to pH 5.[128] Although data are not available for overdose
conditions, such an intervention is unlikely to alter the clinical course of an MAOI-poisoned patient. In
addition, MAOI-toxic patients are at risk for rhabdomyolysis. Urinary acidification should not be performed,
because its benefit has not been shown to outweigh the risk of acute renal failure from myoglobin
precipitation in the nephron.
There is no specific antidote for MAOI poisoning. Chlorpromazine, with its strong antiadrenergic and weak
antiserotonin activity, has been an effective adjunct, particularly when hypertension and confusion are
prominent features.[27][29][48][50][62][103][107] However, administration of this drug to MAOI-toxic patients may
result in prolonged hypotension. Cyproheptadine, a histamine H 1 antagonist whose structure resembles that
of a phenothiazine, exhibits powerful 5-HT antagonism. This drug is the single most effective agent for
serotonin syndrome and may be useful in the treatment of severe MAOI overdose or 5-HT–mediated drug
interactions.[10][47][51][71][91][92][95][108]
Flumazenil is contraindicated when neuromuscular irritability, seizure activity, or suspicion of CA toxicity is

present in the overdose patient.[57][94][118][133] Seizure potential, and the close similarity between MAOI and
CA poisoning, precludes the use of flumazenil in an MAOI-toxic patient.


DISPOSITION
The hallmark of MAOI overdose is the delayed onset of minimal symptomatology combined with the drug’s
potential for catastrophic sequelae after this latent period. Initial CNS symptoms have been delayed up to 32
hours after ingestion.[77] Based on this report any suspicion of MAOI overdose warrants patient admission to
a monitored setting for 24 to 36 hours, even if the patient is asymptomatic. Those who begin to display
evidence of toxicity should be admitted to an intensive care unit anticipating the onset of autonomic
instability and hyperthermia. Asymptomatic patients can be discharged after 24 to 36 hours of observation,
and, if necessary, receive psychiatric intervention.


SEQUELAE
Complications of MAOI toxicity include intracranial hemorrhage, myocardial infarction, disseminated

intravascular coagulation, adult respiratory distress syndrome, and myoglobinuric renal failure. Patients who
recover from overdose or toxicity without irreversible end organ damage should not endure any permanent
direct sequelae. Because MAO activity levels only return to 50 per cent of normal after 2 weeks, a careful
diet and medication regimen must be resumed on discharge to avoid future incident.


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Chapter 67 – Sedative-Hypnotics
ERICA L. LIEBELT
Essentials
• Central nervous system: euphoria, agitation, sedation, coma
• Hypotension (variable)
• Respiratory depression (variable)
• Withdrawal syndromes: hallucinations, sympathetic stimulation, hyperreflexia, delirium,
seizures
INTRODUCTION
Sedative-hypnotic drugs are used therapeutically to produce calm and facilitate sleep. A variety of these
agents have been developed over the past century, each with adverse effects, toxicity, and problems with
tolerance as well as drug withdrawal. Chloral hydrate and the bromides, popular sedatives before 1900,
were replaced by the barbiturates at the turn of the twentieth century but regained popularity in the 1950s
and 1960s. Recognition of the abuse potential of barbiturates led to the development of newer
pharmacologic agents in the 1950s. Most of these drugs, which include meprobamate, ethchlorvynol,
glutethimide, and methaqualone, either have been withdrawn from the market or are prescribed very
infrequently owing to their toxicity and abuse potential and so are primarily of historical significance. The
benzodiazepines were marketed as safe and nonaddictive sedative and anxiolytic agents but now are
recognized as having significant potential for dependence. The new non-benzodiazepine hypnotic agents,
zolpidem and buspirone, are emerging as the safest sedative-hypnotic drugs and thus far have not
demonstrated serious toxicity or potential for abuse.
This chapter deals with the older sedative-hypnotic drugs and the two newer agents zolpidem and
buspirone. Benzodiazepines and barbiturates are covered in Chapters 69 and 68 , respectively. A broad
overview of sedative-hypnotics is presented, followed by detailed information on individual agents.
Pharmacology
See individual agents.
In general, depression of the respiratory, cardiovascular, and central nervous systems characterizes the
toxicity of the sedative-hypnotic drugs ( Table 67–1 ). Each of these symptoms manifests in various degrees
depending on the particular drug exposure. In addition, each agent has distinguishing features in its toxicity
profile that may lead to a more specific diagnosis and guide therapy ( Table 67–2 ).
Table 67-1 -- Clinical Presentation of Sedative Hypnotic Overdoses *

Ataxia, dysarthria, nystagmus, lethargy, coma
Hypothermia
Hyporeflexia/areflexia
Bradycardia or tachycardia
Hypotension
Respiratory System
Hypoventilation
Apnea
* See Table 67–2 for distinguishing characteristics of specific drugs.
Table 67-2 -- Signs and Symptoms Produced by Specific Sedative-Hypnotic Drugs

Bromides
Neuropsychiatric symptoms—dementia, delirium, depression, psychoses
Bromoderma—acneiform eruption on face and upper trunk, erythema nodosum, pemphigus-like vesicles
Pseudohyperchloremia with low anion gap
Chloral Hydrate
Gastrointestinal irritation (nausea, vomiting, abdominal pain)
Radiopaque pills on abdominal radiograph
Pearlike odor
Ethchlorvynol
Prolonged, deep coma
Prolonged apnea
Pungent odor (vinyl or plastic)
Glutethimide
Cyclical coma
Anticholinergic signs and symptoms
Meprobamate
Shorter coma, relapse of coma after clinical improvement, or prolonged coma
Concretions of drug in stomach
Profound hypotension
Seizures
Methaqualone
Coma with myoclonus
Hyperreflexia
Seizures
Respiratory depression, hypotension rare
Blood extravasation (purpura, retinal hemorrhages, GI bleeding)
Zolpidem
Somnolence
Stable vital signs
Symptoms reversed by flumazenil
All sedative hypnotic agents have the capacity to induce tolerance to their effects, followed by withdrawal
syndromes characterized by sympathetic stimulation, hallucinations, delirium, and seizures.
The differential diagnosis of any comatose state should include other toxins that depress the central nervous
system (CNS). Structural lesions and infectious causes must also be considered. Metabolic disturbances
that cause altered mental status include hypoglycemia, hyperglycemia (nonketotic coma), hypercalcemia,
hypernatremia, hyponatremia, and hepatic and uremic encephalopathy ( Table 67–3 ).
Table 67-3 -- Differential Diagnosis of Sedative-Hypnotic Toxicity

CNS anatomic lesions—subarachnoid bleed, intraventricular hemorrhage, brain contusion, infarction
Infections—encephalitis, meningitis, sepsis syndrome
Metabolic abnormalities—hypoglycemia, hypercalcemia, hypernatremia, hyponatremia, hepatic and uremic
encephalopathy, hypoxia, hypercarbia
Other selected toxins
Antihistamines
Barbiturates
Clonidine
Ethanol
Opioids
Phenothiazines
Salicylates
Other sedative-hypnotics (see Table 67–2 )
Laboratory Evaluation
Blood levels of the specific sedative-hypnotic agents do not correlate with or predict toxicity, although they
are helpful in confirming the presence of the toxic agent. As in all seriously poisoned patients, co-ingestants,
such as acetaminophen, that may require special therapies should be excluded by laboratory testing.
Routine assessment by measurement of electrolytes, arterial blood gas, and creatine phosphokinase (to
detect rhabdomyolysis) is useful in the diagnosis and supportive management of the critically poisoned
patient. Chest radiography is indicated to detect aspiration pneumonia or noncardiogenic pulmonary edema,
both of which can occur in severe sedative-hypnotic overdoses. When the diagnosis is not clear, head
computed tomography (CT) scanning and lumbar puncture should be used to exclude other causes of
altered mental state (see Table 67–3 ).
Management
Treatment is supportive ( Table 67–4 ). Depending on the clinical severity of the overdose, aggressive
supportive care may be indicated, including monitoring in an intensive care unit (ICU); endotracheal
intubation; mechanical ventilation; fluids, inotropes, and vasopressors; and invasive central hemodynamic
monitoring. Oral activated charcoal is indicated in all cases in which a significant exposure has occurred,
assuming appropriate airway protection. Agent-specific approaches to decontamination are discussed later.

Supportive Measures
Monitor vital signs, oxygenation with pulse oximetry, and ventilation with arterial blood gases.
Establish airway.
Maintain adequate ventilation and oxygenation.
Use fluid boluses with isotonic saline for hypotension.
Use inotropes (dopamine/dobutamine) and vasopressors (norepinephrine) in conjunction with limited fluids for
noncardiogenic pulmonary edema as clinically indicated.
Use PEEP for pulmonary edema (CPAP or BiPAP for nonintubated patients).
Maintain normal body temperature.
Consider gastric lavage for potentially lethal pure sedative-hypnotic, mixed ingestions, or meprobamate
ingestions to prevent formation of concretions.
Administer single dose of activated charcoal 1 g/kg body weight.
Additional doses of activated charcoal should be considered:
• Prevent ongoing absorption due to delayed motility (all sedative-hypnotics)
• Interrupt enterohepatic circulation (glutethimide)
• For potential drug concretions (meprobamate).
Consider whole bowel irrigation in meprobamate ingestions.
Elimination Enhancement
Consider hemodialysis or hemoperfusion only when patient fails to improve with aggressive supportive care.
Enhanced elimination has been shown in poisoning with bromides, chloral hydrate, and meprobamate.
Antidotes
Flumazenil can reverse CNS and respiratory depression due to severe zolpidem toxicity.
Specific Treatments
Chloral hydrate–ventricular dysrhythmias
Adult: Propranolol 1.0–2.0 mg IV followed by an infusion of 1.0–2.0 mg/hr until cessation of the dysrhythmia.
Esmolol loading dose of 500 µg/kg given over 2 minutes followed by an infusion of 25–100 µg/kg/min (titrating
to heart rate reduction/dysrhythmia cessation)
Children: Propranolol 0.01–0.1 mg/kg, maximum 1.0 mg
Esmolol 100–500 µg/kg given over 1 minute followed by an infusion of 25–100 µg/kg/minute titrating to
dysrhythmia cessation
Methaqualone
Benzodiazepines (diazepam) or paralysis for prolonged myoclonus, hypertonicity, seizures
Platelets, vitamin K, fresh frozen plasma for uncontrolled bleeding
Sequelae
The long-term sequelae of most sedative hypnotic overdoses are related primarily to the effects of
hypoxemia, hypotension, and prolonged intubation. Anoxic encephalopathy, myoglobinuric renal failure,
thromboembolic events, compression neuropathy, line sepsis, pneumonia, and adult respiratory distress
syndrome (ARDS) may occur as complications of a prolonged ICU stay.


BROMIDES
Essentials
Chronic Toxicity (Bromism)
• Mental status depression—stupor, coma
• Neuropsychiatric symptoms—dementia, delirium, depression, psychoses
• Bromoderma—acneiform eruption on face and upper trunk, erythema nodosum, pemphigus-like
vesicles
• Pseudohyperchloremia with low anion gap
Introduction
Bromides have been used since the mid-1800s as sedative-hypnotics and anticonvulsants and are found in
a variety of over-the-counter sleep aids and “nerve remedies” such as Bromo-Seltzer and Miles Nervine. The
organic bromides carbromal and bromisoval, sometimes formulated with barbiturates, were widely available
in Europe as sleep agents. Paxarel (acetylcarbromal) is marketed in the United States. Chronic bromide
toxicity is now recognized as the cause of neuropsychiatric disturbances in many patients hospitalized for
mental illness in the early 1900s.[49] Recognition of this toxicity led to the removal of bromide salts from most
pharmaceutical products by 1978, although they are still found in some over-the-counter agents, such as
brompheniramine and cough and cold preparations (dextromethorphan), and other therapeutic drugs such
as halothane, pancuronium, and pyridostigmine. Rarely, exposure to these agents results in significant
toxicity.[7] Toxic exposures continue to occur, as some older products are still found in homes and
pharmacies.
Bromide salts are rapidly absorbed in the gastrointestinal (GI) tract and distributed in extracellular water, with
a volume of distribution of 0.3 L/kg. Like the chloride ion, bromide is concentrated in erythrocytes and
neurons. Its main physiologic action results from displacement of chloride. Bromide is eliminated by the
kidneys. The renal tubules have a higher affinity for bromide than for chloride so that bromide is
preferentially reabsorbed. This results in a long elimination half-life (7–12 days) and in accumulation of
bromide and depletion of chloride during chronic use. Bromide alters the active and passive transport of
chloride in neuronal membranes, producing membrane stabilization that results in CNS depression.
Acute bromide toxicity is uncommon, since significant ingestions cause vomiting due to the gastric irritant
effects of bromide salts. Chronic bromide toxicity, or bromism, affects the GI tract, skin, and CNS.[34][49]
Neuropsychiatric symptoms are manifested as delirium, agitation, tremor, incoordination, dysarthria,
hallucinations, stupor, and coma as well as depression, schizophrenia, and psychoses.[4] These symptoms
usually have an insidious onset suggestive of an organic brain syndrome or dementia. Ocular findings
consist of mydriasis, color disturbances, blurred vision, micropsia/macropsia, papilledema, and opsoclonus.
The primary dermatologic manifestation is bromoderma, which is characterized by an acneiform eruption on
the face and upper trunk, erythema nodosum–like lesions on the lower extremities, pemphigus-like vesicles
containing bromide, tumor-like lesions, and nonspecific morbilliform dermatitis. Gastrointestinal symptoms
include nausea, vomiting, fetid odor, anorexia, and weight loss.
Bromism should be included in the differential diagnosis of patients presenting with altered mental status
and behavioral changes (see Table 67–3 ).
Laboratory Studies
Serum bromide levels will help confirm the diagnosis but do not consistently correlate with the severity of
toxicity. Bromide levels consistent with a therapeutic effect are less than 50 mg/dL, while levels >100 mg/dL
are commonly seen in patients with bromism. Laboratory studies useful in assessing patients with suspected
bromide toxicity include measurement of electrolytes, blood urea nitrogen, and serum creatinine level.
Routine laboratory methods for the measurement of chloride do not distinguish chloride from bromide,
resulting in an artifactual elevation of chloride in the presence of bromide ion.[17] This artifactual chloride
elevation does not provide a reliable quantitative estimate of the serum bromide concentration. The low
anion gap that results from this pseudohyperchloremia is a useful biochemical marker that suggests the
diagnosis of bromide toxicity. Bromide is radiopaque and may be seen on an abdominal radiograph.
Treatment
Gastrointestinal decontamination may be indicated in cases in which an acute ingestion has occurred.
Activated charcoal does not bind the bromide anion but may be effective for organic bromides. Whole bowel
irrigation should be considered when a significant amount of bromide is still present in the GI tract. The
treatment of chronic bromide toxicity relies on the preferential renal excretion of bromide that follows chloride
loading. In cooperative patients, oral sodium chloride at a dose of 2–3 g, three to four times per day, can be
administered, supplemented with 4–10 L of fluid per day. Severely intoxicated patients can be treated with
intravenous sodium chloride (0.45% normal saline) in conjunction with intravenous furosemide (1 mg/kg) to
maintain a urine output of 3 to 6 mL/kg/hr. This combination has been shown to effectively accelerate
bromide excretion.[37] Fluid, electrolyte, and acid-base status must be carefully monitored during therapy.
Therapy can be discontinued when the bromide concentration falls below 50 mg/dL and symptoms improve.
Bromide is also effectively removed by hemodialysis, which should be reserved for patients with chronic
heart or renal failure, in whom chloride loading may not be possible.
Disposition
Patients with severe intoxication should be hospitalized for monitoring and for intravenous chloride loading.
Outpatient therapy may be used in selected individuals.
Sequelae
Resolution of CNS symptoms is slow, and a transient amnesia may follow recovery. Bromoderma may take
6 months to resolve completely.
Specific Situations
Neonatal bromism has been reported secondary to in utero exposure from maternal bromide use. Features
are CNS depression and hypotonia (weak suck and cry), which resolve slowly as bromide levels
decrease.[35]


CHLORAL HYDRATE
Essentials
• Respiratory depression, hypotension
• Gastrointestinal irritation
• Ventricular dysrhythmias
• Radiopaque pills on abdominal radiograph
• Pearlike odor
Introduction
Chloral hydrate, synthesized in 1832, has been used as a sedative-hypnotic throughout this century. It is still
used today for short-term treatment of insomnia in adults and for sedating children prior to medical
procedures. Although it has not been a significant drug of abuse, it has appeared as a recreational drug in
combination with ethanol, the so-called Mickey Finn or knockout drops.
Chloral hydrate is rapidly absorbed from the GI tract and widely distributed, with an onset of action within 30
minutes. It is metabolized by alcohol dehydrogenase in the liver and erythrocytes to trichloroethanol (TCE),
the primary active metabolite responsible for its sedative and hypnotic effects. TCE has a half-life of 6–12
hours. TCE is metabolized to trichloroacetic acid or conjugated with glucuronide and renally excreted as
urochloralic acid. In adults, the parent compound has a half-life of a few minutes. However, children
metabolize chloral hydrate more slowly than adults, so that unchanged chloral hydrate can be detected for
several hours after administration in the blood of neonates and children up to 2 years of age and for 28–40
hours in preterm neonates. In these patients the effects of the TCE metabolite following cumulative dosing
or an acute overdose may persist for 35–50 hours or longer.
The sedative action of TCE appears to be mediated by the GABAA receptor complex, the same site of action
for barbiturates and benzodiazepines. TCE activates GABAA receptors directly and also blocks NMDA (N-
methyl-D-aspartate) receptors, actions that result in altered chloride ion currents.[42] Pharmacodynamic
interactions between various sedative-hypnotics and other CNS depressants can result in more profound
depressant effects. For example, ethanol enhances the formation of TCE by alcohol dehydrogenase by
increasing the availability of NADH. Furthermore, ethanol potentiates the effects of chloral hydrate by
inhibiting the conjugation of TCE with glucuronide, while TCE inhibits the oxidation of ethanol.[47] Thus, TCE
concentrations are higher and reach earlier peak concentrations when the two agents are taken
concomitantly. This interaction is the pharmacologic basis for the potency of the Mickey Finn and knockout
drops.[22] Chloral hydrate directly decreases myocardial contractility, shortens the myocardial refractory
period, and sensitizes the myocardium to catecholamines, effects that account for its cardiovascular toxicity.
The clinical features of chloral hydrate toxicity are similar to those of barbiturates—coma, respiratory
depression, hypotension, and hypothermia. Gastrointestinal irritant effects produce esophagitis and gastritis
in the overdose setting, resulting in nausea, vomiting, retrosternal burning, abdominal pain, and occasionally
hemorrhage. Rarely, gastric necrosis and perforation as well as development of esophageal strictures have
been reported.[50] Mild hepatic and renal dysfunction manifest as elevations of serum hepatic
transaminases, jaundice, and albuminuria. A distinguishing characteristic of serious chloral hydrate toxicity is
cardiac dysrhythmias that may be atrial or ventricular. Ventricular dysrhythmias are responsible for the
serious morbidity and mortality associated with chloral hydrate poisoning. Unifocal and multifocal premature
ventricular beats, bigeminy, ventricular tachycardia, torsades de pointes, ventricular fibrillation, and asystole
have been reported in both adults and children in the absence of pre-existing heart disease. [8] TCE, like
other halogenated hydrocarbons, appears to sensitize the myocardium to endogenous catecholamines
rather than directly affecting automaticity.[9] Death has been reported following ingestions of 10 g or more.
Gastrointestinal symptoms, pearlike odor, and cardiac dysrhythmias may help distinguish chloral hydrate
from the other sedative-hypnotics (see Tables 67–2 and 67–3 ). Other causes of altered mental status must
also be considered.
Laboratory
Chloral hydrate and TCE levels can confirm ingestion but are seldom necessary to guide acute
management. Toxicity occurs at a level of 100 mg/L and fatalities at 250 mg/L. Chloral hydrate is reportedly
radiopaque, and abdominal radiographs may help confirm an ingestion and document the efficacy of GI
decontamination.
Treatment
Aggressive supportive care should be directed at the respiratory and cardiovascular systems (see Table
67–4 ). The administration of activated charcoal should be the primary method of GI decontamination.
Gastric lavage may be beneficial if the ingestion was very recent (within 15–30 minutes), particularly if the
preparation was a liquid form.
Beta-adrenergic receptor antagonists are effective in the treatment of ventricular dysrhythmias due to chloral
hydrate toxicity. [15] Propranolol can be administered intravenously at an initial dose of 1.0–2.0 mg in adults
followed by an infusion of 1.0–2.0 mg/hr until the dysrhythmia is terminated, titrating the heart rate in an
adult to 80–100 beats per minute. In children, incremental doses of 0.01–0.1 mg/kg (maximum 1.0 mg) can
be administered. Esmolol may also be considered because of its short half-life and duration of action. In
adults, a loading dose of 500 µg/kg can be administered followed by an infusion of 25–100 µg/kg/min titrated
to cessation of dysrhythmia. In children, initial loading doses of 100–500 µg/kg given over 1 minute followed
by an infusion of 25–100 µg/kg/minute titrated to cessation of dysrhythmia may be tried. Hemodialysis and
hemoperfusion have been reported to remove TCE effectively and may be useful in cases of severe
poisoning or inadequate response to supportive care.[10]
Disposition
Any patient exhibiting mental status changes needs to be observed and monitored for cardiac dysrhythmias
for at least 24 hours and until symptoms clear. Asymptomatic patients with suspected ingestions can be
observed and monitored for 6–8 hours and released either to home or to psychiatric care if they remain
asymptomatic.
Sequelae
In addition to the sequelae that may follow any significant sedative-hypnotic exposure, esophageal stricture
has been reported following chloral hydrate overdose.[50]


ETHCHLORVYNOL
Essentials
• Prolonged, deep coma
• Prolonged apnea
• Pungent odor (vinyl or plastic)
• Noncardiogenic pulmonary edema
Introduction
Ethchlorvynol (ECV) was introduced in the mid-1950s as a sedative-hypnotic with a more rapid onset and
shorter duration of action than barbiturates. Like many sedative-hypnotic agents, it has significant addictive
potential and is a commonly abused street drug in some areas of the country. On the street, ECV is called
“pickles,” “jelly beans,” or “Mr. Green Jeans.” Despite the development of safer and more effective sedative-
hypnotic agents, ECV continues to be marketed as Placidyl. Its formulation as a red or green gelatin capsule
with liquid ethchlorvynol and polyethylene glycol diluent increases its potential for abuse by intravenous
injection.
Ethchlorvynol is structurally similar to chloral hydrate. The onset of action is 15–30 minutes, and duration of
action is 5 hours. It is highly lipid soluble and is distributed and stored in adipose tissue and brain. ECV
exhibits a biphasic pharmacokinetic pattern manifested by peak serum levels at 1 hour and again at 7–14
hours, with an elimination half-life of 10–25 hours. This second peak represents redistribution out of the
adipose tissue and is responsible for the prolonged effects seen in overdose, in which the elimination half-
life may be as long as 100 hours. Although the exact mechanisms have not been fully defined, ECV has
been shown to undergo biotransformation in the liver and is excreted in the urine and bile or by the lungs as
a volatile alcohol. ECV does not induce microsomal oxidation enzymes like most of the other sedative-
hypnotics, so its potential for pharmacokinetic interaction with other medications is limited. The exact
mechanism of its sedative effects has not been determined. Animal as well as human studies have
implicated a direct toxic effect of the drug on the alveolar capillary membrane as the cause of the
noncardiogenic pulmonary edema seen in overdoses.[20]
The clinical presentation of ECV toxicity depends on its route of administration.[45] The primary
characteristics of an oral overdose are depressed level of consciousness, hyporeflexia, hypotension, relative
bradycardia despite hypotension, and hypothermia. Prolonged, deep coma and marked respiratory
depression are distinguishing characteristics of severe ECV toxicity, lasting up to 17 days in some reports. A
distinctive pungent aromatic odor may be detected on the breath. Gastric fluid often has a pink or green
color depending on the capsule form. The intravenous abuse of ECV causes a mintlike taste in the mouth
followed by sudden onset of shortness of breath and dry cough. Central nervous system depression may
follow.[13] Noncardiogenic pulmonary edema is more commonly seen with intravenous ECV administration,
although it has been described in oral ECV overdoses as well. It presents clinically as respiratory distress,
rales, hypoxemia, and hypercarbia. Other reported rare toxicities of ECV include cholestatic jaundice,
blindness, hemolysis, pancytopenia, thrombocytopenia, and subepidermal bullae that contain ECV and that
are similar to those seen with barbiturate intoxication.[28] A withdrawal syndrome similar to that seen with
other sedative-hypnotic agents occurs following the chronic abuse of ECV.[54]
Prolonged deep coma, noncardiogenic pulmonary edema, and the distinctive odor of ECV may allow the
physician to distinguish the overdose with ECV from that with other sedative-hypnotic agents (see Tables
67–2 and 67–3 ).
Laboratory Studies
The utility of ethchlorvynol levels in the acute management of the overdose is limited because plasma
concentrations do not correlate well with clinical symptoms. Levels may be obtained for confirmation of the
diagnosis.
Treatment
If there is a history of a substantial ingestion of ECV, gastric lavage may be beneficial in removing the liquid
medication even several hours after ingestion because of delayed gastric motility. Activated charcoal should
be administered. Aggressive supportive treatment should be initiated. The use of positive end-expiratory
pressure (PEEP) in intubated patients may improve oxygenation and aid in the resolution of noncardiogenic
pulmonary edema. Continuous positive airway pressure (CPAP) or BiPAP (commercially available system)
can be used in nonintubated patients.
Hemodialysis, peritoneal dialysis, and charcoal and resin hemoperfusion have not been shown to shorten
the duration of coma or affect morbidity or mortality.[5] Their lack of efficacy is related to the very high volume
of distribution of ECV conferred by its high lipid solubility and to its protein binding.
Disposition
Any patient with severe CNS depression or pulmonary edema should be admitted to an intensive care unit
for close monitoring and supportive care. Other patients with significant symptoms that improve initially
should be observed for at least 24 hours because of the biphasic distribution of ECV.
Sequelae
Complications of ECV include those associated with hypoxemia and prolonged coma.
Specific Situations
Neonatal withdrawal following therapeutic ingestion of ECV during pregnancy has been reported. It is
characterized by jitteriness, irritability, and hunger within 24 hours after birth.[44]


GLUTETHIMIDE
Essentials
• Fluctuating, cyclic coma
• Sudden onset of apnea
• Hypotension
• Anticholinergic signs and symptoms
Introduction
Introduced in 1954, glutethimide (previously marketed as Doriden) is a sedative-hypnotic drug structurally

related to phenobarbital. Its popularity faded quickly as its serious toxicity became apparent. There was a
resurgence in glutethimide abuse in the early 1980s, when it was taken orally with codeine in fixed doses
known as “sets,” “hits,” or “loads.” “Hits” were popular with heroin users as an inexpensive, readily available
oral substitute for heroin that produced euphoria of longer duration. This combination of an opiate with a
sedative-hypnotic agent resulted in unexpected mortality attributed to the purity of the two drugs as well as to
their synergistic effects.[18] Glutethimide was withdrawn from the U.S. market in 1990.
The absorption of glutethimide from the intestine is highly variable and erratic because of its poor water
solubility. It has a rapid onset of action (within 20 minutes) and a long duration of action that is similar to
phenobarbital. Glutethimide is highly lipid soluble and is widely distributed in adipose tissue and the brain.
Like ethchlorvynol, glutethimide has a biphasic pharmacokinetic pattern with an initial elimination phase that
has a half-life of 4 hours and a second phase that has a half-life of 12 hours. This second phase is
responsible for its long elimination half-life and prolonged clinical symptoms in overdose. Glutethimide has
an active metabolite, 4-hydroxyglutethimide (4-HG), which has been shown to accumulate and even exceed
plasma concentrations of glutethimide in acute toxicity.[24] Although animal studies have demonstrated that
4-HG is a more potent CNS depressant than glutethimide, human studies have failed to show a consistent
correlation between this metabolite and severity of coma.[14][24] Glutethimide causes cyclical coma, the
etiology of which is probably multifactorial, related to release of glutethimide from lipid stores, enterohepatic
circulation of the parent drug, the presence of active metabolites, saturation of biotransformation pathways,
and delayed absorption from the GI tract. Glutethimide also possesses anticholinergic properties. The
biochemical and physiologic basis for its sedative actions are not known but are probably similar to the
action of phenobarbital on the GABAA receptor complex.
Glutethimide intoxication presents similarly to barbiturate intoxication with coma, hypotension, and
respiratory depression, although there are important differences.[11] Apnea may be sudden in onset. The
coma is prolonged and fluctuating. Mydriasis, dry mouth, urinary retention, paralytic ileus, tachycardia, and
mild hyperthermia may be seen because of the anticholinergic properties of glutethimide. Other reported
clinical symptoms include seizures, pulmonary edema, cerebral edema, and papilledema. A withdrawal
syndrome occurs in chronic abusers.
Distinguishing characteristics of glutethimide include its cyclical coma and accompanying anticholinergic
symptoms (see Tables 67–2 and 67–3 ).
Laboratory Studies
Blood levels of glutethimide will help confirm ingestion but have no predictive value, as they correlate poorly
with morbidity and the duration of coma. Toxicity has been reported with serum levels >10 mg/L.
Treatment
Good supportive care in an intensive care environment is the mainstay of treatment. Because of delayed
gastric emptying, gastric lavage may be beneficial in removing significant amounts of the drug up to 12
hours after ingestion. Activated charcoal should be administered. In the past, glutethimide’s high lipid
solubility led to recommendations of lavage and catharsis with castor oil.[3] This is of historical significance
and is no longer recommended. Numerous clinical studies failed to show any benefit of hemodialysis on the
duration of coma, number of complications, or mortality with serious glutethimide intoxication.[12][53]
Disposition
Patients with depressed mental status and/or any other abnormal vital sign should be monitored for 24
hours. Asymptomatic patients may be observed for 6–8 hours for development of signs and symptoms.
Sequelae
Pulmonary and neurologic sequelae secondary to hypoxemia, prolonged coma, and intubation may occur,
as with any serious sedative-hypnotic overdose. In one series, age less than 60 years was the only
statistically significant determinant of survival regardless of severity of coma, glutethimide dose,
concentration, or co-ingestion of barbiturates.[23]
Specific Situations
Neonatal withdrawal symptoms associated with glutethimide addiction in a pregnant female have been
reported and include anxiousness, hypertonicity, tremors, and relentless crying.[43] Glutethimide crosses the
placenta easily, with equivalent fetal and maternal blood concentrations.


MEPROBAMATE
Essentials
• CNS sedation, coma
• Relapse following recovery from coma
• Concretions of drug in stomach
• Profound hypotension
• Seizures
Introduction
Meprobamate is a nonbarbiturate sedative-hypnotic that was advertised in 1955 as the first “modern” major
tranquilizer that was safe and lacked the side effects seen with phenothiazines. In addition to its sedative
properties, it has anticonvulsant and muscle relaxant properties. Owing to its high abuse potential, it is no
longer routinely used in outpatient settings. It is currently marketed as Miltown, Equagesic, and Equanil.
Peak plasma concentrations of meprobamate occur within 1–2 hours following absorption from the GI tract.
The elimination half-life is approximately 11 hours. Unlike the other sedative-hypnotics previously discussed,
meprobamate does not concentrate in the brain and lipid tissues and has a low volume of distribution and
low protein binding. Meprobamate is a metabolite of the muscle relaxant carisoprodol. It is thought to exert a
selective action on the thalamus and to inhibit multineuronal spinal reflexes. The profound hypotension
reported in serious meprobamate overdoses is due to direct myocardial depression, decreased systemic
vascular resistance from arterial vasodilation, and generalized skeletal muscle relaxation with marked
reduction in muscular tone.[6] Relapse into coma following apparent recovery as well as prolonged coma has
been reported with this drug. It has the propensity to form bezoars in the stomach because of its low water
solubility, stability in gastric and intestinal fluids, and ability to decrease gut motility, properties that contribute
to delays in absorption.[47] Another proposed mechanism for coma relapse is that absorption is impeded by
decreased splanchnic blood flow during the initial period of hypotension. When splanchnic blood flow
improves following treatment of hypotension, residual enteric meprobamate is absorbed more effectively.[27]
Of all the nonbarbiturate sedative-hypnotics, meprobamate has been described as the one most likely to
produce euphoria, even in therapeutic doses. CNS symptoms following acute intoxication with meprobamate
range from ataxia, dysarthria, hallucinations, and confusion to lethargy, coma, and seizures.[2][33] Pulmonary
edema and respiratory depression have also been reported as well as cardiac dysrhythmias, tachycardia,
bradycardia, and bullous skin lesions. Profound and protracted hypotension has been reported with large
meprobamate ingestions.[6][16] In some cases the duration of coma following meprobamate overdose is
shorter than that seen in ethchlorvynol and glutethimide overdoses, especially if early decontamination is
undertaken. Other case reports describe patients who recover to full consciousness and then relapse into
coma.[27] The proposed mechanisms for coma relapse were discussed earlier.
In chronic meprobamate abusers, symptoms of withdrawal occur 12 to 48 hours following discontinuation of

the drug; they include anxiety, restlessness, insomnia, confusion, GI disturbances, and seizures.
Prolonged or fluctuating coma or coma of shorter duration may distinguish meprobamate from other
sedative-hypnotics (see Tables 67–2 and 67–3 ). Profound hypotension and seizures may also be seen.
Laboratory Studies
As with other sedative-hypnotics, serum meprobamate levels are not clinically useful because they do not
correlate with clinical symptoms owing to factors such as tolerance, co-ingested drugs, and body distribution.
Serum levels greater than 20 mg/dL have been associated with severe intoxication. Rising levels may
suggest continued absorption, which would mandate evaluation for retained drug concretions. Other
standard laboratory tests should be obtained, as with evaluation for other sedative-hypnotic drugs.
Treatment
Similar to all sedative-hypnotic overdoses, resuscitation and supportive care are most important.
Hypotension can be corrected with fluids, inotropes, and vasopressors with the aid of invasive hemodynamic
monitoring if clinically indicated.[16][31] Aggressive gastric decontamination should be undertaken in a
meprobamate overdose. Prolonged gastric lavage should be considered early, to facilitate mechanical
removal of pills before concretions form, and may be useful several hours after ingestion because of delayed
gastric motility. Multiple doses of activated charcoal (MDAC) may be beneficial because activated charcoal
retards further absorption of the drug, which may have already formed concretions, and interrupts
gastroenteric recycling of the drug.[25] These patients should be observed carefully for the development of
an ileus. Whole bowel irrigation in conjunction with charcoal may also facilitate drug movement through the
GI tract. If a patient fails to improve with these measures, gastroscopy and/or a barium contrast study should
be considered to search for a retained drug mass.[47] Surgical gastrotomy is rarely indicated. Because of the
low volume of distribution and low protein binding, hemodialysis, charcoal, resin hemoperfusion, and
continuous arteriovenous hemoperfusion have all demonstrated efficacy in enhancing elimination of
meprobamate. With current GI decontamination modalities and aggressive supportive care, these methods
are rarely indicated today.[32][33]
Disposition
Careful prolonged monitoring of the patient’s clinical course despite initial clinical improvement is essential
because of the potential for recurrent toxic manifestations. Patients with mild symptoms should be observed
for 12–24 hours for symptom progression.
Sequelae
There are no permanent sequelae except for consequences secondary to prolonged hypotension and
respiratory depression. Most meprobamate ingestions are not fatal with the exception of cases of massive
ingestions or delayed treatment.


METHAQUALONE
Essentials
• Coma
• Hyperreflexia
• Seizures
• Respiratory depression and hypotension rare
• Blood extravasation (purpura, retinal hemorrhages, GI bleeding)
Introduction
Methaqualone (previously marketed as Quaalude, Sopor) was the last nonbarbiturate sedative-hypnotic to
be released before the emergence of the benzodiazepines. Serious toxicity and abuse of Mandrax, a
combination of methaqualone and diphenhydramine, were reported from England and Australia just as
methaqualone was being released in the United States. Several years after its introduction in the United
States in 1965, methaqualone became one of the most popular sedative-hypnotics and drugs of abuse.
Abuse of methaqualone (“ludes”), which was glamorized by the media as a “love drug,” increased to the
proportions of a silent epidemic in the early 1970s among high school and college students. The use of
methaqualone declined in the mid-1970s but resurged in the late 1970s, coinciding with counterfeit street
production and illegal importation. The pattern of fatal methaqualone abuse changed from overdose in the
early 1970s to traumatic death in the 1980s.[51] The drug has been withdrawn from the market.
Methaqualone is an oxoquinazoline pharmacologically similar to the short- and intermediate-acting

barbiturates. It has a rapid onset of action (1 hour) and is rapidly distributed into peripheral fat stores with a
half-life of 2–6 hours. Like glutethimide and ethchlorvynol, methaqualone has a biphasic elimination pattern
with a slow terminal elimination half-life (ranging from 20–50 hours) that is prolonged in overdose.
Methaqualone is extensively metabolized in the liver, with one metabolite believed to be a more potent CNS
depressant than the parent compound.[40]
Methaqualone selectively depresses polysynaptic spinal reflexes, resulting in increased muscle tone and
motor activity. This hyperactivity is in contrast to the other sedative-hypnotics, which characteristically
depress muscle tone and reflexes. The incidence of hypotension is less than occurs with other sedative-
hypnotics. It results from direct effects on myocardial contractility. Methaqualone inhibits platelet
aggregation, prolongs prothrombin and partial thromboplastin times, and decreases factors V and VII, all of
which predispose to hemorrhage.[38]
In the setting of overdose, CNS toxicity may produce symptoms ranging from lethargy, ataxia, slurred
speech, and agitation to seizures and coma. Serious methaqualone toxicity can produce muscular
hyperactivity manifest as increased tone, clonus, and myoclonus. These symptoms are unique among the
sedative-hypnotics.[41] “Coma with myoclonus” has been a characteristic description. Hallucinations, painful
hyperacusis, blurred vision, variation in pupillary diameter and reaction, and paresthesia have also been
reported.[26][41] Some of these symptoms may be due to the anticholinergic effects of diphenhydramine in
the combination drug Mandrax rather than to pure methaqualone toxicity.[36] Agitation and excitation may
precede lethargy and coma. Hypotension and respiratory depression occur less commonly and are usually
associated with co-ingested CNS depressants such as ethanol. Conjunctival, retinal, and GI hemorrhages
attributed to the effects on coagulation have been reported. [48]
“Ludes” were abused for their euphoric effects, which were accompanied by acroparesthesias and followed
by a relaxed, somnolent state (sometimes described as a “downer-high”).[26]“Luding out” (methaqualone with
ethanol) led to a rampant increase in abuse and addiction. Withdrawal symptoms occur 3–5 days after
cessation of the drug and include GI distress, headaches, anxiety, anorexia, disturbed sleep patterns,
tremor, and occasionally seizures.
Intraventricular or pontine hemorrhage or extensive injury to the upper part of the brainstem may also
present with varying combinations of coma, paralysis, muscular rigidity, seizures, and pupillary abnormalities
(see Tables 67–2 and 67–3 ). The myoclonus, seizures, and depressed consciousness of methaqualone
toxicity may also suggest organophosphate poisoning if accompanied by salivation, lacrimation, and
bradycardia.
Laboratory Studies
Methaqualone levels have limited prognostic value. Toxic levels are in the range of 10–30 µg/mL. Complete
blood count with platelet count, coagulation studies (PT/PTT), and creatine phosphokinase (monitoring for
rhabdomyolysis) should be included in the standard laboratory tests. If the diagnosis is unclear, a head CT
or magnetic resonance imaging (MRI) scan should be performed to exclude a CNS structural lesion.
Treatment
After initial resuscitation, activated charcoal should be administered for acute toxicity. Owing to decreased
GI motility, charcoal may be beneficial several hours after reported acute ingestion. Increased muscular
tonicity, myoclonic spasms, and seizures can be treated with diazepam and may necessitate paralysis with
electroencephalographic monitoring to prevent rhabdomyolysis and hyperthermia.[1] Administration of
platelets, fresh frozen plasma, and vitamin K may be indicated for uncontrolled bleeding. Hemoperfusion
and hemodialysis have been reported to increase clearance of methaqualone but do not alter the clinical
outcome.
Disposition
All patients with depressed consciousness and muscular hypertonicity should be admitted and monitored for
at least 24 hours or until symptoms resolve. Asymptomatic patients can be observed for 2–4 hours. Those
with mild symptoms require no decontamination and may be observed until symptoms resolve.
Sequelae
Untreated protracted myoclonus and hypertonicity may cause rhabdomyolysis and renal insufficiency.
Retinal hemorrhages usually resolve in 6 weeks without visual loss.


ZOLPIDEM
Essentials
• Somnolence
• Stable vital signs
• Symptoms reversed by flumazenil
Introduction
Zolpidem (Ambien) is a non-benzodiazepine hypnotic introduced in the United States in 1993. It has a fast
onset of action and short half-life in addition to reportedly fewer “hangover” effects and less rebound
insomnia than benzodiazepine sleep agents. The potential for tolerance, dependence, and withdrawal
appears to be relatively small. There are very few reports of zolpidem overdose, and thus far the drug has
been shown to be relative safe. Serious morbidity has been described only when zolpidem has been co-
ingested with other CNS or respiratory depressant drugs.
Zolpidem is an imidazopyridine, which is chemically different from benzodiazepines. It binds selectively to

type I (omega) central benzodiazepine receptors, which confers a narrow spectrum of clinical activity; its
binding is enhanced in the presence of GABA. It has no anxiolytic or muscle relaxant properties. Zolpidem
has a rapid onset of action, within 30 minutes–1 hour after ingestion, and a short half-life of 2–2½ hours.
Metabolites are inactive. Zolpidem is not lipophilic and is rapidly distributed into and out of the CNS,
accounting for its short duration of action.
Acute toxicity secondary to zolpidem ingestion is usually benign and presents as drowsiness and
dizziness.[19][29] Hypotonia, blurred vision, mydriasis, gait disturbances, memory impairment, and
hallucinations have also been reported. Deep coma, respiratory depression, and hypotension have been
reported only in mixed ingestions that include other CNS depressants, such as alcohol and
phenothiazines.[30][52]
Zolpidem toxicity is less severe than other sedative-hypnotic toxicity. Mild lethargy may be the only
presenting symptom, and this resolves within several hours unless there is a co-ingestant (see Tables 67–2
and 67–3 ).
Laboratory Studies
Zolpidem levels are not clinically useful for the evaluation or management of an overdose. No specific
laboratory studies are needed unless clinically indicated.
Treatment
Activated charcoal should be administered to prevent further absorption. Because of zolpidem’s relatively
low potential for toxicity, gastric lavage is not indicated except in cases of mixed ingestions of potentially
lethal compounds that may benefit from gastric evacuation. Flumazenil has been shown to reverse the CNS
and respiratory depression.[30][39] Because zolpidem toxicity is rarely serious, only supportive care with
monitoring of vital signs and oxygen saturation will be needed in most cases.
Disposition
Patients with known or suspected zolpidem ingestions can usually be observed for 6–8 hours or until
symptoms resolve. Toxicity from pure ingestions rarely dictates intensive care monitoring or continuous
cardiac monitoring.
Sequelae
There are no serious sequelae from pure zolpidem toxicity, as the clinical course is usually benign.


OTHERS
Buspirone (BuSpar) is an azaspiraodecanedione, a new non-benzodiazepine sedative used primarily for

treatment of anxiety and for obsessive-compulsive disorder. It antagonizes serotonin activity. There are a
limited number of reported human overdoses. Acute buspirone toxicity is mild, drowsiness being the most
common reported symptom.[21] Observation and monitoring of vital signs are the only necessary treatment.
Methprylon (Noludar) was another nonbarbiturate sedative-hypnotic introduced in the mid-1950s. The
product was not prescribed with great frequency and is no longer available in the United States. Signs and
symptoms of toxicity are similar to those for barbiturates and include ataxia, nystagmus, lethargy, coma,
hypotension, hypothermia, and pulmonary edema. There is no specific treatment.


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and glutethimide. Am J Epidemiol 1984; 119:202.
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20. Glauser FL, Smith WR, Caldwell A, et al: Ethchlorvynol (Placidyl)–induced pulmonary edema. Ann
Intern Med 1976; 84:46.
21. Goetz CM, Krenzelok EP, Lopez G, et al: Buspirone toxicity: A prospective study. [Abstract]. Vet Hum
Toxicol 1989; 31:371.
22. Graham SR, Day RO, Lee R, et al: Overdose with chloral hydrate: A pharmacological and therapeutic
review. Med J Aust 1988; 149:686.
23. Greenblatt DJ, Allen MD, Harmatz JS, et al: Correlates of outcome following acute glutethimide
overdosage. J Forensic Sci 1979; 24:76.
24. Hansen AR, Kennedy KA, Ambre JJ, et al: Glutethimide poisoning: A metabolite contributes to morbidity
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25. Hassan E: Treatment of meprobamate overdose with repeated oral doses of activated charcoal. Ann
Emerg Med 1986; 15:73.
26. Inaba DS, Gay GR, Newmeyer JA, et al: Methaqualone abuse: “Luding out.”. JAMA 1973; 224:1505.
27. Jenis EH, Payne RJ, Goldbaum LR: Acute meprobamate poisoning: A fatal case following a lucid
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28. Klock JC: Hemolysis and pancytopenia in ethchlorvynol overdose. Ann Intern Med 1974; 81:131.
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32. Lin JL, Lim PS, Lai BC, et al: Continuous arteriovenous hemoperfusion in meprobamate poisoning. J
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34. Maes V, Huyghens L, Dekeyser J, et al: Acute and chronic intoxication with carbromal preparations.
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patients. Br Med J 1968; 2:101.
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Dermatologica 1978; 156:111.
38. Mills DG: Effects of methaqualone on blood platelet function. Clin Pharmacol Ther 1978; 23:685.
39. Naef MM, Forster A, Nahory BS, et al: Flumazenil antagonizes the sedative action of zolpidem, a new
imidazopyridine hypnotic. [Abstract]. Anesthesiology 1989; 71:A298.
40. Oram M, Wilson K, Burnett D, et al: Metabolic oxidation of methaqualone in extensive and poor
metabolizers of debrisoquine. Eur J Clin Pharmacol 1982; 23:147.
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42. Peoples RW, Weight FF: Trichloroethanol potentiation of gamma-aminobutyric acid–activated chloride
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43. Reveri M, Pyati SP, Pildes RS: Neonatal withdrawal symptoms associated with glutethimide (Doriden)
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44. Rumack BH, Walravens PA: Neonatal withdrawal following maternal ingestion of ethchlorvynol
(Placidyl). Pediatrics 1973; 52:714.
45. Schottstaedt MW, Nicotra MB, Rivera M: Placidyl abuse: A dimorphic picture. Crit Care
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47. Sellers EM, Lang M, Koch-Wesser J, et al: Interaction of chloral hydrate and ethanol in man. I.
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48. Trese M: Retinal hemorrhage caused by overdose of methaqualone (Quaalude). Am J

49. Trump DL, Hochberg MC: Bromide intoxication. Johns Hopkins Med J 1976; 138:119.
50. Veller ID, Richardson JP, Doyle JC, et al: Gastric necrosis: A rare complication of chloral hydrate
intoxication. Br J Surg 1971; 59:317.
51. Wetli CV: Changing patterns of methaqualone abuse: A survey of 246 fatalities. JAMA 1983; 249:621.
52. Winek CL, Wahba WW, Janssen JK, et al: Acute overdose of zolpidem. Forensic Sci
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Engl J Med 1976; 295:1177.


Chapter 68 – Barbiturates
NICOLA SCHIEBEL INGRID VICAS
Essentials
• Central nervous system (CNS) sedation—common
• Hypothermia
• Respiratory depression and hypotension in severe cases
• Bullous skin lesions in rare cases
INTRODUCTION
Because of their potential toxicity, barbiturates have largely been supplanted by benzodiazepines as the
most frequently prescribed sedative-hypnotics. They nevertheless remain widely available and continue to
be used therapeutically for seizure control and general anesthesia, as well as for sedative-hypnotic effects.
Current mortality rates from severe overdoses admitted to intensive care settings remain at 6 per cent. [44]
Early deaths are due to respiratory and cardiovascular arrest, whereas delayed deaths are due to acute
renal failure, pneumonia, pulmonary edema, and cerebral edema.[1][20]


Pharmacology
Barbiturates are reversible general depressants of nerve and muscle tissues. Although their biochemical
mechanism of action is not completely understood, potentiation of -aminobutyric acid–mediated chloride
ion conduction seems to play a significant role in some of their effects.[36][39] Barbiturates are traditionally
classified as long, intermediate, short, and ultra-short acting based on the duration of action of a single dose
in rabbits ( Table 68–1 ).[40] However, this separation of barbiturates seems poorly supported in human
pharmacokinetics, particularly in the overdose setting. Because the duration of action varies with dose, rate
of absorption, and rate of distribution and elimination, this classification may be misleading and should not
be used to predict clinical course in overdose.[40]
Table 68-1 -- Common Barbiturates[14]

Ultrashort-Acting
Thiopental
Methohexital
Thiamylal
Short-Acting
Pentobarbital
Secobarbital
Butalbital
Hexobarbital
Intermediate-Acting
Amobarbital
Aprobarbital
Butabarbital
Long-Acting
Phenobarbital
Mephobarbital
Barbital
Metharbital
Primidone
This classification, however, does have some value in predicting the physicochemical properties of
barbiturates. The shorter-acting agents are highly lipid soluble and rapidly penetrate the CNS. This tends to
induce toxicity more rapidly and at lower concentrations than with longer-acting barbiturates.[37][40] In
addition, the shorter-acting barbiturates are more highly protein bound and have a higher pKa and a larger
volume of distribution than their longer-acting counterparts.[37] The shorter-acting agents, therefore, have a
greater dependence on hepatic metabolism for excretion. Long-acting agents are metabolized more slowly
by the liver, with a greater fraction of unchanged drug excreted by the kidney. These factors likely explain
why methods to enhance renal elimination work most effectively for a long-acting agent such as
phenobarbital. There is also evidence that phenobarbital undergoes enterohepatic recirculation, perhaps
explaining its favorable response to treatment with multiple-dose activated charcoal.[32][35]
Pathophysiology
The CNS is particularly sensitive to the effects of barbiturates, with depressant effects demonstrable at blood
levels well below those affecting the cardiovascular system. CNS effects include anticonvulsant, anesthetic,
anxiolytic, and sedative-hypnotic actions. The reticular activating system and the cerebellum appear to be
the most susceptible to barbiturate effects.[37] In particular, the hypoxic drive for respiration is exquisitely
sensitive to barbiturates, and doses only three times greater than the usual hypnotic dose have been shown
to depress respiratory drive. [21]
Cardiovascular effects include vasodilation of peripheral capacitance vessels, a negative inotropic effect on
the heart, and decreased sympathetic output from the CNS.[13][14][41][43] In hypnotic or respiratory depressant
doses the barbiturates produce only minor cardiovascular effects. At several times the respiratory
depressant dose, these cardiovascular depressive effects can become significant. In practice, however, the
commonly observed hypotension with large barbiturate ingestions results primarily from an absolute fluid
deficit (due to inadequate intake) as well as a relative hypovolemia due to increased venous capacitance. [41]
The pathophysiology underlying the other clinical effects of barbiturate overdose is not well defined. The
hypothermia frequently associated with barbiturate overdose is likely multifactorial. However, it does appear
to include some direct effect on central temperature regulation, because hypothermia has been noted at
anesthetic doses in a rodent model.[39] The bullous skin lesions that can be associated with barbiturate
coma demonstrate a characteristic pattern of eccrine sweat duct necrosis.[12] Mechanisms such as direct
cutaneous toxicity, immunologic causes, or local anoxia exacerbated by shock and uninterrupted pressure
on dependent regions of the body have all been suggested as possible causes.[3][12] Delayed complications
of acute renal failure, pneumonia, pulmonary edema, and cerebral edema result largely from secondary
insults. Hypotension, depth of coma, and excess fluid administration have all been implicated as risk
factors.[19][37]


The signs and symptoms of acute barbiturate poisoning reflect the profound CNS and cardiovascular effects
( Table 68–2 ). Typical features include impaired consciousness, respiratory depression, hypotension, and
hypothermia.[30] Mild to moderate intoxication may resemble ethanol intoxication with initial manifestations of
slurred speech, ataxia, lethargy, nystagmus, incoordination, headache, and confusion. Patients with severe
intoxication present with progressive CNS depression, followed by respiratory and circulatory failure.[17][38] It
is important to recognize that the severity of all these effects is exacerbated by the co-ingestion of ethanol or
other sedative-hypnotic agents. Hypoglycemia can also contribute to the CNS depression in a severe
overdose.[31]
Table 68-2 -- Clinical Presentation of Barbiturate Toxicity

Altered CNS/PNS signs
Slurred speech
Ataxia
Nystagmus
Lethargy
Incoordination
Decreased level of consciousness
Depressed or absent deep tendon reflexes
Depressed or absent brainstem reflexes
Hypotension
Hypothermia
Bullous skin lesions
CNS, Central nervous system; PNS, peripheral nervous system.
Ocular examination may reveal constricted pupils early on, followed by dilated pupils later in the course of
the overdose. Brainstem reflexes and deep tendon reflexes are depressed or absent, and the Babinski sign
is often positive. The presence of focal neurologic signs in the setting of barbiturate poisoning has also been
described.[8] This is an unusual presentation, however, and other causes such as coexisting head trauma or
hypoglycemia must be considered in the differential diagnosis. In severe coma, the electroencephalogram is
isoelectric but does not indicate irreversible damage, and the patient may recover without sequelae.[42] The
absence of ocular microtremor has been suggested as an objective indication of brain death. However, this
may be unreliable in the setting of barbiturate overdose, given that a case report exists of a barbiturate
overdose showing a virtually flat ocular microtremor record that gradually improved as the patient’s coma
lightened.[10]
Patients acutely poisoned with barbiturates can demonstrate low cardiac output, arterial hypotension,
prolonged circulation time, normal central venous pressure, and normal or increased peripheral arterial
resistance.[41] Hypoxia and acidosis can further potentiate the existing myocardial depression as well as
precipitate dysrhythmias. Clinically significant pulmonary edema can also occur.[19]
Hypothermia ranging from 30°C to 36°C is a frequent finding.[31] Although this may be a primary result of the
barbiturate, other factors such as concurrent cold exposure, sepsis, or hypoglycemia in a comatose patient
should always be considered.
Bullous skin lesions have been reported in up to 6 per cent of cases.[6] These skin lesions are usually
located on dependent portions of the body and between the fingers, knees, and ankles. Although these self-
limited lesions are most commonly associated with barbiturate overdose, they are not specific and can occur
in coma due to other drugs or CNS disease.[3]


The differential diagnosis of barbiturate toxicity includes any potential cause for a depressed level of
consciousness ( Table 68–3 ). In addition to structural and medical causes for coma, toxicologic causes
must always be considered. It is important to recognize that barbiturate overdose can present with many
features of an opioid overdose, including pinpoint pupils, respiratory depression, and altered mental status.
The depth of a barbiturate coma may also be so deep that a patient can lose all reflexes and meet criteria for
brain death.[26][42] As stated earlier, the presence of bullous skin lesions, although rare, may indicate the
possibility of barbiturate overdose. Other causes of these lesions are listed in Table 68–4 .
Table 68-3 -- Differential Diagnosis: Depressed Level of Consciousness

Structural Causes
Intracranial hemorrhage (spontaneous or trauma)
Tumor
Cerebral edema
Medical Causes
Hypoglycemia
Hypoxia
Renal/liver failure
Postictal state
Central nervous system infection/sepsis
Environmental hypothermia
Hypothyroidism
Vasculitis
Acquired immunodeficiency syndrome
Toxicologic Causes
Central Nervous System Depressants
Sedative-hypnotics
Antidepressants
Anticholinergics
Antihistamines
Ethanol/other alcohols and glycols
Opioids
Clonidine
Neuroleptics
Cellular Toxins
Carbon monoxide
Cyanide
Hydrogen sulfide
Other Mechanisms
Salicylates
Lithium
Hypoglycemic agents
Asphyxiant gases
Sedative-hypnotic drug withdrawal
Table 68-4 -- Differential Diagnosis of Coma Blisters

Medications Associated with Coma and Blisters
Acetylcarbromal
Amitriptyline
Barbiturates
Carbon monoxide
Ethchlorvynol
Glutethimide
Heroin
Hydrocodone bitartrate
Imipramine
Meprobamate
Methadone
Methaqualone
Morphine
Nitrazepam
Phenobarbital
Neurologic Disorders Associated with Blisters Demonstrating Sweat Gland Necrosis
Cerebrovascular accidents
Ependymoma
Glioblastoma
Head trauma
Syringomyelia
Viral encephalitis
Adapted from Dunn C, Held JL, Spitz J, et al: Coma blisters: Report and review. Cutis 1990; 45:423–426.


LABORATORY STUDIES
Initial laboratory studies should be focused to exclude other common metabolic and toxicologic causes of a
depressed level of consciousness. These should include electrolytes with calculation of anion gap, blood
glucose, blood urea nitrogen, creatinine, arterial blood gases with measured oxygen saturation, and
consideration of specific quantitative levels of other suspected toxins or co-ingestants (e.g., acetaminophen,
salicylates, ethanol). Urine drug screens can be used to qualitatively detect the presence of barbiturates. As
with any screening test, however, the predictive value of the test will depend on the pretest probability of
barbiturates being present, as well as the sensitivity and specificity of the test procedure involved. Given that
these three parameters are frequently not well defined in any given case, caution must be exercised in the
interpretation of such screens. Positive screens should be confirmed by quantitative methods, and the
possibility of false-negative results must always be considered. It is also important to recognize that the
simple presence of barbiturates on a screening test does not preclude the possibility of other causes for the
patient’s clinical presentation. A urine screen for barbiturates, then, should be ordered only when the
management of the patient will be significantly affected by the result.
Specific quantitative levels are of limited clinical value in the overdose setting. In general, higher levels are
associated with more severe toxicity.[20] However, absolute levels are not reliable prognostic indicators in the
individual patient. This may be partly due to the development of tolerance in chronic abusers, may result
from the delayed onset of pharmacologic effects in the overdose setting, or may be related to the clinical and
pharmacologic effects of co-ingestants.[33][40] Single quantitative levels, however, may be helpful to confirm
or rule out the presence of a suspected barbiturate overdose. In addition, blood levels of greater than 35
µg/mL for short-acting barbiturates or greater than 80 to 90 µg/mL for long-acting barbiturates are
considered to be predictive of a potentially grave prognosis.[17][28][33] Serial blood levels may also be helpful
in determining whether continued absorption is occurring, given that delayed gastric emptying and
absorption are often associated with significant overdose.[40]


TREATMENT
The most significant advances in reducing mortality from barbiturate poisoning came in the 1960s with the
realization that prolonged hypoxia and hypotension were the main determinants of poor outcome. [9] Before
this time management principles stressed the use of CNS stimulants (analeptics) and mortality rates were
estimated to be about 20 per cent.[9] However, with aggressive life support measures instead of analeptics
as the mainstay of therapy, the reported mortality rates for all cases dropped to levels less than 2 per cent.[9]
Currently, management strategies fall into three major areas: supportive care, decontamination, and
enhancement of elimination ( Table 68–5 ).

Basic Supportive Care
Coma ± respiratory depression • Ensure adequate oxygenation, ventilation, and airway protection
• Fluid challenge with intravenous crystalloid (isotonic)
• Intravenous vasopressors as required:
Hypotension
Dopamine, 5–20 µg/kg/min
Epinephrine, 1 µg/min (titrate to effect)
• Prevent further heat loss:
Hypothermia: body temperature Insulation (e.g., blankets)

>32°C Warm intravenous fluids
Heated humidified oxygen if intubated
Hypothermia: body temperature • Consider aggressive active core rewarming techniques

<32°C • Consider cardiopulmonary bypass in cardiac arrest
• Aggressive management of sepsis
Pneumonia
• Adequate antibiotic coverage
Coma blisters • Local wound care to prevent secondary infection
Decontamination
• Adult, 50–100 g
Activated charcoal
• Pediatric, 1 g/kg
Gastric lavage • Consider if massive ingestion
Elimination
• Reduces elimination half-life of phenobarbital (no evidence to show that it
Repeated-dose charcoal improves outcome)
• 15–20 g (0.25 g/kg) q4–6 hr
Alkalinization of urine • See text
• May be indicated for intractable hypotension
Hemoperfusion
• Most effective for long-acting barbiturates
Supportive Care
The mainstay of therapy is optimal supportive care, with treatment interventions aimed at specific problems
as they develop. The most common clinical problem is coma with or without respiratory depression. The
priority in management, therefore, must focus on providing adequate oxygenation, ventilation, and airway
protection. Respiratory rate may be an inadequate measure of ventilatory status because the respiratory
pattern in deep barbiturate coma is usually characterized by a high frequency of respiration but low tidal
volumes, leading to an overall low minute ventilation.[18] In the comatose patient, then, arterial blood gases
and oxygen saturation monitoring become mandatory.
Careful hemodynamic monitoring for significant hypotension should occur. Initial management includes
intravenous crystalloids, either 0.9 per cent saline or Ringer’s lactate, at 10 to 20 mL/kg. Pulmonary edema
can result in significant morbidity and mortality, and volume overload should be avoided. In severe refractory
hypotension, invasive central venous pressure or pulmonary capillary wedge pressure monitoring may be
required. The use of vasopressors such as dopamine, epinephrine, or norepinephrine should be considered
after optimal crystalloid therapy. Selection of specific agents should depend on patient response, because
no data exist as to which agent is optimal.
Although hypothermia is a frequent associated finding in barbiturate overdose, core temperatures do not
usually fall below 32°C. At this level, prevention of further heat loss is all that is required. Insulating the
patient with blankets and using warm intravenously administered fluids and heated humidified oxygen
accomplishes this goal.[17] If the core temperature drops below 32°C, however, the patient is at increased
risk for cardiac dysrhythmias and aggressive active core rewarming may be required.[11] Techniques such as
warm peritoneal lavage or extracorporeal rewarming techniques should be employed, particularly if the
temperature continues to drop. Detailed methods outlining these different techniques and their indications
are extensively reviewed elsewhere[11] and in Chapter 27 . If cardiac arrest occurs in this setting the use of
cardiopulmonary bypass might be considered if available.
Coma blisters can be treated with local wound care and dressings. The lesions usually heal with no
scarring.[12]
Pneumonia is a major secondary cause of morbidity and mortality in barbiturate overdose.[19] Careful
monitoring for the presence of pneumonia and early, aggressive management of pulmonary infection and
sepsis are mandatory.
Decontamination
Most barbiturates are well adsorbed by activated charcoal. Therefore, an initial dose (1 g/kg) should be
administered orally or by nasogastric tube.[22] Often a cathartic such as sorbitol or magnesium sulfate is
administered to prevent constipation and facilitate more rapid passage of the charcoal through the
gastrointestinal tract, although the clinical efficacy of this treatment remains unproven. Barbiturates slow
intestinal motility. Although there is no conclusive evidence to support the use of gastric lavage, it may
remove significant quantities of drug even several hours after the overdose.[28][33][37]
Elimination
Multiple doses of activated charcoal (MDAC) have been shown to enhance the nonrenal clearance of
intravenous phenobarbital in healthy volunteers.[4][15] They have also been shown to significantly reduce the
serum half-life of phenobarbital in overdose.[35] In this small clinical trial, however, no definite improvement
in clinical outcome or reduction in requirement for mechanical ventilation could be demonstrated. Because
the risks of MDAC are minimal in patients with normal intestinal motility, the use of repeated doses of
charcoal to enhance elimination in severe overdose is a reasonable treatment option. The recommended
adult dose is 15 to 20 g given orally every 4 to 6 hours. A single case report suggests that MDAC may also
be safe and effective in the pediatric population. [2] A dose of 1 g/kg initially followed by 0.25 g/kg every 4 to 6
hours is recommended. Administration of repeated doses of cathartic can be associated with significant
diarrhea and fluid loss and therefore should be avoided as a routine order. Small doses of cathartic (e.g.,
sorbitol, 0.2 to 0.5 g/kg) may be given as required to prevent constipation.
Alkalinization of urine to a pH greater than 7.5 to 8.0 has been shown to enhance elimination of
phenobarbital (but not other barbiturates) independent of urine flow rate.[7][15] The risks of this procedure
include hypokalemia, tetany, and potentially dangerous elevations in arterial pH. Pulmonary edema can also
occur if excess fluid is administered in the process.[17] No evidence exists to show that this enhanced
elimination improves patient outcome. It has also never been demonstrated that patient prognosis is directly
related to the serum barbiturate level. The use and indications for urinary alkalinization, therefore, remain
controversial. It seems reasonable, however, that if the risks of the procedure can be minimized, enhancing
the elimination rate might shorten duration of coma in severe phenobarbital overdose. Alkalinization can be
accomplished with an initial sodium bicarbonate bolus of 1 mEq/kg followed by a constant infusion. This
infusion is made by adding 100 to 150 mEq of sodium bicarbonate to 850 mL of dextrose 5 per cent in water
and titrating to maintain a urine pH of greater than 7.5 with an arterial pH less than 7.50. An initial flow rate
of 150 to 250 mL/hr is a reasonable starting point, but this rate must be reassessed hourly to avoid potential
excess fluid or bicarbonate administration.
Forced diuresis, previously recommended to enhance the urinary elimination of many barbiturates,[7][29] is
fraught with significant problems, including pulmonary edema.[19] Therefore, in the absence of randomized
clinical trials showing a benefit to patient outcome, its use must be discouraged.
Extracorporeal elimination is rarely indicated in barbiturate overdoses. No controlled studies exist

demonstrating a benefit on patient outcome. The only evidence available relies on plasma clearance rates,
elimination half-life, total drug removal, and case reports of outcomes in treated cases. [16][25][27][34] Existing
data suggest hemoperfusion is preferable to hemodialysis in terms of absolute clearance rates obtained.[27]
Long-acting barbiturates with small volumes of distribution and slow intrinsic elimination rates demonstrate
the best clearance rates and total drug removal.[34] Indeed, cases of phenobarbital toxicity are those most
frequently reported as benefiting from hemoperfusion.[24][25][27][34] Short- and intermediate-acting
barbiturates have a larger volume of distribution, shorter intrinsic elimination rates, and less affinity for the
adsorbent surfaces of the hemoperfusion cartridges. As a result, data on clearance show less impressive
drug removal and case series do not note consistently dramatic improvements in level of coma.[27][34]
Because the majority of patients do well with supportive care alone and blood levels do not correlate with
length of coma or patient outcome, routine extracorporeal drug removal is not recommended.[9] Patients who
might benefit from hemoperfusion include those who remain unstable despite aggressive supportive care.
Rising blood levels in an unstable patient who has been adequately decontaminated would further support
the use of hemoperfusion.


DISPOSITION
All patients with a depressed level of consciousness require close monitoring of respiratory, CNS, and
hemodynamic status. Patients with a significant barbiturate overdose can require extended periods of
intensive supportive care. Because of scant data on the pharmacokinetics of barbiturates in overdose, the
decision on the disposition of the minimally symptomatic or asymptomatic patient is often a dilemma. The
amount of ingestion, time of ingestion, co-ingestants, and underlying medical conditions must all be taken
into account when determining periods of observation required. Serial blood levels may help to ensure levels
are not rising when a question as to appropriateness of discharge arises.
Once the acute effects and secondary complications have resolved, psychiatric assessment is required for
all intentional ingestions.


SEQUELAE
Secondary insults to the brain, lungs, and kidney are the main sequelae that result from barbiturate
intoxication. Pulmonary infection, pulmonary edema, anoxic brain injury, and acute ischemic renal failure
have all been identified as major contributing factors to morbidity and mortality.[19][37] Case reports of
pulmonary embolism,[45] brachial plexus injuries,[23] and acute intestinal ischemia[5] illustrate that
complications secondary to prolonged immobility are also potential complications. Recognition, anticipation,
and prevention of potential complications, therefore, becomes an important aspect of the aggressive
supportive care required in severe overdose cases.


REFERENCES
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infant. J Emerg Med 1990; 8:449-450.
3. Arndt KA, Mihm MC, Parrish JA: Bullae: A cutaneous sign of a variety of neurologic diseases. J Invest
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4. Berg MJ, Berlinger WG, Goldberg MJ, et al: Acceleration of the body clearance of phenobarbital by oral
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7. Bloomer HA: A critical evaluation of diuresis in the treatment of barbiturate intoxication. J Lab Clin
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15. Frenia ML, Schauben JL, Wears RL, et al: Multiple-dose activated charcoal compared to urinary
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17. Gary NE, Tresznewsky O: Barbiturates and a potpourri of other sedatives, hypnotics and tranquilizers.
Heart Lung 1983; 12:122-126.
18. Gauthier H, Offenstadt G, Kaczmarek R, et al: Pattern of respiration in patients recovering from
barbiturate overdose. Br J Anaesth 1982; 54:1041-1045.
19. Goodman JM, Bischel MD, Wagers PW, Barbour BH: Barbiturate intoxication: Morbidity and mortality.
West J Med 1976; 124:179-186.
20. Greenblatt DJ, Allen MD, Harnatz JS, et al: Overdosage with pentobarbital and secobarbital:
Assessment of factors related to outcome. J Clin Pharmacol 1979; 19:758-768.
21. Harris EA, Slawson KB: The respiratory effects of therapeutic doses of cyclobarbitone, triclofos and
ethchlorvynol. Br J Pharmacol 1965; 24:214-222.
22. Hayden JW, Comstock EG: Use of activated charcoal in acute poisoning. Clin Toxicol 1975; 8:515.
23. Hsu JD: Brachial plexus injury following barbiturate overdose: Report of three cases with five-year
follow-up. J Bone Joint Surg [Am] 1979; 61:1252-1253.
24. Iversen BM, Willassen Y, Bakke OM, et al: Assessment of barbiturate removal by charcoal
hemoperfusion in overdose cases. Clin Toxicol 1979; 15:139-149.
25. Jacobsen D, Wiik-Larsen E, Dahl T, et al: Pharmacokinetic evaluation of hemoperfusion in

phenobarbital poisoning. Eur J Clin Pharmacol 1984; 26:109-112.
26. Kaufman HH, Lynn J: Brain death. Neurosurgery 1986; 19:850-856.
27. Koffler A, Bernstein M, LaSette A, et al: Fixed-bed charcoal hemoperfusion—Treatment of drug

overdose. Arch Intern Med 1978; 138:1691-1694.
28. Lindberg MC, Cunningham A, Lindberg NH: Acute phenobarbital intoxication. South Med
J 1992; 85:803-807.
29. Linton AL, Luke RG, Briggs JD: Methods of forced diuresis and its application in barbiturate poisoning.
Lancet 1967; 2:377-379.
30. Matthew H, Lawson AAH: Acute barbiturate poisoning—a review of two years experience. Q J
Med 1966; 35:539-552.
31. McCarron MM, Schultze BW, Waldberg CB, et al: Short-acting barbiturate overdosage.
JAMA 1982; 248:55-61.
carbamazepine and phenylbutazone in man. Eur J Pharmacol Ther 1980; 6:823-827.
33. Osborn H, Goldfrank LR: Sedative-hypnotic agents. In: Goldfrank LR, Flomenbaum NE, et
al ed. Toxicologic Emergencies, . 5th ed. Norwalk, CT: Appleton & Lange; 1994:787-804.
34. Pond S, Rosenberg J, Benowitz NL, et al: Pharmacokinetics of haemoperfusion for drug overdose. Clin
35. Pond SM, Olson KR, Osterloh JD, Tong TG: Randomized study of the treatment of phenobarbital
overdose with repeated doses of activated charcoal. JAMA 1984; 251:3104-3108.
36. Rabow LE, Russek SJ, Farb DH: From ion currents to genomic analysis: Recent advances in GABA
receptor research. Synapse 1995; 21:189-274.
37. Rall TW: Hypnotics and sedatives. In: Gilman AG, Rall TW, Nies AS, Taylor P, ed. Goodman and
Gilman’s The Pharmacological Basis of Therapeutics, . 8th ed. New York: Pergamon; 1990:345-382.
38. Reed CE, Driggs MF, Foote CC, et al: Acute barbiturate intoxication. Ann Intern Med 1952; 37:290-
300.
39. Richter JA, Holtman JR: Barbiturates: Their in vivo effects and potential biochemical mechanisms.
Prog Neurol 1982; 18:275-319.
40. Rosenberg J, Benowitz NL, Pond S: Pharmacokinetics of drug overdose. Clin

41. Shubin H, Weil MH: The mechanism of shock following suicidal doses of barbiturates, narcotics, and
tranquilizer drugs, with observations on the effect of treatment. Am J Med 1965; 38:853-863.
42. Silverman D, Saunders MG, Schwab , et al: Cerebral death and the electroencephalogram.
JAMA 1969; 209:1505-1510.
43. Skovsted P, Price ML, Price HL: The effects of short-acting barbiturates on arterial pressure,
preganglionic sympathetic activity and barostatic reflexes. Anesthesiology 1970; 33:10-18.
44. Strom J, Thisted B, Krantz T, et al: Self-poisoning treated in an ICU: Drug pattern, acute mortality and
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45. Toscano J, Kussin PS, Samuelson W, et al: Pulmonary embolism complicating barbiturate overdose.
Crit Care Med 1990; 18:777-778.


Chapter 69 – Benzodiazepines
SUSAN E. FARRELL
Essentials
• Central nervous system (CNS) depression: confusion, drowsiness, sedation, lethargy, stupor, low-grade
coma without focal neurologic abnormalities.
• Diminished psychomotor skills: decreased reaction times, slowed voluntary movements, motor
retardation, hypotonia.
• Anterograde amnesia and short-term memory impairment.
• Cognitive impairment, dysarthria, ataxia, incoordination.
• Mild cardiovascular and respiratory depressant effects secondary to CNS depression.
INTRODUCTION
Since their introduction in the 1960s, benzodiazepines have become the most widely prescribed group of
psychoactive drugs in therapeutic use. Introduced in 1963, diazepam is the most commercially successful
drug of this class. Unlike older sedative-hypnotics, such as the barbiturates, chloral hydrate, glutethimide,
and meprobamate, the benzodiazepines have a very high therapeutic index and their safety has enhanced
their medical and psychiatric use.[42]
Benzodiazepines are beneficial for the treatment of anxiety, insomnia, phobias, and panic disorder
syndromes.[18][19] Benzodiazepines have been used during the acute manic phase of bipolar disorder,[1] as
adjunctive therapy in chronic pain syndromes,[8] for “jet lag,”[35] for neuroleptic-induced dystonias,[38] and in
the management of muscle rigidity or spasm secondary to neuromuscular diseases and neuroleptic
malignant syndrome. These drugs are the first line of therapy in the management of cocaine intoxication,
sedative-hypnotic drug and ethanol withdrawal, and the control of agitation and muscle hyperactivity due to
other sympathomimetics. Finally, benzodiazepines have an important role in rapid sequence intubation,
conscious sedation, and the acute control of seizures.
Because of their widespread availability, benzodiazepines are subject to misuse, often as a secondary drug
to diminish the unpleasant symptoms of stimulants or hallucinogens, or to self-treat withdrawal symptoms
after the cessation of other depressant agents. Though their addictive potential is less than that of opioids,
cocaine, or ethanol, benzodiazepines do induce physiologic tolerance and withdrawal symptoms on
subsequent drug discontinuation. Benzodiazepines are common ingestants or co-ingestants in overdoses.


PHARMACOLOGY
To some degree, all benzodiazepines have anxiolytic, muscle relaxant, sedative-hypnotic, amnestic, and
anticonvulsant properties. They are less likely to induce significant respiratory depression or cardiovascular
instability compared to many sedative-hypnotics, unless used with other CNS depressants. The potency and
specificity of individual agents vary for each of the above-mentioned effects and account for the choice of
certain benzodiazepines for specific disease states. For example, triazolam and temazepam are commonly
used as hypnotic agents, alprazolam and lorazepam as anxiolytics, and clonazepam as a long-term
antiepileptic.
Benzodiazepines also vary in rapidity of onset and duration of action, dependent on lipid solubility and the
presence of active metabolites, respectively. The more lipid-soluble the agent, the more rapidly it crosses
the blood-brain barrier and exerts its CNS depressant effect. Conversely, highly lipid-soluble agents also
redistribute from the CNS to less well-perfused organs more rapidly, terminating their central effect. For
example, midazolam has a more rapid onset of action than diazepam, which acts more rapidly than
lorazepam. However, the duration of effect in the CNS is more prolonged for lorazepam because it
redistributes more slowly than diazepam or midazolam. Duration of action may also be prolonged
independent of the parent drug because of active metabolites, which are more slowly biotransformed. For
example, flurazepam exerts a CNS depressant effect that is prolonged owing to its active metabolite, N -
desalkylflurazepam. For these reasons, the duration of action of a benzodiazepine may not be related to the
terminal elimination half-life of the individual drug. See Table 69–1 for a general overview of the
benzodiazepines.
Table 69-1 -- Benzodiazepine Comparison

Alprazolam
PO
9–15
Hydroxyalprazolam
0.25 mg
Antidepressant, anxiolytic, antipanic
Clorazepate
PO
50–80
N -Desmethyldiazepam
3.75 mg
Anticonvulsant, anxiolytic
Chlordiazepoxide
PO, IV, IM
5–15
Desmethylchlordiazepoxide, oxazepam
25 mg
Anxiolytic
Clonazepam
PO
24–56
None
2 mg
Anticonvulsant, antipanic
Diazepam
PO, IV, IM
30–60
Desmethyldiazepam, oxazepam
5 mg
Muscle relaxant, preanesthetic, anxiolytic, anticonvulsant
Daytime drowsiness
Flurazepam
PO
50–100
N -Hydroxyethylflurazepam, N -Desalkylflurazepam
15 mg
Daytime drowsiness
Lorazepam
PO, IV, IM
10–20
None
1 mg
Hypnotic, preanesthetic, anxiolytic, continuous sedation
Memory impairment, rebound insomnia
Midazolam
IV, IM
1.5–2.5
1-Methylhydroxymidazolam
2.5 mg
Preanesthetic, continuous sedation
Oxazepam
PO
5–10
None
30 mg
Anxiolytic
Temazepam
PO
7–17
Oxazepam
(N/A)
Triazolam
PO
2–4
1-Methylhydroxytriazolam
0.5 mg
Hypnotic
Memory impairment, early AM awakening
Route of Half-Life Active Diazepam 5 mg Special Adverse
Benzodiazepine
Administration (hr) Metabolites Equivalent Uses Effects
Benzodiazepines are organic bases, consisting of a benzene ring fused to a seven-member diazepine ring.
Substitutions at various sites on this ring confer variable potency to a particular agent.[34 ] The effects of
these drugs are primarily due to their potentiation of -aminobutyric acid (GABA), a major inhibitory
neurotransmitter in the CNS.
GABA receptors are located throughout the CNS in the basal ganglia, hippocampus, cerebellum,
hypothalamus, and spinal cord.[11 ] GABA is believed to be involved in sleep induction, inhibition of
neuroexcitation, modulation of anxiety, and memory formation. When it binds to its postsynaptic receptor,
GABA facilitates the opening of chloride ion channels, allowing influx of chloride into the neuronal cell, thus
hyperpolarizing the membrane potential and preventing or limiting the cell’s response to excitatory stimuli.
Benzodiazepines bind to a receptor that is adjacent to the GABA receptor. The benzodiazepine-GABA
pharmacophore is a complex of heterogeneous receptor subunits that have been isolated and termed alpha,
beta, gamma, delta, and rho subunits.[17 ] These subunits are arranged in various combinations, which
confer more or less sensitivity and specificity of a receptor to individual benzodiazepine agents, depending
on the location of a particular receptor within the CNS.
The most well characterized receptor combination consists of alpha, gamma, and beta subunits. When a
benzodiazepine binds to its receptor site at the alpha-gamma subunit interface, it causes a conformational
change in the receptor complex, enhancing the binding of GABA to its own receptor site on the beta subunit.
Benzodiazepines potentiate GABA’s inhibitory effect by facilitating GABA binding and increasing the
frequency of chloride ion channel opening, further hyperpolarizing the cell. It is important to note that the
depressant effect of benzodiazepines is due to their interaction at this pharmacophore in conjunction with
GABA. If the GABA concentration in the brain is not sufficient to allow GABA binding to its receptor site, the
overall depressant effect of benzodiazepines is greatly limited. The pharmacologic profile of a particular
benzodiazepine depends on the heterogeneity of the benzodiazepine-GABA receptor complex at which it is
acting (especially that of the alpha subunit), and its location in the CNS.
In summary, the depressant effects of benzodiazepines are due to their potentiation of GABA inhibitory
activity, clinically manifested as impaired psychomotor skills, cognitive dysfunction, short-term memory
impairment, sedation, and low-grade coma. Tolerance to the CNS effects of benzodiazepines occurs over
days to weeks, and has been hypothesized to occur over periods as short as hours. Acute tolerance,
particularly to the sedative effects, may be due in part to the down-regulation of GABA-benzodiazepine
receptor sensitivity. With chronic use, tolerance to the sedative and anticonvulsant effects arises from the
down-regulation of both GABA-benzodiazepine receptor sensitivity and receptor synthesis.


The hallmark of acute benzodiazepine intoxication is sedation. CNS depression may range from mild
drowsiness to lethargy to low-grade coma. Minimal cardiorespiratory instability is generally the rule.
Despite their marked safety profile, some degree of morbidity has been reported in relation to
benzodiazepine overdose. In one review of 702 patients[16] admitted to an intensive care unit (ICU) with
benzodiazepine overdose, patients with pure benzodiazepine overdose did not differ from those with mixed
benzodiazepine overdose in the degree of coma or the length of ICU stay. However, patients with pure
benzodiazepine overdose experienced hypotension less frequently and required airway intubation less often.
The most common complication was aspiration pneumonia. Only two deaths in this series could be
attributed primarily to benzodiazepines, and they resulted from fatal respiratory compromise and circulatory
arrest. In general, deaths related to benzodiazepine overdose are very rare, but if benzodiazepines are
ingested in combination with ethanol or other sedative-hypnotic agents, especially in the elderly or in
patients with chronic obstructive pulmonary disease, the outcome may be fatal ( Table 69–2 ). Respiratory
and cardiac arrest and hypotension are uncommon events that have also been reported after intravenous
administration, usually in the setting of excessively rapid injection,[13] and especially in patients with pre-
existing pulmonary or cardiac dysfunction.
Table 69-2 -- Clinical Presentation of Benzodiazepine Toxicity

Central
Nervous Neuromuscular Cardiovascular Respiratory Gastrointestinal
System
Mild depression in heart
Slowed voluntary
Drowsiness rate and blood pressure Mild respiratory depression Nausea
movements
possible
Nystagmus Ataxia may be more pronounced Vomiting
after IV administration
Dysarthria Hypotonia Diarrhea
Incontinence (all
Sedation
rare)
Impaired
cognition
Delirium
Low-grade
coma
Rare cyclic
coma
Central
Nervous Neuromuscular Cardiovascular Respiratory Gastrointestinal
System
Anterograde
amnesia
The physical examination is characterized by sedation without the presence of a classic toxicologic
syndrome. The skin is neither very dry nor diaphoretic. Pupils are generally midposition and reactive.
Nystagmus and disconjugate gaze may be present. Bowel sounds are usually present, but may be slightly
diminished, and muscle tone tends to be decreased. The presence of a toxidrome should alert the examiner
to other potential co-ingestants.
Rare, paradoxical “excitatory” effects of certain benzodiazepines have been reported, particularly with
triazolam. In the 1970s and 1980s, adverse reactions occurring in elderly patients who used this drug were
described as “dysinhibition” or “dyscontrol” reactions, characterized by unusual behavior such as hostility,
rage, and aggression.[21][39] Further evaluation and subsequent reports have determined that unusual
responses to triazolam or other benzodiazepines are probably related to the unmasking of a pre-existing
psychopathologic disorder and pretreatment aggression and hostility.[31] These reactions, while interesting,
are not at all prototypic for the usual clinical presentation of benzodiazepine overdose (see Table 69–2 ).
The clinical presentation of chronic benzodiazepine use is similar to that for acute intoxication, although it is
less severe in nature. Of note are studies that have investigated cognitive defects and memory acquisition
impairment in patients with long-term, chronic use of these sedatives.[46] These effects may not be
reversible, even after discontinuation of the drug. Animal studies of fetal exposure to benzodiazepines are
investigating the role of benzodiazepines in chronic interactions with GABA, particularly in regard to the
development of certain areas of the brain.[41][47]


Benzodiazepines used alone do not cause profound coma, respiratory depression, or cardiovascular
depression or instability when compared to other drug-induced causes of depressed CNS function. In
addition, seizures and toxicologic syndromes are not part of the clinical picture of pure benzodiazepine
overdose ( Table 69–3 ).
Table 69-3 -- Differential Diagnosis of Benzodiazepine Toxicity

Benzodiazepines
Pupils midposition, sedation to low-grade coma
Minimal CV depression
Minimal respiratory depression
N/A
Barbiturates
Miosis (inconsistent), lethargy to profound coma
Myocardial depression, hypotension
Respiratory depression, apnea
N/A
Hypoglycemia, hypothermia, skin bullae
Chloral hydrate
Miosis, sedation
Myocardial sensitization to catecholamines; atrial and ventricular dysrhythmias, hypotension
GI irritation, nausea, vomiting, abdominal pain, hemorrhagic gastritis, perforation
Radiopaque tablets, hepatotoxicity, nephrotoxicity
Meprobamate
Euphoria, sedation
Hypotension, dysrhythmias
Respiratory depression, pulmonary edema
GI concretions possible
Glutethimide
Mydriasis, prolonged or cyclic coma, psychosis, seizures possible
CV depression at high doses
Respiratory depression, apnea, excess bronchial secretions
Diminished bowel sounds
Anticholinergic properties, thermoregulatory dysfunction, skin bullae
Ethchlorvynol
Prolonged coma
Bradycardia, hypotension
Respiratory depression, noncardiogenic pulmonary edema
N/A
“Vinyl” odor, hypothermia, skin bullae possible
Opioids
Miosis, depression and coma; tremors, seizures with normeperidine and norpropoxyphene
Bradycardia, hypotension; dysrhythmias with norpropoxyphene
Depression, hypoventilation, noncardiogenic pulmonary edema
Vomiting, abdominal colic with withdrawal
Hypothermia, synthetics require high dose naloxone, adulterants, HIV risk with IVDA
Mydriasis (inconsistent), agitation to lethargy, coma, seizures
Tachycardia, conduction defects, hypotension
Hypoventilation, pulmonary edema
Anticholinergic properties
Neuroleptics
Miosis/midposition/or mydriasis, sedation, delirium, coma, seizures
Orthostatic hypotension, tachycardia, conduction defects, ventricular dysrhythmias
Mild respiratory depression, pulmonary edema
Anticholinergic properties, thermoregulatory dysfunction, movement disorders, some agents radiopaque
Ethanol
Pupils midposition, initial euphoria, loss of inhibition; then sedation, incoordination, coma
Myocardial depression, bradycardia, dysrhythmias rare; hypotension
Respiratory depression at high doses
GI distress, vomiting, incontinence at high doses
Hypothermia, hypoglycemia, hepatotoxicity, malnutrition
Hypoglycemia
Pupils midposition or mydriasis, anxiety, tremulousness, irritability, delirium, coma, seizures
Tachycardia
Deep, heavy respirations; apnea
Dry mouth, nausea initially
Hypothermia, diaphoresis, focal neurologic abnormalities reported
IVDA, intravenous drug abuse.
Agent Central Nervous System Cardiovascular Respiratory Gastrointestinal Other


LABORATORY STUDIES
Initial laboratory studies to assess toxicity include rapid serum glucose, pulse oximetry, and arterial blood
gas measurements. Benzodiazepines do not cause significant acid-base or electrolyte abnormalities, but
hypoglycemia as a cause of CNS depression should be ruled out, and adequacy of oxygenation and
ventilation must be assessed. Plasma concentrations of individual benzodiazepine agents correlate poorly
with the severity of CNS depression. Quantitative analysis of benzodiazepines is not rapidly available at
most hospitals, and is of no significant benefit when making therapeutic decisions about patients with acute
benzodiazepine overdose.[42] For example, the toxic level for diazepam is reported to be 5–20 µg/mL,
although patients with serum concentrations within this range often display minimal clinical effects.
Treatment should be guided by the history and physical examination of the intoxicated patient, and by any
necessary laboratory measurements based on the clinical status of the patient during observation.
Qualitative screening of urine samples with rapid assays that determine the presence of benzodiazepines or
their metabolites is available in most hospitals. These immunoassays employ radioimmunoassay or
fluorescence polarization technology, usually standardized to detect oxazepam and benzodiazepines with a
similar structure that cross-react immunologically with oxazepam. False-negative assays do occur,
especially with lorazepam or the metabolites of clonazepam, alprazolam, or triazolam.[9][30][48] False-positive
results have been reported when the metabolites of certain nonsteroidal anti-inflammatory drugs (oxaprozin,
etodolac, fenoprofen calcium, naproxen sodium, tolmetin sodium) are present in the urine.[5][25][33] Because
the acute care of patients with benzodiazepine intoxication is primarily supportive, the initial evaluation,
diagnosis, and treatment should be based largely on physical examination and history. Laboratory assays
for these sedative-hypnotics are not routinely necessary when the diagnosis is known or suspected. In cases
of depressed consciousness of unknown cause, a positive urine screening test for benzodiazepines may
confirm a previously unknown diagnosis.
Chest radiography should be performed if hypoxia or aspiration is suspected. Computed tomography (CT) of
the head and a lumbar puncture should be considered if intracranial hemorrhage or infection is suspected.


TREATMENT
The mainstay of general treatment for benzodiazepine overdose consists of supportive therapy, with
attention to the adequacy of airway, breathing, and circulatory status. Respiratory support and mechanical
ventilation should be provided as necessary. Gastrointestinal decontamination with one dose of activated
charcoal (1 g/kg), is sufficient. Because benzodiazepines are commonly ingested with other drugs, the
patient should be monitored for the development of toxicity from other more dangerous agents. Other
causes of CNS depression should be sought, such as coexisting medical, surgical, or traumatic
emergencies, including hypoglycemia, carbon monoxide poisoning, cerebrovascular accident, CNS
infections, and head trauma.
Toxin-specific treatment for benzodiazepine toxicity consists of flumazenil, a specific benzodiazepine

antagonist. Flumazenil is a 1,4-imidazobenzodiazepine that competitively binds at the benzodiazepine
receptor, displacing a benzodiazepine from the site and reversing its potentiation of GABA effects in the
CNS.[7][23][26] This antagonist is very lipid-soluble and crosses the blood-brain barrier quickly after
intravenous administration, reversing benzodiazepine-induced sedation within 1 to 2 minutes. It also
reverses the anxiolytic, anesthetic, muscle relaxant, and anticonvulsant effects of benzodiazepines. Partial
antagonism has been reported to occur after the use of flumazenil. These reports involve mixed ingestions
of CNS depressant drugs or inadequate dosing of flumazenil.[6] Finally, respiratory depression secondary to
potent benzodiazepines may be incompletely reversed by flumazenil. In these cases, improvement in
respiratory status is likely due to the improvement in patient alertness, while alveolar hypoventilation
persists. Therefore, the use of flumazenil does not preclude the necessity of airway observation and support.
As a specific benzodiazepine antagonist, flumazenil has 100 per cent efficacy in the reversal of
benzodiazepine-induced CNS depression. Its utility in the setting of benzodiazepine-induced anesthesia and
sedation in short procedure units and intensive care units is accepted. However, the use of flumazenil in the
setting of coma of unclear etiology or in the case of mixed drug ingestion has met with some debate.
The most consequential adverse effect of flumazenil administration is the induction of seizures, with the
potential for cardiovascular compromise.[24] Reports of such events are uncommon and have often involved
the use of flumazenil in patients with mixed ingestions, particularly cyclic antidepressants.
In 1991, animal and human studies evaluating the efficacy and safety of flumazenil, and case reports of
adverse events, were reviewed.[10] Of 750 patients from 30 studies, the most frequently noted adverse
effects were anxiety, agitation, nausea, sweating, and shivering. Five patients experienced seizures after
receiving large bolus injections of flumazenil. Three of the five had taken large overdoses of tricyclic
antidepressants. Of 497 patients in one study, eight serious events occurred in seven patients, including six
seizures and two EKG abnormalities. Six of the seven patients had taken cyclic antidepressants, had a
history of seizure disorder, or had the presence of jerking movements prior to the administration of
flumazenil. A 1992 study evaluated patients who had experienced seizures temporally related to the
administration of flumazenil. [43] Seizures occurred most commonly in patients who had ingested
epileptogenic agents, particularly cyclic antidepressants. Seizures were also reported in patients taking
benzodiazepines therapeutically as anticonvulsants, in patients with chronic use of benzodiazepines who
developed withdrawal after flumazenil administration, and in patients with medically induced seizures that
were being suppressed by benzodiazepines.
In an attempt to develop clinical guidelines for the safe and effective use of flumazenil in suspected
benzodiazepine overdose, Gueye et al created criteria to classify patients as low-risk and non-low-risk,
based on patient history, physical examination, and EKG abnormalities.[14] They retrospectively reviewed 35
cases of suspected overdose in which flumazenil was administered. Despite a limited number of patients
who met all of the criteria for low risk, these criteria would have successfully excluded all patients who
experienced adverse events after flumazenil.
The dose of flumazenil is 0.5–5 mg in adults, and 0.005–0.2 mg/kg in children, infused over 3–5 minutes.
Incremental dosing in small, titrated amounts of 0.05–0.1 mg infused slowly over several minutes may
produce adequate arousal and reverse respiratory depression, while limiting the risk of adverse events and
obviating the need for a larger dose. The half-life of flumazenil is 57 minutes, and resedation commonly
occurs after single doses. Flumazenil may be given by constant intravenous infusion at a rate of 0.1–0.3
mg/kg/hour. Continuous infusion of flumazenil has been reported to be beneficial in cases of small children
with significant benzodiazepine-induced CNS and respiratory depression.[45]
In summary, flumazenil is an antidote that reverses the CNS and respiratory depressant effects of
benzodiazepines. Its use may avert airway intubation, and when used as an infusion, it may maintain
arousal, while limiting airway compromise. Although the situation has not been studied, in the proper setting,
the use of flumazenil could potentially shorten ICU stay. In selected patients who are at low risk for adverse
events after administration of flumazenil, its use may assist in the diagnosis of coma of unclear etiology.
However, the use of flumazenil should not replace appropriate primary supportive care of the poisoned
comatose patient. In the presence of hypoxia, hypotension, and dysrhythmias, flumazenil is contraindicated.
Adverse events associated with flumazenil occur commonly in patients who have ingested proconvulsant
agents, particularly cyclic antidepressants. Flumazenil should not be used in patients with a history of such
an ingestion, or those with evidence of abnormal neurologic findings, including myoclonic jerking, or in those
with altered vital signs or EKG conduction abnormalities. In these patient populations, flumazenil is
contraindicated, as the risk of seizures outweighs the potential benefit. Other side effects of flumazenil
include dizziness, flushing, anxiety, and headache. Increased intracranial pressure (ICP) has been reported
to occur in head-injured patients who receive flumazenil, and the presence of elevated ICP is another
contraindication to flumazenil administration. Finally, excessively large doses and overly rapid infusion of
flumazenil increase the risk of adverse side effects ( Table 69–4 ).
Table 69-4 -- Treatment of Benzodiazepine Toxicity

1. Airway
Suction
Check gag reflex
Evaluate posterior tongue displacement
Intubate if necessary
2. Breathing
Determine hypoventilation, hypercarbia
Assess oxygenation
Assess possible aspiration
Intubation with mechanical ventilation if necessary
3. Circulation
Assess volume depletion or vasodilation
Fluid and dopamine if necessary
4. Other
Assess hypoglycemia
Activated charcoal
Assess other causes of coma
5. Flumazenil
Indications: history of benzodiazepine overdose
Contraindications: (a) history of seizures, (b) chronic use of benzodiazepine and potential for withdrawal, (c)
suspected co-ingestion of epileptogenic agent, e.g., cyclic antidepressant, phenothiazine, cocaine
Dose:
Adults: slowly titrate up to 0.5–5 mg
Children: slowly titrate to 0.005–0.2 mg/kg


DISPOSITION
Owing to the acute tolerance of the benzodiazepine receptor to the drug effect, and the redistribution from
the CNS to the peripheral compartment, the termination of clinical effects and subsequent improvement in
arousal and awakening occur within 12 to 36 hours in most patients.[12] Coma may be prolonged in elderly
patients because of age-related changes in benzodiazepine pharmacokinetics, including increased volume
of distribution and decreased hepatic clearance of certain benzodiazepines, such as diazepam and
chlordiazepoxide.
In studies of pure benzodiazepine ingestion, hospital admission is rarely, if ever, required.[3][37] After
administration of activated charcoal and a 4- to 6-hour period of observation, most patients may be safely
discharged if they are cleared psychiatrically. Patients with persistent or profound CNS depression,
cardiovascular or respiratory compromise, or a history of taking co-ingestants having potential delayed
significant toxicity should be admitted to the appropriate hospital setting. Patients who receive flumazenil
should be observed for at least 2 to 4 hours for recurrent sedation. Patients who are discharged from the
emergency department may follow up with their primary care provider or psychiatrist.


SEQUELAE
Once the patient has been medically cleared, the sequelae following acute benzodiazepine ingestion are not
common nor are they serious. Patients may experience apathy, depression, and motor retardation for
several hours after acute ingestion. Sequelae after long-term use of benzodiazepines are the subject of
study, as persistent cognitive defects, impaired delayed recall, and learning abnormalities have been
reported. Persistent deficiencies in verbal memory, learning, and psychomotor abilities have been reported,
especially in elderly patients who have been detoxified from benzodiazepines.[40]


SPECIAL SITUATIONS: BENZODIAZEPINE WITHDRAWAL
Physiologic dependence on benzodiazepines does occur and is characterized by increasing drug doses
necessary to achieve the same pharmacologic effect and the presence of withdrawal symptoms on
decreasing or discontinuing the drug. Tolerance to benzodiazepines develops rapidly as a result of down-
regulation of benzodiazepine-GABA receptors, probably because of decreased receptor synthesis during
chronic administration.[22][27] In the United Kingdom, 15 to 33 per cent of patients reported experiencing
benzodiazepine withdrawal symptoms when decreasing their dose.[50] Risk of dependence is related to the
use of high-potency benzodiazepines, prolonged duration of high-dose use, previous drug use, and
personality predisposition to dependence.[15] However, physiologic dependence may also occur after
prolonged use (greater than 3 months) of benzodiazepines at appropriate and therapeutic doses.
The onset and severity of benzodiazepine withdrawal symptoms are dependent on the potency and half-life
of the individual agent. Symptoms may occur after overly rapid dose tapering or abrupt discontinuation.
Withdrawal symptoms due to long-acting benzodiazepines, such as diazepam, tend to appear in 3 to 7 days
after the last dose, and may persist for weeks. [32][49] Short-acting benzodiazepines lose their pharmacologic
effect more rapidly, and withdrawal symptoms may occur within 24 hours after the last dose. Compared to
that of their long-acting counterparts, abrupt withdrawal from short-acting benzodiazepines tends to be more
severe, but less prolonged.[4][29][42]
Clinically, the syndrome of benzodiazepine withdrawal is similar to that of ethanol or other sedative-hypnotic
withdrawal. Symptoms are referable to neuronal excitation unopposed by benzodiazepine-enhanced GABA
tone. Anxiety, apprehension, insomnia, agitation, psychosis, tremor, nausea, vomiting, diaphoresis, fever,
seizures, and death have been reported.[2][20][36] Additional symptoms include restlessness, myalgias,
paresthesias, hyperacusis, and tinnitus.
Treatment of benzodiazepine withdrawal consists of reinstitution of long-acting benzodiazepines, such as

diazepam, and gradual tapering of the dose over several weeks under the supervision of a physician.[44]
Patients presenting to an emergency department with acute withdrawal after benzodiazepine discontinuation
should be loaded with diazepam intravenously in doses sufficient to ameliorate the unpleasant symptoms
and prevent seizures. In cases of severe agitation, 20 mg/hour or greater may be required. These patients
should be admitted to a monitored setting until stabilized and ready to begin a gradual taper.
Benzodiazepine tapering should be instituted with a long-acting agent, such as diazepam. Diazepam should
be substituted for the patient’s current benzodiazepine at an equivalent dose, and then tapered gradually
over 6–8 weeks. Withdrawal and benzodiazepine detoxification may be managed on an outpatient basis, but
require patient motivation and behavioral therapy for dependence syndromes. Fetal exposure to
benzodiazepines can induce fetal tolerance and neonatal withdrawal similar to that of neonatal opiate
withdrawal, characterized by irritability, tremors, increased muscle tone, tachypnea, and vomiting.[44]
Treatment of neonatal benzodiazepine withdrawal may be accomplished with barbiturates.


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15. Higgit AC, Lader MH, Fonagy P: Clinical management of benzodiazepine dependence.
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17. Hollister LE: Benzodiazepines—An overview. Br J Clin Pharmacol 1981; 11:117S.
18. Jefferson JW: Social phobia: A pharmacologic treatment overview. J Clin Psychiatry 1995; 56(suppl
5):18.
19. Johnson MR, Lydiard RB, Ballenger JC: Panic disorder pathophysiology and drug treatment.
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20. Lader M, Peturrson H: Long-term effects of benzodiazepines. Neuropharmacology 1983; 22:527.
21. Laux G, Puryear D: Benzodiazepine—Misuse, abuse and dependency. Am Fam

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22. Livingston MG: Benzodiazepine dependence. Br J Hosp Med 1994; 51(6):281.
23. Longmire AW, Seger DL: Topics in clinical pharmacology: Flumazenil, a benzodiazepine antagonist.
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24. Marchant B, Wray R, Leach A, Nama M: Flumazenil causing convulsions and ventricular tachycardia.
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42. Sellers EM: Anxiolytics, hypnotics, and sedatives. New York, Oxford University Press, 1985.
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48. Weddington WW, Carney AC: Alprazolam abuse during methadone maintenance therapy [Letter].
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49. Woods JH, Winger G: Current benzodiazepine issues. Psychopharmacology 1995; 118:107.
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Chapter 70 – Withdrawal Syndromes
CALVIN CHIANG PAUL M. WAX
Essentials
• Clinically well-defined withdrawal syndromes are associated with abstinence that follows chronic use of
sedative hypnotics and opiates.
• Less well-defined abstinence syndromes are associated with withdrawal from caffeine, nicotine, and
cocaine.
• Sedative hypnotic withdrawal is characterized by sympathetic stimulation (tachycardia, hypertension,
tremors, mydriasis, and diaphoresis) that may progress to seizures and delirium.
• Opioid withdrawal is characterized by nausea and vomiting, diarrhea, yawning, lacrimation, rhinorrhea,
piloerection, and mydriasis. It is not associated with seizures, fever, or altered mental status.
INTRODUCTION
Withdrawal syndromes can be a vexing clinical problem for the emergency physician. Difficulties arise in
diagnosing the withdrawal syndrome. Many patients will deny significant ethanol and opioid use. Patients
withdrawing from ethanol may present with significant alterations in mental status, either from the withdrawal
syndrome or due to other comorbid conditions, that prohibit the elucidation of ethanol use. Additionally,
patients suffering from the effects of withdrawal may present with a spectrum of signs and symptoms that
may be confused with other illnesses. However, a high index of clinical suspicion, urgent and appropriate
treatment, and close observation will prevent most of the serious complications associated with withdrawal
syndromes.
Withdrawal syndromes are most commonly seen in patients who use ethanol, sedative-hypnotic agents, or
opioids on a chronic basis. The most severe withdrawal symptoms are usually associated with ethanol and
other sedative-hypnotic agents. Withdrawal from these sedative agents can produce life-threatening
problems. The withdrawal syndrome associated with opioid abstinence is generally not life-threatening. The
severity of a withdrawal syndrome is affected by multiple factors, including the particular agent or agents that
have been abused, the length of abuse, and the length of time since the last use of such agents.
Additionally, it is not uncommon for a complicating illness to cause a reduction in substance use and thus
trigger a withdrawal syndrome. Ethanol-related gastritis, pancreatitis, or head trauma will lead to a reduction
in ethanol intake. Various medical and surgical illnesses—such as pneumonia, myocardial infarction, injury
due to motor vehicle accidents or falls, and surgical emergencies—may lead to hospitalization, decreased
intake, and withdrawal.


DRUG CLASSES
Sedative-Hypnotic Drugs
Ethanol Withdrawal
The earliest known mention of ethanol has been dated to Babylonian times. Ethanol has been used for
medicinal, social, and religious purposes. Alcoholic beverages are usually initially created by the
fermentation of sugars found in grains and fruits by yeast. The concentration of ethanol is often augmented
by distillation. Ethanol is frequently abused with a high cost to society.[3]
Delirium tremens, the most severe form of ethanol withdrawal, was described as early as 1813 by Thomas
Sutton. However, ethanol abstinence and withdrawal symptoms were not associated with one another until
the 1950s with the work of Victor and Adams[73] and confirmed by Isbell et al.[36] Since that time, the ethanol
withdrawal syndrome has become a well-defined clinical syndrome.
Ethanol is an odorless, colorless liquid at room temperature. Absorption of ethanol through the
gastrointestinal tract is rapid, reaching peak levels 30–90 minutes after ingestion, although complete
absorption may take up to 6 hours. [26] Complete absorption may be delayed by several factors, including
amount of liquid and food ingested and gastric motility.[33] Certain medications such as cimetidine increase
blood ethanol concentrations.[61]
Ethanol is oxidized by alcohol dehydrogenase into acetaldehyde, which is subsequently converted to acetate
by aldehyde dehydrogenase. Most ethanol oxidation is performed by hepatic alcohol dehydrogenase;
however, gastric alcohol dehydrogenase has been shown to be very important in the first-pass metabolism
of ethanol, and inhibition of gastric alcohol dehydrogenase will increase blood ethanol concentration.[61] With
chronic use, ethanol induces the cytochrome P-450 hepatic microsomal enzyme system, which can produce
highly toxic metabolites and free radicals. These metabolites further contribute to the toxic effects of
ethanol.[41]
Pathophysiology
The precise etiology for ethanol withdrawal is unknown. Several mechanisms have been postulated. One
current hypothesis was derived from observations regarding the severe sympathetic overdrive state seen in
this disorder. Ethanol withdrawal is characterized by intense autonomic stimulation and is associated with a
significant release of norepinephrine in the central nervous system. Many of the withdrawal symptoms may
be due to excess catecholamines that result in part from a compensatory mechanism that develops with
chronic ethanol use. Normally, presynaptic a2-adrenergic receptors function by inhibiting the release of
norepinephrine. Diminished sensitivity of these receptors may be responsible for the increased
catecholamines found in ethanol withdrawal.[42] The effectiveness of clonidine in controlling some of the
symptoms supports this hypothesis.[6] Additionally, these compensatory mechanisms are normally
counteracted by the depressant effects of ethanol. Withdrawal of these depressant effects may result in
unopposed sympathetic stimulation.
A second theory invokes the apparent decrease in GABA activity found in chronic ethanol abusers.[1] GABA
is an inhibitory neurotransmitter that is modulated by benzodiazepines. Ethanol enhances GABA’s inhibitory
effect by interacting with the GABAA receptor complex, potentiating inhibitory GABA receptor function by
inducing chloride flux through the chloride channels of the benzodiazepine receptor complex.[12][28] Ethanol
withdrawal has multiple effects on GABA, including reduced sensitivity to GABA inhibition and binding to
GABA receptors. Ethanol’s enhancing effect on chloride flux is lost, resulting in a decrease in GABA
activity.[19] In addition, up-regulation in glutamate receptors may also contribute to the neurologic stimulation
associated with ethanol withdrawal by increasing calcium flux through these receptors. [18]
Other mechanisms contributing to ethanol withdrawal syndrome have been postulated, including increased
dopaminergic transmission contributing to ethanol withdrawal hallucinations,[18] zinc deficiency,[47]
hypomagnesemia, abnormal hypothalamic-pituitary-thyroid axis function, and hormonal imbalance.[5]
Finally, patients who undergo several episodes of ethanol withdrawal tend to have worsening symptoms with
each episode. Subsequent episodes of withdrawal appear to sensitize the patient to these symptoms over
time. This phenomenon is known as “kindling.”[42]
Clinical presentation of ethanol withdrawal was initially described as four distinct stages by Victor and
Adams [73] consisting of tremulousness, seizures, hallucinations, and delirium. However, the range of
symptoms is more consistent with a continuum, extending from very subtle (e.g., mild anxiety) to blatant
(e.g., agitated delirium) manifestations. Symptoms from ethanol withdrawal usually manifest within 6–8
hours of the last consumption of ethanol, and symptoms can start even though the patient still has a blood
ethanol level above 100 mg/dL; the level is usually lower than the patient’s base line. Earlier and milder
symptoms include tremor, anxiety, and tachycardia. As the illness progresses and symptoms worsen,
hypertension, severe anxiety, and seizures develop. Hallucinations, extreme restlessness, and hyperpyrexia
signify severe withdrawal symptoms. Delirium tremens represents the most severe state of withdrawal, and
is manifested by an agitated delirium and pronounced sympathetic overdrive, eventually leading to complete
cardiovascular collapse.
Early symptoms of ethanol withdrawal are hyperadrenergic in nature and include tachycardia, tachypnea,
hypertension, tremor, and hyperreflexia. The acute onset of tremulousness or “the shakes” is often the
principal complaint of the patient; tachycardia with tremor may be the initial presenting signs on arrival to the
emergency department. In some cases, the tremor may not be apparent, although the patient may feel quite
“shaky inside.” Anxiety and insomnia are often prominent symptoms. Nausea, vomiting, and anorexia can
also occur.
Mild ethanol withdrawal is associated with a clear sensorium, although some patients are disoriented to
time. In the majority of these patients, symptoms peak by 24 to 36 hours, and severe complications do not
develop. However, as many as 20–25 per cent of untreated patients will progress to worsening withdrawal
manifestations, including seizures and hallucinations. Delirium tremens, the most severe withdrawal state,
occurs in fewer than 5 per cent of cases of ethanol withdrawal.[40] Unfortunately, it is very difficult to predict
which patients will progress.[46]
Seizures, or “rum fits,” are another early presenting symptom of ethanol withdrawal. Although controversy
continues, ethanol is not a proconvulsant.[62] Seizure activity without significant autonomic manifestations
occasionally heralds the onset of the withdrawal syndrome. In other cases, the patient will already be quite
jittery and tachycardic prior to the initial seizure. Withdrawal seizures are usually generalized tonic-clonic
seizures and are self-limited. Although a brief flurry of seizures occasionally occurs, multiple recurrent
seizures and status epilepticus are unusual in patients who are withdrawing, and such developments should
prompt evaluation for another cause. Patients with an underlying seizure disorder usually worsen with
ethanol use.[28] Historically, untreated patients presenting with ethanol-related seizures were more likely to
progress to delirium tremens than were those who presented with tremulousness alone.
Hallucinations in the patient with an intact sensorium are relatively common manifestations of ethanol
withdrawal. The hallucinations are often visual, although auditory hallucinations occur in about 20 per cent of
cases. Visual hallucinations of crawling bugs are common.[72] Tactile and olfactory hallucinations are rare.
Hallucinations usually last up to 3 days. Some patients undergoing ethanol withdrawal will present with
auditory hallucinations, often of a persecutory nature, without any concomitant symptoms of sympathetic
excess. This particular presentation is known as acute alcoholic hallucinosis and may be misdiagnosed as a
functional psychosis.[66][71] Acute alcoholic hallucinosis occasionally lasts for months.[66]
Confusion, obtundation, and delirium are the hallmarks of delirium tremens and usually develop 3 to 7 days
after cessation of ethanol. Delirium tremens represents the most malignant form of ethanol abstinence and
has a much higher morbidity and mortality rate, especially when associated with hyperpyrexia. Unlike other
ethanol withdrawal presentations, patients with delirium tremens present with significant clouding of the
sensorium. Severe psychomotor agitation is present, and patients commonly and characteristically pick at
their bedclothes. Global confusion, unintelligible speech, and extreme restlessness may be present, and
physical restraints are often required in the initial approach to gain control over these patients.
Rhabdomyolysis causing renal damage is not uncommon and is primarily attributable to the elevated
temperature and severe agitation. A severe hyperadrenergic state usually accompanies delirium tremens
and is manifested by tachycardia, profuse diaphoresis, hypertension, and dehydration that, if untreated,
ultimately lead to cardiovascular collapse.[67] The hemodynamic instability, in conjunction with the
complications of hyperpyrexia and agitation, are the main causes of morbidity and death. The mortality rate
from delirium tremens was previously as high as 35 per cent prior to World War II.[49] The current mortality
rate from delirium tremens is less than 5 per cent owing to better recognition and treatment.[58]
Many other illnesses present with symptoms similar to those seen with ethanol withdrawal ( Table 70–1 ).
Withdrawal from other sedative hypnotic agents such as benzodiazepines presents with similar symptoms,
albeit with a different time course. Intoxication from cocaine, amphetamines, and monoamine oxidase
inhibitors will produce massive sympathetic surge and present in a similar fashion. Anticholinergic drug
overdose also cause tachycardia, agitation, and hyperpyrexia. Phencyclidine and LSD (lysergic acid
diethylamide) also cause hallucinations and delirium.
Table 70-1 -- Differential Diagnosis of Ethanol and Sedative-Hypnotic Withdrawal Manifestations

Tremors Seizures Hallucinations Delirium
Barbiturates Opioids (neonates)
Caffeine Amphetamines Amphetamines Amphetamines
Lithium Anticholinergics Anticholinergics Anticholinergics
Theophylline Cocaine Cocaine Cocaine
Cyclic
Organophosphates Ergot LSD
antidepressants
LSD (lysergic acid
Mercury Phencyclidine Phencyclidine
diethylamide)
ß-Adrenergic
Theophylline Mescaline
Withdrawal agonists
syndrome Cocaine Salicylates Peyote
intoxications
Amphetamines Cyclic antidepressants Phencyclidine
Monoamine oxidase
Phencyclidine inhibitor overdose/drug Ketamine
interaction
Nicotine Psilocybin
Organochlorines Cyclic antidepressants
Hyperosmolar state Belladonna alkaloids
Mushrooms: psilocybin,
muscarine, ibotenic
acid/muscimol
Hypoglycemia Hypoglycemia Hypoglycemia Hyperglycemia
Thyroid storm Hypoxia Hypoxia Hypoglycemia
Pheochromocytoma Renal failure Hypocalcemia
Metabolic Liver failure Hypoxia
Thyroid storm
Wernicke
syndrome
Cerebellar stroke Bleed Bleed Bleed
Encephalitis Encephalitis Encephalilits
Central nervous Mass Mass Mass

system Seizure disorder Seizure disorder Seizure disorder
Stroke Infection Trauma
Trauma
Tremors Seizures Hallucinations Delirium
Psychiatric-
Parkinsonism Psychiatric Psychiatric
pseudoseizures
Other Causes
Heat stroke Heat stroke Heat stroke
Porphyria
Patients with neuroleptic malignant syndrome present with hyperthermia, alteration in mental status, muscle
rigidity, and symptoms of autonomic instability, including hyper- and hypotension, tachycardia, and
diaphoresis. A history of haloperidol or other neuroleptic use is a major distinguishing factor. Serotonin
syndrome can present in a similar fashion. Again, a history of selective serotonin receptor inhibitor
overdose[38] or the use of two or more drugs that increase central nervous system (CNS) serotonin levels[63]
lends support to this diagnosis.
Central nervous system illnesses must be considered in the differential diagnosis of ethanol withdrawal.
Mass lesions, cerebrovascular accidents, traumatic head injury, meningitis, and encephalitis can present
with seizures, hallucinations, or delirium. Head injury is more common in the alcoholic patient, partially
because of the frequent intoxicated state. Pre-existing idiopathic epilepsy and post-traumatic epilepsy may
be the actual cause of a seizure in a patient who abuses ethanol. Poor anticonvulsant compliance often
contributes to the likelihood that these patients will present with seizures.
Metabolic causes such as hypoglycemia and hypocalcemia and acute renal failure cause some symptoms
similar to those seen with ethanol withdrawal. Patients with thyroid storm present with tachycardia, fever,
and delirium.
Ethanol intoxication can cause clouding of the sensorium, but symptoms should resolve as the ethanol level
diminishes. Patients with underlying psychiatric disorders can present with bizarre behavior that may mimic
the seizures and hallucinations associated with ethanol withdrawal. However, these disorders generally do
not cause either the delirium or the severe autonomic derangements that are common with ethanol
withdrawal.
Laboratory Findings
The patient with ethanol withdrawal often has significant laboratory abnormalities. Minimal laboratory testing
includes serum electrolytes, glucose, blood urea nitrogen, creatinine, and hemoglobin. A complete blood
count may reveal thrombocytopenia, and the red blood cell indices may offer clues to the etiology of an
anemia. A low serum bicarbonate should prompt a search for alcoholic ketoacidosis or other causes of
metabolic acidosis. Hypoglycemia may be present because of poor oral intake, depleted hepatic glycogen
stores, or the shunting of pyruvate to lactate due to increases in the NADH:NAD redox ratio. A measurable
ethanol level does not preclude alcohol withdrawal. In nutritionally depleted patients, magnesium and
phosphorus levels may reveal deficiencies requiring supplementation, although a normal serum magnesium
level does not rule out total body magnesium deficiency. Further testing is dictated by the clinical
presentation. Psychomotor agitation can result in elevated creatine phosphokinase and myoglobin levels.
Liver function tests may uncover an alcoholic hepatitis. In patients who present with an altered mental status
or fever, other CNS emergencies such as intracranial hemorrhage and meningitis or encephalitis need to be
considered and ruled out with a head computed tomography (CT) scan and lumbar puncture. Urine drug
screens are rarely helpful, and should be used only if the clinical symptoms are thought to be due to some
other ingested substance.
Treatment
Gaining control of the agitated patient is essential for medical evaluation as well as to prevent injury to
patient and staff. Physical restraints followed by chemical restraints may be required to establish control.
Hypoxia and hypoglycemia should be quickly evaluated using pulse oximetry and bedside glucose check.
The airway should be managed appropriately, and supplemental oxygen administered as needed.
Intravenous access should be established and 50 g of dextrose administered immediately to any patient with
hypoglycemia. Intravenous crystalloids should be infused for dehydration and maintenance of normal urine
output; patients with alcoholic ketoacidosis will require vigorous volume resuscitation. Thiamine 100 mg
should be administered IV to initially treat or prevent the development of Wernicke syndrome.
Evaluation should eliminate other potential causes for the presenting symptoms. A quick assessment for
other serious and potentially life-threatening emergencies that may mimic or coexist with withdrawal should
be accomplished. The patient and family should be asked about use of ethanol, sedative-hypnotic agents,
and other drugs or medications. Vital signs may reveal important clues as to the degree of withdrawal and
need for evaluation of coexisting illnesses, such as sepsis or hypoxia. Coexisting illnesses such as gastritis,
pancreatitis, gastroenteritis, or trauma may have prompted a reduction in ethanol ingestion and indirectly
caused the withdrawal syndrome.[10] In addition, the diagnosis and treatment of coexisting medical and
surgical conditions is critically important in reducing morbidity and mortality.[16]
Chemical Restraints.
The use of physical restraints must be followed quickly with appropriate chemical restraints in the agitated
patient in order to avoid complications such as hyperthermia, physical injuries, and rhabdomyolysis
developing as the patient fights against the restraints. The high mortality rate associated with delirium
tremens in the past was in part due to the liberal use of and reliance on strait jackets and other restraining
devices without the use of effective sedation, cooling, and rehydration. Effective sedation with
benzodiazepines remains the mainstay of treatment.[43] Benzodiazepines alleviate the manifestations of
withdrawal as they are cross-tolerant with ethanol and increase GABAA-mediated transmission.
Benzodiazepines may also halt progression to delirium tremens. Despite their effectiveness, however, the
benzodiazepines are not completely cross-tolerant with ethanol and do not completely reverse the altered
sensorium associated with delirium tremens.
Lorazepam, initial dose 2 mg IV or IM, or diazepam, initial dose 5 mg IV, is usually an effective chemical
restraint and is the preferred initial treatment for agitation, seizures, and the withdrawal hyperadrenergic
state ( Table 70–2 ). Lorazepam offers the advantages of IM administration, one-pass hepatic metabolism
and more prolonged CNS sedation due to its CNS distribution. Additionally, the lack of active metabolites is
advantageous in patients with hepatic insufficiency and in the elderly.[48] Diazepam offers the advantage of a
long serum half-life with the production of active metabolites that afford a gradual self-titration of the
benzodiazepine over several days. Chlordiazepoxide is an older drug that has long-acting active metabolites
but does not offer any particular advantages over the other benzodiazepines. The total benzodiazepine dose
is titrated to achieve control of the patient’s symptoms while maintaining adequate ventilatory status.[59]
Large doses may be required. Up to 100 mg diazepam every 6 hours and rarely even up to 1000 mg over 24
hours have been reported.[52]
Table 70-2 -- Benzodiazepines Used in the Treatment of Ethanol Withdrawal: Pharmacokinetics and
Dosing
Lorazepam (Ativan) Diazepam (Valium)
Onset to action Immediate Immediate
Absorption IM route Good Unpredictable
Hepatic Yes Yes
Metabolism
Active metabolites No Yes
Half-life 14 hr 43 hr
Prolonged effect in elderly, liver disease No Yes
Starting dose 1–2 mg every 15 min 5–10 mg every 15 min
Maintenance dose 1–2 mg every 6 hr * 5–10 mg every 8 hr *
* Dosage is quite variable and should be individually titrated.
Other medications have been used for alcohol withdrawal. Phenobarbital and other barbiturates such as
pentobarbital directly open the neuronal chloride channels to produce inhibition similar to that seen with
GABAA-mediated activity. They may prevent seizures and relieve withdrawal symptoms.[75] However, the
significant respiratory depression and sedation make these drugs second- and third-line agents unless
seizures are particularly problematic. Phenobarbital at an initial dose of 5 mg/kg IV and titrated to effect can
be used adjunctively in the patient requiring large doses of benzodiazepines. Respiratory depression and
hypotension are potential complications that must be anticipated. Sodium pentobarbital should be reserved
for the patient unresponsive to benzodiazepines and phenobarbital. Use of this agent may necessitate
airway management with intubation. The initial dose is 3–5 mg/kg followed by a 100 mg/hour infusion to
maintain sedation.[24]
The use of neuroleptics [60] such as haloperidol is controversial. Haloperidol has been used in combination
with benzodiazepines, in an attempt to reduce the total benzodiazepine dose, with controversial results.[58]
Disadvantages of using a neuroleptic include lowering of the seizure threshold, hypotension, and impaired
thermoregulation.[23] Use of phenothiazines such as chlorpromazine has been particularly problematic.
Neuroleptic monotherapy is a dangerous therapeutic approach. In a clinical trial comparing a barbiturate,
benzodiazepine, and butyrophenone for acute ethanol withdrawal, the butyrophenone-treated group
experienced a higher incidence of seizures.[9] In general, butyrophenones should never be used as a sole
therapeutic agent because of their lack of GABA effect.
Intravenous ethanol should not be used to treat withdrawal. Titration and control of symptoms without
oversedation and potential airway compromise are more difficult and time-consuming and do not ameliorate
the metabolic or psychological derangements of ethanol use.[14] Additionally, the short elimination half-life of
intravenous ethanol requires continuous infusion to maintain effect. Phenytoin does not prevent ethanol
withdrawal seizures,[2][11] and its use should be limited to the treatment of underlying non–ethanol-related
seizure disorders.[50]
Sympatholytic Agents.
A number of studies have examined the role of sympatholytic agents such as clonidine or the ß-adrenergic
receptor antagonists in the management of ethanol withdrawal. Clinical trials using clonidine, a CNS a-
adrenergic receptor agonist, have produced equivocal results.[57] Clonidine decreases the sympathetic
symptoms, including hypertension and tachycardia, but is no more effective than placebo in treating other
important symptoms of withdrawal, such as anxiety and tremors, and in preventing delirium tremens. Beta-
adrenergic receptor antagonists such as atenolol can normalize vital signs more rapidly in a select outpatient
population.[39] However, the effects of decreased GABA effect, including agitation, hallucinations, and
seizures, are not prevented with their use. Normalization of vital signs with either clonidine or a ß-adrenergic
receptor antagonist may mask clinical progression to serious CNS complications from ethanol withdrawal,
and monotherapy with either of these agents is not recommended.
Specific treatment of non–life-threatening ethanol withdrawal involves close observation, benzodiazepine

therapy to control the symptoms and prevent complications, and counseling. Early treatment of ethanol
withdrawal should also include management of nutritional deficiencies. Thiamine 100 mg should be
administered empirically for thiamine deficiency. Supplementation should be given intravenously or
intramuscularly initially, as gastritis and withdrawal symptoms prohibit adequate thiamine absorption. Other
nutritional deficiencies of vitamins, especially folate, and phosphorus may require supplementation. The use
of magnesium remains controversial. Chronic alcoholics have deficient magnesium stores because of
inadequate nutrition; however, there is little evidence that aggressive replacement of magnesium prevents
complications or progression of the ethanol withdrawal syndrome.[37]
Disposition
Patients with mild withdrawal symptoms may be managed as outpatients with close observation. Giving
these patients prescriptions for the outpatient administration of benzodiazepines can be dangerous.
Benzodiazepine use by an unsupervised chronic alcoholic may result in significant complications, including
potential resale of the drug and synergistic interactions with ethanol in those patients who continue to drink.
Consequently, respiratory depression and diminished mental alertness may occur. Patients with moderate to
severe symptoms should be admitted to the hospital or to an intensive rehabilitation facility with the
capability to provide intravenous therapies. Patients with delirium tremens require admission to an intensive
care unit. Patients who are stable should undergo psychological evaluation and counseling and possible
referral to rehabilitation facilities.
Benzodiazepines
Benzodiazepines have been commonly used for anxiety disorders since the 1960s. Benzodiazepine
withdrawal is more common than withdrawal from other sedative-hypnotic agents, partly because
benzodiazepines are more commonly used and abused. Withdrawal from benzodiazepines and other
sedative-hypnotic drugs is similar to ethanol withdrawal with a few caveats. Benzodiazepine withdrawal may
begin considerably longer after the last dose and have a more protracted course as a result of the longer
elimination half-life and active metabolites of these drugs.[8]
Pathophysiology
Benzodiazepines interact with a specific GABAA/benzodiazepine postsynaptic receptor complex to enhance
GABA-induced chloride currents. This increased chloride conductance increases intracellular chloride,
neuronal cell hyperpolarization, and decreased cell depolarization. Other sedative-hypnotic agents also
appear to modulate this receptor complex. Benzodiazepine cessation results in a decrease in the inhibitory
effects of GABAA at the receptor complex, leading to the symptoms of withdrawal. Ethanol also affects the
GABAA receptor with subsequent synaptic inhibition, [70] and this shared effect may explain some of the
signs and symptoms common to both ethanol and benzodiazepine withdrawal.
Flumazenil may precipitate benzodiazepine withdrawal by competing for binding at the receptor. This is
especially problematic in patients who are chronically taking benzodiazepines and who have developed
dependence. Fortunately flumazenil is rapidly metabolized, and severe withdrawal symptoms including
seizures can be managed by phenobarbital, a barbiturate that does not require the GABAA receptor and can
directly open neuronal chloride channels. Although there have been few case reports of flumazenil-induced
withdrawal,[74] seizures and death have been reported after its use.[64][29]
The clinical course of sedative-hypnotic withdrawal depends to a large extent on the elimination half-life of
the particular drug. Benzodiazepines with shorter elimination half-lives that are dosed more frequently, such
as lorazepam, develop earlier and more intense signs and symptoms of withdrawal. Manifestations of
withdrawal from drugs with shorter elimination half-lives may present within 1–2 days after the last dose,
whereas symptom onset may be delayed for as long as 1–2 weeks after cessation of benzodiazepines with
longer half-lives such as diazepam. Symptoms may last as long as 6 weeks.
Symptoms of sedative-hypnotic withdrawal may be quite subtle. Common manifestations include anxiety,
tremor, panic attacks, and insomnia.[54] Unfortunately, benzodiazepines are frequently used to treat anxiety
disorders, and differentiating benzodiazepine withdrawal from an underlying anxiety disorder may be
difficult.[53] More severe withdrawal symptoms include vomiting, cramps, tremors, orthostatic hypotension,
hallucinations, delusions, seizures, and hyperthermia. These symptoms generally appear after the onset of
anxiety and insomnia.
The differential diagnosis for sedative-hypnotic withdrawal is similar to that for ethanol withdrawal.
Laboratory Studies
There are no specific laboratory tests. Hypoglycemia should be evaluated with bedside glucose testing or
serum measurement. Other testing should focus on evaluating for differential or confounding diagnoses.
Treatment
Treatment is similar to that for ethanol withdrawal. Initial control can be obtained with lorazepam or
diazepam. After withdrawal symptoms are under control, a more prolonged taper with a more slowly
eliminated benzodiazepine such as diazepam can be initiated to gradually withdraw the patient over a period
of 2–4 weeks or longer. Barbiturates such as phenobarbital have also been used for the treatment of
benzodiazepine withdrawal.[56] Additionally, sympatholytic agents can be used as adjunctive therapy.
Opioid Withdrawal
Opioid withdrawal, although potentially uncomfortable, is considerably less life-threatening than sedative-
hypnotic withdrawal. It occurs in people addicted to heroin as well as in patients taking a variety of opioid-
containing medications or methadone.
Pathophysiology
The clinical effects of opioids are mediated through opiate receptors. Stimulation of certain receptor
subtypes reduces the firing rate of noradrenergic neurons located in the locus ceruleus, reducing CNS
norepinephrine release. Chronic use of opioids results in an increase in number or in the up-regulation of
these receptors. Subsequent withdrawal of opioids causes increased sympathetic discharge and
noradrenergic hyperactivity at the locus ceruleus.[20] Onset of withdrawal symptoms varies according to the
half-life and dosing of the abused agent. Symptoms of heroin withdrawal may occur as early as 4–8 hours
after the last dose, and usually peak by 3–4 days. Methadone withdrawal may not manifest itself until 36–72
hours after the last use, and symptoms can last for several weeks. Opioid withdrawal may be iatrogenically
precipitated with the antagonist naloxone, and develops precipitously after such use.[22] Fortunately,
withdrawal under these circumstances is usually short-lived because of the short half-life of naloxone,
usually 20–60 minutes. A concern about the recently introduced opioid antagonist nalmefene involves its
potential to precipitate a protracted withdrawal period owing to its considerably longer half-life. The use of
agonist-antagonist agents such as nalbuphine (Nubain), butorphanol (Stadol), and pentazocine may
precipitate withdrawal in an opioid-dependent patient.
Psychological symptoms from opioid withdrawal include craving, dysphoria, anxiety, and insomnia and may
develop prior to physiologic symptoms. Tachycardia, tachypnea, and hypertension are common physiologic
markers. Although both opioid and ethanol withdrawal are mediated by increased sympathetic activity, the
sympathetic overdrive is less with opioid withdrawal. The patient remains alert and oriented, an important
point differentiating opioid from sedative-hypnotic drug and barbiturate withdrawal. Hyperpyrexia in this
setting should suggest another etiology such as a concurrent infectious process or ethanol withdrawal. Other
characteristic symptoms of opioid withdrawal include diaphoresis, tearing, yawning, rhinorrhea, myalgias,
and piloerection. Not infrequently, patients’ subjective complaints appear out of proportion to their generally
benign clinical appearance. More severe withdrawal symptoms include abdominal cramping and pain,
diarrhea, and vomiting. The complaints of abdominal pain may be misleading, as these patients complain of
severe pain with few peritoneal findings. Severe symptoms associated with ethanol withdrawal such as
seizures, delirium, and cardiovascular collapse should not occur with opioid withdrawal; their presence
should prompt further investigation into other etiologies. An exception are the seizures seen in neonates
born to opioid-addicted mothers (see Neonatal Abstinence Syndrome).
Differential diagnostic considerations are found in Table 70–2 .
Laboratory Studies
Serum electrolytes, glucose, and blood counts may be indicated.
Treatment
Emergency department evaluation of opioid withdrawal includes consideration of other disease processes
that may mimic withdrawal. Acute gastroenteritis can be easily confused with opioid withdrawal. A thorough
drug history, physical examination, and neurologic evaluation should be performed. Aggressive intravenous
hydration with crystalloids and potassium replacement is often necessary to replace gastrointestinal volume
loss. Most important, evaluation for the more life-threatening complications of opioid abuse, such as
endocarditis or complications from AIDS, should be performed.
Methadone has been used for heroin withdrawal, and its longer duration of action makes it an attractive
substitute for the shorter-acting heroin. An oral dose of 10–25 mg every 24 hours will usually prevent further
withdrawal symptoms, but the dose can be increased to titrate to effect. Parenteral intramuscular use is
sometimes required, especially in the patient who is actively vomiting. An initial dose of 10 mg IM is used.
Symptomatic relief usually occurs within 30 minutes to an hour after parenteral administration, and
somewhat longer if the methadone is given orally. Larger doses such as 60–80 mg a day for methadone
maintenance are not usually required in the emergency department setting. The use of methadone has
generally been limited to the inpatient setting or through an accredited drug rehabilitation program. Its
availability and use for outpatient therapy to the emergency physician may be limited.
Clonidine has been used effectively to treat the sympathetic symptoms of opioid withdrawal by stimulating
central presynaptic a2-adrenergic receptors, and thus reduce noradrenergic outflow.[21] Clonidine may be
given in a dose of 0.1–0.2 mg to adults, and repeated every 4–6 hours to control tachycardia and
hypertension as well as to ameliorate some of the dysphoric feelings. Hypotension is the major complication
of clonidine therapy, and blood pressure monitoring after the initial dose is highly recommended.
Benzodiazepines are not cross-tolerant with opioids but are effective in controlling the anxiety from opioid
withdrawal and can be used to control some symptoms when methadone or clonidine cannot be used.
Antiemetics such as promethazine can ameliorate the nausea and vomiting.
Disposition
Unfortunately, the treatment of opioid withdrawal in the emergency department setting is often unsatisfactory
to both the physician and patient. Once the withdrawal symptoms have been temporarily ameliorated and
necessary intravenous hydration and other care rendered, proper referral to a detoxification program is often
the best care that can be provided.


OTHER WITHDRAWAL STATES
Neonatal Abstinence Syndrome
Neonatal abstinence syndrome results from maternal drug abuse, primarily of opioids. Infants suffering from
neonatal abstinence syndrome have a significantly higher incidence of neurobehavioral complications.[7]
Premature birth and its antecedent complications are more common in drug-abusing mothers. Some of the
characteristic symptoms of neonatal abstinence syndrome include restlessness, tremor, high-pitched cry,
and an odor.[68] Seizures may also occur in up to 7 per cent of neonatal opioid withdrawal.[31]
The exact cause of neonatal abstinence syndrome is unclear, but evidence suggests that noradrenergic
hyperactivity may contribute to the development of the syndrome.[44]
Various treatment modalities have been used to treat neonatal abstinence syndrome, including tincture of
opium, paregoric, diazepam, and phenobarbital. One clearly superior agent has not been identified.[69]
Cocaine Withdrawal
Other substances of abuse have until recently received little attention regarding their propensity for causing
withdrawal syndromes. Cocaine is one of the most frequently abused substances in the United States with
as many as 6 million Americans using cocaine regularly.[55] Cocaine appears to stimulate the sympathetic
nervous system by preventing clearance of stimulatory neurotransmitters as well as by causing direct CNS
stimulation. Cocaine causes short-lived euphoria, sexual arousal, and feelings of invincibility. Both the desire
for the “high” and the tolerance that develops from continued use contribute to cocaine dependence.
Three phases of cocaine withdrawal have been described: an initial “cocaine crash” phase, followed by two
longer phases of mood alteration—the withdrawal phase and extinction phase. [13] An intense craving for
more of the drug is the cardinal feature of cocaine withdrawal. Symptoms of the acute “cocaine crash”
include fatigue, insomnia, alterations of mood, and depression.[17] These symptoms may last as long as a
few days. Long-term symptoms include dysphoria, anxiety, impotence, and craving.[55] These mood
alterations slowly abate, leading to the “extinction phase,” but may recur, along with episodes of intense
craving for cocaine.[13] Treatment for cocaine withdrawal is supportive only. Patients presenting with
apparent cocaine withdrawal should be evaluated for manifestations of the serious complications from
cocaine use itself, including cerebrovascular and cardiovascular ischemia, seizures, and gastrointestinal
problems. Long-term therapy typically requires counseling and management by a drug treatment center and
is associated with a high potential for relapse. Multiple drugs are being investigated for their efficacy in
preventing this relapse.[45]
Nicotine Withdrawal
The potential for cessation of nicotine to cause discomfort is well recognized. Nicotine stimulates specific
nicotinic receptors in the mesolimbic system, and may enhance dopamine release,[34] although this is not its
only mechanism of action. The etiology of nicotine withdrawal is unclear.[4] Signs and symptoms include
anxiety, craving, tremor, depressed mood, weight gain, and bradycardia, and can be reproduced consistently
upon nicotine withdrawal.[34] Interestingly, some of these symptoms are similar to those seen in patients
withdrawing from ethanol and sedative-hypnotics, albeit to a milder degree. Nicotine withdrawal in general
causes mild physiologic symptoms, and thus little significant morbidity. Obviously, recidivism is associated
with highly significant long-term morbidity and mortality. Nicotine withdrawal does appear approximately
6–12 hours after smoking cessation, and peaks in 1–3 days. Symptoms may last as long as 4 weeks. There
is no definitive clinical evidence that larger amounts and greater intensity of smoking are more likely to
cause withdrawal symptoms.[34]
Nicotine patches and nasal sprays lessen the effects of withdrawal; however, symptoms are not completely
ameliorated with either product. Use of spray and patch does impact positively on smoking cessation
therapy.[16][32] Bupropion, a monocyclic antidepressant, has been shown to be effective in smoking
cessation in a dose-related manner. [35] However, it is not completely effective, and even with appropriate
use, a significant proportion of individuals will fail treatment. Although bupropion is generally considered
safe, there have been case reports of seizures and death due to bupropion overdose.[27]
Caffeine Withdrawal
Caffeine is another commonly ingested substance. At present, caffeine withdrawal is not formally recognized
as a clinical syndrome by criteria of the American Psychiatric Association’s Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV).[17] However, there is some clinical evidence that a
physical dependency syndrome does exist.[65] Withdrawal from caffeine is well known and is noted to cause
headaches, lethargy, weakness, and depressed mood. Headaches may be quite severe, usually start 12
hours after the last dose, and typically resolve within 4 days. Symptoms appear to correlate with the doses
typically ingested prior to cessation. Treatment for caffeine withdrawal includes a gradual reduction in intake
over a few days. Caffeine tablets have been used prophylactically with some success to prevent
postoperative headaches in caffeine-dependent patients.[25]


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Chapter 71 – Disulfiram
WILLIAM A. WATSON
Essentials
• A history of disulfiram ingestion or the availability of disulfiram
• A history of ethanol dependence and recent exposure to ethanol
• Adults:
° Chronic or subchronic dosing: encephalopathy, neuropathy, and psychosis commonly
associated with higher daily doses of disulfiram[11][23]
° Acute ingestion: delirium, agitation, somnolence, and tachycardia
• Children: central nervous system (CNS) depression[22]

• Disulfiram-ethanol reaction: headache, flushing, hypotension, and tachycardia temporally associated
with ethanol exposure[6]
INTRODUCTION
Disulfiram (tetraethylthiuram disulfide; Antabuse, Antabus, other trade names) is used as aversive therapy to
prevent the continued ingestion of ethanol. It is used primarily in those individuals who are motivated to stop
drinking, and its use may be court ordered. It is available in oral dosage forms and in Europe as dermal
implants.[13][24] Toxicity associated with acute disulfiram ingestion is infrequently reported. More frequent are
significant adverse effects associated with disulfiram therapy and with the disulfiram-ethanol reaction.
Between 1984 and 1994 the Toxic Exposure Surveillance System (TESS) reported between 500 and 700
cases of toxic disulfiram exposure annually. It is unclear how many of these exposures involved disulfiram
without ethanol. Approximately 5 per cent of cases were in children younger than 6 years of age.[17]
Severe toxicity is infrequently reported to the TESS. Between 1984 and 1994, 5 to 10 per cent of patients
had moderate toxicity, and there was major toxicity in 3 to 16 patients per year. Seven deaths from
disulfiram toxicity or the disulfiram-ethanol reaction occurred over the 10-year period.


Pharmacology
The ability of disulfiram to inhibit copper-containing enzymes was noted during its early medical use as a
vermicide, and reactions to ethanol in workers exposed to disulfiram suggested an impact on ethanol
metabolism.[20] Disulfiram chelates various metals, including copper, zinc, lead, nickel, iron, and
molybdenum. The primary pharmacologic effect is the inhibition of the aldehyde dehydrogenases (ALDH) by
disulfiram as well as its metabolites diethylthiomethylcarbamate (Me-DTC), diethyldithiocarbamate (DDC),
diethylamine, and carbon disulfide. [20][21] Inhibition occurs quickly, suggesting a competitive process, and is
followed by a more slowly developing irreversible ALDH inhibition.[12] Inhibition of ALDH results in increased
concentrations of acetaldehyde. A median daily disulfiram dose of 300 to 500 mg is required for effective
aversive therapy to ethanol exposure. Therapeutic doses produce 50 per cent inhibition of leukocyte ALDH
activity within the 3 days after initiation of therapy.[20][24]
Pharmacokinetics
The peak plasma concentrations of disulfiram occur 8 to 10 hours after administration, and peak metabolite
concentrations occur from 5 to 10 hours after oral disulfiram administration. Bioavailability is greater than 80
per cent with oral administration, with some disulfiram absorbed as the copper complex with
diethyldithiocarbamic acid, which is formed in gastric fluid.[12] Disulfiram is metabolized primarily by hepatic
cytochrome P-450 IIE1, glucuronidated and sulfated, with resultant sulfone and sulfoxide metabolites. Both
disulfiram and its metabolites are greater than 80 per cent bound to plasma protein and are not present in
red blood cells.[12] The volume of distribution is not reported. The plasma elimination half-life of disulfiram is
approximately 7 hours, and the half-lives of the metabolites range from 9 to 22 hours. Most metabolite
elimination is renal, and carbon disulfide is also extensively eliminated in breath.[20]
The pharmacokinetics of disulfiram and its metabolites support the observation that symptoms of the
disulfiram-ethanol reaction occur with ethanol administration 3 to 12 hours after a single oral disulfiram dose.
The disulfiram-ethanol reaction should not be observed more than 24 hours after dosing. After chronic
dosing the disulfiram-ethanol reaction can occur as long as 2 weeks after stopping therapy secondary to the
irreversible ALDH inhibition.
Pathophysiology
Disulfiram toxicity is secondary to the inhibition of various enzymes by disulfiram and its metabolites. The
primary enzymes inhibited after disulfiram administration are the ALDH, and this inhibition results in the
accumulation of acetaldehyde.[7][20] Although increased acetaldehyde concentrations correlate with some of
the clinical effects seen with the disulfiram-ethanol reaction, it does not explain all the toxic manifestations
that occur.[14] Acetaldehyde toxicity is most likely both direct and secondary to the release of histamine.
Other toxic mechanisms that may play a role in disulfiram effects include the inhibition of other sulfhydryl-
containing enzymes secondary to either disulfiram or carbon disulfide. Disulfiram may inhibit dopamine-ß-
hydroxylase, resulting in blockade of the conversion of dopamine to norepinephrine; however, this has not
been consistently demonstrated in animal models. Dopamine-ß-hydroxylase inhibition may be more
common with high-dose therapy associated with adverse effects and toxicity.[5][20] This blockade may be
secondary to the accumulation of acetaldehyde and may play a role in the hypotension seen with the
disulfiram-ethanol reaction.[7] Neurotoxicity may be secondary to carbon disulfide–mediated enzyme
inhibition or to production of pyridoxine deficiency.[7] Chronic neurotoxicity is usually associated with axonal
degeneration and may be reversible, similar to carbon disulfide toxicity.[17] Hepatotoxicity is not dose related;
a disulfiram metabolite has been implicated in the alteration of hepatocyte lipid peroxidation.[7][8]
Disulfiram therapy also inhibits various subspecies of hepatic cytochrome P-450 enzymes, which decrease
the metabolism of other drugs. Disulfiram can alter the pharmacokinetics of numerous drugs, including
benzodiazepines, cocaine, cyclic antidepressants, phenothiazines, phenytoin, and acetaminophen.[3][9][10]


The clinical presentation of disulfiram toxicity varies depending on whether the exposure is acute or chronic
and appears to be different in adults compared with children ( Table 71–1 ). The disulfiram-ethanol reaction
has a different presentation and requires the presence of both disulfiram and ethanol. The frequency of
disulfiram-ethanol reactions would be expected to vary significantly in different areas based on how
commonly disulfiram is used as aversive therapy in alcohol-dependent patients.
Table 71-1 -- Clinical Presentation of Disulfiram Toxicity

Acute Toxicity
Adults
Distinctive odor on breath (rotten eggs, garlic)
Headache, confusion, agitation
Hallucinations
Coma
Nausea, vomiting
Children (in addition to adult findings)
Ataxia, weakness
Lethargy
Seizures
Coma
Chronic Toxicity
Confusion
Psychotic behavior
Encephalopathy
Peripheral sensory and motor neuropathy
Disulfiram-Ethanol Reaction
Flushing of face, neck, and upper torso
Pruritus
Diaphoresis
Dyspnea, bronchospasm
Hypotension (rarely hypertension)
Dizziness, weakness, anxiety
Nausea, vomiting, abdominal pain, diarrhea
Disulfiram Ingestion
Either a history of disulfiram ingestion or the potential availability of disulfiram is the key aspect of
diagnosing disulfiram toxicity. In adults, this would be suggested by significant ethanol abuse and attempts
at detoxification either in the patient, family members, or friends. In children, this would be suggested by a
parent, family member, or caretaker who has a history of significant alcohol abuse or a household member
with such a history.
Acute toxicity can be delayed up to 10 to 12 hours after ingestion, and there may be no initial symptoms that
would be useful in directing the clinician to the diagnosis of potential disulfiram toxicity. [22] A distinctive
breath odor, described as characteristic of either rotten eggs (sulfhydryl) or garlic, is secondary to exhaling
metabolites.[15][21]
Adult Considerations
In adults a wide range of CNS symptoms can develop, including headache, confusion, agitation,
hallucinations, CNS depression, and encephalopathy. Protracted nausea and vomiting occur. Hypotension
and tachycardia may be seen with significant intoxications. Choreoathetoid movements have also been
noted.[15][21][23]
With chronic toxicity, which is a more common presentation in adults, CNS toxicity also predominates, and
signs and symptoms include confusion, encephalopathy, and various psychoses. Peripheral sensorimotor
neuropathy presents in the legs more than the arms and is secondary to axonal degeneration. It is
associated with chronic high-dose administration of disulfiram and is partially reversible.[18][16][11]
Pediatric Considerations
Acute poisonings have more severe CNS toxicity in children than in adults. Ataxia, weakness, lethargy,
seizures, and, in severe cases, a “Reye’s syndrome–like” encephalopathy have been described. Symptoms
seen in adults may also be present.[1][22]
The concurrent presence of ethanol with disulfiram indicates that the clinical presentation is most likely due
to the disulfiram-ethanol reaction. This presentation can be difficult to differentiate from chronic ethanol
intoxication. The classic findings are flushing of the face, neck, and upper chest; pruritus; diaphoresis;
dyspnea; and a throbbing headache. Bronchospasm will require treatment.[2] CNS symptoms include
dizziness, confusion, weakness, and anxiousness. Abdominal complaints are nausea, vomiting, abdominal
pain, and diarrhea. Most patients have a decrease in blood pressure and increase in heart rate, which
resolves spontaneously. With more severe reactions the hypotension can be profound and may be
associated with seizures, coma, and, in fatal cases, respiratory and cardiovascular collapse.
Electrocardiographic effects include sinus tachycardia, premature atrial contractions, flattened T waves, and
ST segment depression.[7] Chest pain and deaths have been described secondary to cardiac dysrhythmias,
pulmonary edema, and myocardial infarction.[4][7]


Disulfiram Toxicity
The differential diagnosis in children is primarily toxicity to CNS depressants such as benzodiazepines,
barbiturates, and anticonvulsants ( Table 71–2 ). Nondrug causes of metabolic encephalopathy should be
excluded, including Reye’s syndrome. In both children and adults, drugs that produce agitation,
hallucinations, confusion, or delirium such as amphetamines, cocaine, phencyclidine, and drugs with
pronounced anticholinergic activity should be strongly considered. Because some symptoms may be
secondary to disulfiram metabolism to carbon disulfide, primary exposure to carbon disulfide should also be
considered. The other primary differential diagnoses in adults are psychiatric disease, ethanol intoxication,
and chronic abuse.
Table 71-2 -- Differential Diagnosis of Disulfiram Toxicity

Acute or Chronic Toxicity
Ethanol intoxication
Chronic ethanol abuse
Central nervous system depressant drug ingestion (especially in children)
Metabolic encephalopathy or infection
Psychiatric disease
Other causes of peripheral neuropathy (see Chapter 19 )
Amphetamines, cocaine, phencyclidine, anticholinergics, and other drugs that produce agitation, hallucinations,
confusion, or delirium
Carbon disulfide toxicity
Other Drug/Chemical Interactions
Coprinus atramentarius mushroom
Cephalosporins: cefamandole, cefotetan, cefmenoxime, cefoperazone, moxalactam
Chlorpropamide
Griseofulvin
Metronidazole
Procarbamazine
Tolbutamide
Trichloroethylene + ethanol (“degreaser’s flush”)
Carcinoid
Vancomycin
Scombroid toxicity
Anaphylactic/anaphylactoid reactions
The differential diagnosis includes ethanol intoxication or chronic abuse, drug and ethanol withdrawal
symptoms, and disulfiram-like reactions between other drugs and ethanol. The most significant reactions
occur with the parenteral cephalosporins cefamandole, cefotetan, cefmenoxime, cefoerazone, and
moxalactam. Interactions have also been described with chlorpropamide, tolbutamide, and procarbazine.
The mushroom Coprinas atramentarius (inky cap) and the organic solvents dimethyl formamide,
tricholorethylene, and n-butyraldoxine may also produce a mild reaction. Drugs that possibly react include
griseofulvin and metronidazole.


LABORATORY STUDIES
There are no laboratory findings specific for disulfiram toxicity. The identification of ethanol in breath or
serum is useful in the diagnosis of the disulfiram-ethanol reaction. Additional laboratory studies are indicated
to evaluate other potential causes and for the presence of concurrent toxins or disease states that could
produce similar symptoms. Determination of hepatic enzymes to evaluate possible disulfiram hepatotoxicity
in symptomatic patients on chronic therapy is appropriate. Patients with tachycardia, hypotension, or
complaints of chest pain should have an electrocardiogram performed and continuous cardiac monitoring
instituted.
Identification of disulfiram metabolites in plasma or urine and of carbon disulfide in breath indicates the
ingestion of disulfiram. Measurement of erythrocyte or leukocyte aldehyde dehydrogenase activity can
demonstrate the activity of disulfiram and its metabolites.[20] The analytical methods to perform these
determinations are not available in most clinical settings.


TREATMENT
Supportive therapy is the cornerstone of treatment ( Table 71–3 ). A single dose of oral activated charcoal, 1
g/kg, is recommended to interrupt the delayed absorption of disulfiram after a recent oral ingestion. There
may be a limited role for gastric lavage in cases that present within 1 hour after ingestion. Ipecac-induced
emesis is not recommended, owing to the CNS depression that can result with acute ingestion.
Extracorporeal methods of drug removal have not been evaluated but are unlikely to be effective.
Benzodiazepines such as diazepam and lorazepam are the initial treatment for agitation and seizures.
Table 71-3 -- Treatment of Disulfiram Toxicity

Acute Disulfiram Ingestion
Supportive care (airway, breathing, circulation)
Oral activated charcoal: 1 g/kg
Dextrose (D50W) and thiamine (100 mg IV/IM) in patients with evidence or history of chronic ethanol abuse or
hypoglycemia
Seizures: Lorazepam or diazepam
Supportive care (airway, breathing, circulation); correct dehydration
Hypotension: Intravenous crystalloids, norepinephrine
Hypoglycemia, ethanol abuse: Dextrose (D50W) and thiamine (100 mg IM)
Flush, pruritus: Diphenhydramine and cimetidine
Treatment of the disulfiram-ethanol reaction is also supportive, including intravenous crystalloids for
hypotension and to replace increased fluid loss from protracted emesis. Norepinephrine is the preferred
vasopressor.[19]
The combination of histamine H1 and H2 antagonists may block the disulfiram-ethanol reaction flush. The
alcohol dehydrogenase inhibitor 4-methylpyrazole (fomepizole) may have a role in preventing the
progression of the disulfiram-ethanol reaction, although it cannot be generally recommended until further
information is available. Specific treatments including iron salts, ascorbic acid, antihistamines, and
phenothiazines have no clearly established benefit and should not be used.[7]


DISPOSITION
Because of the potential delay in onset of toxicity after acute ingestion and the lack of information about an
acute dose-toxicity relationship, patients should be observed for a minimum of 18 to 24 hours before
discharge. Patients with toxicity due to chronic exposure can be followed on an outpatient basis after the
disulfiram dose is decreased or therapy discontinued. Patients who experience mild or moderate disulfiram-
ethanol reactions should be observed for 1 to 2 hours after resolution of all symptoms. They can be
discharged with appropriate follow-up and treatment for alcohol dependence. Patients with more severe
symptoms, including hypotension, chest pain, or the persistence of abnormal blood pressure or heart rate,
should be hospitalized for continued therapy and observation.


SEQUELAE
The acute sequelae of disulfiram toxicity are generally reversible and not life-threatening. Individual cases of
persistent cognitive dysfunction with subacute therapy and of musculoskeletal dysfunction after an acute
disulfiram exposure have been described.[22][23] Peripheral neuropathies associated with chronic disulfiram
toxicity slowly improve after disulfiram is discontinued. [18]


REFERENCES
1. Benitz WE, Tatro DS: Disulfiram intoxication in a child. J Pediatr 1984; 105:487-489.
2. Berti F, Rossoni G, Bella DD: Bronchospasm during disulfiram-ethanol test reaction [letter].
BMJ 1993; 306:396.
3. Brown CG, Kaminsky MJ, Feroli ER, Gurley HT: Delirium with phenytoin and disulfiram administration.
Ann Emerg Med 1983; 12:310-313.
4. Cahill CA: Safety of disulfiram [letter]. N Engl J Med 1972; 287:935-936.
5. Caroldi S, Paris PD, Zotti S, et al: Effects of disulfiram on serum dopamine-beta-hydroxylase and blood
carbon disulphide concentrations in alcoholics. J Appl Toxicol 1994; 14:77-80.
6. Elenbaas RM: Drug therapy reviews: Management of the disulfiram-alcohol reaction. Am J Hosp
Pharm 1977; 34:827-831.
7. Eneanya DI, Bianchine JR, Duran DO, Andresen BD: The actions and metabolic fate of disulfiram. Ann
Rev Pharmacol Toxicol 1981; 21:575-596.
8. Forns X, Caballeria J, Bruguera M, et al: Disulfiram-induced hepatitis: Report of four cases and review of
the literature. J Hepatol 1994; 21:853-857.
9. Hameedi FA, Rosen MI, McCance-Katz EF, et al: Behavioral, physiological, and pharmacological
interaction of cocaine and disulfiram in humans. Biol Psychiatry 1995; 37:560-563.
10. Hardman M, Biniwale A, Clarke CE: Temazepam toxicity precipitated by disulfiram [letter].
Lancet 1994; 344:1231-1232.
11. Hotson JR, Langston W: Disulfiram-induced encephalopathy. Arch Neurol 1976; 33:141-142.
12. Johansson B: A review of the pharmacokinetics and pharmacodynamics of disulfiram and its
metabolites. Acta Psychiatr Scand 1992; 86:15-26.
13. Johnsen J, Morland J: Depot preparations of disulfiram: Experimental and clinical results. Acta
Psychiatr Scand 1992; 86:27-30.
14. Johnsen J, Stowell A, Morland J: Clinical response in relation to blood acetaldehyde levels. Pharmacol
Toxicol 1992; 70:41-45.
15. Kirubakaran V, Liskow B, Mayfield D, Faiman MD: Case report of acute disulfiram overdose. Am J
Psychiatry 1983; 140:1513-1514.
16. Liddon SC, Stran R: Disulfiram (Antabuse) psychosis. Am J Psychiatry 1967; 123:1284-1289.
17. Litovitz TL, Felberg L, Soloway RA, et al: 1994 annual report of the American Association of Poison
18. Mokri B, Ohnishi A, Dyck PJ: Disulfiram neuropathy. Neurology 1981; 31:730-735.
19. Motte S, Vincent JL, Gillet JB, et al: Refractory hyperdynamic shock associated with alcohol and
disulfiram. Am J Emerg Med 1986; 4:323-325.
20. Petersen EN: The pharmacology and toxicology of disulfiram and its metabolites. Acta Psychiatr
Scand 1992; 86:7-13.
21. Rainey JM: Disulfiram toxicity and carbon disulfide poisoning. Am J Psychiatry 1977; 134:371-377.
22. Reichelderfer TE: Acute disulfiram poisoning in a child. Q J Stud Alcohol 1969; 30:724-728.
23. Ryan TV, Sciara AD, Barth JT: Chronic neuropsychological impairment resulting from disulfiram
overdose. J Stud Alcohol 1993; 54:389-392.
24. Wright C, Moore RD: Disulfiram treatment of alcoholism. Am J Med 1990; 88:647-655.


Chapter 72 – Androgenic-Anabolic Steroids
PETER A. CHYKA
Essentials
• In men, the presence of acne, testicular atrophy, scrotal pain, and gynecomastia and anabolic effects
such as disproportionate muscular development of the upper torso
• In women, the presence of hirsutism, male-pattern alopecia, clitoral hypertrophy, deepening of the voice,
reduced breast size, and menstrual irregularities
• A history of androgenic-anabolic steroid use or a high index of suspicion in adolescents and adults
engaged in athletics
• Athletes who develop myocardial infarction, left ventricular hypertrophy, stroke, sleep apnea, acute
psychosis, suicidal ideation, hepatomas, jaundice, and aggressive, combative behavior
• Laboratory confirmation of the presence of exogenous androgenic-anabolic steroids
INTRODUCTION
The use of androgenic-anabolic steroids to promote physical strength, athletic endurance, a muscular
appearance, or penile size is widespread in adolescents and adults who may or may not participate in
sports.[34][55][57] For example, an estimated 5 to 12 per cent of boys and 0.5 to 2.5 per cent of girls in high
school have self-reported use of androgenic-anabolic steroids, with more than one third not participating in
organized sports. More than two thirds of those who used androgenic-anabolic steroids claim they began
their use at age 16 years or younger.[54] In a survey of 9- to 13-year-old students, steroid use in boys (2.7 per
cent) and in girls (2.8 per cent) was similar[17]; moreover, the use of androgenic-anabolic steroids by female
adolescents may be increasing.[56] Over 1 million Americans probably use androgenic-anabolic steroids
regularly, according to the Drug Enforcement Agency.
The health effects of androgenic-anabolic steroids have been extensively reviewed in books[15][21][53] and
articles.[1][9][43][34][51] However, variations in usage patterns, differences among the more than 40 available
drugs ( Table 72–1 ), and other confounding variables make it difficult to reach any conclusion on the true
risks and benefits. Nonetheless, adverse effects have been reported and some are undoubtedly due to
androgenic-anabolic steroid abuse. Data are also available from patients using androgenic-anabolic steroids
for hormonal replacement (e.g., hypogonadism[52]) or augmentation (e.g., female-to-male transsexuals[49]),
but the doses and patterns of use are different.[1]
Table 72-1 -- Commonly Used Androgenic-Anabolic Steroids

Oral Agents
17a-Alkyl Substituted Derivatives
Methyltestosterone Stanozolol
Fluoxymesterone Oxandrolone
Oxymetholone Danazol
Methandrostenolone * Norethandrolone *
Oxymesterone * Ethylestrenol *
1-Methyl Derivatives
Mesterolone * Methanolone acetate *
Testosterone Esters
Testosterone undecanoate
Parenteral Agents
Testosterone proprionate Testosterone cypionate
Testosterone enanthate Methanolone enanthate *
Nandrolone phenproprionate Nandrolone decanoate
Boldenone undecylenate † Mibolerone †
* Not available in United States for human therapeutic use but available through illicit channels.
† Veterinary product.
The abuse of androgenic-anabolic steroids is characterized by doses in excess of 1 to 100 times

pharmacologic doses in variable patterns of administration.[1][9][15][21][34][43][51][53][54] Many athletes will use
the drugs in a “cyclic” pattern, taking them for periods ranging from 4 to 18 weeks, alternating with drug
holidays of 1 month to 1 year. Some individuals use a “pyramid” administration scheme whereby they begin
with a low daily dose and increase to higher dosages. Others employ a “stacked” or “stacking” schedule in
which several androgenic-anabolic steroids are taken simultaneously. Many users “stack the
pyramid.”[9][21][34] The pattern of administration varies by sport, region, availability, and popularity. Some
androgenic-anabolic steroid products are diverted from veterinary use, produced by clandestine laboratories,
or smuggled into the United States. The drugs are typically obtained from the black market by trainers or
associates or on prescription of a physician or veterinarian. Magazines, books, and the Internet are sources
of information on means to obtain and abuse androgenic-anabolic steroids. Pursuant to the Anabolic
Steroids Control Act of 1990, androgenic-anabolic steroids are considered to be Schedule III controlled
substances in the United States.


Pharmacology
Testosterone is the male steroid prohormone that is metabolized by 5a-reductase to dihydrotestosterone,

and both hormones react with androgen receptors throughout the body.[9][52] Physiologic release of
testosterone is controlled by the hypothalamic-adrenal-gonadal axis. [1] Testosterone is primarily responsible
for the wolffian stimulation phase of sexual differentiation, and dihydrotestosterone produces androgenic
(virilizing) and anabolic (muscle promoting) effects in humans ( Fig. 72–1 ).[52] Testosterone is also
metabolized by aromatase in the cytochrome P-450 system to form estradiol, which in excess may lead to
feminizing effects ( Fig. 72–2 ). Androgenic-anabolic steroids have been synthesized by modification of
testosterone to minimize first-pass hepatic metabolism, prolong the duration of action, enhance the potency
of the molecule, and/or enhance gastrointestinal absorption.[52] The three major types of modifications
include esterification of the 17ß-hydroxyl group, alkylation at the 17a-position, and modification of the steroid
ring structure (see Table 72–1 ). These modifications influence their potential for toxicity and laboratory
detection (see Fig. 72–2 ). All androgenic-anabolic steroids in current use, whether administered orally or
parenterally, possess anabolic and androgenic actions.[1][51]
Figure 72-1 Regulation of testosterone release and activity in the male. Stimulatory effects indicated by a plus sign; inhibitory
feedback indicated by a minus sign.
Figure 72-2 Relationship of testosterone, precursors, synthetic analogs, and metabolites to effects.
Pathophysiology
Some physiologic actions of the hormone can be considered toxic when they occur inappropriately, such as
virilizing action in women and young children. Other adverse effects (e.g., gynecomastia in men) are a
consequence of estrogenic metabolites of androgenic-anabolic steroids (see Fig. 72–2 ). Some of these
drugs (e.g., fluoxymesterone and nandrolone) possess little estrogenic activity in therapeutic doses, but
estrogenic activity may occur with massive doses.[21] Some toxic effects associated with androgenic-
anabolic steroid use are not related to the hormonal effects but are related to chemical manipulation of the
testosterone structure (e.g., hepatic dysfunction due to androgenic-anabolic steroids with a 17a-alkyl
substitution). The mechanism of the development of some adverse effects linked to androgenic-anabolic
steroids, such as changes in lipoprotein metabolism, is unknown. There is wide variability in the
development of adverse effects, just as there are differences in the degree of virilization in normal men at
puberty. The susceptibility to the toxic, virilizing and feminizing effects is greatest in children, and the
virilizing effects are typically more obvious in women.[9] Much of the information on the toxic effects or the
innocuous use of androgenic-anabolic steroids is based on anecdotes, surveys, or therapeutic doses. There
has been no systematic evaluation of potential toxic effects in relation to the duration of use, patterns of
administration and dose, interactions among the androgenic-anabolic steroids, and influence of other agents
concomitantly consumed.


Acute Presentation
There are few, if any, reported cases of toxic effects from the acute ingestion or single intramuscular
injection of androgenic-anabolic steroids in humans. Conceivably, minor gastrointestinal effects after
ingestion could occur. Infectious complications[19][33][42] and abscesses[28] from intramuscular injection have
been reported. Allergic reactions from oils (i.e., sesame or cottonseed) used as diluents in some
intramuscular preparations may occur in hypersensitive individuals. Androgenic-anabolic steroids may
interact with anticoagulants and antidiabetic drugs to increase the effect of these drugs.[29]
Chronic Presentation
With regular use of suprapharmacologic doses of androgenic-anabolic steroids, most individuals will
experience physical changes ( Table 72–2 ) that are well recognized.[9][21][34][51][52][53] These individuals will
unlikely seek medical help until the changes become disturbing or embarrassing.
Table 72-2 -- Clinical Presentation of Androgenic-Anabolic Steroid Excess

Effects in Children and Adolescents
Stunting of growth
Precocious puberty in boys
Contrasexual precocity in girls
Effects in Women
Hirsutism
Acne, oily skin
Deepening of the voice
Clitoral hypertrophy
Decreased breast size
Augmented muscular development of upper torso
Menstrual irregularities
Effects in Men
Acne, oily skin
Disproportionate muscular development of upper torso
Testicular atrophy, scrotal pain
Recession of temporal hairline
Gynecomastia
Other Potential Effects
Impaired liver function
Hepatomas, cholestasis, pelosis hepatis
Peripheral edema
Cellulitis, abscesses, keloidal scarring
Aggressive behavior and mood swings
General Effects
Most individuals who abuse androgenic-anabolic steroids will appear to be athletic in build, particularly in the
upper body. In both sexes, findings associated with androgenic-anabolic steroid abuse include acne, oily
skin, edema from sodium and water retention, jaundice, aggressive behavior with mood swings, rapid weight
gain, disproportionate development of the upper torso, needle marks and keloidal scarring in large muscle
groups, and increased susceptibility to tendon strains and injuries. [11][30] Men may experience testicular
atrophy, scrotal pain, priapism, gynecomastia, and recession of the temporal hair line. Except for the
alopecia, the foregoing effects are eventually reversible in both sexes, but they can persist for 12 weeks or
longer on discontinuation of the drugs.[9][51] Women may develop irreversible hirsutism, male pattern
alopecia, clitoral hypertrophy, deepening of the voice through laryngeal hypertrophy, and reduced breast
size.[45] Amenorrhea and menstrual irregularities also occur in women, but are usually reversible on
discontinuation of the hormones. Other effects such as myocardial infarction,[18][25] left ventricular
hypertrophy,[39] sudden cardiac death,[13] stroke,[39] sleep apnea,[41] acute psychosis (e.g., “road
rage”),[37][46] suicidal ideation,[3] physical dependence and a withdrawal syndrome,[4][36] anorexia
nervosa,[36] and tumors (hepatocellular adenoma) [20][44] have been attributed to androgenic-anabolic steroid
use, but the association with androgens is unclear, unpredictable, and rare. Moreover, these effects may be
causally linked to premorbid conditions, other predisposing variables, or coincidence. Significant morbidity or
mortality in athletes who have consumed androgenic-anabolic steroids is rare, and approximately 100 cases
have been summarized.[20]
Hepatic Effects
Abuse of androgenic-anabolic steroids has been linked to cholestatic jaundice, peliosis hepatis, and
hepatomas. Asymptomatic elevation of transaminase liver enzymes appears to be the most common
manifestation of androgenicanabolic steroid–associated effects on the liver, and is reversible on
discontinuation of the hormones.[20][44] These transaminase elevations are also transient in some patients
who continue their use of androgenic-anabolic steroids; peak transaminase concentrations are noted after
10 to 12 days of administration. [24] Elevations of serum transaminase concentrations are not predictable,
may be related to strenuous physical exercise, and rarely lead to jaundice. Cholestasis is a recognized
complication of the use of the 17a-alkyl substituted androgenic-anabolic steroids, such as stanozolol and
oxymetholone.[20][23][51] Resolution of the jaundice may take several months. Many cases have involved
therapeutic regimens in the elderly or ill patients; most athletes avoid the 17a-alkyl substituted hormones or
discontinue their use when icterus develops. Many of the 17a-alkyl substituted androgens are no longer
available for human therapeutic use in the United States due to the risk of hepatotoxicity, but they are still
available through illicit channels.[15][21][51]
Peliosis hepatis is characterized by microscopic to grossly visible blood-filled cysts in the liver, which may
produce subclinical hepatoxicity or life-threatening internal hemorrhage. Since the potential link between
androgenic-anabolic steroid use and peliosis hepatis was proposed in 1952, approximately 70 cases of
hepatic or splenic peliosis have been associated with androgenic-anabolic steroid use. [5][20] Most of the
reported cases involve patients who consumed 17a-alkyl substituted androgenic-anabolic steroids, such as
fluoxymesterone, norethandrolone, oxymetholone, methenolone, and methyltestosterone. Subclinical cases
may not be readily diagnosed by standard clinical laboratory studies.
The incidence of developing hepatic tumors has been projected to be 1 to 3 per cent within 2 to 8 years of
regular exposure to greater than physiologic replacement doses of 17a-alkyl substituted androgenic-
anabolic steroids,[20] but the incidence of hepatic tumors in athletes using these analogues with stacked or
pyramid dosing regimens is unknown. Since the first awareness of the potential link of hepatic tumors and
androgenic-anabolic steroid use in 1971, approximately 90 cases have been reported.[20][44] Most of the
cases developed hepatocellular adenoma, a relatively benign epithelial tumor; and nearly half of the patients
were diagnosed with comorbid inherited anemias, such as Fanconi’s syndrome. The development of other
tumors, such as Wilms’ tumor and prostatic carcinoma, after using androgenic-anabolic steroids is so rare
that this may be coincidental. Difficulty in attributing a causal risk of hepatotoxicity and hepatomas from
androgenic-anabolic steroid use arises from the absence of epidemiologic studies in athletes who observe a
consistent regimen known to be free of contaminants or other drugs.
Other Factors
In evaluating a patient with androgenic-anabolic steroid abuse, consideration should also be given to the
effects produced by strenuous physical exercise (e.g., nonpathologic, transient increased concentrations of
transaminase enzymes)[24]; use of nutritional supplements or specialized training diets; the competitive
aggressiveness of athletes; cellulitis from intramuscular injection with contaminated needles; the risk of
transmittable diseases, such as hepatitis and the acquired immunodeficiency syndrome (AIDS), from needle
sharing[19][28][33][42]; abscesses from intramuscular injection of androgens in oil; use of other drugs to
minimize the undesirable effects of androgenic-anabolic steroids,[15][20][21][51] such as antiestrogens
(tamoxifen or clomiphene), human chorionic gonadotropin to prevent testicular atrophy and oligospermia,
and furosemide (for edema and urine dilution); and use of drugs, such as probenecid and epitestosterone, to
mask analytical detection of androgenic-anabolic steroid use.
Certain patients receiving androgenic-anabolic steroids therapeutically may be at risk for excess
consumption.[1] They include female-to-male transsexuals,[49] patients with wasting diseases (e.g., aplastic
anemia, AIDS), and those on replacement testosterone (e.g., hypogonadism, bilateral orchidectomy).[52]
Several behavioral, physical, and social characteristics have been associated with abusers of androgenic-
anabolic steroids.[34][47] They include recent personality or behavioral changes, recent significant increase in
appetite and food consumption, frequent attendance or competition in body building contests, and
employment as a night-club “bouncer,” professional wrestler, male nude dancer, or law enforcement officer.
Chronic abusers may also self-treat steroid-related adverse effects with other drugs (e.g., tamoxifen, acne
medications, diuretics, anxiolytics) and use nutritional supplements. A rapid weight gain of 25 pounds or
more over 3 to 6 months and recent gains in muscular strength and build may also be associated with
chronic androgenic-anabolic steroid use.
Children of both sexes can develop the life-long effects of premature virilization, feminization, and
epiphyseal closure.[9][51]


The diagnosis of excessive intake of androgenic-anabolic steroids is straightforward with an accurate history
of intentional and unintentional use. In the absence of a clear history or laboratory confirmation, other
causes of androgen excess,[40] such as congenital adrenal hyperplasia, and the differential diagnoses of
hirsutism,[32] jaundice,[27] and drug-induced hepatotoxicity,[31] should be considered ( Table 72–3 ). Many of
the considerations in the differential diagnosis of androgenic-anabolic steroid excess may require
consultation or referral to an experienced endocrinologist.
Table 72-3 -- Differential Diagnosis of Androgenic-Anabolic Steroid Excess

Androgen-Secreting Conditions
Neoplasms of the ovary
Neoplasms of the adrenal
Congenital adrenal hyperplasia, late-onset
Polycystic ovary syndrome
Stromal hyperthecosis
Central precocious puberty in boys
Peripheral precocious puberty in boys
Contrasexual precocity in girls
Causes of Hirsutism
Drug-induced (e.g., phenytoin, danazol, minoxidil, diazoxide)
Associated conditions (e.g., anorexia nervosa, Cushing’s syndrome)
Causes of Jaundice and Impaired Liver Function
Drug-induced (e.g., oral contraceptives, ethanol, isoniazid)
Overproduction of bilirubin (e.g., hemolysis)
Decreased bilirubin conjugation (e.g., sepsis)
Hepatocellular disease (e.g., viral hepatitis)
Intrahepatic biliary obstruction (e.g., hereditary disorders)
Extrahepatic biliary obstruction (e.g., malignancies)


LABORATORY STUDIES
Most hospital laboratories will not be able to determine the presence of androgen-anabolic steroids in urine
or blood; a specimen will need to be sent to appropriate reference laboratories. Radioimmunoassays that
are directed toward reaction with the testosterone ring lack specificity and have been generally abandoned
as screening tests. Oversight bodies, such as the National Collegiate Athletic Association and the
International Olympic Committee, have adopted techniques that use gas chromatography and mass
spectroscopy to detect unique metabolites in urine.[21][26][51] The 17a-alkyl substitution on androgenic-
anabolic steroids is not metabolically altered, and hence these agents produce unique metabolites that can
be detected in the urine and blood. Alkylation of the steroid ring at the 1 position, such as mesterolone and
methenolone acetate, also produces unique and detectable metabolites. The detection of esterified
testosterone is more difficult because their metabolites are similar to those of endogenous testosterone.
Because an increase in testosterone metabolites may occur as a consequence of physical training,
increased concentrations by themselves do not indicate consumption of androgenic-anabolic steroids. A
technique to detect testosterone esters involves the measurement of testosterone and epitestosterone in the
urine.[6] Epitestosterone is an endogenous C-19 steroid that is devoid of androgenic activity and is typically
found in a 1:1 ratio with testosterone in the urine. Because exogenous testosterone apparently is not
epimerized to epitestosterone, the equal ratio would be altered with exogenous testosterone administration.
Although a 6:1 ratio of testosterone to epitestosterone has been adopted as a means to detect exogenous
testosterone use, data supporting the quality assurance and clinical correlation of this ratio have not been
published in detail and have been questioned.[2]
Several approaches have been used to circumvent detection of exogenous androgenic-anabolic steroids. To
maintain a 6:1 ratio of testosterone to epitestosterone some individuals take epitestosterone or human
chorionic gonadotropin, which stimulates endogenous testosterone production.[26][51] Other strategies
include dilution of urine by using diuretics and diminution of urinary excretion of testosterone by using
probenecid; both approaches are illegal for athletic competition.[21][26] Detection of androgenic-anabolic
steroid use is influenced by many factors, such as interpersonal variability in metabolism and laboratory
variability in specimen handling and analysis. Typically, oral agents with short serum half-lives or
transdermal testosterone patches can be used up to several days before specimen collection and not be
detected. In contrast, parenteral agents with long half-lives (e.g., nandrolone decanoate) can be detected for
months (some for more than 6 to 9 months) after cessation of use.[26][51]
Chronic use of androgenic-anabolic steroids has been associated with the alteration of several clinical
laboratory studies. The lipoprotein profile of some users of androgenic-anabolic steroids is indistinguishable
from the profile associated with increased risk for coronary heart disease (high low-density lipoprotein, low
high-density lipoprotein) but is more likely with the 17a-alkyl substituted derivatives and certain types of
athletes such as weight lifters.[22][39] The fasting glucose concentration may be decreased with recent
androgenic-anabolic steroid use, and insulin resistance has been reported.[9][20][51] Growth hormone
concentrations may be elevated during use of some androgenic-anabolic steroids,[9][51] whereas thyroid-
stimulating hormone, total and free thyroxine, triiodothyronine, and thyroid hormone binding globulin are all
suppressed.[12] The significance of these laboratory changes is unclear, and they typically do not result in
any clinical effects. Men may develop reversible oligospermia. [9][51]
For chronic users of androgenic-anabolic steroids who do not heed warnings to stop, periodic monitoring of
liver function tests may be prudent.


TREATMENT
General Measures
For acute massive ingestions of androgenic-anabolic steroids, decontamination of the gastrointestinal tract
with oral administration of activated charcoal may reduce absorption if employed within 1 to 2 hours of
ingestion. Activated charcoal is used empirically as a general adsorbent, because there is no evidence to
support or refute its efficacy. Because there appears to be minimal risk from ingesting pharmacologic doses
of androgenic-anabolic steroids, gastrointestinal decontamination should not be indicated in these cases.
For intramuscular injections of androgenic-anabolic steroids, cleansing and examination of the injection site
would be advisable. Complications associated with androgenic-anabolic steroid use may require
symptomatic treatment, such as lorazepam, diazepam, or haloperidol for excessively aggressive and
combative patients ( Table 72–4 ).
Table 72-4 -- Treatment Essentials of Androgenic-Anabolic Steroid Excess

Acute Exposure
1. For massive, recent ingestions, consider oral administration of activated charcoal, 1 g/kg, typically 30 to 60 g
in adults and adolescents.
2. For combative behavior, consider lorazepam, 1 to 2 mg IM; diazepam, 2 to 10 mg IV or 2 to 20 mg IM; or
haloperidol, 2 to 5 mg IM.
Chronic Exposure
1. Discontinue use.
2. Incision and drainage of abscesses.
3. Cleanse areas of cellulitis, débride necrotic areas, and administer systemic antibiotics as indicated by culture
and sensitivity results.
4. Psychiatric and endocrinologic treatment for dependence and withdrawal.
Toxin-Specific Measures
There are no specific antagonists for acute or chronic exposures to androgenic-anabolic steroids.
Discontinuation of further androgenic-anabolic steroid use should be emphasized to the patient.
Management of a withdrawal syndrome associated with androgenic-anabolic steroids has been
described,[4][53] but the risks and benefits of such an approach have not been reported.


DISPOSITION
The need for hospitalization of patients abusing androgenic-anabolic steroids depends on the severity of the
illness. Patients with suicidal ideation or inappropriate behavior may benefit from a psychiatric evaluation to
assess the need for hospitalization. Most patients can be more appropriately treated under the care of a
primary care physician, who may consult with an endocrinologist when warranted. Because many
androgenic-anabolic steroids have a long duration of action, patients should be monitored periodically for
several months for the development of any complications.


SEQUELAE
Acute
The acute sequelae of chronic androgenic-anabolic steroids use include bacterial or viral infections from use
of contaminated needles for parenteral administration.[19][28][42]
Chronic
The virilizing effects of androgenic-anabolic steroids can have profound life-long effects on women
(irreversible hirsutism, male pattern alopecia, clitoral hypertrophy, deepening of the voice, and reduced
breast size) and children (premature virilization and epiphyseal closure). Physically mature men may
experience short-term effects (testicular atrophy, scrotal pain, priapism, gynecomastia) that diminish on
discontinuation and also permanent changes (recession of the temporal hair line).[9][21][34][51][52][53] There is
evidence that abuse of androgenic-anabolic steroids may lead to abuse of other substances,[16][50][57]
patterns of antisocial behavior,[8][57] and development of psychiatric illness. [48] Long-term health effects of
androgenic-anabolic steroid use are unknown and require a more rigorous methodologic assessment.[58]


SPECIAL SITUATIONS
Other drugs have been used for their purported anabolic effects[9][14][15][21][26][35] or ergogenic
potential[7][15][21][26][38] ( Table 72–5 ). Most of these agents have been banned or limited by athletic
oversight organizations,[21] but inconsistencies abound. The use of androstenedione, a precursor of
testosterone (see Fig. 72–2 ), has been banned by the International Olympic Committee, but its use is still
allowed in some U.S. professional sports.[14] Creatine and nutritional supplements are used by a wide
variety of athletes,[21][38] but little is known of their inherent toxicity. Concomitant use of these agents with
androgenic-anabolic steroids may complicate or obscure the evaluation of a patient with suspected adverse
effects. The recent chemical synthesis of nonsteroidal androgens[10] and their eventual marketing portends
other challenges in determining toxicity from anabolic-androgenic steroids.
Table 72-5 -- Agents with Purported Anabolic or Ergogenic Activity

Anabolic Claims Ergogenic Claims
Androstenedione Amphetamines
Clenbuterol Caffeine
Human chorionic gonadotropin Creatine
Human growth hormone Erythropoietin
Orotic acid Gamma-hydroxybutyrate
Smilax officinalis Selegiline
Zeranol Sodium bicarbonate


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Chapter 73 – Thyroid Hormones
MILTON TENENBEIN
Essentials
• History of thyroid hormone ingestion
• Symptoms and signs are delayed for many hours to a few days after levothyroxine overdose
• Symptoms and signs (rare): tachycardia, fever, diaphoresis, diarrhea, tremor, anxiety
• Chronic overdose or thyroid hormone abuse can present as a clinical picture of thyrotoxicosis
INTRODUCTION
Thyroid hormone poisoning is an uncommon event of low morbidity and no mortality. In their 1997 annual
report, the American Association of Poison Control Centers documented 2.2 million human exposure cases,
of which 6621 were thyroid hormones (0.3 per cent), and there were no deaths attributable to thyroid
poisoning.[8] Several case series of thyroid hormone ingestion have been published reporting minimal
morbidity and no mortality.[3][4][7][9][15][17] Most cases involve levothyroxine (T 4) rather than ingestion of
thyroid extract because the former is more frequently prescribed. Onset of toxicity after levothyroxine
overdose is later compared with that for thyroid extract.[15] Chronic overdose or thyroid hormone abuse is
more likely to produce toxicity. [14] These patients are typically referred to endocrinologists rather than to
toxicologists.


PATHOPHYSIOLOGY
Thyroid hormones are essential for normal growth and development and have an important function in
energy metabolism. The thyroid gland produces tetraiodothyronine (thyroxine or T4), which is the
predominant circulating hormone, and some triiodothyronine (T3), which is the biologically active hormone.
Most T3 is derived in the peripheral tissues from T4. This conversion takes several days and is regulated by
a negative feedback loop. Excess T4 suppresses secretion from the thyroid gland and the conversion of T4
to T3 in the peripheral tissues,[2][12] increases the rate of disposal of both T 4 and T3,[2] and down-regulates
the T3 nuclear receptors.[13] These regulatory mechanisms afford considerable tolerance to even large
overdoses of levothyroxine.
Very large doses of thyroid hormones are required to produce toxicity, well in excess of 20 therapeutic doses
(2.0 mg of levothyroxine). Significant toxicity is unlikely after the ingestion of as much as 50 therapeutic
doses (5.0 mg of levothyroxine).[17] Therefore, the ingestion of 20 therapeutic doses of thyroid hormones can
be considered as a conservative dose of concern.


The typical presentation is a history of ingestion with few, if any, signs and symptoms.[3][4][7][9][15][17] Because
of the previously discussed regulatory mechanisms, the expected manifestations of hyperthyroidism,
including tachycardia, widened pulse pressure, tremor, diaphoresis, heat intolerance, diarrhea, and
emotional instability, are rarely seen. Signs and symptoms are more likely from the overdose of thyroid
extract because of its T3 content than from levothyroxine.[15]
The few patients who experience toxicity may have fever, tachycardia, diarrhea, diaphoresis, tremors,
restlessness, and anxiety ( Table 73–1 ). This occurs within hours of thyroid extract ingestion and up to
several days after the ingestion of levothyroxine. Although there is a report of significant toxicity with
seizures after an acute ingestion,[6] significant manifestations are more likely after chronic ingestion or
thyroid hormone abuse.[14]
Table 73-1 -- Clinical Presentation * of Thyroid Hormone Overdose

Fever
Diaphoresis
Heat intolerance
Diarrhea
Tachycardia
Tremors
Restlessness
Anxiety
* Signs and symptoms are uncommon and are more likely after chronic overdose or abuse.


In the symptomatic patient presenting with a concealed or unknown history of thyroid hormone ingestion or
abuse, the differential diagnosis can be challenging. Considerations include endogenous hyperthyroidism,
pheochromocytoma, organic brain syndrome, central nervous system infection, toxicity from psychoactive
drugs (cocaine, amphetamines, hallucinogens, and anticholinergics), psychosis, and acute withdrawal states
( Table 73–2 ).
Table 73-2 -- Differential Diagnosis of Thyroid Hormone Overdose

Endogenous hyperthyroidism
Pheochromocytoma
Organic brain syndrome
Central nervous system infection
Other psychoactive drugs (cocaine, amphetamines, hallucinogens, anticholinergics)
Psychosis
Acute withdrawal states (sedative-hypnotic, opioid)


LABORATORY STUDIES
The only important laboratory study after acute overdose is a serum thyroxine concentration that should be
obtained whenever a patient has ingested a dose of concern (greater than 20 therapeutic doses). Patients
with values greater than 25 µg/dL require close follow-up. If chronic thyroid hormone ingestion is suspected,
a serum thyroglobulin concentration should be obtained. A decreased value supports this diagnosis,
whereas an elevated serum thyroglobulin supports a diagnosis of endogenous hyperthyroidism.[10]


TREATMENT
Supportive care is provided as needed ( Table 73–3 ). Gastrointestinal decontamination is performed with
oral aqueous activated charcoal in patients who present early after ingesting more than 20 therapeutic
doses. A serum thyroxine concentration is obtained, which can be helpful in predicting toxicity and for
selecting patients for follow-up. For symptomatic patients, fever is treated with acetaminophen. For
symptomatic sympathetic hyperactivity, propranolol, 1 to 4 mg/kg/day divided every 6 to 12 hours for children
and 80 to 160 mg/day in divided doses for adults, is considered. In asymptomatic patients, prophylactic
antithyroid therapies such as propylthiouracil, propranolol, cholestyramine, and prednisone are
unnecessary.[3][9][15]
Table 73-3 -- Treatment of Thyroid Hormone Overdose

1. Supportive care as needed
2. If more than 20 therapeutic doses ingested:
a. Activated charcoal (aqueous)
b. Obtain serum thyroxine concentration (follow as an outpatient if >25.0 µg/dL)
c. Acetaminophen for fever
d. Propranolol for sympathetic hyperactivity
Child: 1.0–4.0 mg/kg/d
Adolescent or adult: 80–160 mg/kg/d
The role of extracorporeal removal techniques is unclear. Because of the extensive plasma protein binding
of circulating thyroid hormones, plasmapheresis would be expected to be superior to hemodialysis and
hemoperfusion. There are reports of both failure[5][11] and success[1] for plasmapheresis in thyroid hormone
overdose. Given the benign outcome of thyroid hormone ingestion, extracorporeal elimination techniques
would rarely, if ever, be indicated.
In toxic chronic overdose patients, further ingestion of thyroid hormones is discontinued and treatment is as
for endogenous hyperthyroidism.[16]


DISPOSITION
Asymptomatic acute overdose patients who have ingested a dose of concern should be discharged from the
emergency department after activated charcoal administration and blood specimen collection. They should
be advised to obtain medical reassessment for any of the following symptoms: fever, palpitation, diarrhea,
tremors, diaphoresis, or irritability. Patients with a serum thyroxine concentration greater than 25.0 µg/dL
should be reassessed the following day.
Symptomatic chronic thyroid overdose patients should be admitted to hospital, particularly if there is a
history of cardiac disease. Consultation with an endocrinologist should be considered. All patients with
purposeful ingestions should have a psychiatric assessment.


SEQUELAE
Sequelae are uncommon after thyroid hormone overdose. The chief risk is the aggravation of pre-existing
cardiac disease after chronic thyroid ingestion or abuse.


REFERENCES
1. Binimelis J, Bassas L, Marruecos L, et al: Massive thyroxine intoxication, evaluation of plasma extraction.
2. Braverman LE, Vagenakis A, Downs P, et al: Effects of replacement doses of sodium l-thyroxine on the
peripheral metabolism of thyroxine and triiodothyronine in man. J Clin Invest 1973; 52:1010-1017.
3. Golightly LK, Smolinske SC, Kulig KW, et al: Clinical effects of accidental levothyroxine ingestion in
children. Am J Dis Child 1987; 141:1025-1027.
4. Gorman RL, Chamberlain JM, Rose SR, et al: Massive levothyroxine overdose: High anxiety/low toxicity.
Pediatrics 1988; 82:666-669.
5. Henderson A, Hickman P, Ward G, Pond SM: Lack of efficacy of plasmapheresis in a patient overdosed
with thyroxine. Anaesth Intensive Care 1994; 22:463-464.
6. Kulig K, Golightly LK, Rumack BH: Levothyroxine overdose associated with seizures in a young child.
JAMA 1985; 254:2109-2110.
7. Lewander WJ, Lacouture PG, Silva JE, Lovejoy Jr FH: Acute thyroxine ingestion in pediatric patients.
Pediatrics 1989; 84:262-265.
8. Litovitz TL, Klein-Schwartz W, Dyer KS, et al: 1997 annual report of the American Association of Poison
9. Litovitz TL, White JD: Levothyroxine ingestions in children. An analysis of 78 cases. Am J Emerg
Med 1985; 3:297-300.
10. Mariotti S, Martino E, Cupini C, et al: Low serum thyroglobulin as a clue to the diagnosis of
thyrotoxicosis factitia. N Engl J Med 1982; 307:410-412.
11. May ME, Mintz PD, Lowry P, et al: Plasmapheresis in thyroxine overdose, a case report. J Toxicol Clin
Toxicol 1983; 20:517-520.
12. Pitman CS: Hormone metabolism. In: Degroot LJ, Cahil Jr CF, Martini L, et al ed. Endocrinology, New
York: Grune & Stratton; 1979:369.
13. Samuels HH, Stanley F, Shapiro LE: Dose-dependent depletion of nuclear receptors by l-
triiodothyronine: Evidence for a role in induction of growth hormone synthesis in cultured GH1 cells. Proc
Natl Acad Sci U S A 1976; 73:3877-3881.
14. Schottstaedt ES, Smaller M: “Thyroid storm”: Produced by acute thyroid hormone poisoning. Ann
Intern Med 1966; 64:847-849.
15. Tenenbein M, Dean HJ: Benign course after massive levothyroxine ingestion. Pediatr Emerg
Care 1986; 2:15-17.
16. Tietgens ST, Leinung MC: Thyroid storm. Med Clin North Am 1995; 79:169-184.
17. Tunget CL, Clark RF, Turchen SG, Manoguerra AS: Raising the decontamination level for thyroid
hormone ingestions. Am J Emerg Med 1995; 13:9-13.


Chapter 74 – Ethanol
EDWARD J. OTTEN KATHERINE M. PRYBYS LAURIE BETH GESELL
Essentials
• Initial loss of inhibition followed by decreased level of consciousness, ataxia, nausea, and possibly the
odor of ethanol
• Hypoglycemia and respiratory depression more common in children
• Is a common co-ingestant and is synergistic with other central nervous system (CNS) depressants
• Associated with trauma, seizures, cardiac dysrhythmias, pancreatitis, gastritis, liver disease,
hypothermia, aspiration pneumonia, and nutritional disorders
INTRODUCTION
Ethanol is the most frequently ingested toxin throughout the world.[8] The legal manufacturing of beer, wine,
and liquor and the use of ethanol as a solvent in the food and pharmaceutical industries make ethanol one
of the most available drugs in our society. It is also formulated into numerous household products (e.g.,
mouthwash and perfumes, which may contain as much as 70 per cent ethanol). These products are an
important source of intentional and unintentional overdoses.
Ethanol’s cost to society is enormous, possibly 200 billion dollars annually in the United States alone, with
200,000 alcohol-related deaths (most frequent cause after heart disease and cancer), lost work and medical
bills (approximately 20 per cent of all health care expenditure dollars), and other expenses. It has been
estimated that ethanol may be partially causal in up to 40 per cent of emergency department visits and one
third of hospital admissions.[26][30][36][71] Approximately 6 per cent of the population can be classified as
being alcoholic, with a much larger proportion of society being problem drinkers.[15] Ethanol has been
associated with 67 per cent of murders, innumerable sexual assaults, the majority of drownings and deaths
secondary to burns, 50 per cent of all fatal motor vehicle accidents, and 35 per cent of all suicides.[3][62]
Ethanol clearly dwarfs the untoward effects of all other drugs of abuse.
As a multisystem toxin, the chronic use of ethanol is associated with a myriad of medical illnesses, leading
to acute complications such as esophageal variceal hemorrhages, hemorrhagic gastritis, pancreatitis, and
cerebrovascular accidents. Other pathology is of more gradual presentation, such as the development of
cardiomyopathy and liver disease.


Pharmacology
Ethanol is a small, weakly polar, aliphatic hydrocarbon molecule that is both water and lipid soluble with a
volume of distribution that approaches that of water. It is rapidly absorbed from the gastrointestinal tract
within 30 to 60 minutes after ingestion. The stomach extracts about 20 per cent, with the remainder of
absorption occurring in the small intestine. Factors that delay absorption include the amount and
concentration of ingested ethanol, co-ingested drugs, food, and medical conditions that inhibit gastric
emptying. Ethanol distributes throughout body fluids and tissues, easily crossing the blood-brain barrier and
placenta. Its mean volume of distribution ranges from 0.56 to 0.72 L/kg.[10]
Metabolism of ethanol begins in the gastrointestinal cells by gastric mucosal alcohol dehydrogenase. This
gastric alcohol dehydrogenase activity is diminished in females, in the elderly with atrophic gastritis, and in
patients taking drugs such as aspirin and histamine-2 blockers, resulting in increased ethanol levels in these
individuals.[18][53] Most metabolism is primarily through two hepatic enzyme systems: (1) alcohol
dehydrogenase (ADH), which is generally the predominant mechanism, and (2) the microsomal ethanol
oxidizing system (MEOS), which is inducible and allows chronic drinkers to degrade ethanol at high rates.[27]
A third system, the peroxidase catalase pathway, has only a minimal role in humans. Because of mucosal
and hepatic metabolism, an oral dose of ethanol will yield a lower blood ethanol level than an equivalent
dose administered intravenously.
The alcohol dehydrogenase system (the main metabolic pathway) uses alcohol dehydrogenase to oxidize
ethanol to acetaldehyde and then aldehyde dehydrogenase to oxidize acetaldehyde to acetate ( Fig. 74–1 ).
Acetate ultimately becomes acetyl coenzyme A (acetyl-CoA), which then either enters the Krebs cycle,
undergoes ketone body formation, or is synthesized into fatty acids. Acetate is also converted to
acetone.[20][32][63][69] During this oxidative process, nicotinamide adenine dinucleotide (NAD+) is reduced to
NADH, thus changing the cytosol redox potential (NADH/NAD+ ratio). Alterations in the NADH/NAD+ ratio
impair cellular oxidative processes, such as conversion of lactate to pyruvate and gluconeogenesis ( Figs.
74–2 and 74–3 ). Because gluconeogenesis is vital to maintaining serum glucose homeostasis, profound
metabolic abnormalities such as acidosis, hypoglycemia, and other electrolyte disturbances may result.
Figure 74-1 Ethanol metabolism. NADH, nicotinamide-adenine dinucleotide, reduced form; CoA, coenzyme A. (From Kleinschmidt
KC, Delaney KA: Ethanol. In Haddad LM, Shannon MW, Winchester JF [eds]: Clinical Management of Poisoning and Drug Overdose,
3rd ed. Philadelphia, WB Saunders, 1998.)
Figure 74-2 Ethanol causes hypoglycemia through (1) decreased intake of glucose, (2) depletion of glycogen, and (3) blockade of
gluconeogenesis.
Figure 74-3 Some effects of the increased NADH/NAD+ ratio. (From Kleinschmidt KC, Delaney KA: Ethanol. In Haddad LM,
Shannon MW, Winchester JF [eds]: Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders,
1998.)
The dehydrogenase enzymes have variable activity in individuals depending on genetic makeup, gender,
and other factors.[73] Many Asians (approximately 50 per cent) and Native Americans have decreased
aldehyde dehydrogenase activity, resulting in higher acetaldehyde levels, which often produce a skin
flushing and nausea similar to a disulfiram reaction.
The microsomal ethanol oxidizing system (MEOS), a cytochrome P450–dependent system (CYP2E1 is the
specific P-450 enzyme), is usually a minor metabolic path, but its activity can be induced as much as 10-fold
to make it a prominent metabolic pathway.[11][38][41][65] Ethanol is metabolized to acetaldehyde and then
acetate in a manner similar to the dehydrogenase enzymes. However, reduced NAD phosphate (NADPH) is
oxidized instead. Induction of the MEOS system can be responsible for multiple drug interactions for other
drugs normally metabolized by this system, including increased production of N-acetyl-p-quinoneamine
(NAPQI), the toxic acetaminophen metabolite.[37]
Ethanol metabolism approximates Michaelis-Menten kinetics. At high ethanol levels, physiologic saturation
of the ADH and MEOS enzyme systems occur, and the elimination half-life prolongs as metabolism shifts
from concentration dependent first-order kinetics to time-dependent zero-order kinetics. Individuals
metabolize ethanol at rates of 100 to 200 mg/kg/hr or more, depending on previous exposure and genetic
differences.[21][32] Chronic exposure and high blood ethanol levels cause induction of the MEOS system,
which accounts for the significant increase in ethanol metabolism and clearance seen in chronic drinkers.
Other factors influencing the rate of ethanol clearance include continued absorption, liver disease, drug
induction of MEOS, and genetic variation, both ethnic and individual.[5][6][32][39][40][54][70]
About 10 per cent of ethanol is excreted unchanged through the kidneys and lungs. The ratio of ethanol
exhaled in the alveoli to blood remains constant, allowing for an accurate estimation of blood ethanol
concentration from the patient’s breath.
Pathophysiology
Ethanol is a CNS depressant, but it may have variable effects on individuals. In early acute intoxication, a
paradoxical stimulatory effect with euphoria, giddiness, and loss of inhibition may predominate. This is
because ethanol selectively depresses the cerebral cortex, impairing concentration and judgment.
Depression of the inhibitory control centers results in excitatory behavior and loss of restraint. As intoxication
worsens (serum levels of approximately 150 mg/dL in the casual drinker), CNS depression becomes
generalized, leading to ataxia, slurred speech, and sedation. This may progress to coma (serum levels
usually greater than 200 mg/dL), loss of protective reflexes, autonomic dysfunction, hypothermia, and death
(generally at serum levels greater than 400 mg/dL) ( Table 74–1 ).
Table 74-1 -- Association of Acute Adult Blood Ethanol Levels to Clinical Symptoms in the Nonchronic
Drinker
Blood Ethanol Concentration (mg/dL) Clinical Symptoms
No influence by general observation
<50
Special tests may elicit mild abnormalities
Euphoria, giddiness, garrulousness
Increased sociability
Loss of inhibitions
25–100 Impaired judgment and control
Bolstered self-confidence
Increased reaction time
Decreased precision in fine performance tests
Excitement, boisterousness, emotional instability
Loss of critical judgment
Poor memory and comprehension
100–200
Increased reaction time
Slurred speech
Blood Ethanol Concentration (mg/dL) Clinical Symptoms
Clumsiness, impaired balance, ataxia
Drowsiness
Confusion, disorientation
Exaggerated emotional states
150–300
Nausea and vomiting
Altered/impaired sensation, perception, balance
Slurred speech, ataxia, muscular incoordination
Apathy
Somnolence, stupor
Significant decreased response to stimuli
250–400
Significant muscular incoordination
Vomiting
Incontinence of urine and feces
Coma
Decreased or absent reflexes
300–500 Hypothermia
Hemodynamic or respiratory instability/collapse
Possible death
>400 Possible death
In experienced drinkers much higher levels may be required to produce significant depression of the central
nervous system.
Data from references 1 , 55 , 56 , 60 , and 69 .
Ethanol-induced intoxication is poorly understood and may be multifactorial in etiology. It has been
suggested that ethanol reacts with hydrophobic sites on certain receptors causing minor deformation to
three-dimensional structures, thus modulating their activity. The modulation of these receptors affects ion
channels, which hyperpolarizes the cell, increasing the threshold value potential necessary to fire.[7]
Two important receptors, the glutamate ion channel, N-methyl-d-aspartate (NMDA) and -aminobutyric acid
(GABA)A receptors, have been partially implicated in ethanol’s effects. This may involve the antagonism of
excitatory NMDA receptors (inhibiting normal calcium influx) and the potentiation of the inhibitory GABAA
receptor (increasing the chloride influx). The net effect would be hyperpolarization of the neuron and then,
when enough neurons are affected, the onset of sedation. Other receptors also appear to be involved in this
process, with subsequent modification of ionic flow. Ethanol also dissolves in the lipid bilayer of cell
membranes similar to anesthetic agents, altering the membrane fluidity of the cell membrane.[7][12][29][51]
With long-term ethanol abuse, receptor activity may also be affected by down-regulation, alterations of the
receptor-cytoskeleton structure, and phosphorylation.[7] The lipid profile of the neuron may be altered to
contain larger and more hydrophobic lipids in an attempt to regulate cell membrane viscosity and ideal lipid
packing. These mechanisms could partially address withdrawal states.


METABOLIC EFFECTS/ENDOCRINE EFFECTS
Hypoglycemia.
Hypoglycemia is common in the setting of ethanol use, especially in children, and may be a delayed effect.
The inhibition of gluconeogenesis is secondary to the depletion of NAD+. The chronic drinker is often in a
poorly fed, glycogen-depleted state and has multiple other nutritional deficiencies that can exacerbate this
effect. Children and adult patients with poor nutritional status or fasting states are particularly susceptible
because their hepatic glycogen stores are low. Ethanol-induced hypoglycemia should be suspected in
chronic drinkers, dieters, or chronically ill patients. Many common nutrients are affected, including vitamins,
especially thiamine. Electrolyte disturbances such as hypokalemia, hypocalcemia, hypophosphatemia, and
hypomagnesemia may exist.
Hypomagnesemia.
Profound hypomagnesemia can be a subtle yet common and life-threatening complication of chronic ethanol
ingestion. The etiology behind this involves poor dietary intake combined with decreased gastrointestinal
absorption and ethanol-induced increase in urinary excretion. Because 50 to 70 per cent of magnesium is
contained in bone, serum magnesium levels may not reveal significant magnesium losses. Many chronic
drinkers have profound intracellular magnesium losses despite normal blood levels. Hypomagnesemia is
often complicated by hypocalcemia, owing to inhibition of parathyroid hormone release.[42]
Alcoholic Ketoacidosis.
Alcoholic ketoacidosis (AKA) is defined as an increased anion gap metabolic acidosis associated with the
consumption of ethanol. This illness is usually seen in chronic drinkers, although AKA has also been
documented occasionally in first-time drinkers. Alcoholic ketosis typically occurs 2 to 3 days after an ethanol
binge. Its multifactorial etiology leads to a deleterious cascade of metabolic events. Abdominal pain and
protracted vomiting lead to poor nutritional intake and intravascular volume depletion. Glycogen depletion
accompanied by ethanol-inhibited gluconeogenesis leads to hypoglycemia (see Fig. 74–2 ). The resulting
increase in catecholamine levels inhibits insulin secretion and triggers the release of counter-regulatory
hormones (glucagon, growth hormone, and cortisol). Lipase activity increases, which promotes lipolysis.
Free fatty acids are generated and catabolized to acetyl-coenzyme A, which is converted into ketones,
predominantly ß-hydroxybutyrate. These ketone bodies accumulate, causing ketosis and metabolic acidosis
( Fig. 74–4 ).
Figure 74-4 Factors causing ketonemia in alcoholic ketoacidosis. ADH, antidiuretic hormone. *The tricarboxylic acid cycle is
significantly slowed owing to intermediates being used for gluconeogenesis. (From Kleinschmidt KC, Delaney KA: Ethanol. In Haddad
LM, Shannon MW, Winchester JF [eds]: Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders,
1998.)
Other Endocrine Effects.
Multiple other endocrine effects can be seen. Ethanol affects most levels of the hypothalamic-pituitary axis.
This may lead to decreased testosterone production in men and amenorrhea in women. Elevated
glucocorticoid states are also seen, and many chronic drinkers have physical manifestations resembling
Cushing’s syndrome. General metabolism is altered because elevated NADH/NAD+ levels slow the
oxidation of fats. Many of these effects are reversible with cessation of ethanol use.[1][2][25]
Wernicke’s Encephalopathy.
Wernicke’s encephalopathy is a medical emergency that may be encountered in chronic drinkers. It results
from thiamine (vitamin B1) deficiency, and genetic predisposition plays a role. Chronic drinkers are prone to
thiamine deficiency for several reasons: (1) malnourishment; (2) ethanol’s interference with gastrointestinal
absorption of thiamine; and (3) hepatic dysfunction, which hinders thiamine storage and activation. Thiamine
is a vital cofactor for pyruvate dehydrogenase and a-ketoglutarate dehydrogenase, which are involved in
carbohydrate metabolism, and for transketolase, an important enzyme in the pentose phosphate pathway.
Other Disorders.
Neurologic manifestations can include seizures (both during intoxication and withdrawal states), alcohol
hallucinosis (persistent, often threatening auditory hallucinations), and peripheral neuropathy (tends to be
symmetric and distal and can affect multiple sensory modalities and motor strength). Dilated cardiomyopathy
may be present. Atrial fibrillation or other dysrhythmias not related to magnesium deficiency can occur.[8][31]
Thiamine deficiency can result in “wet beriberi” with high-output congestive heart failure. Other disorders can
include skeletal muscle myopathy and thrombocytopenia and neutropenia.[8][39]


Acute Intoxication
The diagnosis is based on a history of ingestion plus altered mental status and possibly a verifying blood
alcohol concentration. The characteristic odor of ethanol may be noted. In early acute intoxication euphoria,
giddiness, and loss of inhibitions may predominate. As intoxication worsens, CNS depression becomes
generalized, leading to ataxia, nystagmus, slurred speech, and sedation. This may progress to coma, loss of
protective airway reflexes, autonomic dysfunction, hypothermia, and death. Systemic symptoms can include
nausea, vomiting, abdominal pain, facial flushing, ataxia, and diminished reflexes.[8][66]
The clinical presentation of acute ethanol toxicity depends on the patient’s underlying tolerance, because the
chronic drinker may tolerate a blood alcohol concentration that causes coma or death in the novice drinker.
A spectrum of clinical signs and symptoms (see Table 74–1 ) parallels the blood alcohol concentration in the
nonchronic drinker that may help differentiate ethanol intoxication from other associated problems.
Children may metabolize ethanol faster than adults but are more susceptible to hypoglycemia and
respiratory depression at lower blood alcohol concentrations.[8][22][39][60][68] Pediatric ethanol exposure can
occur when children imbibe remnants from a party or ethanol-containing products such as mouthwash or
with deliberate administration. The clinical manifestations of ethanol intoxication in children range from
sleepiness to ataxia, vomiting, seizure, and coma. Ethanol-induced hypoglycemia reportedly occurs in 10 to
22 per cent of children. Prolonged observation of symptomatic patients is necessary because hypoglycemia
may be delayed up to 6 hours after ingestion and does not correlate with ethanol doses.[35][59][64]
Wernicke-Korsakoff Syndrome
Classically, the clinical presentation of Wernicke’s encephalopathy is described as a triad of oculomotor

disturbance, cerebellar ataxia, and mental confusion. However, this full-blown clinical presentation is seldom
encountered. The clinical findings are variable and often isolated to ophthalmoplegia or to disorientation,
stupor, or coma. Wernicke’s encephalopathy is a clinical diagnosis that may often be unrecognized. In one
study, 18 of 22 cases of pathologically confirmed Wernicke’s encephalopathy presented as coma. In 21 of
these patients the diagnosis was not made until autopsy.[49] It would thus seem prudent to administer
thiamine to all patients with confusion or coma, patients suspected of being nutritionally depleted, or chronic
drinkers.[49][58]
Korsakoff’s psychosis is more a memory deficit than a true psychosis. Typically, retrograde and anterograde
memory is affected but distant memories are not. Confabulation manifests as the patient attempts to fill in
the details. In some individuals the symptoms may be reversible with discontinuance of ethanol and the
assumption of a healthier lifestyle.
Alcoholic cerebellar degeneration manifests clinically with the gradual onset of ataxia. This may appear
similar to Wernicke’s encephalopathy; however, nystagmus and confusion are not present. Some
improvement may be seen when ethanol is discontinued.
Gastrointestinal disease can include esophagitis and gastritis, Mallory-Weiss tears and Boerhaave’s
syndrome from barotrauma during emesis, and esophageal or gastric cancer secondary to unknown
mechanisms, which could include direct contact, acetaldehyde, or oxygen radicals. Pancreatitis occurs
commonly. Hepatic disease can range from mild hepatic steatosis to steatonecrosis or cirrhosis, with
subsequent hepatic encephalopathy and the formation of esophageal varices.
Alcoholic Ketoacidosis
Patients with alcoholic ketoacidosis present with dehydration, diaphoresis, and an anion gap metabolic
acidosis. Complaints include abdominal pain, nausea, vomiting, and weakness. Vital signs reveal an
increased pulse and respiratory rate and possibly hypotension secondary to hypovolemia. Alcoholic
ketoacidosis may be complicated by the presence of gastritis, gastrointestinal hemorrhage, pancreatitis,
pneumonia, hepatitis, cirrhosis, and nutritional deficiencies. Blood ethanol levels are low or absent. Arterial
blood gas analysis may reveal metabolic acidosis or a mixed acid-base disorder with metabolic acidosis,
metabolic alkalosis due to intravascular volume contraction, and compensatory respiratory alkalosis. Serum
glucose levels may be low, normal, or mildly elevated.
Hypomagnesemia
Symptoms of hypomagnesemia include malaise, weakness, anorexia, nausea, tremor, paresthesia, ataxia,
delirium, seizure, syncope, obtundation, and coma. Physical findings include clonus, increased deep tendon
reflexes, and Chvostek’s and Trousseau’s signs. Electrocardiographic abnormalities such as increased PR
and QT intervals, nonspecific ST segment changes, U waves, and flipped T waves may occur. Ventricular
dysrhythmias, particularly torsades de pointes, are potential fatal complications. Recognition of torsades de
pointes and emergent administration of magnesium sulfate can be lifesaving.


Assessing the patient to establish that the ethanol level “fits” the degree of CNS depression being seen and
frequent repeated examinations to ensure that the patient’s clinical state is resolving are useful methods for
ensuring that CNS depression is due to ethanol alone.[8][39][43][49][55] Other causes of altered mental status
should always be considered in the ethanol-intoxicated patient ( Table 74–2 ). Many serious conditions
masquerade as ethanol intoxication. Head injury, hypoxia, hypercapnia, hypoglycemia, hypothermia, sepsis,
meningitis, and hepatic encephalopathy not only resemble ethanol intoxication but also may coexist. Chronic
ethanol abuse predisposes an individual to significant nutritional and metabolic conditions that mimic acute
intoxication.
Table 74-2 -- Differential Diagnosis of Acute Ethanol Intoxication

Head trauma
Hyperglycemia
Hyperthermia
Hypocalcemia
Hypoglycemia
Hyponatremia
Hypothermia
Hypothyroidism
Hypoxia
Infection—sepsis
Intoxication from other drugs/poisons
Anticholinergics
Antidepressants
Carbon monoxide
Opioids
Other alcohols: isopropyl, methanol, ethylene glycol
Sedative-hypnotics
Intracranial hemorrhage (acute/chronic)
Meningitis/encephalitis
Seizure—postictal state
Stroke
Wernicke-Korsakoff syndrome
Data from references 1 , 5 , 45 , 55 , and 66 .
Poisoning from other sedative-hypnotic drugs, drugs of abuse, antidepressants, and other alcohols should
be considered. Hypotension may be from dehydration secondary to ethanol intoxication but could represent
blood loss from the gastrointestinal tract or other causes. A rectal temperature should be obtained to exclude
hypothermia and hyperthermia from environmental exposure, from sympathomimetics or anticholinergics, or
from febrile illnesses such as sepsis or meningitis. Postictal states typically resolve faster than ethanol
intoxication. Petechiae, jaundice, angiomas, and ascites suggest hepatic encephalopathy.


LABORATORY STUDIES
Electrolyte, blood urea nitrogen, creatinine, and glucose studies may be clinically useful. Additional
diagnostic studies that may be obtained as warranted include a complete blood cell count; magnesium,
phosphate, and coagulation studies; arterial blood gas analysis; and liver function tests. In chronic drinkers
with fever, infection should be considered and blood cultures, urine studies, cerebrospinal fluid analysis, and
chest radiography obtained as needed to localize the source. Computed tomography of the head and lumbar
puncture should be considered when the clinical findings are not consistent with the blood ethanol level or if
there is no clinical improvement after several hours of observation.
Metabolic acidosis resulting from ethanol intoxication is uncommon. If a high anion gap metabolic acidosis is
present, it can usually be attributed to lactic acidosis or alcoholic ketosis. Clinically significant lactic acidosis
due to ethanol rarely occurs without coexisting conditions such as seizure, infection, hypoxia, or
hypoperfusion states.[45][52] The finding of an anion gap metabolic acidosis in ethanol intoxication should
prompt a search for other toxic causes or concurrent medical conditions.[19]
The definitive diagnosis of ethanol intoxication requires quantification of the patient’s ethanol level. The
definitive laboratory test is a blood ethanol level. Bedside breath alcohol analysis is a useful, inexpensive
screening tool that can be used in the emergency setting. Current breath alcohol analyzers use infrared
technology and generally have excellent accuracy and precision, especially when well calibrated and used
with good technique. False-positive results occur if the analyzer lacks specificity for ethanol or if the sample
is contaminated with oral vapors when tested shortly after belching, vomiting, or ingestion of ethanol-
containing products. Pulmonary disease, diabetes mellitus, gasoline and acetone vapors, aerosolized mouth
sprays, paint thinner fumes, and radio waves have also reportedly interfered with results. [14][16][22] A poor
breath sample will usually underestimate the blood alcohol concentration but may still be clinically helpful.
As the patient awakens, subsequent samples may actually show an increase in the level because of
improved sampling in a more cooperative patient.


TREATMENT
Treatment of Acute Intoxication
Treatment begins with evaluation of the patient’s level of consciousness, airway patency, and adequacy of
ventilation ( Table 74–3 ). If trauma is suspected, cervical spine immobilization should be instituted. In
somnolent patients with adequate ventilatory efforts, airway patency can often be improved by placement of
an oropharyngeal or nasopharyngeal airway. Prevention of aspiration includes positioning the patient in the
left lateral recumbent position with the head of the bed elevated. Comatose or markedly somnolent patients
require close monitoring to detect signs of clinical deterioration. This includes pulse oximetry, continuous
cardiac monitoring, and repeat neurologic examinations. If the gag reflex is absent in a poorly responsive
patient or there is evidence of significant respiratory depression, endotracheal intubation and ventilatory
support is indicated.
Table 74-3 -- Treatment of Ethanol Toxicity

1. Supportive care with careful attention to airway
2. Abnormal mental status
Glucose (25–50 g)
Naloxone (2 mg)
Thiamine (100 mg)
3. Gastric lavage or nasogastric suction—usually not indicated unless a substantial ethanol ingestion (=1 g/kg)
has occurred within 30 minutes or a co-ingestant is suspected
4. Treat seizures with benzodiazepines (e.g., lorazepam, 2 mg IV and repeat PRN)
5. Hypothermia—rewarming
6. Correct dehydration and electrolyte or acid-base imbalance
7. Replace nutritional deficiencies initially with:
Folate (1 mg)
Thiamine (100 mg)
Magnesium (2 g)
Multivitamins
Data from references 1 , 4 , 9 , 17 , 24 , 43 , 47 , 50 , 57 , 61 , and 72 .
Circulatory status should be assessed and intravenous access established with special attention to
hydration, electrolyte status, and rewarming or cooling as indicated. Nutritional supplements such as
thiamine, folate, multivitamins, and magnesium should be given to chronic drinkers and nutritionally deficient
patients. Hypoglycemia may be mistaken for ethanol intoxication. Because untreated hypoglycemia causes
devastating irreversible neurologic injury, a rapid bedside blood glucose determination should be made or
dextrose administered whenever the clinical presentation of altered mental status is encountered. If brain
injury is suspected, testing for serum glucose level is preferable because glucose can be detrimental to
ischemic brain tissue and worsen neurologic outcome.[13] Opioids can be synergistic or mimic ethanol
intoxication and can easily be confirmed with a favorable clinical response to naloxone. In addition, naloxone
may obviate the need for intubation in a patient with opioid-induced respiratory depression.
Gastric decontamination plays a limited role in the treatment of ethanol toxicity. Gastric emptying may be
beneficial if performed shortly (<30 to 60 minutes) after massive ethanol ingestion or when a toxic co-
ingestion has occurred. Limited studies attest that significant amounts of ethanol can be removed by
aspiration of gastric contents.[57] Activated charcoal does not significantly adsorb ethanol, and its use is not
indicated unless co-ingestants are suspected.[28][47]
Ethanol shares some clinical neuropharmacologic effects in common with opioids and benzodiazepines,
leading to the idea of using opioid or benzodiazepine antagonists to reverse the effects of ethanol. Despite
several positive case reports, controlled studies using either naloxone or flumazenil demonstrate
inconsistent reversal.[4][9][17][50][61] Ethanol’s multifactorial mechanisms of action preclude specific and
complete antagonism by these agents.
Most patients recover with supportive care.[34][44] Blood ethanol concentration usually decreases at a rate of
20 mg/dL/hr, although individual variations exist.[21] Chronic drinkers have been reported to have elimination
rates as high as 50 mg/dL/hr.[32] Hemodialysis increases ethanol elimination by three to four times the
average physiologic rate, but it is very rarely needed.[48] Several case reports describe survival with full
recovery from ethanol toxicity despite profoundly high ethanol levels and conservative treatment
measures.[23][44][56] Administration of high intravenous doses of fructose may enhance ethanol’s elimination,
but this is associated with serious adverse side effects, precluding its clinical use.[6] Peritoneal dialysis
appears to increase ethanol elimination only slightly faster than spontaneous elimination.[24][72]
Other Interventions
Alcoholic ketoacidosis is treated with intravascular volume repletion with crystalloids, dextrose, and
thiamine. Hepatic glycogen stores are usually depleted in patients with AKA or hypoglycemia, and prolonged
feeding is required for restoration. Thiamine should be administered to all patients and is specific therapy for
Wernicke’s encephalopathy and “wet beriberi.” Doses of 500 to 1000 mg or more, in 100-mg increments,
may be needed for Wernicke’s encephalopathy. Further therapy is dictated by any underlying or coexisting
diseases.


DISPOSITION
Most patients with ethanol toxicity can be managed in the emergency department and, once clinical
inebriation has resolved and the patient is able to safely ambulate, may be transferred to a detoxification
facility or discharged. The average observation period for uncomplicated ethanol toxicity is 5 hours.[33]
Ethanol intoxication can delay the discovery of traumatic injuries. Careful clinical re-evaluation before
discharge should be performed to avoid missing injuries initially masked by intoxication. Patients who
develop severe toxicity, have alcoholic ketoacidosis, or have serious coexisting disease or trauma require
hospital admission. Chronic drinkers requesting detoxification should be referred for outpatient substance
abuse counseling or admitted for inpatient rehabilitation.[1]


SEQUELAE
With supportive care, recovery from acute ethanol intoxication should be complete. Permanent neurologic
sequelae and death have been reported after prolonged hypoglycemia.[46] Memory difficulties can persist
after resolution of Wernicke’s encephalopathy, and one fourth of patients with Wernicke-Korsakoff syndrome
do not recover.[67]


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119.


Chapter 75 – Cocaine
JUDD E. HOLLANDER ROBERT S. HOFFMAN
Essentials
• The presence of sympathomimetic effects directly related to cocaine toxicity: hypertension, tachycardia,
hyperthermia, diaphoresis, and/or agitation
• The demonstration of cocaine metabolites in a urine toxicology assay or a history of cocaine use in a
patient with an unexpected vascular disaster such as acute cerebrovascular accident, myocardial
infarction, mesenteric ischemia, or aortic dissection
patient with a first-time seizure
patient with acute rhabdomyolysis or myoglobinuric renal failure
INTRODUCTION
Cocaine is a natural alkaloid found in Erythroxylon coca, a shrub indigenous to South America. The
recreational use of cocaine has reached epidemic proportions, with 30 per cent of males and 20 per cent of
females between the ages of 26–34 years having used cocaine at least once.[41] Twenty-three million
Americans have used cocaine at some time, and 1–2 per cent of the U.S. population uses cocaine
monthly.[41]


Pharmacology
Cocaine is well absorbed following contact with the oral, nasal, gastrointestinal, rectal, and vaginal mucosa;
by the pulmonary alveoli following inhalation; and by intravenous injection. Oral administration reaches peak
concentrations in approximately 60 minutes. Effects from nasal insufflation begin almost immediately, and
peak concentrations occur within 30–60 minutes. Intravenous and inhalational use of cocaine produces very
rapid distribution of cocaine to both the central nervous system and the systemic circulation. “Crack” or
“freebase” cocaine is the direct precipitate that results from alkalinization of aqueous cocaine hydrochloride.
Cocaine is rapidly hydrolyzed to its major metabolite, ecgonine methyl ester (EME).[28] EME, formed by
hydrolysis by liver and plasma esterases, accounts for 30–50 per cent of the parent product. Nonenzymatic
hydrolysis results in the formation of the other major metabolite, benzoylecgonine, which accounts for
approximately 40 per cent of the parent product. Other minor metabolites (norcocaine, ecgonine, and
cocethylene) constitute the remainder of cocaine’s degradation products. The activity of plasma
cholinesterase determines the relative concentrations of the various metabolites and quite possibly affects
the degree of toxicity that develops.
The biologic half-life of cocaine is 0.5–1.5 hours. A relatively minor amount is excreted unchanged in the
urine.[28] Despite the short half-life of cocaine, vascular catastrophes apparently related to cocaine can occur
for several weeks after its last use. Benzoylecgonine and EME are also excreted in the urine with half-lives
of 5–8 hours and 3.5–6 hours, respectively.[28] Because of a long elimination half-life, assays typically detect
benzoylecgonine for as long as 48–72 hours following cocaine use. [1]
Pathophysiology
The effects of cocaine are related to its sympathetic nervous system effects, central nervous system
stimulation, and local anesthetic effects. The initial effect of cocaine on the cardiovascular system is
vagotonic, producing a transient bradycardia; however, the increased sympathetic stimulation rapidly
produces tachycardia and hypertension. In the peripheral nervous system, cocaine inhibits the reuptake of
both epinephrine and norepinephrine and stimulates the presynaptic release of norepinephrine. The
resulting increased concentration of norepinephrine at the postsynaptic a and ß receptors accounts for the
stimulatory effects of cocaine. In the central nervous system, the mechanism of increased stimulation has
not been as well defined. Enhanced release of norepinephrine and excitatory amino acids and/or blockade
of neuronal reuptake of dopamine, serotonin, and excitatory amino acids might account for the observed
effects.
The vascular effects of cocaine are multifactorial. Arterial vasoconstriction, in situ thrombus formation,
platelet aggregation, and accelerated atherosclerosis are the principal factors responsible for cocaine-
induced ischemia in many vascular beds.[20][22] These effects have been best described in the heart.
Cocaine-induced hypertension, tachycardia, and left ventricular hypertrophy increase myocardial oxygen
demand at the same time that blood flow is diminished by coronary artery vasoconstriction, enhanced
platelet aggregation, in situ thrombus formation, and premature atherosclerosis. This combination makes
cocaine a potent precipitant of myocardial ischemia. Coronary vasoconstriction is further exacerbated by ß-
adrenergic blockade.[32][33] Most cocaine-using patients are also cigarette smokers and the combination of
cocaine and nicotine has a synergistic effect on coronary vasoconstriction.[38]


Based on the mechanism of action of cocaine, the clinical presentation of the cocaine intoxicated patient is
easily understood ( Table 75–1 ). Cocaine toxicity is characterized by a sympathomimetic toxidrome with
hyperthermia, hypertension, tachycardia, tachypnea, altered mental status, seizures, mydriasis, diaphoresis,
and hyperactive bowel sounds.
Table 75-1 -- Clinical Presentation of Cocaine Toxicity

Signs and
Physical Findings * Laboratory and Imaging Abnormalities †
Symptoms
Chest pain Sympathomimetic toxidrome Electrolyte imbalance (lactic acidosis,
hyperglycemia, hypokalemia, hyperkalemia,
renal failure)
Shortness of Altered mental status Chest radiography (pneumothorax,
breath pneumomediastinum, pneumonia, pulmonary
infarction)
Anxiety Hyperthermia (rectal temp) Electrocardiography (dysrhythmias, ST-T wave
changes, conduction blocks)
Palpitations Hypertension Arterial blood gas (hypoxia, respiratory
alkalosis, metabolic acidosis)
Dizziness Tachycardia Head CT (subarachnoid, intracranial
hemorrhage, bland infarcts)
Headache Mydriasis Lumbar puncture (subarachnoid bleed)
Nausea Tachypnea Creatine phosphokinase (rhabdomyolysis)
Vomiting Diaphoresis CK-MB isoenzymes (myocardial infarction)
Hallucinations Hyperactive bowel sounds Troponin I (myocardial infarction)
Psychosis Epistaxis, nasal perforation Urine toxicology screen
Confusion “Track marks”
Fevers Other findings specific to presenting
complaints (such as rales for congestive
heart failure)
Seizures
Suicidal or
homicidal ideation
Spontaneous
abortion
Adapted from Hollander JE, Hoffman RS: Cocaine and other stimulants. In Howell JM (ed): Emergency Medicine.
Philadelphia, WB Saunders, 1996, p 1444.
* Other important physical findings that are specific to chief complaint are described in this chapter.
† The appropriate diagnostic studies for each patient will depend on the specific medical complaint.
Cocaine-induced complications occur in all organ systems, especially in the brain, eyes, ears, nose, throat,
heart, lungs, intestines, kidneys, extremities, and skin.[15] Cocaine-related complaints are mostly
cardiovascular, neurologic, and psychiatric. Chest pain is the most common emergency department (ED)
complaint.[6] The most emergent concerns are psychomotor agitation and seizures,[19][39][43] myocardial
infarction,[2][14][20][22][23][24][51][57] cardiac dysrhythmias,[40] aortic dissection,[13] pulmonary infarction,[10]
pneumothorax,[45] intracranial hemorrhage or bland CNS infarcts, [34][47][56] and visceral infarction.[15]
Because cocaine is a sympathomimetic stimulant, cocaine-intoxicated patients frequently will be
hypertensive and/or tachycardic. [4] Hyperthermia and tachypnea occur but are less common.
Acutely, cocaine causes arterial vasoconstriction[32] and enhanced thrombus formation.[31][37][44] Chronic
cocaine use can result in accelerated atherosclerosis,[11][12][29][30][36][50] and left ventricular hypertrophy.[5]
These effects provoke myocardial ischemia or infarction. Aortic dissection and rupture occur less commonly
after use of cocaine.[13] Supraventricular and ventricular dysrhythmias may occur either as a direct result of
cocaine (a type Ic antidysrhythmic) or as a complication of myocardial ischemia. The negative inotropic
effects of cocaine may cause acute depression of left ventricular function and congestive heart failure.[9][17]
Chronic cocaine use can result in dilated cardiomyopathy.[18]
Neurologic Effects
Most cocaine-intoxicated patients are anxious or agitated. This behavior can be a transient effect of cocaine
or may reflect underlying organic pathology. Bland cerebral infarcts, hemorrhagic infarcts, and subarachnoid
hemorrhages occur.[19][39][43] Seizures may occur secondary to infarction or hemorrhage or in their absence.
Patients who remain extremely lethargic and are difficult to arouse for up to 24 hours after cocaine use may
have the “cocaine washed-out syndrome.”[49] Patients with the cocaine washed-out syndrome assume
normal sleep postures and can occasionally be aroused to full orientation, in contrast to lethargic patients
with subarachnoid hemorrhage or other intracranial catastrophes.
Vascular Ischemia
In addition to cardiovascular and cerebrovascular ischemia, ischemia of the mesenteric, renal, pulmonary,
and ophthalmic arteries can occur. The clinician should assume that ischemia of any vascular bed is
possibly secondary to cocaine use.
Rhabdomyolysis
Skeletal muscle injury may result in rhabdomyolysis.[55] Although some patients may have overt clinical
signs, such as muscle tenderness, this is rare. Most patients present without signs and symptoms of muscle
injury, and the diagnosis of rhabdomyolysis is made by demonstration of myoglobinuria and/or measurement
of serum creatine kinase. Patients with severe rhabdomyolysis may have lactic acidosis and life-threatening
hyperkalemia.
Body Packers
Patients with continued toxicity despite treatment may be body packers. Most body packers will be
asymptomatic unless leakage occurs. Recent travel or transportation of the patient from an airport should
raise suspicion of body packing. Symptomatic patients should be considered a major medical emergency
and must be evaluated for surgical removal of the packets.
Obstetric and Neonatal Effects
Obstetric complications secondary to cocaine use include premature labor as a result of increased uterine
contractility as well as abruptio placenta. Symptoms of neonatal cocaine withdrawal usually begin within
24–48 hours of birth. Withdrawal results in infants with jitteriness, irritability, poor eye contact, and vigorous
sucking. In utero cocaine exposure may also result in infants with a small head circumference and low birth
weight. Rapid diagnosis and treatment of neonatal withdrawal are imperative because of the risk of seizures
and cardiovascular collapse. The physician should be thorough and exclude alternative diagnoses such as
sepsis, hypoglycemia, and electrolyte abnormalities. The use of drug screens is unreliable for assessing
neonatal withdrawal because the drug may have been metabolized and excreted prior to birth.
Benzodiazepines and phenobarbital are effective agents for the treatment of stimulant withdrawal.
Other Issues
Recreational drug users should always be questioned about suicidal or homicidal ideation. Chronic users
may be predisposed to HIV disease.


The differential diagnosis of cocaine toxicity can be subdivided into three areas of consideration: the
sympathomimetic toxidrome; specific complaints directly related to cocaine; and organic disease processes
masked or confounded by cocaine.
Sympathomimetic and anticholinergic toxidromes are both characterized by hyperthermia, hypertension,

tachycardia, tachypnea, altered mental status, seizures, and mydriasis. Diaphoresis and hyperactive bowel
sounds suggest a sympathomimetic toxidrome, while urinary retention and dry skin characterize an
anticholinergic toxidrome. Table 75–2 shows the differential diagnosis for the sympathomimetic toxidrome.
Table 75-2 -- Differential Diagnosis of the Sympathomimetic Toxidrome in Cocaine Toxicity

Toxins
Cocaine, phencyclidine, amphetamines, hallucinogens, caffeine, phenylpropanolamine, theophylline,
ephedrine, pseudoephedrine, tyramine, monoamine oxidase inhibitors; serotonin syndrome due to various
drugs and drug interactions
Metabolic derangements
Pheochromocytoma, hypoglycemia, thyrotoxicosis
Psychiatric disturbances
Schizophrenia, psychosis, mania
Drug withdrawal
Ethanol, sedative-hypnotics
Neurologic abnormalities
Complex status epilepticus
Specific complaints directly related to cocaine may include such signs and symptoms as chest pain,
abdominal pain, and shortness of breath. Although cocaine use can result in these symptoms, the
differential diagnosis includes disease processes both related to and unrelated to cocaine. For example,
chest pain may be caused by chest wall rhabdomyolysis, pneumothorax, or myocardial ischemia resulting
from cocaine use, or it may be caused by pneumonia or pleurisy unrelated to cocaine. A history of recent
cocaine use significantly increases the likelihood of serious etiologies for many otherwise common
complaints. Although most cocaine-related adverse events occur within several hours of cocaine use,
remote cocaine use (in the past several weeks) has also been associated with vascular catastrophes in
patients without other known predisposing factors.
Cocaine-intoxicated patients may have concurrent ethanol ingestions, or mixed overdoses that mask some
of the effects of cocaine. On the other hand, serious medical problems should not be falsely attributed to
cocaine without excluding underlying organic pathology. For example, patients with an altered mental status
may still need to undergo computerized tomography to exclude a subdural hematoma that may not have
been caused directly by cocaine. Mental status changes caused by cocaine are short-lived. Failure to return
to a completely normal mental status within 1–2 hours after exposure requires a complete evaluation for
serious etiologies such as subarachnoid hemorrhage or stroke. Waiting to see if the patient’s mental status
“clears” after cocaine is metabolized may have adverse consequences.


LABORATORY STUDIES
Chemistry
Most patients with mild cocaine toxicity do not require laboratory evaluation. When ordered, serum
electrolytes may reflect the adrenergic effects of cocaine with hyperglycemia, hypokalemia and, in severe
cases, metabolic acidosis due to increased lactate. Patients with rhabdomyolysis, particularly if they are
acidemic, may have hyperkalemia. The serum creatinine level may be elevated in cases of rhabdomyolysis,
renal failure, or renal infarction. Serial electrolyte determinations are necessary in patients with
rhabdomyolysis and/or renal failure to monitor for progressive hyperkalemia. Increases in leukocyte count
may also occur. The creatine kinase (CK) will be elevated in cases of rhabdomyolysis and in almost half of
patients with chest pain. Elevated creatine kinase MB usually indicates a myocardial infarction, but false
positive elevations may occur.[35][51] Use of cardiac troponin I may be needed to confirm a myocardial
infarction.[35]
Radiography
Chest radiography should be used to detect pneumonia, pulmonary infarction, pneumothorax,

pneumomediastinum, and pneumopericardium. Abdominal radiography may detect cocaine packages.
Computerized tomography (CT) should be used to detect cerebrovascular events. Magnetic resonance
imaging or angiography may be useful for aortic dissection.
Electrocardiogram
The initial electrocardiogram is less sensitive and less specific for identification of myocardial infarction in
patients with cocaine-associated chest pain than in traditional patients with chest pain.[24][26] Thus, a normal
12-lead electrocardiogram should not be considered sufficient to exclude myocardial infarction.[24][51]
Myocardial infarction clearly occurs in both patients with normal and abnormal electrocardiograms. ST
segment elevation due to early repolarization is common in young cocaine users without myocardial
infarction.[14][24][26] ST segment elevations that meet standard thrombolysis criteria are present in 11–43 per
cent of cocaine-associated chest pain patients who are not found to infarct.[14][24][26]
Toxicology Screen
Urine immunoassays for cocaine metabolites generally detect the major metabolite of cocaine,
benzoylecgonine at or above concentrations of 300 ng/mL. Usually, the presence of cocaine or its
metabolites can be detected for 48–72 hours after use.[1] Rarely, using more sensitive methods (GC/MS),
cocaine metabolites have been detected for up 3 weeks after the last use.[54]
Additional laboratory or diagnostic testing should be considered depending on the clinical condition. For
example, lumbar puncture should be performed in patients with suspected subarachnoid hemorrhage and
normal head computed tomograms; ventilation-perfusion scans should be used in patients suspected of
pulmonary infarction.


TREATMENT
Initial treatment should focus on the ABCs: Maintain or establish a patent airway; assess breathing,
circulation, and neurologic status. Patients should be placed on supplemental oxygen and intravenous
access established. The specific treatments indicated based on signs and symptoms are summarized in
Table 75–3 .
Table 75-3 -- Treatment Essentials in Cocaine Toxicity

Medical Problem Treatment
Dysrhythmias
Observation
Sinus tachycardia Oxygen
Diazepam 5–10 mg IV or lorazepam 2–4 mg IV titrated to effect
Oxygen
Diazepam 5 mg IV or lorazepam 2–4 mg IV
Supraventricular Diltiazem 20 mg IV or verapamil 5 mg IV

tachycardia Adenosine 6 mg or 12 mg IV for AV node re-entry
Digoxin 0.5 mg IV
Cardioversion if hemodynamically unstable
Oxygen
Sodium bicarbonate
Ventricular
Lidocaine 1.5 mg/kg IV bolus followed by 2 mg/min infusion
dysrhythmias
Defibrillation if hemodynamically unstable
Diazepam 5 mg IV or lorazepam 2–4 mg IV
Oxygen
Diazepam 5–10 mg IV or lorazepam 2–4 mg IV
Soluble aspirin 325 mg
Nitroglycerin 1/150 sublingual × 3 every 5 min followed by a drip titrated to a mean
arterial pressure reduction of 10% or relief of chest pain
Ischemic chest pain Morphine sulfate 2 mg IV titrated to pain relief

Phentolamine 1 mg IV; repeat in 5 min
Verapamil 5–10 mg IV
Medical Problem Treatment
Heparin 5000 unit bolus followed by 1000 units/hr
Mechanical reperfusion (angioplasty)
Thrombolytic therapy
Observation
Diazepam 5–10 mg IV or lorazepam 2–4 mg IV titrated to effect
Hypertension
Phentolamine 1 mg IV; repeat in 5 min
Nitroglycerin or nitroprusside drip titrated to effect
Lasix 20–40 mg IV
Morphine sulfate 2 mg IV titrated to pain relief
Pulmonary edema Nitroglycerin drip titrated to blood pressure or respiratory status
Consider phentolamine or nitroprusside
Consider CPAP, BPAP, or PEEP
Cool environment with minimal activity
Hyperthermia Sedation with benzodiazepines
Tepid water with fans, cool water, or ice baths
Neurologic symptoms
Anxiety and agitation Diazepam 5–10 mg IV or lorazepam 2–4 mg IV
Diazepam 5–10 mg IV or lorazepam 2–4 mg IV
Seizures
Phenobarbital 25–50 mg/min up to 10–20 mg/kg
Intracranial hemorrhage Neurosurgery consultation
Cardiac monitor
Serial potassium determination
Rhabdomyolysis IV hydration to maintain urine output at 3 mL/kg/hr
Sodium bicarbonate titrated to an alkaline urine
Hemodialysis as necessary for renal failure
Cocaine washed-out
Supportive care
syndrome
Activated charcoal
Body packers
Admission to monitored setting even if asymptomatic
Laparatomy for obstruction or symptoms
Agitation
If the patient is agitated, sedation with benzodiazepines needs to be accomplished rapidly.[8][16][48] Anxious
and agitated patients should be physically restrained only as a temporizing measure to facilitate chemical
sedation. Inappropriate physical restraints may increase skeletal muscle activity, thus exacerbating
hyperthermia and rhabdomyolysis. The agents of choice for chemical sedation in the cocaine-intoxicated
patient are benzodiazepines, which can be titrated to effect. High dosages may be required.
Hyperthermia
Hyperthermic patients should be cooled with restricted activity; iced water baths or tepid water with fans may
be used, depending on the severity of the hyperthermia and clinical status of the patient. Cooling blankets
are not adequate for severe hyperthermia, and antipyretics are not effective.
Blood Pressure
Hypotensive patients should receive intravenous fluids. If pressor support is necessary, norepinephrine
should be used. Hypertension and sinus tachycardia are generally transient and do not require specific
treatment in most cases. When treatment is necessary for mild to moderate hypertension, benzodiazepines
can be used. For malignant or refractory hypertension, IV nitroglycerin, nitroprusside, or phentolamine can
be used. Beta-adrenergic blockade has not been demonstrated to be useful, and may exacerbate
hypertension and myocardial ischemia by facilitating unopposed a-adrenergic stimulation.[20][33]
Dysrhythmias
Supraventricular tachycardia, in hemodynamically stable patients, can be treated with benzodiazepines

followed by either calcium-channel antagonists or adenosine, depending on whether atrioventricular nodal
re-entry is present. Hemodynamically unstable patients should be cardioverted. Ventricular dysrhythmias
may be managed with benzodiazepines to decrease central sympathetic stimulation and with sodium
bicarbonate or lidocaine as antidysrhythmic agents.[3][46] Unstable patients should be defibrillated.
Myocardial Ischemia
Ischemic chest pain should be treated with benzodiazepines, aspirin, and sublingual nitroglycerin.[20]
Refractory pain can be treated with either morphine sulfate or intravenous nitroglycerin titrated to a 10 per
cent reduction in mean arterial pressure.[7][20][25] Patients who do not respond to this regimen can be treated
with phentolamine or verapamil.[20][21][42] Patients with unstable angina should receive heparin according to
standard protocols. Cocaine-induced acute myocardial infarction is often the result of coronary arterial
obstruction due to thrombus formation, platelet aggregation and premature atherosclerosis. As a result,
either cardiac catheterization with mechanical reperfusion or thrombolytic therapy should be considered for
patients with acute myocardial infarction refractory to medical management.[20] Beta-adrenergic antagonists
and mixed alpha-beta antagonists should not be used in patients with cocaine-induced myocardial ischemia
because they increase coronary artery vasoconstriction and decrease myocardial blood flow.[20][33]
Pulmonary edema should be treated with diuretics, morphine, and nitroglycerin according to standard
protocols, with the addition of CPAP, BPAP, or PEEP as clinically indicated.
Neurologic Complications
Seizures are usually brief and transient. If necessary, seizures can be managed with benzodiazepines. If
high doses do not control the seizures, phenobarbital should be used. Consider the possibility of ongoing
poisoning (for example, body packing) in patients with status epilepticus. Patients with first-time cocaine-
induced seizures should receive CT evaluation. Patients with cocaine-induced seizures and normal CT scan
should also receive a lumbar puncture to exclude subarachnoid hemorrhage unless they are alert without
any complaints (no headache) and have a nonfocal neurologic examination.
Intracranial hemorrhage should be excluded. Patients with cerebrovascular ischemia or subarachnoid

hemorrhages should be managed with neurologic or neurosurgical consultation. Management would follow
standard treatment protocols; however, ß-adrenergic antagonists should not be used for blood pressure
control.
The cocaine washed-out syndrome is self-limited, and patients should be allowed to sleep until freely
arousable. Patients who do not assume normal sleep postures or cannot be easily aroused to full orientation
should be evaluated for intracranial catastrophes. Liberal use of CT should be employed to exclude
underlying organic pathology. Undetected acute myocardial infarction has occurred in at least one patient
too lethargic to describe symptoms.[53]
Rhabdomyolysis
Patients with significant elevation of creatine kinase or myoglobinuria (rhabdomyolysis) require vigorous
hydration to maintain a urine output of at least 3 mL/kg/hour; mannitol as a diuretic; sodium bicarbonate to
alkalinize the urine; and hemodialysis if renal failure occurs. Patients with severe rhabdomyolysis may be
hyperthermic, acidemic, and hypotensive. Frequent monitoring of electrolytes (especially potassium) should
be performed.
Body Packers
Asymptomatic body packers should receive activated charcoal to limit cocaine absorption and whole bowel
irrigation to decrease gastrointestinal transit time.[27][52] All such patients should be monitored until the
cocaine bags have been eliminated, even if they are asymptomatic. In rare cases, surgical removal may be
necessary for bowel obstruction or cocaine toxicity.


DISPOSITION
Most patients without chest pain can be evaluated and released from the ED if serious pathology is not
uncovered, hemodynamic parameters normalize, the mental status returns to normal in a few hours, and
counseling can be provided.
Approximately 6 per cent of patients with cocaine-associated chest pain sustain a myocardial infarction.
These patients are difficult to identify based on history, physical examination, and initial
electrocardiography.[24][51] Unfortunately, patients with atypical histories and normal EKGs have sustained
myocardial infarction.[24][51] Myocardial ischemia usually occurs within several hours of cocaine use;
however, it can occur for several weeks following cocaine use. Most patients with cocaine-induced chest
pain should be “ruled out” for acute myocardial infarction. Because patients with cocaine-associated
myocardial infarction have both a low mortality rate and a low incidence of complications[2][22][23][24][51] and
most cardiovascular complications occur before or shortly after ED arrival, evaluation and rapid “rule out” in
an ED observation unit may be a reasonable alternative to hospital admission, if predischarge counseling
can be provided. [20][22]
Patients with strokes or subarachnoid bleeds require admission. Patients with cocaine-induced seizures may
be released only if a thorough ED evaluation does not reveal intracranial pathology and appropriate follow-
up is ensured. Cocaine-induced psychiatric symptoms and hallucinations are usually short-lived. After they
clear, referral for drug treatment should be provided. Patients with significant rhabdomyolysis, myoglobinuric
renal failure, lactic acidosis, or hyperthermia should be admitted for evaluation and treatment. For most other
complaints, standard indications for admission can be observed.


SEQUELAE
The long-term sequelae of chronic cocaine use have been poorly investigated, but include psychiatric,
neurologic, and cardiovascular effects. Decreased cognitive function, thought disorders, and decreased
organizational skills occur. Accelerated atherosclerosis secondary to cocaine use may make chronic users
at higher risk of cardiovascular and cerebrovascular ischemia later in life, but this has not been well studied.


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46. Shih RD, Hollander JE, Hoffman RS, et al: Lidocaine in cocaine associated myocardial infarction:
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48. Spivey WH, Schoffstall JM, Kirkpatrick R, et al: Comparison of labetalol, diazepam, and haloperidol for
the treatment of cocaine toxicity in a swine model. Ann Emerg Med 1990; 19:467.
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Med 1991; 20:611.


Chapter 76 – Amphetamines
JOHN A. HENRY
Essentials
• Amphetamines cause a sympathomimetic response, including tachycardia, hypertension, hyperthermia,
diaphoresis, and mydriasis.
• Central nervous system stimulant effects can cause anorexia, euphoria, hallucinations, psychosis, and
seizures.
• Hyperthermia can lead to hypotensive collapse, rhabdomyolysis, renal failure, and disseminated
intravascular coagulation.
• Sympathomimetic overstimulation can result in cerebrovascular accidents and fatal cardiac
dysrhythmias.
INTRODUCTION
Amphetamines (phenylisopropylamines) are widely abused for their stimulant or euphoriant effects, for their
anorexiant properties, and, more recently, as dance drugs. Toxicity occurs as a result of abuse and less
commonly as a result of overdose. The prototype drug, amphetamine sulfate, was synthesized in the late
1920s, and its first medical use was in a nasal inhaler for the treatment of rhinitis and nasal congestion. Its
stimulant properties soon became apparent, and it was used during the Second World War to increase
wakefulness. Abuse of amphetamines became common during the 1960s, and legislation was enacted in
1971 classifying amphetamines as U.S. Drug Enforcement Agency (DEA) Schedule II drugs. In 1985,
MDMA (3,4 methylenedioxymethamphetamine; Ecstasy) was classified as a Schedule I drug. The medical
indications for amphetamines are limited to the treatment of narcolepsy, hyperactivity in children, and
appetite suppression in obesity. The most commonly abused amphetamines are described in this chapter.
Amphetamine sulfate is sold under many names: speed, whiz, blues, sulfate, and sulph are among the most
common names. Local slang terms vary and have included bennies, black beauties, eye openers, hearts,
mollies, pep pills, pick-me-ups, purple hearts, splash, truck drivers, uppers, dexies, and wake-ups. The drug
is sold as a powder or tablet and is commonly inhaled or snorted but is also taken orally, smoked, or injected
intravenously. Street amphetamine is an off-white to pink powder with an average purity of usually no more
than 5 per cent, although occasionally purity may be 20 per cent or more. It may also contain other less
potent stimulants (such as caffeine or ephedrine) or inert substances (such as glucose, vitamin C, chalk, or
talc).
Methylamphetamine is most commonly available in crystalline form and is usually smoked. It is similar in its
effects to amphetamine sulfate, but 15–20 times more powerful than the same weight of amphetamine
sulfate. As well as being smoked, it may be injected or snorted. In the United States, it is of high, nearly
pharmaceutical purity.
Mood-modifying amphetamines include MDMA (“Ecstasy” or the “love drug”), MDA (3,4
methylenedioxyamphetamine; “Adam”), MDEA (3,4-methylenedioxethamphetamine; “Eve”), and MDMB
(methylbenzodiolbutanamine), which have recently obtained a reputation as dance drugs. MDMA is an
amphetamine derivative with properties differing from amphetamine sulfate and methamphetamine.[32]
MDMA and MDEA can be further metabolized to MDA and subsequently abused. Often all three substances
are sold as Ecstasy under a variety of names, such as XTC, Adam, E, yellow burger, red and black, Dennis
the Menace, white dove, and white burger. MDMA was first patented in 1914, and was briefly used as a
mood-modifying agent in psychotherapy. Because of its stimulant and mood-enhancing effects (which have
been summarized as euphoria, empathy, and energy), MDMA has been extremely popular in Europe and
most recently in the United States as a “dance drug” in order to facilitate prolonged dancing by large groups
of people at parties and clubs.[17] Ecstasy is sometimes sold as a powder; the color of the powder varies,
depending on purity, from off-white to white. More commonly, it comes as tablets or capsules of varying
colors. The usual street doses are 30 to 150 mg.
Methcathinone (cat)[7] is one of the designer amphetamines that originated in Russia, where it was known as
ephedrone (street named “Jeff” and “mulka”). In the 1990s, it resurfaced in the rural Midwest of the United
States, as it was easily manufactured from over-the-counter ephedrine. Methcathinone is a methyl derivative
of cathinone, a potent amphetamine-like substance that occurs naturally in the evergreen tree, khat.[7]
Other amphetamines may be used in the clinical setting. Several drugs related to amphetamines are
prescribed for hyperactivity in children (methylphenidate, pemoline, methamphetamine,
dextroamphetamine), for narcolepsy (dextroamphetamine, pemoline), and as anorectants for the control of
appetite as an aid to weight loss (benzphetamine, diethylpropion, and mazindol). These drugs are all
capable of abuse and in overdose may produce amphetamine-like effects.


Pharmacology
The amphetamines possess an isopropylamine side chain and are structurally similar to endogenous
catecholamines and neurotransmitters. They are powerful direct a-adrenergic stimulants and also inhibit
neurotransmitter reuptake, the overall effect being marked central and peripheral a- and ß-adrenergic
receptor stimulation, together with central nervous system stimulation.[11] These properties are responsible
for their sympathomimetic effects. Amphetamines are readily absorbed across most biologic membranes,
including the oral cavity and gastrointestinal tract, nasopharynx, pulmonary tract, muscle, and vaginal
mucosa. When amphetamines are taken orally, the peak effects commence within 30–60 minutes, and by
the nasal route the effects occur within about 20 minutes. When taken intravenously or smoked, the effects
occur within a few minutes. Following typical recreational doses, the duration of effects is usually around 4–8
hours, but large doses and alkaline urine may prolong the effects to 24 hours or more.
Amphetamines are weak bases with a pKa value ranging between 8.8 and 10.4.[18] Because of these basic
properties, the elimination half-life is urine pH–dependent due to trapping of ions in the renal tubule. In
patients with a urine pH less than 6.6, the half-life range is 7–14 hours, and with a urine pH greater than 6.7
the range is 18–34 hours. Both active and inactive metabolites are produced. Metabolism consists of
aromatic and aliphatic hydroxylation with dealkylation producing the active hallucinogen p-
hydroxyamphetamine.[18] As much as 30 per cent of amphetamines are excreted in the urine unchanged.
Pathophysiology
The individual response to amphetamines in general varies greatly, and toxicity tends to correlate poorly with
the amount of drug taken because of variations in purity and individual tolerance. Children and first-time
users appear to be more susceptible to the toxic effects. Sympathetic overstimulation can produce cardiac
dysrhythmias and cerebrovascular accidents. Chronic sympathetic overstimulation may be responsible for
cerebral vasculitis.
The CNS effects of amphetamines are due to increased amounts of the neurotransmitters norepinephrine,
serotonin, and dopamine at central synapses, leading to stimulation of the cerebral cortex, medullary
respiratory center, and reticular activating center. The effects produced include alertness, talkativeness,
euphoria, insomnia, and appetite suppression and may include seizures following overdose. Another effect
of the amphetamines is stereotypy—the induction of repetitive behavior, whether it be dancing, cigarette
smoking, or drinking fluids. Tolerance develops rapidly. Amphetamines are not addictive, but many users
tend to continue use for as long as possible before finally entering a rebound phase of prolonged sleep
followed by voracious eating. The aftereffects of lethargy and fatigue can last for several days. A self-limiting
psychosis may occur as a result of chronic alteration of neurotransmission following long-term use.
For many years, animal studies have shown that the amphetamines possess a property called “aggregation
toxicity.” When an amphetamine is given to a single animal such as a mouse, it induces little behavioral
change. However, the same dose of drug given to a group of animals tends to produce hyperactive behavior,
which may lead to death. Thus, the amphetamines affect the interaction between animals, and the
circumstances of use can have an even greater effect than the dose. This may help to explain why some of
these drugs have been considered as psychotherapeutic agents, and may be part of the reason why the
mood-modifying amphetamines have come to be used as “dance drugs.”
In addition to the effects that they have in common with amphetamine sulfate, the mood-modifying
amphetamines induce a positive mood and a feeling of empathy and closeness with others. MDMA
promotes the release of serotonin and blocks its reuptake, which may account for some of the differences
between mood-modifying amphetamines and the other amphetamines.[4]
Animal experiments have shown that methamphetamine, MDMA, and related drugs (including d-
fenfluramine) are toxic to serotoninergic nerve terminals. Administration of MDMA to rodents and nonhuman
primates results in a long-term decrease in serotonin content in several brain regions, and there is clear
biochemical and histologic evidence that this reflects neurodegeneration of serotonin terminals.[17] The
doses in rodents (5–40 mg/kg) and particularly in monkeys (2–10 mg/kg) that produce neurotoxicity are not
very different from the doses taken by some human users. In monkeys the damage appears to be
permanent, but in rats there are signs that neuronal recovery takes place. It has also been shown in rats that
central serotonin axons can undergo regenerative sprouting after injury by MDMA. One study,[10] which
investigated the regeneration pattern in rats and monkeys following induction of toxicity 12–18 months
previously, showed that the reinnervation pattern of serotonin axons was highly abnormal. Axons that had
distant targets or were more highly arborized had a low probability of recovering. The relevance of this
abnormal reinnervation in humans is debatable at present, but the possibility has been raised that heavy
prolonged use of Ecstasy could lead to altered neuronal structures in humans. There is no human
experimental evidence that the animal models of MDMA neurotoxicity apply to humans. However, one
study[14] has shown that cerebrospinal fluid 5-HIAA levels are reduced in MDMA users after 2 weeks of
abstinence.
The use of fenfluramines alone or in combination with phentermine (“fen-phen”) has been associated with
myofibroblast proliferation and central myxoid degenerative changes of heart valves.[35a] These
histopathologic changes are similar to those seen in patients with carcinoid syndrome or with a history of
chronic exposure to ergotamine or methysergide, conditions in which serotonin levels are elevated. The
valvular fibroplasia may be due to stimulation of 5-HT (2B) receptors by norfenfluramine, a fenfluramine
metabolite.[10b]


The typical effects include wakefulness, appetite suppression, talkativeness, anorexia, hyperactivity, and
euphoria. The patient has a dry mouth, has dilated pupils, and may be sweating. Tendon reflexes are brisk.
Cardiovascular effects are common, and the patient who has taken a recreational dose will usually have
tachycardia and hypertension. The effects of amphetamines are summarized in Table 76–1 .
Table 76-1 -- Clinical Presentation of Acute Amphetamine Toxicity

Severity Signs and Symptoms
Mild Nausea, vomiting, abdominal pain, widely dilated pupils, flushing or pallor, sweating, headache,
restlessness, tremor, hyperreflexia, irritability, pallor, bruxism (grinding of teeth), trismus (jaw
clenching), palpitations
Hyperactivity, confusion, aggression, muscle rigidity, tachycardia, tachypnea, hypertension, chest
Moderate
discomfort, mild pyrexia, hallucinations, dehydration.
Delirium, hyperpyrexia (>40°C), hypertension or hypotension, seizures, coma, renal failure
Severe
associated with rhabdomyolysis, cardiac dysrhythmias (atrial and ventricular tachydysrhythmias)
Ventricular fibrillation, myocardial infarction, cerebrovascular accident (usually cerebral
Potentially
hemorrhage), extreme hyperthermia (may precipitate DIC), acute cardiac failure, repeated
fatal
seizures, cerebral edema with brainstem compression secondary to hypoxia or hyponatremia
Apathy, depression, lethargy, anxiety, sleep disturbances, myalgia, abdominal pain, increased
Withdrawal
appetite
Chronic Paranoid psychosis with visual, tactile, or olfactory hallucinations; cardiomyopathy, vasculitis,
toxicity possible serotoninergic hemotoxicity
Acute Complications
Mood-enhancingAmphetamines.
Following ingestion, effects occur within 1 hour and last 2–12 hours following doses of 75–150 mg, and up to
48 hours after 100–300 mg. Adverse effects of MDMA are more commonly due to “recreational” use than to
overdose. Typical signs of moderate toxicity include nausea, increased muscle tone, hyperreflexia, muscle
pain, trismus, mydriasis, blurred vision, sweating, dry mouth, agitation, anxiety, tachycardia, hypertension,
anorexia, and increase in body temperature. Vomiting, abdominal pain, and diarrhea may also occur. Signs
of severe toxicity include delirium, coma, seizures, hypotension, and cardiac dysrhythmias (supraventricular
and ventricular). A small proportion of users develop a marked serotonin syndrome, with increased rigidity,
hyperreflexia, and hyperpyrexia (over 39°C), leading to hypotension, metabolic acidosis, cardiovascular
collapse, rhabdomyolysis, acute renal failure, and disseminated intravascular coagulation (DIC).[4][11] Death
from intracranial hemorrhage has also been reported in hyperthermic patients.[5][12][19]
Cerebrovascular Accidents.
Amphetamines are widely recognized as a cause of cerebrovascular accidents secondary to their potent
sympathomimetic effects or to vasculitis. [13] Most of these patients present with severe headache with or
without nausea, and they are usually conscious but confused and disoriented. Some may have marked
hypertension upon presentation.[3][8][11][22] Deaths have been reported from cerebral infarction, cerebral
hemorrhage, and subarachnoid hemorrhage.[5][12][19][34]
Severe Hyperthermia.
Hyperthermia may result from prolonged seizures, muscular hyperactivity, or a serotonin syndrome. Effects
include hyperpyrexia (above 40°C), rhabdomyolysis, myoglobinuria, DIC, and renal failure ( Fig. 76–1 ).
When the MDMA group of drugs is used as a “dance drug” there is a danger of prolonged exertion without
adequate fluid replacement causing hypovolemia, leading to a syndrome resembling heatstroke.[4][11][13][32]
Severe and sometimes fatal hyperthermic reactions can occur following ingestion of recreational doses
previously tolerated without any problem.
Figure 76-1 Amphetamine-induced hyperthermia and subsequent complications.
Renal Complications.
Renal ischemia and infarction may rarely occur as a result of vasculitis. More commonly, renal failure may
occur due to nontraumatic rhabdomyolysis[18][29] secondary to excessive muscular activity or seizures and
aggravated by metabolic acidosis, hypokalemia, and hyperthermia.
Cardiac Complications.
Cardiac dysrhythmias are common. Marked sinus tachycardia is most common, but ventricular tachycardia
and ventricular fibrillation may occur. Deaths that occur soon after ingestion are usually due to cardiac
dysrhythmias such as ventricular fibrillation.[15] Other cardiac problems induced by amphetamines include
myocardial ischemia and infarction, left ventricular dysfunction, and acute cardiomyopathy.[3][27]
Hyponatremia.
Hyponatremia following MDMA ingestion is an uncommon complication[14][16][21][23] A small proportion of

patients who have taken one of the MDMA group of drugs develop hyponatremia, usually after drinking
excessive amounts of water in the absence of sufficient exertion to eliminate fluid. The cases reported are
not hyperthermic and present with initial vomiting and disturbed behavior, followed by drowsiness and
agitation progressing to epileptiform seizures. Drowsiness, a mute state, and disorientation follow for up to 3
days. The syndrome of inappropriate antidiuretic hormone (SIADH) is usually present. The observed
neurologic dysfunction is caused by hemodilution, with a rapid fall of serum sodium, leading to intracellular
movement of water and subsequently to cerebral edema. Most patients have developed severe illness within
12 hours of ingestion of Ecstasy, suggesting an acute drop in serum sodium secondary to unrestricted fluid
ingestion. Deaths have occurred from this syndrome.
Chronic Adverse Effects
An increased incidence of aortic regurgitation has occurred in patients who took the combination drug “fen-
phen” or fenfluramine alone for weight loss.[14a] One study demonstrated the relation between the duration
of use of “fen-phen” (6 or more months) and the occurrence of valvular abnormalities (predominantly mild
aortic regurgitation).[10a][14a] In September 1997, fenfluramine and dexfenfluramine were voluntarily
withdrawn from the United States market.[10a]
Little is known about the long-term effects of MDMA abuse. A number of cases of chronic psychiatric illness
(mainly schizophrenia-like psychosis) have been reported in the medical literature.[20][21] Other unusual
chronic complications reported include dental infections and trauma,[6] sleep disturbances, and chocolate
craving.[1][30]


The differential diagnosis of amphetamine toxicity is vast and depends on the clinical effects produced
(which can be very wide ranging) and their resemblance to the effects of other abused substances or to
other medical conditions ( Table 76–2 ).
Table 76-2 -- Differential Diagnosis of Amphetamine Intoxication from the Effects of Other Abused
Drugs and from Other Medical Conditions
Abused Drugs Symptoms Other Conditions
Cocaine, phencyclidine, opioid Sympathomimetic Dehydration, infections, thyrotoxicosis,
withdrawal, ethanol sedative- effects or cardiac theophylline toxicity, cardiac dysrhythmias,
hypnotic/barbiturate withdrawal, dysrhythmias cardiac conduction disorders,
anticholinergic agents pheochromocytoma, monoamine oxidase
inhibitor, food/drug interaction, salicylate toxicity
Cocaine, phencyclidine, anabolic Chest pain or cardiac Ischemic heart disease, musculoskeletal pain,
steroid ischemia esophageal pain
Cocaine, phencyclidine, malignant Heat illness, sepsis, thyroid crisis, monoamine
hyperthermia, neuroleptic malignant oxidase inhibitor overdose/interaction,
Hyperthermia
syndrome, anticholinergic agents, amoxapine overdose, serotoninergic drug
withdrawal states interactions, cyanide, salicylates, dinitrophenol
Cocaine, phencyclidine, mescaline,
Thyrotoxicosis, hypoglycemia, anxiety state,
khat, opioid withdrawal, ethanol Central nervous
mania, agitated depression, personality
withdrawal, sedative- system stimulation
disorders
hypnotic/barbiturate withdrawal
Alcohol, sedative-hypnotic agents, Depression, psychosis, bulimia, exhaustion,
Withdrawal
barbiturates, khat viral illness
LSD, mescaline, psilocybin,
phencyclidine, alcohol withdrawal, Paranoid behavior Schizophrenia, organic brain syndromes
cannabis, psychosis
Epilepsy, status epilepticus, theophylline
Cocaine, phencyclidine, opioid, overdose, cyclic antidepressant overdose,
sedative-hypnotic/ethanol/barbiturate amoxapine overdose, theophylline toxicity,
Seizures
withdrawal, gamma-hydroxybutyrate, salicylate toxicity, monomethylhydrazine-
gamma-butyrolactone containing mushrooms, INH toxicity, water
hemlock poisoning or ingestion
Amphetamine toxicity should be considered in patients, especially younger age groups, who present with
chest pain or evidence of myocardial ischemia, focal neurologic findings, muscle fasciculations or seizures,
hyperpyrexia without evidence of infection, or rhabdomyolysis with or without renal failure. Medical
conditions such as thyrotoxicosis and pheochromocytoma, and the effects of sympathomimetic agents, MAO
inhibitor reactions, and anticholinergic agents can mimic the a- and ß-adrenergic receptor stimulation seen
in amphetamine toxicity. Because amphetamines cause marked CNS stimulation, the effects of other CNS
stimulants must be considered: cocaine, hallucinogens (mescaline, LSD, PCP, psilocybin), and
methylxanthines (caffeine and theophylline). Psychotic behavior seen with amphetamine toxicity can also be
seen in patients who have taken hallucinogens or those presenting with hypoglycemia, cerebral hypoxia,
mania, or schizophrenia. Amphetamine abuse should also be considered in trauma patients who have been
involved in “superhuman” incidents (e.g., trying to fly when jumping off a building), or who have had an
accident while driving dangerously.


LABORATORY STUDIES
As with any patient presenting with an unknown overdose, the patient with suspected amphetamine toxicity
should have routine diagnostic studies such as a complete blood count, electrolytes, blood urea nitrogen
(BUN) and creatinine, serum glucose, and urinalysis. Other tests such as arterial blood gas,
electrocardiogram, creatine phosphokinase, and urine drug screen should be performed as the clinical
condition warrants. Laboratory tests may demonstrate a number of abnormalities due to pharmacologic
effects of amphetamines.
Arterial Blood Gas Analysis.
The most common finding is a respiratory alkalosis due to tachypnea secondary to respiratory center
stimulation. This imbalance may be combined with a metabolic acidosis secondary to hyperactivity, muscle
spasms, seizures, hyperthermia, or tissue hypoperfusion consequent to vasospasm. A respiratory acidosis
may occur in the patient with hypermetabolism, seizures, or cardiovascular collapse.
Electrolytes, BUN, and Creatinine.
The sympathomimetic effects of amphetamines may lead to hypokalemia, although hyperkalemia may occur
secondary to hyperpyrexia, rhabdomyolysis, or renal failure. Hypernatremia may result from dehydration,
and hyponatremia (serum sodium less than 130 mmol/L) and syndrome of inappropriate antidiuretic
hormone secretion may follow excessive water drinking.[21] BUN and creatinine levels may be elevated in
patients with volume depletion but may also indicate renal failure secondary to rhabdomyolysis.[29]
Glucose.
Hyperglycemia may result from excessive sympathetic stimulation.
Creatine Phosphokinase and Transaminases.
These levels may be markedly elevated owing to rhabdomyolysis associated with hyperthermia, seizures, or
excessive physical activity, but the combination of high CPK-MB fraction, troponin I, and transaminase
elevation may be used to confirm a suspected myocardial infarction.
Hematologic Studies.
A leukocytosis commonly occurs with marked clinical toxicity. DIC may produce thrombocytopenia, a
prolonged prothrombin time and partial thromboplastin time, a reduced plasma fibrinogen concentration, and
a high level of fibrin degeneration products in the serum.
Urine Testing.
Routine urinalysis may reveal glycosuria and may give a positive test for blood without red blood cells seen
microscopically, indicating the presence of myoglobinuria. A specific test for myoglobin should be used to
confirm this finding.
Toxicology Screens.
Blood and urine tests for amphetamines may confirm amphetamine intoxication and possibly exclude other
common illicit drugs of abuse. Screening can also confirm the specific drug involved, although several of the
designer amphetamine analogs may give a false negative result.[7] Plasma concentration correlates poorly
with the clinical effects. Management decisions should not be deferred pending laboratory confirmation of
the diagnosis of amphetamine toxicity, because the management strategies are directed at symptomatic
control of the clinical manifestations of toxicity.


TREATMENT
There is no specific antidote for amphetamine toxicity. Management is generally supportive and should be
directed at the pharmacologic effects encountered. After the patient is stabilized, treatment should be
focused on GI decontamination. If the patient presents within 1 to 2 hours of a potentially life-threatening
ingestion, gastric lavage may be indicated, followed by oral administration of activated charcoal ( Fig. 76–2 ).
Beyond this time period, charcoal alone may be efficacious.[24] Syrup of ipecac should be avoided because
its emetic effect may not occur until after the patient deteriorates. It is difficult to establish a toxic amount
because of the uncertainty in purity of amphetamines sold on the street, but it is worth instituting gastric
decontamination on clinical suspicion. Treatment is generally recommended for recent ingestion of greater
than 2 mg of amphetamine. Although understudied, there may be a role for whole bowel irrigation with
polyethylene glycol solution both in patients who swallow prewrapped drugs in a hurried fashion to hide
illegal contraband and in those smuggling drugs who are arrested by authorities (i.e., body stuffers and
packers).
Figure 76-2 Management of acute amphetamine toxicity.
Acute Mental Disturbances or Seizures
Benzodiazepines (lorazepam 1–2 mg IV or diazepam 5 mg IV) are the initial treatment of choice for agitated,
aggressive, or hyperactive patients. Repeated doses can be titrated to achieve sedation. Reassurance and a
calm environment may help in some cases. Haloperidol should be considered in patients unresponsive to
benzodiazepines. Chlorpromazine should be avoided because it may produce hypotension and lower the
threshold for seizures. Diazepam or lorazepam should also be used for seizures, followed by barbiturates
(phenobarbital or thiopentone). If routine drug therapy fails to control seizures, the patient should be
paralyzed with neuroparalytic agents to avoid the complications of worsening metabolic acidosis and
hyperthermia. Pharmacologic treatment of the seizures should continue with midazolam infusion, propofol
infusion, and maximal barbiturate therapy followed by general anesthesia for continued status epilepticus.
Bedside EEG monitoring should be used to guide the need for further therapy in a paralyzed patient.
Hyperthermia
In severe cases, management should be aggressive because hyperthermia can be rapidly fatal. If the rectal
temperature exceeds 39°C, a rapid crystalloid fluid challenge should be given (1–2 L or 20 mL/kg) to reduce
the pulse rate, raise the blood pressure, and facilitate thermoregulation. Further fluid should be given
according to central venous pressure measurements. If the rectal temperature exceeds 40°C, rapid cooling
measures should be instituted with evaporation techniques using mist/sprays, circulating fans, and strategic
ice placement (see Chapter 27 ). If the patient presents with severe muscle rigidity causing hyperthermia,
metabolic acidosis, or rhabdomyolysis, treat initially with benzodiazepines. If response to benzodiazepines is
inadequate, the patient should be paralyzed with pancuronium or vecuronium and ventilated. Dantrolene has
been advocated by some[35][36] for muscle rigidity. However, cooling may be delayed, [37] and it should not be
used for muscle rigidity producing life-threatening hyperthermia or metabolic acidosis.
Cardiovascular Complications
Similar to cocaine-induced cardiotoxicity, tachycardia and hypertension that result from amphetamine
overdose should initially be treated with intravenous benzodiazepines (lorazepam or diazepam). Refractory
or malignant cases of hypertension may require sodium nitroprusside. Its advantages include sole drug
therapy and cessation of effect within 3 minutes of stopping the infusion. A ß-adrenergic receptor antagonist
is discouraged because it can lead to unopposed a-adrenergic stimulation, exacerbating the
sympathomimetic effects of the amphetamine. If a ß-adrenergic receptor antagonist is selected, it should be
short-acting (e.g., esmolol), and coupled with an a-adrenergic receptor antagonist such as phentolamine.
Although labetalol seems an attractive drug of choice for amphetamine toxicity (blocking both a- and ß-
adrenergic receptors), it is essentially a ß-adrenergic receptor antagonist (80%) and acts accordingly.
Myocardial ischemia should be treated with therapies standard for unstable angina and myocardial
infarction, with emphasis on nitroglycerin administration for chest pain refractory to benzodiazepines and
avoidance of ß-adrenergic receptor antagonists. Acute cardiomyopathy can be managed with appropriate
diuretics, ACE inhibitors, and antidysrhythmic agents.
Drug Elimination and Renal Impairment
Although an acidic urine shortens the elimination half-life of amphetamines by increasing renal excretion, it
also worsens myoglobin precipitation in the renal tubules. Therefore, urinary acidification is discouraged. If
there is evidence of myoglobinuria, aggressive crystalloid administration to assure adequate urinary output
and alkalinization is more appropriate in order to prevent myoglobinuric renal failure. Renal function must be
monitored closely, especially in patients with hypotension, hyperthermia, or rhabdomyolysis. Hemodialysis is
of limited effectiveness in elimination of amphetamines, and its use is reserved for cases of acute renal
failure.
Hyponatremia
Patients who develop hyponatremia, usually after drinking excessive amounts of water, are generally not
hyperthermic. As a result, fluids should be restricted. SIADH may be present; serum and urine osmolality
should be measured. Most cases recover spontaneously over 24–48 hours. In severe cases, intravenous
mannitol, loop diuretics, or hypertonic saline are indicated.
Uncommon Complications
The effect of accidental intra-arterial injection should be treated supportively with pain relief, sodium
nitroprusside, heparinization, and appropriate antibiotics. Liver function should be monitored, especially in
hyperthermic patients. Hepatic complications usually resolve after discontinuing the drug, but fulminant
hepatitis has occurred.[31]


DISPOSITION
Patients with mild symptoms usually can be observed in the emergency department and discharged once
they have become asymptomatic. Patients with evidence of moderate toxicity or unstable vital signs should
be admitted to the hospital for cardiac monitoring and observation. Those with severe toxicity or any major
complications should be admitted to an intensive care unit. Those with psychiatric complications should
have a psychiatric assessment.


SEQUELAE
The acute effects of amphetamine toxicity usually resolve without permanent sequelae. Withdrawal states
tend to be less severe than withdrawal from other drugs such as opioids or cocaine. The following
withdrawal symptoms have been reported: apathy, lethargy, depression, anxiety, sleep disturbance,[1]
myalgia, abdominal pain, and hyperphagia. The effects peak after 2–3 days and last up to 6 days. Other
psychiatric effects such as psychosis resolve within days or weeks, but this depends to some extent on
previous personality.[31][32]
Patients who develop a cardiomyopathy may be left with a permanently reduced ejection fraction even after
discontinuing drug use. Valvular abnormalities may develop in patients who took fenfluramines.
Amphetamine-induced vasculitis will resolve if drug use is discontinued, but the ischemic sequelae usually
remain.[20] The prognosis of cerebrovascular accidents depends on the site and severity of the lesions but is
often relatively good because of the younger age group involved. If the patient suffers severe
rhabdomyolysis, permanent acute tubular necrosis (ATN) and renal failure/insufficiency may develop as a
consequence.[29]
Death due to amphetamine toxicity is unusual, and is usually secondary to cardiac dysrhythmias,
cerebrovascular accidents or cerebral hemorrhage, extreme hyperthermia, acute cardiac failure, seizures, or
cerebral edema with brainstem compression. [15][18]


REFERENCES
1. Allen RP, McCann UD, Ricaurte GA: Persistent effects of (+/-) 3,4-methylenedioxymethamphetamine
(MDMA, “Ecstasy”) on human sleep. Sleep 1993; 16:560.
3. Carson P, Oldroyd K, Phadke K: Myocardial infarction due to amphetamine. Br Med J 1987; 294:1525.
4. Dar KJ, McBrien ME: MDMA-induced hyperthermia: Report of a fatality and review of current therapy.
Intensive Care Med 1996; 22:995.
5. Delaney P, Estes M: Intracranial hemorrhage with amphetamine abuse. Neurology 1980; 30:1125.
6. Duxbury AJ: Ecstasy—Dental implications. Br Dent J 1998; 175:38.
7. Emerson TS, Cisek JE: Methcathinone: A Russian designer amphetamine infiltrates the rural Midwest.
Ann Emerg Med 1993; 22:1897.
8. Ellenhorn MJ, Schonwald S, Ordog G, et al: Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of
Human Poisoning, Baltimore: Williams & Wilkins; 1997:340-355.
10. Fischer C, Hatzidimitriou G, Wlos J, Ricaurte G: Reorganization of ascending 5-HT axon projections in
animals previously exposed to the recreational drug (+/-) 3, 4-methylenedioxymethamphetamine (MDMA,
“Ecstasy”). J Neurosci 1995; 15:5476.
10a. Gardin JM, Schumacher D, Constantine G, et al: Valvular abnormalities and cardiovascular status
following exposure to dexfenfluramine or phentermine/fenfluramine. JAMA 2000; 283:1703.
10b. Fitzgerald LW, Burn TC, Brown BS, et al: Possible role of valvular serotonin 5-HT (2B) receptors in the
cardiopathy associated with fenfluramine. Mol Pharmacol 2000; 57:75.
11. Ginsberg MD, Hertzman M, Schmidt-Nowara WW: Amphetamine intoxication with coagulopathy,
hyperthermia and reversible renal failure. Ann Intern Med 1970; 73:81.
12. Harrington H, Heller A, Dawson D, et al: Intracerebral hemorrhage and oral amphetamine. Arch
Neurol 1983; 40:503.
13. Henry JA, Jeffreys KJ, Dawling S: Toxicity from 3,4-methylenedioxymethamphetamine (“Ecstasy”).
Lancet 1992; 340:384.
14. Holden R, Jackson MA: Near-fatal hyponatremic coma due to vasopressin oversecretion after “Ecstasy”
(3,4-MDMA). Lancet 1996; 347:1052.
14a. Jollis JG, Landolfo CK, Kisslo J, et al: Fenfluramine and phentermine and cardiovascular findings:
effect of treatment duration on prevalence of valve abnormalities. Circulation 2000; 101:2071.
15. Kalant H, Kalant OJ: Death in amphetamine users: Causes and rates. Can Med J 1975; 112:299.
16. Kessel B: Hyponatremia after ingestion of “Ecstasy.”. Br Med J 1994; 308:414.

17. Kuczenski R, Segal DS: Neuropsychopharmacology.. In: Cho AK, Segal DS, ed. Amphetamine and Its
Analogs, xx San Diego, CA: Academic Press; 1994:81-104.
18. Linden CH, Kulig KW, Rumack BH: Amphetamines. Trends Emerg Med 1985; 7:18.
19. Lukes SA: Intracerebral hemorrhage from an arteriovenous malformation after amphetamine injection.
Arch Neurol 1983; 40:60.
20. Matick H, Anderson D, Brumlik J: Cerebral vasculitis associated with oral amphetamine overdose. Arch
Neurol 1983; 40:253.
21. Matthai SM, Davison DC, Sills JA, et al: Cerebral oedema after ingestion of MDMA (“Ecstasy”) and
unrestricted intake of water. Br Med J 1996; 312:2359.
22. McCann UD, Rideour A, Chaham Y, et al: Serotonin neurotoxicity after (+/-) 3,4-
methylenedioxymethamphetamine (MDMA, “Ecstasy”). A controlled study in humans.
Neuropsychopharmacology 1994; 10:129.
23. Maxwell DL, Polkey MI, Henry JA: Hyponatremia and catatonic stupor after taking “Ecstasy.”. Br Med
J 1993; 307:1399.
24. McKinney PE, Tomaszewski C, Phillips S, et al: Methamphetamine toxicity prevented by activated
charcoal in a mouse model. Ann Emerg Med 1994; 24:220.
27. Packe GE, Garton MJ, Jennings K: Acute myocardial infarction caused by intravenous amphetamine
abuse. Br Heart J 1990; 64:23.
29. Scandling J, Spital A: Amphetamine-associated myoglobinuric renal failure. South Med

J 1982; 75:237.
30. Schifano F, Magni G: MDMA (“Ecstasy”) abuse: Psychopathological features and craving chocolate: A
case series. Biol Psychiatry 1994; 36:763.
31. Schifano F: Chronic atypical psychosis associated with MDMA (“Ecstasy”) abuse.
Lancet 1991; 338:1335.
32. Schwartz RH, Miller NS: MDMA (“Ecstasy”) and the “rave”: A review. Pediatrics 1997; 100:705.
34. Shukla D: Intracranial hemorrhage associated with amphetamine use. Neurology 1982; 32:917.
35. Singaraja C, Laries NG: An overdose of “Ecstasy”: A role for dantrolene. Anesthesia 1992; 47:686.
35a. Steffee CH, Singh HK, Chitwood WR: Histologic changes in three explanted native cardiac valves
following use of fenfluramines. Cardiovasc Pathol 1999; 8:245.
36. Ward A, Chaffman MO, Sorkin EM: Dantrolene. A review of its pharmacodynamic and pharmacokinetic
properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an
update of its use in muscle spasticity. Drugs 1986; 32:130.
37. Watson JD, Ferguson C, Hinds CJ, et al: Exertional heatstroke induced by amphetamine analogues.
Anaesthesia 1993; 48:1057.


Uncited references
Arieff AI: Management of hyponatremia. Br Med J 1993; 307:305.
Ellis AJ, Wendon JA, Portmann B, Williams R: Acute liver damage and “Ecstasy” ingestion.
Gut 1996; 38:454.
Molliver ME, Berger UV, Manounas LA, et al: Neurotoxicity of MDMA and related compounds: Anatomic
studies. Ann NY Acad Sci 1990; 600:682.
Morley JE, Shafer RB, Elston MK, et al: Amphetamine-induced hyperthyroxinemia. Ann Intern
Med 1980; 93:707.
Randall T: Ecstasy-fueled “rave” parties become dances of death for English youths. Med News
Perspect 1992; 268:1505.
Series H, Boeles S, Korkins E, et al: Psychiatric complications of “Ecstasy” use. J

Psychopharmacol 1994; 8:60.


Chapter 77 – Opioids
KURT C. KLEINSCHMIDT MICHAEL WAINSCOTT MARSHA D. FORD
Essentials
• Respiratory depression
• Miosis
• Clinical response to naloxone
INTRODUCTION
Opioids are naturally occurring or synthetic drugs that have opium- or morphine-like activity. Opiate refers
only to those drugs derived from opium, which include morphine, codeine, and paregoric. The term narcotic,
originally used to describe any drug that could induce sleep, became associated with opioids. However, it is
nonspecific and is no longer clinically useful.[1] Opioids are used clinically for analgesia and anesthesia and
are available illicitly for oral, inhalational, or parenteral abuse. The poppy plant, Papaver somniferum, is the
source of opium. It contains more than 20 alkaloids, including morphine and codeine. Altering the structure
of morphine produces many semisynthetic opioids, including heroin, hydrocodone, hydromorphone, and
thebaine (a precursor to oxycodone and naloxone).
The challenge of managing patients experiencing opioid overdose continues to confront physicians. In the
1998 American Association of Poison Control Centers data, opioids were involved either primarily or as a
co-ingestant in 90 (11.6 per cent) of a total of 775 deaths reported.[2] International opioid consumption
continues to rise.[3] Surveys by the Monitoring the Future project, sponsored by the National Institute on
Drug Abuse, have found an 80 per cent increase in abuse of opiates among high-school youth from 1991 to
1998.[4] Data from the Drug Abuse Warning Network in the United States reflect a 31 per cent increase in
emergency department (ED) visits from 1992 to 1998.[5] A new heroin epidemic has developed; it is abused
either singly or in combination with cocaine (a “speedball”).[6]


Pharmacology
Opioids produce their effects by interacting with specific receptors distributed throughout the central and
peripheral nervous systems and in the gastrointestinal tract. Their activity resembles that of the body’s three
known endogenous opioid peptides: enkephalins, endorphins, and dynorphins.[1] These endogenous
peptides are natural ligands for the opioid receptors and function either as short-acting neurotransmitters or
as long-acting neurohormones.[7]
Unlike local anesthetics, pain sensory thresholds are not altered by opioids. Opioid-receptor activation
results in inhibition of adenyl cyclase activity, activation of receptor-operated K+ currents, and suppression of
voltage-gated Ca2+ currents. These effects cause hyperpolarization of the cell membrane, which decreases
neurotransmitter release, resulting in less pain transmission.[1] Patients still perceive some pain, but it does
not bother them.[7]
Three main receptors have been identified: mu (µ), kappa ( ), and delta (d).[1][7] Each receptor is associated
with certain clinical effects, and subtypes exist, such as µ 1, and 2 ( Table 77–1 ). Most analgesia results
from supraspinal µ1 receptors. It is the only opioid receptor in the brain and is primarily responsible for the
euphoria produced by opioids. The µ 2 receptor is associated with spinal analgesia and with many of the
complications of opioids, including respiratory depression, constipation, physical dependence, and pruritus.
Kappa receptors produce spinal analgesia distinct from that produced by other opioid receptors. Unlike the
euphoria resulting from µ1 activation, 2 receptor activation results in dysphoria and depersonalization. The d
receptors, which produce spinal analgesia, are the most poorly defined of the three.[1][7] All three types of
opioid receptors exist in peripheral tissues too, and are unregulated during periods of inflammation.[8] Local
immune cells secrete endogenous opioid peptides, resulting in local analgesia. This peripheral action
provides an opportunity for a new approach to analgesia that might avoid central nervous system (CNS) side
effects.[8]
Table 77-1 -- Opioid Receptors and Clinical Effects

Receptor Clinical Effect
Mu µ1 Supraspinal analgesia (provides most analgesic effects)
Peripheral analgesia
Spinal analgesia
Respiratory (depression)
Gastrointestinal ( motility constipation)
µ2
Miosis
Euphoria
Receptor Clinical Effect
Physical dependence
Spinal analgesia
1
Miosis (less contribution than µ2)
Kappa Dysphoria
2
Psychotomimesis (disoriented and/or depersonalized feelings)
3 Supraspinal analgesia
Delta d Spinal analgesia
, decreases; , results in
The sigma (s) receptor was once considered to be an opioid receptor. However, because it is not
antagonized by naloxone, it is no longer considered to be a classic opioid receptor. Certain opioids
(pentazocine, butorphanol, and dextromethorphan) do interact with the s receptor, resulting in
psychotomimetic symptoms (hallucinations, delusions, dysphoria, depersonalization, and affective
lability).[9][10]
Opioids can be classified on the basis of function into three groups: morphine-like opioid agonists, opioid
antagonists, and mixed agonist-antagonists/partial agonists ( Table 77–2 ).[1] Most opioids interact with more
than one opioid receptor. Morphine-like agonists act primarily on µ and receptors. Agonists also may
weakly interact with d receptors, resulting in the alteration of pain perception. Antagonists occupy but do not
activate receptors sites, thereby competitively blocking receptor activation by opioid agonists. Mixed agonist-
antagonist opioids produce varied effects depending on the predominance of agonistic or antagonistic
activities in the different types of receptors. Use of mixed agents in opioid-nai¨ves subjects results in
analgesia and potentially in physical dependence if chronically administered. However, use of mixed agents
in opioid-dependent individuals may cause a withdrawal syndrome. An agent that is a partial agonist binds
with low affinity to an opioid receptor. Although it has agonistic activity and causes analgesia when given
alone, it acts as an antagonist when given with another agonist of higher affinity. Partial agonists usually
produce less analgesia than full agonists.[11]
Table 77-2 -- Classification, Potencies, and Characteristics of Opioid Agents

Analgesic Dose (mg) Analgesic
Agent (Sample Brand Equivalent to 10 mg Duration of Comments, Uses,
Name) Derivation Morphine IM Action (hr) Side Effects
Agonists
Codeine Natural 120 PO 4–6 Use: AT
Diphenoxylate (Lomotil) Synthetic Nonanalgesic (2.5 PO) — Use: AD
Fentanyl (Sublimaze) Synthetic 0.125 IM <1 1,2
Heroin Semisynthetic 3–5 SC 3–4 Rush
Hydrocodone (Lortab) Semisynthetic 10 PO 4–5 3
Hydromorphone
Semisynthetic 1.3–1.55c 4–5
(Dilaudid)
Levorphanol (Levo
Semisynthetic 2 SC/IM 2.0–2.3 4–5 Long-acting
dromoran)
Loperamide (Imodium) Synthetic Nonanalgesic (2 PO) — Use: AD
Meperidine, pethidine
Synthetic 75 SC/IM 75–80 2–5 S,4,5,6
(Demerol)
Methadone (Dolophine) Synthetic 10 IM 4–5 Long-acting
Morphine Natural 10 SC/IM 4–5 The standard
Oxycodone (Percocet) Semisynthetic 10–15 PO 4–5 3
Oxymorphone
Semisynthetic 1 SC 4–6
(Numorphan)
Paregoric (Parapectolin) Natural 25 mL PO 4–5
Propoxyphene (Darvon) Synthetic 65 PO 2–6 DYS,S,3,5
Tramadol (Ultram) Synthetic 50–100 PO 4–6 S,6
Agonist-Antagonists
Buprenorphine
Semisynthetic 0.4 IM 5–9 8
(Buprenex)
Butorphanol (Stadol) Semisynthetic 2 IM 3–6 7,8,PSY
Nalbuphine (Nubain) Semisynthetic 10 IM 4–6 7,8,PSY
Pentazocine (Talwin) Semisynthetic 50 SC 4–6 7,8,PSY
Antagonists
Semisynthetic Nonanalgesic (0.1–0.2
Nalmefene (Revex) 4–6
IV/IM)
Semisynthetic Nonanalgesic (0.1–0.4
Naloxone (Narcane) 0.5
IV/IM)
Naltrexone (ReVia) Semisynthetic Nonanalgesic (50 PO) 24
Other
Dextromethorphan Semisynthetic Nonanalgesic (10–30 PO) — Use: AT,6
Side effects: CV, cardiovascular; S, seizures; PSY, psychotomimetic or dysphoric effects; 1, no histamine
release; 2, very lipophilic and transdermal preparation available; 3, often combined with other analgesics; 4,
use cautiously with renal compromise; 5, significant active metabolite; 6, affects serotonin; 7, may cause
withdrawal symptoms in opioid dependent patients; 8, has ceiling for analgesia and respiratory depression.
Uses: AD, antidiarrheal; AT, antitussive.
Discussion of pharmacokinetics is beyond the scope of this chapter; more detailed references exist.[1][12]
However, several points need emphasis. Most oral opioids are completely absorbed from the gastrointestinal
tract and peak in 1 to 1½ hours. First-pass metabolism is significant, resulting in low bioavailability. For
example, the bioavailability of oral morphine is only 22 to 24 per cent.[12] Conversely, codeine and
methadone have higher oral/parenteral potency ratios and have bioavailabilities of 60 per cent[1] and 79 per
cent,[13] respectively. Protein binding of morphine is only 20 to 40 per cent,[12] whereas it is up to 90 per cent
for methadone.[14] Rectal mucosal absorption is also good, and some opioids are available in suppository
form. The more lipophilic agents are also easily absorbed through the nasal and buccal mucosa.[1] The
extremely lipophilic fentanyl can even be absorbed through the skin.[1] Morphine and meperidine are often
given intramuscularly, but the absorption of meperidine is erratic by this route.[15] Inhaling heroin fumes
(“chasing the dragon”) or smoking cigarettes dipped in heroin (“ack ack”) results in pharmacokinetics similar
to those of intravenous heroin. In one comparative series, both inhaled and intravenous heroin peaked within
1 to 5 minutes and rapidly decreased to the level of detection within 30 minutes.[16]
Various factors can alter the time of onset and of effect. Sublingual, buccal, and sustained-release
preparations result in delayed absorption of morphine, attenuating and delaying the peak plasma
concentrations.[17] Sustained-release morphine attains half the peak plasma level of a comparable dose of
immediate-release morphine, and levels do not peak until 3 to 4 hours. [1][12] Absorption of diphenoxylate-
atropine (Lomotil) can be delayed by the atropine (anticholinergic) component of the compound.[18] A
sustained-release morphine preparation (MS Contin) converts to immediate-release morphine when
crushed, resulting in a potentially massive morphine overdose if ingested (M. Fanucchi, personal
communication). Although the clinical effects of most opioids persist for 3 to 6 hours, exceptions have been
noted (see Table 77–2 ). Fentanyl lasts 1 hour, whereas methadone persists for 24 to 48 hours. [1][14]
Morphine pharmacokinetics in children aged 1 to 15 years are comparable to those in adults.[12] Elderly
patients have been reported to have increased sensitivity to opioids. This impression may actually be the
result of altered disposition of these agents. Elderly patients have smaller drug volumes of distribution, which
results in higher peripheral compartment concentrations than occur in younger adults who are receiving
comparable doses of opioids.[19]
Hepatic biotransformation is the primary route of metabolism of all opioids. Patients with severe hepatic
disease have impaired metabolism and are theoretically at increased risk of toxicity because of
accumulation of active metabolites.[12] The presence of active metabolites can be significant. Morphine’s
primary metabolite, morphine-6-glucuronide, is actually more potent than morphine.[12] It is present in large
quantities soon after intravenous or oral administration and it provides the majority of the clinical effects of
morphine treatment.[17] Elimination is primarily renal. The active metabolites of morphine, meperidine, and
propoxyphene (morphine-6-glucuronide, normeperidine, and norpropoxyphene, respectively) all have
significant renal excretion.[12] Kidney dysfunction can contribute to toxicity because of the accumulation of
active metabolites.[13]
Opioids interact with many drugs. Phenothiazines potentiate opioids, possibly by interfering with opioid
metabolism.[12] Cyclic antidepressants increase oral bioavailability and thus increase plasma levels of
opioids.[12] Opioid absorption from the gastrointestinal tract is decreased by kaolin.[12] Many antibiotics
interact, including erythromycin (increased opioid effect) and rifampin (decreased opioid effect).[20]
Cimetidine may increase opioid effects by increasing their duration of action.[20] The idiosyncratic interaction
between meperidine and monoamine-oxidase inhibitors is discussed later.
Pathophysiology
The adverse clinical effects of opioids are caused by their action at the receptors discussed earlier,
especially the µ2 receptor, which mediates many of the life-threatening effects, including respiratory
depression (see Table 77–1 ). The ability of agonist-antagonist drugs to produce opioid withdrawal and the
clinical effects of the metabolites of meperidine and propoxyphene are discussed in detail later.


The classic triad of opioid toxicity is CNS depression, respiratory depression, and miosis. However, multiple
organ systems can be affected ( Table 77–3 ). Patients may be hyporeflexic, hypothermic, or hypotensive or
may have decreased bowel sounds. These toxic effects are mediated primarily through stimulation of the µ,
, and d receptors.[21] Miosis results primarily from µ-related stimulation of the visceral nuclei of the
oculomotor nuclear complex and the parasympathetic nerve that innervates the pupil. [6][22] Miosis usually
occurs within 5 minutes of intravenous administration and lasts for at least 6 hours.[16] Mydriasis or normal
pupils can also result when one of the following circumstances occurs: (1) overdose of meperidine,
morphine (rare), propoxyphene, dextromethorphan, or pentazocine; (2) hypoxia; (3) early stages of Lomotil
poisoning when the atropine effects predominate; (4) after the use of naloxone; and (5) potentially after the
use of a co-ingestant whose pupillary effects override those of the opioid (for example, sympathomimetics,
cyclic antidepressants, glutethimide).[1][23][24]

Body System Presentation Etiology
Cardiovascular Orthostatic hypotension Histamine
Peripheral vasodilation Histamine
Heart rate , , or
Dysrhythmias Hypoxia, norpropoxyphene, adulterants
Flushing Histamine
Dermatologic
Pruritus
Gastrointestinal Constipation GI motility and secretions
Analgesia Opioid receptors
Dysphoria/Psychotomimesis receptors
Euphoria µ receptors
Miosis Most opioids: parasympathetic effects on cranial nerve III
Neurologic
Mydriasis Hypoxia, adulterants, meperidine, propoxyphene
Nausea, vomiting Agonism at chemoreceptor trigger zone
Hypoxia, meperidine, propoxyphene, tramadol, co
Seizures
ingestants
Bronchospasm Unclear etiology; irritant if inhaled
Pulmonary Noncardiogenic pulmonary

Unclear etiology
edema
Respiratory depression µ receptors
Body System Presentation Etiology
, increased; , decreased; , no change; GI, gastrointestinal.
The level of consciousness can vary from euphoria to dysphoria and from mild sedation to coma.[21] Patients
presenting to the ED are usually stuporous or in a coma. The profound CNS depression, impaired gag
response, and centrally mediated nausea and vomiting place the patient at risk for pulmonary aspiration of
gastric contents. Generalized seizures can occur after intravenous fentanyl and sufentanil
administration,[25][26] the prolonged use of meperidine (see later section),[27][28] large ingestions of
propoxyphene[29][30] or pentazocine,[31] and use of tramadol[32] and in neonates who have received high
doses of continuous intravenous morphine or who are in opioid withdrawal.[33]
Respiratory depression causes most opioid-related deaths. However, diagnosis of respiratory depression
may be subtle in some patients. Small decreases in tidal volume may occur before the respiratory rate
declines, so the rate can be an unreliable measure of ventilation.[11][21] Appropriate respiratory evaluation
includes assessment for decreased ventilation, decreased respiratory rate, cyanosis, hypoxia on pulse
oximetry, and hypercarbia or hypoxia on determination of arterial blood gas. Opioid-induced respiratory
depression probably results from a combination of central and peripheral effects. Areas of the medulla
oblongata that control ventilation (nucleus tractus solitarius and nucleus ambiguus) have many opioid
binding sites. These respiratory neurons are inhibited by opioid agonists, as has been demonstrated in
animal studies.[34] Opioid attenuation of normal chemoreceptor-mediated ventilatory responses to
hypercapnia and hypoxia may also affect ventilatory depression.[11][35]
Noncardiogenic pulmonary edema (NCPE) is associated with certain opioids; the precise etiology remains
unknown.[6] Hypoxia secondary to ventilatory compromise may result in precapillary pulmonary hypertension
with increased pulmonary capillary permeability and fluid leak. [36][37] Other proposed pathophysiologic
mechanisms include a hypersensitivity reaction to heroin,[36] direct toxicity to the alveolar membrane,[36]
central neurogenic effects in response to increased intracranial pressure, and increased capillary
permeability secondary to opioid-mediated release of leukotrienes and histamine.[37] Pink, frothy bronchial
secretions, cyanosis, and rales in a stuporous or comatose patient with respiratory depression and miotic
pupils is a typical clinical picture. Parenteral and inhalational use of heroin are particularly associated with
NCPE.[36][38] The incidence of NCPE in patients hospitalized with heroin overdose has been 48 to 80 per
cent.[36][39][40] More recent evaluations of nonhospitalized patients have found the rate to be less than 3 per
cent.[41][42] Methadone, morphine, and propoxyphene have also been associated with NCPE.[43][44][45] The
time interval between exposure and symptom onset is usually less than 2 hours for heroin-related cases[6]
and less than 6 to 12 hours for those caused by methadone.[43]
Bronchospasm may occur acutely after inhalation or intravenous use of heroin or it may be delayed in
onset.[46][47][48] Dyspnea and wheezing can begin a few days to 18 months after starting regular heroin use
and are relieved with standard therapy.[46][48] The mechanism is unclear. Except for some findings of
eosinophils in the blood or sputum, other immunologic evaluations have been negative.[48]
Opioids cause a variety of gastrointestinal effects. Their antidiarrheal action results from decreased intestinal
motility and secretions (pancreatic, biliary, and electrolyte/fluid) and increased intestinal fluid absorption.[49]
These same actions result in the common complication of constipation. Morphine is associated with spasm
of the sphincter of Oddi, resulting in the classic recommendation that it not be used for the treatment of
biliary colic. However, clinical studies comparing morphine with meperidine have not revealed significant
differences in sphincter effects.[15]
Opioid-induced cardiovascular effects are minimal at therapeutic doses. Even in toxicity, cardiovascular
function is usually well preserved until it deteriorates due to hypoxia secondary to the respiratory
compromise. Morphine decreases peripheral vascular tone and is used in the management of pulmonary
edema.[50][51][52] Many opioids cause the release of histamine through an undefined, direct, nonallergic
mechanism. Cutaneous symptoms include itching, warmth, and urticaria. Histamine-induced vasodilation
commonly causes orthostatic hypotension. Pretreatment with a combination of H1 and H2 antagonists
decreases these hemodynamic effects.[53] A blinded comparison of four opioids found that meperidine most
frequently caused elevated histamine; it is followed by morphine. Fentanyl did not cause histamine
release.[53] Hypotension after high doses may also result from decreased central sympathetic outflow.
Significant chronotropic changes are unusual. Mild bradycardia may result reflexively from increased
vasovagal tone associated with nausea and vomiting or from decreased central sympathetic outflow.
Conversely, mild tachycardia can result from the histamine-induced vasodilation or from the increased
systemic epinephrine levels.[53][54] Propoxyphene in overdose can be associated with direct myocardial
toxicity (see the later section on propoxyphene).
Other, less common clinical effects also occur. Acute rhabdomyolysis with renal failure has been associated
with use of heroin, methadone, and propoxyphene.[55][56][57][58][59] All opioid agonists may produce skeletal
muscle rigidity. Increases in chest and abdominal wall tone severe enough to cause impaired ventilation
occur primarily in patients receiving very high (anaesthetic) doses of highly fat-soluble opioids (for example,
fentanyl).[60] However, muscle rigidity has been noted even in patients receiving lower doses.[61] This rigidity
may be mediated through central µ receptors with attenuation by d1 and 1 receptors.[62] A parkinsonian
syndrome has been associated with some opioid-based designer drugs (see the later section on designer
drugs).
Intravenous opioid abuse can cause many medical complications. These include bacterial endocarditis;
septic pulmonary emboli; aspiration pneumonia; tuberculosis; venous thrombosis; talc and cornstarch emboli
to the retina, lungs, liver, and kidney[63][64][65]; heroin-, morphine-, and pentazocine-associated
nephropathy[66][67]; tetanus; hepatitis[68]; human immunodeficiency virus infection; pneumothorax;
pseudoaneurysms; mycotic aneurysms; neck abscesses[69]; cellulitis; septic arthritis[70]; polymyositis; fibrous
myopathy[71]; osteomyelitis; wound botulism[72][73]; compartment syndrome[59]; transverse myelitis[58]; and
intestinal pseudo-obstruction secondary to fecal impaction.[63]


The complete classic triad of miosis, CNS depression, and respiratory depression is not always present,
making the diagnosis of opioid toxicity more difficult ( Table 77–4 ). One series of 43 hospitalized patients
reflected the fact that the complete triad occurs infrequently. Many patients did not have respiratory
depression; however, the definition of respiratory depression was limited to a rate of fewer than 8 breaths
per minute.[74] A rapid response to naloxone may obviate the need to search for other diagnoses, but the
response to naloxone may be incomplete, thus resulting in confusion in diagnosis. Clinical parameters may
be as accurate for making the diagnosis as is the response to naloxone.[75] If the response is partial or
absent, other causes of depressed mental status and miosis must be considered, including central a2
receptor agonists (e.g., clonidine), organophosphates or carbamates, phenothiazines, phencyclidine,
sedative-hypnotic drugs, and pontine hemorrhage. Olanzapine, a newer neuroleptic agent, has been
associated with depressed mental status and miosis.[75a] Clonidine toxicity, typically seen in young children,
most closely approximates opioid toxicity but is distinguished by recurrent apneic episodes that are often
easily terminated with stimulation of the child. Patients exposed to organophosphates or carbamates are
likely to have other symptoms of the cholinergic toxidrome as well. Phenothiazines are more likely to cause
hypotension, conduction delays, or dysrhythmias than are opioids. Phencyclidine produces erratic behavioral
swings, from catatonia to marked agitation and is accompanied by nystagmus, tachycardia, and
hypertension. Sedative-hypnotic drugs can produce miosis secondary to CNS depression, particularly in
children, but this is inconsistent. Opioid toxicity may be mimicked by patients who present with depressed
consciousness and who also happen to be using ophthalmic solutions that produce miosis. Pontine
hemorrhage, classically associated with pinpoint pupils, may be distinguished by the presence of neurogenic
hyperventilation or irregular breathing, decerebrate rigidity, and quadriplegia.

Medication
Carbamates
Central a2 agonists, e.g. clonidine *
Olanzapine *
Organophosphates
Phencyclidine
Phenothiazines
Sedative-hypnotics *
Nonmedication
Altered mental status or miotic ophthalmic solution
CNS infection
CNS trauma
Encephalopathy
Ethanol
Hypoglycemia
Hypoxia
Pontine hemorrhage
* Toxicity from these agents will most closely mimic opioid toxicity. Other differential diagnoses included because they can produce miosis,
altered mental status, or both.
Other causes of CNS depression should be considered. Hypoglycemia, hypoxia, hypothermia, and
Wernicke encephalopathy can be reversed with appropriate substrate repletion. Opioids are often co-
administered with other drugs whose pharmacologic effects persist after the opioid effects have been
reversed with naloxone. Consideration should be given to CNS trauma and infections, postanoxic
encephalopathy, a postictal state, sepsis, hypercalcemia, carbon monoxide poisoning, and ethanol
intoxication.


LABORATORY STUDIES
Toxicologic screens are not generally helpful in the management of patients with opioid toxicity. Screening
results are not available until after significant patient management has already occurred. Opioid screens lack
sensitivity, and many may not detect some of the synthetic and semisynthetic opioids, including
hydrocodone, oxycodone, and propoxyphene.[75b] Fentanyl and its illicit derivatives are not detectable on
routine screens. Urine drug screens provide qualitative data sufficient to confirm the presence of opioids.
However, true-positive screens of no clinical significance can occur after the ingestion of poppy seeds.
Serum quantitative levels are of no clinical benefit and generally are not used. Acetaminophen levels should
be checked in all patients with oral exposures because it is frequently combined with propoxyphene,
oxycodone, hydrocodone, and codeine preparations.


TREATMENT
General Management
Aggressive airway management and the use of naloxone, an opioid antagonist, are the mainstays of therapy
( Table 77–5 ). Patients whose respiratory status is compromised should be supported with bag-valve-mask
ventilations and 100 per cent oxygen while naloxone is administered. If there is no response to the naloxone
or if adequate ventilations cannot be achieved with the bag-valve-mask, the airway should be secured by
means of endotracheal intubation. Intubation with cuff inflation obtains optimal airway control, decreases the
risk of aspiration if vomiting occurs, provides access for airway suctioning and institution of positive airway
pressure if pulmonary edema develops, and enables the administration of naloxone via the endotracheal
route if intravenous access cannot be obtained.

General Management
Airway, breathing, and ventilatory support
Bag-valve-mask support
Suction apparatus prepared
Intubation if resuscitation progresses slowly
Oxygen
Circulation: Assess
Glucose: Point-of-care testing or administration of one to two ampules of D-50-W to an adult or 0.5 to 1 g/kg D-
25-W or D10 to a child
Thiamine: Administer 100 mg IV to patients with altered mental status
Gastric lavage: Consider for ingestions within 1 to 2 hours postingestion
Activated charcoal 1 g/kg for an ingestion
Acetaminophen level: Obtain for a potential suicidal ingestion
Specific Management
Multidose activated charcoal: Consider with diphenoxylate
Whole bowel irrigation: Consider with body packing
Naloxone
• If immediately life threatening: 0.4–2.0 mg IV (goal is to correct ventilatory compromise)
• If less life-threatening: 0.1–0.4 mg IV (goal is to relieve respiratory depression without precipitating
withdrawal)
• Children: 0.1 mg/kg (less than 5 years old or less than 20 kilograms weight); 2 mg IV for life-threatening
toxicity
• Titrate doses every 3–5 minutes to effect
• IM and SQ routes are viable alternatives if IV line is not available; can be administered via endotracheal tube
in intubated patient
• If clinically suspicious of opioid toxicity, administer up to 10 mg (isolated opioid toxicity unlikely if no response
by this dose)
• Infusion: Consider if patient has recurrent symptoms and/or has used a long-acting agent (see text for details)
IV, intravenous; IM, intramuscular; SQ, subcutaneous.
Serum glucose levels should be evaluated by immediate bedside testing and thiamine should be
administered to all patients with altered levels of consciousness. Gastrointestinal decontamination should be
considered in patients who have had oral exposure to opioids, particularly opioids that can have delayed
absorption such as diphenoxylate-atropine (Lomotil) and sustained-release morphine products. Activated
charcoal should be administered to patients with oral ingestions in a dose of 1 g/kg. Concomitant use of
naloxone may facilitate gastrointestinal decontamination by decreasing the gastrointestinal atony. Although
they occur rarely, seizures and cardiac dysrhythmias should be treated with standard therapies along with
reassessment of the airway.
Opioid Antagonists
Naloxone
Naloxone is a synthetic N-allyl derivative of oxymorphone and is the opioid antagonist of choice. It
competitively binds opioid receptors, including , d, and, particularly, µ.[76] It has a greater affinity for
receptors than do the agonists. For example, the effects of 25 mg of heroin are blocked by 1 mg of
naloxone.[1] It is highly lipophilic, moves rapidly into the CNS, and usually has an onset of action of 1 minute
when given intravenously.[76] Clinical effects typically last 45 to 70 minutes.[76]
Life-threatening toxicity in adults should be treated with 2 mg and children up to 5 years of age or 20 kg of
body weight with 0.1 mg/kg. Children who exceed either of these parameters should receive 2 mg.[77] If
there is no response initially, repeat doses should be administered every 3 minutes until either an effect
occurs or a dose of 10 mg is given. If no response occurs with 10 mg, isolated opioid toxicity is unlikely.[78]
Patients without life-threatening toxicity should be treated with 0.4 mg intravenously, with repeat doses
titrated to each patient’s response. The goal in this population is to awaken patients without precipitating
withdrawal. Patients with adequate respirations and who are arousable may not need any naloxone.
Except for fentanyl and its derivatives, naloxone’s duration of action is shorter than that of most opioids.
Repeat doses may be necessary, and a continuous infusion should be considered in patients who require
repeat doses. Continuous infusion can be administered by determining the amount of naloxone required to
reverse respiratory depression, then administering two thirds of this dose every hour in a continuous
infusion. One half of the loading dose should be administered 15 minutes after the initial dose because of
transient decline in the naloxone level 20 to 30 minutes after the initial bolus.[78] The rate of the infusion
should be titrated to keep the patient breathing but not in withdrawal. Naloxone can be mixed in any
intravenous fluid and in any concentration.[78] The infusion is continued for the typical duration of effect of
the involved opioid, then gradually reduced while the patient’s respiratory and mental status are closely
monitored. Continuous infusions have been used safely in both adults and children.[78][79] Larger-than-
customary doses may be required to reverse the effects of codeine, diphenoxylate, methadone,
propoxyphene, pentazocine, butorphanol, buprenorphine, and nalbuphine.[21][76][80]
Intravenous (IV) administration is the standard, but naloxone has also been given by way of the
endotracheal, intralingual, intramuscular (IM), and subcutaneous (SQ) routes.[76] Previously, the IM and SQ
routes have not been recommended because of concerns about erratic absorption and delayed onset of
action.[81] However, a prospective, observational study of SQ naloxone administration in 196 out-of-hospital
patients compared naloxone given 0.8 mg SQ and 0.4 mg IV. The time intervals from arrival with the
Emergency Medical Service to the development in the patient of a respiratory rate of 10 breaths or more per
minute were measured. Outcomes for the two groups were equal. The slower absorption via the SQ route
was offset by the delay required to establish an IV line. [82] IM administration was safe and effective in a
separate urban, out-of-hospital population.[41] IM or SQ administration may decrease the risk of needlestick
injury to health care providers.
Naloxone administration is generally safe in patients with suspected opioid toxicity. Complications of
naloxone use are reported in 1 per cent of heroin users.[41][42][83] Naloxone doses up to 4 mg/kg have been
given to human volunteers with no serious side effects.[84] Although the safety of naloxone has been
questioned in anecdotal reports that pulmonary edema has developed after naloxone administration in
postoperative patients,[85][86][87] these patients also received many other drugs. Few reports exist regarding
pulmonary edema after naloxone administration in patients with opioid toxicity,[88][89] and cause and effect
have not been proven. Other complications anecdotally associated with naloxone include hypotension,
hypertension, atrial and ventricular dysrhythmias, and sudden death,[76][90] but again, cause and effect
remain unproven. Precipitation of withdrawal is the primary consideration. The withdrawal is not life
threatening and typically subsides in 20 to 30 minutes as the effect of the naloxone diminishes; the agitation,
nausea and vomiting, and anxiety result in much distress and dysphoria.[91] Patients in acute withdrawal may
also become violent, potentially causing harm to both themselves and health care providers.[92] Neonates
born to heroin-dependent mothers may seize after naloxone administration. Use of naloxone in patients with
heroin mixtures may unmask the other drugs. For example, naloxone administration in a patient who has
injected a speedball (heroin plus cocaine) has been associated with ventricular and atrial dysrhythmias.[93]
Naloxone has been empirically given in clinical practice to all patients with altered mental status. However,
this approach has been questioned.[75] One series demonstrated that 92 per cent of patients who responded
to naloxone had diminished respirations (<12 per minute), pinpoint pupils, or a clinical presentation
consistent with opioid use. The authors strongly recommended that naloxone be administered only to
patients with altered mental status and diminished respirations.[75]
Nalmefene
Nalmefene is a long-acting parenteral antagonist whose use in the acute care setting is controversial.
Potential advantages include fewer fluctuations in patients’ levels of consciousness than with the use of
naloxone and decreased risk for recurrent opioid toxicity in patients who leave against medical advice soon
after resuscitation.[94] Doses of 0.5 to 2.0 mg have been reported to be safe and effective.[96] Its duration of
action is dose-related: 4 to 8 hours if using 0.5 to 1.0 mg and longer than 8 hours if using 2.0 mg.[94][95][96]
Concerns raised about the use of nalmefene acutely include precipitation of prolonged withdrawal in opioid-
dependent patients[97] and recurrent toxicity from synthetic opioids that have durations of action as long as
or longer than nalmefene. [1] There is also concern that discharged patients may attempt to override
nalmefene’s opioid-antagonism with very large doses of heroin. Then, as nalmefene’s effect wears off,
patients may actually be at greater risk for recurrent opioid toxicity.[97] Nalmefene might be used safely in
potentially opioid-dependent patients after a trial dose of naloxone has been safely tolerated.[96] Potential
realistic indications for nalmefene in the acute care setting include pediatric patients after a single exposure
and patients being admitted to a hospital who have not experienced withdrawal after naloxone
administration.[96] Adverse effects include nausea and vomiting, tachycardia, myoclonus, dizziness,
drowsiness, and mental fatigue.[94][96][98] Anecdotally, noncardiogenic pulmonary edema has been reported
after nalmefene use in a healthy, postoperative patient.[98]
Naltrexone
Naltrexone is an oral opioid antagonist with a longer duration of action than that of naloxone. It is used
primarily for long-term opioid detoxification therapy. Because it is administered orally and because it can
induce a very prolonged withdrawal state, naltrexone is not used in the treatment of acute opioid toxicity.[99]


DISPOSITION
Disposition, observation guidelines, and indications for admission of opioid-toxic patients, particularly those
who are opioid-dependent, are controversial. Primary concerns that indicate the need for observation or
admission include recurrence of respiratory depression, development of NCPE, or ingestion of long-acting
opioids or opioids with anticipated delayed absorption. Sporer’s review of the heroin literature found that in
61 of 64 patients with heroin-related NCPE, symptom onset occurred within 2 hours of their presentation to
the ED. Based upon this review, it is likely that NCPE will develop in a delayed fashion in less than 1 per
cent of patients, and that a 12 to 24 hour observation for NCPE is not required.[6] A retrospective review of
124 patients with heroin overdose revealed that NCPE or hypoxic encephalopathy was evident upon arrival
at the ED or within 20 minutes of presentation.[42] No patients had recurrence of respiratory depression. A
criticism of this review is that most patients who were not admitted were observed for fewer than 8 hours, 40
per cent were observed for fewer than 2 hours, follow-up was poor, and the data are retrospective and do
not answer the question “Is admission necessary?”[42][100] Another retrospective study evaluated recurrence
of opioid toxicity in 84 patients exposed to any opioid and subsequently treated with naloxone.[101]
Exposures were ingestions in 81 per cent and IV administration in 16 per cent. Toxicity recurred in 31 per
cent, usually in the form of increased lethargy or somnolence. Long-acting opioids such as methadone were
significantly more likely to cause recurrence of toxicity. All recurrences of toxicity were evident within 2 hours
of presentation. [101]
Opioid-dependent patients who are interested in rehabilitation should be directed to an appropriate local
source for assistance. Medical management of opioid withdrawal may be provided.


SEQUELAE
Permanent sequelae related to opioid toxicity include the secondary effects of hypoxia due to respiratory
insufficiency, infectious complications resulting from intravenous abuse, renal insufficiency and failure due to
myoglobinuric renal failure, and the parkinsonian effects that result from the use of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP).


SPECIFIC SITUATIONS
Additives
A thorough review of additives is beyond the scope of this chapter, but some excellent reviews exist.[65][102]
Evaluation of heroin-exposed patients should include assessment for complications resulting from the typical
additives. The agents most commonly added are quinine, mannitol, lactose, glucose, sucrose, starches, and
caffeine.[65][102] Between 1995 and 1996 a major outbreak of scopolamine poisoning occurred among heroin
users in East Coast cities.[103][104] The cases were particularly impressive because of the agitation and
combativeness noted in patients after naloxone administration. [103]
Agonist-Antagonist Agents
Agonist-antagonist agents were developed to provide strong analgesia while reducing serious adverse
effects, especially respiratory depression and the potential for drug abuse and dependence. [1][10] Nalorphine
was the first mixed agent to be developed. It is a competitive µ antagonist and a agonist. Other agents are
nalbuphine and butorphanol; both have receptor activity similar to that of nalorphine.[10] Pentazocine differs
in that it has mixed activity at µ (primarily antagonistic), with agonist activity at . Buprenorphine is a partial µ
agonist, but it exhibits antagonistic activity at receptors in some animal species.[1] All of these agents can
provide analgesia in opioid-nai¨ve patients. These agents have a ceiling effect for analgesia that results in
an inability to titrate to relieve pain as can be done with pure opioid agonists.[1][11] However, use in opioid-
dependent patients will not ameliorate a withdrawal syndrome and may actually precipitate one.[1][105] They
are, in general, less commonly abused than are the pure agonists because of the -induced dysphoric
effects and the precipitation of withdrawal in opioid-dependent individuals.[105]
Although pentazocine causes typical opioid effects at lower doses, higher doses result in dysphoric and
psychotomimetic effects.[105] Unlike typical µ agonists, pentazocine and butorphanol are associated with
cardiovascular stimulation, so blood pressure and heart rate often increase at high doses.[1] Dysphoric and
psychotomimetic effects occur at high doses with, in decreasing order of frequency and severity,
pentazocine, butorphanol, and nalbuphine.[1][105] Patients with pentazocine overdose do not present with the
classic opioid toxidrome. They are commonly awake and without respiratory depression and can have
seizures, hypertension, dysphoria, and agitation.[31][106] Buprenorphine differs from the other mixed agents
in that its onset is slow and its duration long. Maximum respiratory depression does not occur until 3 hours
after ingestion, and peak miosis occurs at 6 hours.[105]
Pentazocine hydrochloride (Talwin) and the antihistamine tripelennamine hydrochloride (a blue pill), known
as “Ts and blues” and injected intravenously, were an inexpensive street substitute for heroin in the Midwest
in the late 1970s and early 1980s.[107] Tripelennamine enhanced the euphoric effects and decreased the
dysphoric effects associated with pentazocine.[106] Beginning in 1983, the manufacturer of Talwin replaced it
with Talwin NX, a mixture of pentazocine HCl 50 mg and naloxone HCl 0.5 mg. This was an attempt to block
the effects of pentazocine, should the Talwin tablet be injected intravenously. This attempt was only partially
successful. Another Ts and blues combination, Talwin plus methylphenidate, has been reported.[106]
Body Stuffers and Packers
Drug smuggling by body “packers” who ingest multiple packets of heroin or insert them into the rectum or
vagina can result in an atypical opioid poisoning. Prolonged or cyclical coma in a patient with signs and
symptoms of opioid toxicity should raise the possibility of continued or periodic gastrointestinal leakage from
these packets. Death among heroin packers is usually associated with NCPE.[108] Bowel obstruction can
also occur, and death secondary to peritonitis resulting from bowel ischemia has been reported.[108][109]
Various techniques can be used to make the diagnosis. Packets can often be left on physical examination.
Abdominal radiographs typically reveal multiple, radiopaque intraintestinal packages. In one series,
radiographs were positive in 13 of 14 patients and the only false-negative x-ray occurred in a patient with
only 2 packets.[109] Computed tomography has a high sensitivity for detecting packets, but ultrasound is
poor.[110] Bowel opacification may be done with Gastrografin, 0.9 mL/kg, with the first radiograph to be
obtained 5 or more hours after the swallow.[110] Patients should be monitored for evidence of opioid
intoxication and for abdominal problems including bowel obstruction. Patients should be placed on monitors,
IV lines established, and activated charcoal administered. Gastric emptying is not recommended.
Metoclopramide and various laxatives have been used to enhance bowel activity, and polyethylene glycol
(PEG) electrolyte solution (Colyte, GoLYTELY) have been used to enhance elimination of drug
packets.[109][110] There are concerns about the use of PEG in this setting. A large amount of PEG solution
may solubilize heroin (which is usually poorly soluble), and it actually increased intoxication in one
patient.[109] Enemas have been used once radiographs or digital rectal exams have revealed the presence
of packets within the large intestine.
Designer Drugs: Fentanyl Derivatives and MPTP
Designer drugs are drugs synthesized as substitutes for other chemicals that are popular with illicit drug
users; they are inexpensively created in clandestine laboratories. Two types of designer opioids are of
medical significance.
In 1980 a powerful new drug appeared on the streets; China white was named after the rare, pure Asian
heroin for which it was sold as a substitute.[111] Its potency was tremendous, and it was common to find an
addict dead with the needle still in his arm.[112] Survivors could not recall finishing the injection.[111] The drug
produced a clinical picture of opioid toxicity, yet routine drug screens were negative for opioids. The drug
was eventually identified as a-methylfentanyl. Other fentanyl derivatives have also been produced, including
3-methylfentanyl.
Fentanyl is a highly lipophilic µ receptor agonist with a 30 to 60 minute duration of action and a potency 100
times greater than that of morphine.[113] The most powerful analog reported to date, 3-methylfentanyl, is
2000 times stronger than morphine.[1] These agents do not provide the “rush” that heroin does but instead
produce a longer, painless, sleepy euphoria.[112] In overdose, any of these agents can quickly cause
respiratory arrest.[111] Various outbreaks of fentanyl-based designer drug use have occurred, including in
northern California in the early 1980s, in the western states in 1984 and 1985, in the eastern states in
1988,[112] and in Europe in the mid 1990s. [114][115]
In 1979, the case of a young graduate student who developed a parkinsonian-like syndrome after injecting a
homemade meperidine-like compound was reported.[116] After the student’s subsequent suicide, autopsy
findings revealed marked loss of the nigrostriatal brain cells. In 1982, intravenous drug abusers developed a
similar syndrome within 1 week after using a new synthetic heroin.[117][118] Eventually, MPTP was identified
as the etiologic agent. It was later shown to specifically destroy substantia nigra cells, producing a syndrome
similar to idiopathic parkinsonism.[117] MPTP had been inadvertently produced during the careless synthesis
of 1-methyl-4-phenyl-4-propion-oxy-piperidine (MPPP), a meperidine analog sold on the streets for
intravenous use.
Within 1 week of using the MPTP-MPPP mixture, patients experienced sudden jerking of the extremities
followed by bradykinesia and near-total immobility; hence the term “frozen addict.” Physical examination
revealed parkinsonism: difficulty in moving and speaking, flexed posture, constantdrooling, increased
muscle tone, cogwheel rigidity in the upper extremities, and a positive glabellar tap test.[118] Unlike patients
with idiopathic parkinsonism, these patients were young, had acute onset, had postural tremor of the
proximal muscles of the extremities that was more pronounced than the typical resting tremor, and did not
have dementia.[119]
Further study revealed the pathophysiology. MPTP is converted by monoamine oxidase-B into a positively
charged compound, 1-methyl-4-phenyl pyridine (MPP+). MPP+ is then actively transported via the
dopaminergic uptake carriers to the nigrostriatal dopamine neurons, where it induces cellular death, possibly
by inhibiting mitochondrial respiration.[120]
The drug-induced syndrome is permanent, but like idiopathic parkinsonism, treatment with L-dopa,
bromocriptine, and anticholinergic drugs may improve the clinical condition. Although few cases have been
documented,[116][118] many more intravenous drug abusers may have suffered subclinical nigrostriatal
destruction. As these people age, further loss of dopaminergic neurons may result in clinical parkinsonism.
Dextromethorphan
Dextromethorphan is the d-isomer of the codeine analog levorphanol. However, unlike the l-isomer, it has no
analgesic, respiratory, or CNS effects at therapeutic doses.[24] Its active metabolite, dextrophan, accounts for
much of dextromethorphan’s effects, which include inhibition of reuptake and stimulation of release of
serotonin as well as the blocking of the N-methyl-D-aspartate receptor complex at the phencyclidine
site.[121][122] This latter mechanism accounts for its abuse as a hallucinogen.[24] It may present with an opioid
toxidrome.[123] More often, toxicity consists of hyperexcitability, lethargy, ataxia, slurred speech, diaphoresis,
hypertension, and nystagmus.[24][121] Other, less common events include seizures,[122] respiratory
depression,[123] and acute dystonia.[122][124] Most over-the-counter dextromethorphan products are
hydrobromide salts, and bromide intoxication has been reported.[125] Naloxone infrequently reverses
symptoms.[24] Dextromethorphan does not appear to cause false-positives on urine toxicology screens.[126]
Diphenoxylate and Loperamide
Diphenoxylate is a weak, long-acting opioid derived from meperidine. Lomotil is an antidiarrheal medication
containing diphenoxylate 2.5 mg and atropine 0.025 mg. It is highly metabolized and its metabolite,
diphenoxylic acid, is five times more active than and has twice the serum half-life of diphenoxylate.[127] Most
significant overdoses involve very young children; adults and older children generally tolerate the exposure
well.[18][127] Overdose is classically associated with a two-phase toxicity in young children. [18][128] Phase one
manifests with anticholinergic symptoms such as flushing and dry mouth, and phase two consists of opioid
effects.[128] However, in a review of 36 cases, this pattern was noted in only 4 patients.[127] Anticholinergic
symptoms occurred in only 58 per cent of the patients and all had opioid symptoms.[127] Delayed
presentations or recurrences of respiratory and CNS depression have been reported.[18][127][129] Opioid
toxicity is reversed with opioid antagonists. Delayed symptoms could result from delayed gastric emptying
and gastrointestinal atony. Pills have been removed from the stomachs of patients up to 27 hours after
exposure.[18][127] Because of the potential delays in presentation, young children should be observed in a
monitored setting for at least 24 hours.[18][127] Gastrointestinal decontamination should be performed;
multiple doses of activated charcoal may be helpful because of delayed absorption and prolonged excretion
by enterohepatic circulation (at least 50 per cent undergoes biliary elimination).[127][130]
Loperamide is a nonprescription antidiarrheal agent derived from diphenoxylate and created to further
decrease opioid effects.[49] Less than 1 per cent is absorbed, and it poorly penetrates the CNS.[131] There
are numerous reports of adverse effects as a result of both therapeutic use and overdose. Acute overdoses
can cause coma, bradycardia, apnea, miosis, and opisthotonos. However, most problems have involved a
highly concentrated solution that is no longer available. Drowsiness is the most common symptom.
Naloxone has reversed CNS depression.[131]
Heroin
Heroin reaches peak effects rapidly by all routes (1 minute intravenously, 3 to 5 minutes intranasally or
intramuscularly, 5 to 10 minutes subcutaneously). It is more lipid-soluble than other opioids and it can easily
cross the blood-brain barrier within 30 seconds of IV administration.[6] This rapid entry into the brain results
in the rush experienced by users.[6] Although heroin use is associated with many medical complications, as
discussed earlier, most patients who have experienced overdose do not require hospitalization and can be
released after only a few hours of observation.
Long-Acting Agents
Some opioids have very long durations of action, including methadone (24 hours), levo-a acetyl methadol
(LAAM) (72 hours), and various sustained-release morphine preparations. They are well absorbed orally.
Methadone exposures in children have resulted in the usual opioid toxicity, prolonged hospital stays,
seizures, and deaths.[132] LAAM is a congener of methadone approved for used for the treatment of opioid
dependence. Its very long duration of action and potency results from its active metabolites, nor-LAAM and
dinor-LAAM.[133] Significant toxicity has resulted from overdose with sustained-release preparations;
symptoms including seizures.[134] Patients who have experienced overdose of a long-acting preparation
should be admitted for observation.[132][134]
Meperidine
Meperidine has some properties that are unusual among opioids. Intramuscular administration is common,
but absorption is variable and the degree of analgesia is unpredictable.[15] It may have weak local anesthetic
activity and thus may be especially useful for epidural anesthesia.[15] It is interesting to note that it causes
mydriasis, which may result from muscarinic activity induced by meperidine or normeperidine.[15]
Normeperidine, the active metabolite of meperidine, results from N-demethylation. It is eliminated by means
of both renal excretion and conversion to normeperidinic acid.[135] Its elimination half-life is 15 to 30 hours as
compared with 3 to 4 hours for meperidine. It has half the analgesic potency but twice the neurotoxicity of
meperidine.[136] At high plasma levels, normeperidine causes agitation, tremor, hyperreflexia, myoclonus,
and seizures.[15][27] Accumulation of normeperidine may result from repetitive administration of meperidine
(especially via the oral route, which significantly increases first-pass metabolism),[135] from renal failure, and
from the use of drugs that induce N-demethylation enzymes, including phenytoin, phenobarbital, and
chlorpromazine.[27][136] The degree of CNS excitation depends on the plasma level of normeperidine as well
as on the ratio of normeperidine to meperidine.[27] Twitches, tremors, and myoclonus occur at lower plasma
normeperidine levels than do seizures, so they are potential warning signs of impending convulsions.[136]
Meperidine should be used cautiously for prolonged analgesia, especially in patients with renal insufficiency.
Seizures are generally transient and should be managed with the usual therapy.[15] Naloxone does not
reverse the excitatory effects and may actually worsen them, even inducing seizures.[27][136][137]
Meperidine has medication interactions similar to those of other opioids, but its interaction with monoamine
oxidase inhibitors (MAOIs) is unique. The concomitant use of these agents can produce CNS depression or
excitation. Adverse reactions occur unpredictably. Enhancement of CNS depression, consistent with opioid
toxicity, results from MAOI inhibition of the hepatic microsomal enzymes responsible for opioid
metabolism.[138] Of greater significance are the excitatory reactions, which include agitation, irritability,
hypertension, hyperpyrexia, tachycardia, seizures, coma, and death.[15][138] Serotonin levels are elevated by
MAOI-mediated decreases in serotonin metabolism and by meperidineinduced blockage of neuronal
reuptake.[138] If opioid analgesia is required in patients taking MAOIs, morphine is the recommended
drug.[138] Little is known about the potential interactions of other opioids with MAOIs.
Propoxyphene
Propoxyphene is widely prescribed for analgesia although it has not been proven to be more effective than
salicylates, acetaminophen, or codeine.[139] It can cause the usual opioid toxidrome, but it also has some
unusual toxicities, including cardiac conduction abnormalities and seizures. [29][30][140] Both propoxyphene
and its major metabolite norpropoxyphene are local anesthetics that block sodium channels in a manner
similar to quinidine.[141] This blockade causes the conduction abnormalities, which include transient bundle
branch blocks, QRS prolongation, bigeminy, bradycardia, and nonspecific ST segment and T-wave changes
and ventricular dysrhythmias.[140][142][143] The cause of the seizures is unclear. They usually occur within 1
hour after overdose, and status epilepticus and respiratory arrest have been reported as early as 15 minutes
after ingestion.[30][144] Both propoxyphene and norpropoxyphene contribute to the cardiotoxicity, whereas
only the propoxyphene causes the neurotoxicity.[141][145] Large doses of naloxone may be required to
reverse propoxyphene-induced CNS depression.[146] Opioid antagonists do not affect the
cardiotoxicity.[142][143] Sodium bicarbonate has been used successfully to manage a patient who had
overdosed with 6500 mg of propoxyphene. The patient’s hypotension, dysrhythmia with a QRS duration of
160 msec, and seizures rapidly corrected after a sodium bicarbonate bolus and infusion.[143]
Tramadol
Tramadol is a synthetic analog of codeine with both opioid and monoamine reuptake inhibitory effects. It is a
pure opioid agonist, but its affinity for the µ receptor is weak, being tenfold less than that of codeine.[147] It is
not classified as a controlled substance. Analgesia results also from its inhibition of the reuptake of
norepinephrine and serotonin, endogenous neurotransmitters that modulate pain.[147] Analgesia is not
abolished by naloxone, reflecting the role of monoamine reuptake inhibition. Its O-desmethyl metabolite has
a greater affinity for the µ receptor and is two to four times more potent than the parent compound.[147] The
contribution of the metabolite to the overall analgesia is unclear. Tramadol is rapidly and almost completely
absorbed and peaks 2 hours after administration. Beneficial aspects include minimal cardiovascular and
respiratory effects, minimal constipation, and low potential for drug abuse.[148][149] It is contraindicated in
patients with past or present histories of opioid dependence.[149] A multicenter prospective series of 126
tramadol overdose cases (87 with tramadol alone) revealed that most of the toxicity resulted from the
inhibition of the monoamine reuptake.[148] Toxic effect included lethargy (30 per cent), tachycardia (13 per
cent), agitation (10 per cent), seizures (8 per cent), hypertension (5 per cent), and coma (5 per cent).[148] No
severe cardiovascular toxicity or hypotension occurred. The lowest dose associated with seizure,
tachycardia, hypertension, or agitation was 500 mg; the lowest dose associated with coma or respiratory
depression was 800 mg.[148] Naloxone reversed sedation/apnea in four of eight patients; however, one
patient had a seizure immediately after administration.[148] Seizures have been reported even with
recommended dosages.[32][150] Tramadol-related deaths have occurred both when it was used with other
drugs[151] and when it was used alone. [152] Tramadol has resulted in physical dependence in both adults and
neonates.[153]


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Chapter 78 – Psychoactive Drugs
LENA C. WILLIAMS CHRISTOPHER KEYES
Essentials
• Hallucinogenic agents produce hallucinations and frequently other symptoms, including anxiety,
disorientation, delirium, dilated pupils, tachycardia, hypertension, hyperthermia, hyperactivity, and
nausea and vomiting.
• Phencyclidine and ketamine toxicity result in unpredictable, bizarre, or violent behavior; agitation; and
combativeness. Physical manifestations can include muscle rigidity, hypertension, tachycardia,
hyperthermia, miosis, nystagmus, seizures, increased deep tendon reflexes, and prolonged coma.
• Gamma-hydroxybutyrate and similar drugs produce a sudden onset of brief coma accompanied by
bradycardia and respiratory depression.
INTRODUCTION
Patients who present to health care facilities after using drugs of abuse usually do so because of unwanted
drug effects or because of an unintentional overdose. All age groups can be exposed to these substances;
small children may inadvertently ingest an adult’s supply. Table 78–1 lists some of the more popular
substances and drugs commonly abused. This chapter focuses on drugs and substances commonly used
by those who are seeking mind-altering experiences.
Table 78-1 -- Common Drugs of Abuse

Amphetamines, methamphetamine, designer amphetamines
Barbiturates
Benzodiazepines
Bufodienolides, Bufo toads
Cocaine
Ethanol
Gamma-hydroxybutyrate (GHB), gamma-butyrolactone (GBL), 1,4-butanediol
Heroin, designer opioids
Inhaled hydrocarbons, e.g., butane
Isopropyl alcohol
Marijuana, hashish
Mescaline/peyote
Mushrooms
Phencyclidine and ketamine
Plants, e.g., jimson weed, morning glory seeds, khat, nutmeg
Yohimbine


INDIVIDUAL DRUGS OF ABUSE
LSD ( D-Lysergic Acid Diethylamide)
Albert Hofmann was the first to synthesize LSD in 1938. Lysergic acid is derived naturally from a rye fungus
(Claviceps purpurea). Morning glory (Ipomoea violacea) and Hawaiian baby woodrose (Argyreia nervosa)
seeds contain a less potent congener, D-lysergic acid amide.[62] LSD-25 is a synthetic combination of
lysergic acid and diethylamine that has illusogenic activity.[41] LSD was investigated as a medical aid to
psychotherapy, an analgesic for cancer patients, a tool to cure alcoholism, a treatment for sexual deviancy,
and a treatment for autistic children and those with other psychiatric problems.[1][48]
In the 1950s and 1960s, LSD became a street drug popular for its hallucinogenic effects. Under United
States federal law, LSD became illegal in 1966. During the 1960s, LSD was believed to damage
chromosomes, and its use declined. In the 1990s, LSD use increased among adolescents. In some areas,
high school students reportedly now use LSD more than cocaine; it is used predominately by white
males.[62]
Toxicokinetics
Lysergic acid is usually ingested but can be smoked, snorted, or injected. Doses of 20 mg produce
hallucinations. The street dose can range from 50 to 300 mg.[40] If ingested, its effects begin within 30 to 60
minutes and peak at 2 to 4 hours. The effects can last for 16 to 24 hours, depending on the dose. Tolerance
can develop with prolonged use but abates over time when drug use stops. It is metabolized in the liver by
hydroxylation and conjugation with glucuronic acid.[44]
Pathophysiology
Lysergic acid acts on serotonin and dopamine receptors. The neurotransmitter serotonin receptors are the
key to understanding the hallucinogenic drug effects. Serotonin (5-hydroxytryptamine [5-HT]) modulates
mood, personality, affect, appetite, temperature, sexual activity, pain, perception, sleep induction, and other
basic functions. It also contributes to increasing gut motility, platelet aggregation, and vasoconstriction,
except in coronary arteries and skeletal muscles, where it contributes to vasodilation.
The hallucinations are mediated by the 5-HT2 receptor.[59] Other behavioral effects include mood changes,
anxiety, and altered perception and feeding behavior.
Clinical Effects
Hallucinations are the main motive for abusing this drug. LSD produces a mixture of true hallucinations,
pseudohallucinations, and illusions. Hofmann, after ingesting a small amount of LSD in 1943, reported that
“… my field of vision wavered and was distorted as if seen in a curved mirror. I also had the
sensation of being unable to move … In spite of my delirious, bewildered condition, I could
think clearly and effectively for brief periods … Everything in the room spun around and the
familiar objects and pieces of furniture assumed grotesque, most threatening forms. They
were in continuous motion, animated … The neighbor woman who brought me milk … was no
longer Mrs. R., but rather a malevolent, insidious witch with a colored mask … A demon had
invaded me … I jumped up and screamed in order to free myself … a dreadful fear grasped
me … I was taken to another world, another place, another time. My body seemed to me to be
without sensation. Lifeless, strange. My fear and despair intensified … Now I gradually began
to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes.
Kaleidoscope-like fantastic images surged in on me, alternating, variegated, opening and then
closing themselves in circles and spirals, exploding in colored fountains, rearranging and
hybridizing themselves in constant flux. It was particularly remarkable how every acoustic
perception, such as the sound of a door handle or a passing automobile, became transformed
into optical perceptions. Every sound generated a vividly changing image, corresponding in
form and color.”[33]
With LSD use, normal cognition alternates with altered mood and perception. Time is distorted, and very
vivid color perception occurs. Normally stationary objects become fluid and may pulsate. Images may
appear. Synesthesias, such as hearing color and seeing sounds, occur. Tactile hallucinations are not
commonly reported with LSD use.
Other effects associated with LSD include mood fluctuations, behavioral changes, tachycardia,
hypertension, twitching, mydriasis, anxiety, nausea, vomiting, and diarrhea. Most patients who present after
using LSD do so because they are experiencing a “bad trip,” usually characterized by feelings of paranoia or
anxiety. Rarely, LSD can produce life-threatening symptoms. Hyperthermia, hypertension, coma, respiratory
arrest, and bleeding have been associated with massive overdoses.[39] Acute psychotic reactions have been
reported, as well as seizures.[1] Trauma resulting from accidents or self-destructive behavior, suicide, and
homicide can also occur while under the influence of LSD. Patients using LSD are at more risk for injuries
and death from trauma than from the toxicologic effects of LSD.
Phencyclidine/Ketamine
Phencyclidine, or PCP, was released in 1957 as a preinduction anesthetic known as Sernylan. It was
abandoned for human use in 1965 because of severe adverse psychological reactions. It was used in
veterinary medicine until 1978, but by 1979 it was no longer legally manufactured. Beginning in the 1960s,
PCP became a popular street drug. PCP is smoked, snorted, ingested, or injected. It is frequently
substituted for, or added to, other illicit drugs. There are at least 60 precursors, derivatives and analogs.[50]
PCP and its analogs are frequently passed off as other hallucinogens, such as mescaline, LSD, psilocybin,
and tetrahydrocannabinol (THC), or added to or “laced” with other illicit drugs.
Ketamine is structurally similar to phencyclidine and is used as a short-acting general anesthetic. It has been
abused since the 1970s, and its popularity rose in the 1990s. On the street, it is often referred to as “Special
K.”
Pharmacokinetics
PCP is absorbed well by the oral, pulmonary, and nasal routes. PCP is a weak acid readily absorbed by the
small intestine. It undergoes enteroenteric recirculation, being excreted into the stomach and then
reabsorbed in the small intestine. PCP is highly lipophilic and distributes widely in the body. It is metabolized
in the liver, then excreted in the urine. Effects typically begin within 15 minutes after ingestion when the drug
is taken orally, and within a few minutes when it is smoked. These effects may last up to 16 hours but have
been reported by users to persist up to 24 to 48 hours.[10] In overdose, the elimination half-life reportedly
ranges from 7 hours to 50 hours.[12] Tolerance can develop with continued use of PCP.
Ketamine has a rapid onset of action of 30 to 40 seconds after intravenous administration, with duration of
unconsciousness of 40 to 60 minutes. The elimination half-life is 3 to 4 hours. It is metabolized in the liver
and excreted in the urine.
Pathophysiology
The binding of PCP to its receptor site within the ion channel of the N-methyl- D-aspartate receptor blocks the
influx of calcium, inhibiting neurotransmitter release. This noncompetitive inhibitory effect cannot be
reversed by increasing the concentration of neurotransmitters.[37] PCP and ketamine decrease dopamine
and norepinephrine reuptake. PCP increases dopamine release and also increases dopamine and
norepinephrine levels by stimulating production of tyrosine hydroxylase, the rate-limiting enzyme in the
production of dopamine and norepinephrine. PCP and ketamine produce either central nervous system
excitation or depression, depending on the dose. Sympathomimetic effects are prominent.
Clinical Effects
Symptoms correlate well with PCP serum concentrations although these are not available clinically.[50] At
lower serum concentrations (25–90 ng/mL), typical symptoms include unpredictable behavior, euphoria,
combativeness, violence, and rage. The patient may be agitated and disoriented and may demonstrate
repetitive movements or catatonic posturing. Other manifestations can include ataxia, grimacing, teeth
grinding, muscle rigidity, and myoclonic movements. Although rotary nystagmus is classic, nystagmus in any
direction and disconjugate gaze are characteristic. Temperature, respiratory rate, heart rate, and blood
pressure are elevated. The patient often has hyperreflexia, and clonus may be present. Nausea, vomiting
diaphoresis, flushing, salivation, and lacrimation are also common at this level. With increasing serum
concentrations (90–300 ng/mL), the patient may experience stupor or coma. Response to deep pain remains
intact, and there is generalized muscle rigidity. The patient may develop hyperthermia. Autonomic responses
at this level can include diaphoresis, lacrimation, flushing, and protracted vomiting as well as salivation. Very
high serum concentrations (>300 ng/mL) result in deep coma with muscle rigidity, opisthotonic or
decerebrate posturing, and absent deep pain response. Temperatures often reach up to 108°F (42.2°C).
Heart rate and blood pressure are elevated, and a hypertensive crisis can develop. Intracranial hemorrhage
has been reported in two cases but cannot be directly attributed to PCP.[4][5][15] Periods of apnea and
pulmonary edema may develop. Diaphoresis, flushing, and hypersalivation are the sympathomimetic
responses present at this level. Death results from hypertensive crisis, rhabdomyolysis, renal failure, trauma,
and self-destructive behavior.
Gamma-Hydroxybutyrate and Precursors

Gamma-hydroxybutyrate (GHB) emerged in the 1990s as a drug of abuse. GHB was synthesized as an
analogue to gamma-aminobutyric acid with the objective of finding a related substance, which could cross
the blood-brain barrier.[42] It was investigated as an anesthetic agent, but its side effects of myoclonus and
emergence delirium caused it to be abandoned. Later, it was promoted as a muscle-building agent, an effect
subsequently found not to occur to any significant degree. Because it causes decreased level of
consciousness, respiratory depression, and seizures, the United States Food and Drug Administration has
banned over-the-counter sales of GHB. However, it is manufactured illicitly and remains a commonly used
drug, both for individual use and as a “date-rape” drug. [19] Fatalities have been reported.[17]
After the Food and Drug Administration banned GHB, its precursors such as gamma-butyrolactone (GBL)
and 1,4 butanediol (BD), have emerged as drugs of abuse with similar effects and similar profiles of
respiratory depression and other complications. GBL is marketed as a drug that is able to induce sleep,
release growth hormone, enhance sexual activity and athletic performance, relieve depression, and prolong
life.[2] It is often referred to as 2(3H)-furanone di-hydro and dihydro-2(3H)-furanone. Brand names include
RenewTrient, Revivarant, Revivarant G, GH Revitalizer, Enliven, Gamma-G and Blue Nitro. Tetramethylene
glycol, or BD, is sold as Revitalize Plus, Serenity, Enliven, GHRE, SomatoPro, NRG3, Thunder Nectar, and
Weight Belt Cleaner.[49] BD has been associated with coma, respiratory depression, vomiting, seizures, and
at least three deaths.[49][65]
Pharmacology
Effects begin 10 to 15 minutes after GHB ingestion, with peak effects occurring within 25 to 45 minutes.
Duration of effects ranges from 1 to 5 hours. GHB is eliminated by biotransformation in the liver, with a small
percent unchanged in the urine. Blood levels are undetectable within 4 to 6 hours.[14]
Pathophysiology
Structurally, GHB is similar to the inhibitory neurotransmitter gamma aminobutryic acid (GABA). It crosses
the blood-brain barrier and can produce loss of consciousness and respiratory depression. GHB alters the
activity of dopaminergic neurons in the substantia nigra by stimulating GABAB receptors.[16a] In experimental
studies, it also decreases release of GABA.[4a] GBL is a solvent that can be converted with sodium
hydroxide to GHB before ingestion. If it is not converted before ingestion, GBL is metabolized in the body by
peripheral lactonases to GHB within minutes. BD is metabolized by alcohol dehydrogenase and aldehyde
dehydrogenase to GHB.
Clinical Effects
The hallmark of GHB, GBL, and BD intoxication is a short-lived loss of consciousness associated with
hypoventilation. Clonic jerking, mild hypothermia, and bradycardia may also be present. Nausea and
vomiting are common, and seizures may occur. Seizure-like activity before the arrival of paramedics has
also been reported, with no further seizure activity occurring during monitoring by health care personnel.[11]
One series reported seven cases of GHB exposure that were confirmed by urine mass spectrometry. All
patients exhibited acute delirium and respiratory depression but no seizures.[45] In another series, four of 14
patients experienced seizures after overdoses of GBL.[2] Duration of coma is typically 2 to 3 hours in patients
who are not intubated; the clinical course of patients who are intubated is complicated by the use of sedating
agents. The degree of obtundation on presentation is indicative of the time required for complete
recovery. [11] On awakening, delirium, confusion, and agitation are common. Central nervous system and
respiratory depression may be increased in individuals who concurrently ingest GHB and ethanol.
During 4 months in 1998, 20 cases involving GBL ingestions were reported to poison centers in Texas.
Symptoms commonly reported were obtundation (65%), prolonged unconsciousness (45%), respiratory
depression (45%), anxiety or nervousness (35%), nausea and vomiting (30%), confusion (30%), tremors or
twitching (20%), tachycardia (15%), and combativeness (15%).[2] One patient had a respiratory arrest, but no
deaths were reported. Alkali burns can potentially result from excess base added to the solvent or
incomplete reaction when prepared by a home chemist.
Long-term high-dose use of GHB or its precursors has been associated with a prolonged withdrawal
syndrome. Symptoms include paranoia, agitation, delirium, hallucinations, irritability, insomnia, hypertension,
and tachycardia. One reported case of GHB withdrawal included rhabdomyolysis along with insomnia,
anxiety, and tremors. Resolution occurred within 9 days.[32]
Jimson Weed
Poisoning by jimson weed was first reported in 1676, when soldiers in Jamestown (in what is now Virginia)
ate a salad of Datura stramonium leaves and hallucinated for days. D. stramonium is a member of the
Solanaceae family, genera Datura, and includes Datura metaloides (downy thorn apple), and Datura
candida (angel’s trumpet). These plants contain the tropine alkaloids atropine, scopolamine, and
hyoscyamine.
Jimson weed grows wild throughout the United States. It stands 2 to 5 feet high with stems that are green to
purple green. The leaves are green and oval, with coarsely toothed margins. The flowers, which bloom in
early spring, are white, violet, or purple and are funnel shaped. The plant and flowers have a foul smell. The
seed pod is a spiny capsule approximately 2 inches long that contains brown-black kidney-shaped seeds. All
parts of the plant are toxic. The fruit, flower, and seeds contain the highest concentration of the tropine
alkaloids.
Jimson weed has been used most commonly for its hallucinogenic and euphoric effects. D. candida (angel’s
trumpet) is also gaining attention for the same effects. This plant grows throughout the southeastern United
States both in wild form and as cultivated ornamental shrubbery. It reaches 8 to 18 feet in height and has
ovate, smooth-edged leaves. It blooms repeatedly, with trumpet-shaped pink/white flowers measuring 10 to
12 inches that hang straight down. During a 6-month period in 1995, the Florida Poison Control System
reported 85 cases of poisoning attributed to angel’s trumpet.[27]
Toxicokinetics
Jimson weed seeds contain approximately 0.1 mg of atropine per seed. The blossom of the angel’s trumpet
contains 0.2 mg of atropine and 0.65 mg of scopolamine. Effects begin within 30 to 60 minutes after the
plant is smoked or after a tea made from plant parts is ingested. Ingestion of the seeds or plant materials
delays the onset to 1 to 4 hours. Duration of effects may persist up to 48 hours.
Pathophysiology
Both plants contain tropane alkaloids, particularly atropine, scopolamine, and hyoscyamine.[28] They
competitively antagonize muscarinic receptors both peripherally and centrally, producing an anticholinergic
toxidrome.
Clinical Effects
Initial symptoms are dry mouth and dilated pupils. Visual and tactile hallucinations, flushed warm dry skin,
tachycardia, delirium, myoclonic movements, decreased bowel sounds, and urinary retention can also
develop. With larger doses hyperthermia, seizures, coma, and respiratory arrest may occur. Death from
jimson weed poisoning has been reported as a result of cardiovascular collapse, dysrhythmias, and
medullary paralysis.[3] Trauma and self-destructive behavior can complicate the clinical picture.
Mescaline
The peyote cactus, Lophophora williamsii, contains a hallucinogenic alkaloid known as mescaline (3,4,5-
trimethoxyphenylethylamine). Mescaline is a hallucinogenic amphetamine similar to MDMA
(methylenedioxymethamphetamine, or “ecstasy”). The cactus is sliced and dried for storage, and these very
bitter slices are later chewed for effect. Mescaline can also be produced synthetically.
Toxicokinetics
The hallucinogenic dose of mescaline is 5 mg/kg. The onset of effects begins within 30 minutes to 2 hours,
and the duration is 8 to 12 hours. Mescaline is metabolized in the liver and excreted in the urine.
Pathophysiology
Mescaline has the phenethylamine structure typical of sympathomimetic agents and produces hallucination
by an amphetamine-like action. Little is known regarding the neuro-receptor binding site.[58] Mescaline does
affect the 5-HT and dopamine receptors.
Clinical Effects
The clinical manifestations are similar to those of LSD. Gastrointestinal effects, such as nausea and
vomiting, occur about 1 hour after ingestion. Diaphoresis, mydriasis, nystagmus, ataxia, and hypertension
may occur at this time. These are followed by the hallucinogenic effects. Trauma from accidents or self-
destructive behavior can result in serious injuries.
Marijuana
Marijuana is the leaf or flowering portion of the plant Cannabis sativa and is commonly known as “pot,”
“grass,” or “weed.” The psychoactive substance in marijuana is delta-9-tetrahydrocannabinol (THC).
Marijuana is smoked as cigarettes or in pipes or is sometimes eaten. A concentrated form of the resin from
the plant is known as hashish. Hash oil is the most concentrated form of resin from C. sativa.
Toxicokinetics
After marijuana smoke is inhaled, the THC is delivered to the brain within 15 seconds. Peak effects occur in
10 to 30 minutes with duration of 1 to 4 hours. The elimination half-life averages from 28 to 56 hours. THC is
metabolized in the liver and eliminated in the urine and feces.
Pathophysiology
Specific cannabinoid receptors have been identified and exist predominantly in the hippocampus, cerebral
cortex, striatum, and cerebellum.[30a] THC also stimulates sympathetic receptors and inhibits
parasympathetic receptors in cardiac tissue.[55]
Clinical Effects
The acute effects of marijuana are variable, including laughter and giggling, increased appetite, alteration of
perception and mood, conjunctival injection, and either stimulant or sedative effect.[30][31] Tachycardia is
commonly described. With very large doses, the patient may also experience hallucinations, anxiety,
paranoia, short-term memory deficit, and unsteady gait.[31] Intravenous use of marijuana may result in
cardiovascular collapse, disseminated intravascular coagulopathy, or death.[7] Memory and attention deficits
have been associated with long-term marijuana use.[52][53] Long-term smoking of marijuana has been
associated with chronic respiratory symptoms similar to those produced by tobacco.[64][68]
Some users soak marijuana cigarettes in formaldehyde to enhance the effects of the drug. This combination
has been referred to as “dank,” “boat,” or “AMP.” One observational study describes psychomotor
retardation during the acute phase effect of this combination.[29] Salivation, diaphoresis, and tremor have
also been described.[63]
Presentation to an emergency department is unusual with marijuana intoxication.
Khat/Methcathinone
The leaves and stems from the Catha edulis shrub, known as khat, are chewed to produce euphoria and
alter moods, mimicking the amphetamines. This shrub is native to Africa and the Middle East. It has been
used for centuries and was used by Arabian physicians to treat depression and to prevent fatigue and
hunger.[22][38] Khat is usually used in a social setting, predominantly in Africa and Arabia, where the fresh
leaves produce the desired effect.[38] However, its use has begun to spread to England and the United
States. The fresh tender leaves and stems are chewed or brewed into tea. Several million people are
estimated to frequently use khat.[22][38]
Methcathinone, a methyl derivative of cathinone, is chemically synthesized by oxidizing ephedrine, using

sodium dichromate in an acid solution. It is then extracted by use of solvents. If the process is not properly
completed, the methcathinone can be contaminated with chromium salts that can lead to chromium
toxicity.[16] Methcathinone (ephedrone, “cat,” or “Jeff”) has been abused in Russia since the 1970s and is
responsible for numerous deaths. It is now available in the United States. Clandestine laboratories have
been found in Michigan and Wisconsin. [25]
Toxicokinetics
Cathinone and cathine are the two important active constituents of khat. Cathinone is absorbed rapidly from
the gastrointestinal tract, and peak levels are reached within 1 hour. Cathinone is cleared from the plasma
within 6 hours. Cathine is slowly absorbed from the gastrointestinal tract and is excreted unchanged in the
urine within 24 hours.[38] Cathine has been found in the breast milk of lactating women.[51] One study
showed that cathinone peak plasma levels were reached within 127 minutes, and the elimination half-life
was 260 minutes. Peak norpseudoephedrine, or cathine, levels were achieved after 200 minutes, and the
elimination half-life could not be determined in this study.[67]
Pathophysiology
An alkaloid, katin, was first isolated from the leaves of khat in 1887. It was later identified as
norpseudoephedrine, and the spelling was changed to cathine. This norpseudoephedrine, a low-potency
stimulant, was not found in sufficient quantities to produce the effects observed with the use of khat. In 1963,
cathinone was identified.[38] Cathinone, an alkaloid, is found in high concentrations in young shoots and
leaves. As the shoots and leaves mature, the quantity of cathinone decreases due to its transformation via
enzymatic reduction into cathine and norephedrine.[38][51] This conversion also occurs rapidly with drying of
the shoots and leaves.[38] Cathinone and cathine produce amphetamine-like effects. Like amphetamines,
cathinone increases central nervous system dopamine by causing the release and inhibiting the reuptake of
dopamine. Cathine, or norpseudoephedrine, also has sympathomimetic properties.
Clinical Effects
Clinical effects of khat include euphoria, excitation, logorrhea, hyperactivity, and sometimes irritability.
Tachycardia, tachypnea, hyperthermia, and increased blood pressure have been described.[51][67] Increased
libido, anorexia, and insomnia can also occur.[51] Khat may precipitate acute psychiatric problems, such as
agitation, manic behavior, and frank psychosis.[23][26][38] It is unclear whether these manifestations are due
to the use of khat or whether the khat is unmasking underlying problems.
Withdrawal from khat usually manifests as drowsiness and dysphoria. Depression can occur and can be
severe.[38]
Usually, unwanted side effects or life-threatening symptoms are rare with the use of khat, unlike
methcathinone. The dose of cathinone one can achieve from chewing khat is limited because of the
bulkiness of the product. However, methcathinone does not have such limitations. Deaths from overdoses of
methcathinone have been reported in Russia.
Yohimbine
Yohimbine is an indolealkylamine alkaloid found in the bark of the West African yohimbe tree (Corynanthe
yohimbe). It is also found in the Rauwolfia root.[24] Historically, yohimbine has been considered an
aphrodisiac used to facilitate penile erection.[9] It is sold in health food stores and is also available by
prescription. It has been called aphrodine, corynine, quebrachine, and hydroergotocin, and on the street it is
commonly referred to as “yo-yo.”
Yohimbine has treated orthostatic hypotension caused by diabetic polyneuropathy and imipramine.[8][36] It
was not effective in treating orthostatic hypotension caused by tranylcypromine.[46] Yohimbine has also been
used to treat hypotension associated with clonidine overdose.[56]
Toxicokinetics
Yohimbine is rapidly absorbed from the gastrointestinal tract, and it reaches peak plasma levels in 45 to 60
minutes. In therapeutic doses, maximal effects occur within 1 to 2 hours and last for 3 to 4 hours. It
undergoes hepatic metabolism, and its elimination half-life is 36 minutes.[18]
Pathophysiology
Yohimbine is a central and peripheral a2-adrenergic receptor antagonist that also possesses cholinergic
activity. It is structurally similar to reserpine.[24] Antagonism of peripheral presynaptic a2-adrenergic
receptors results in increased catecholamine release, whereas increased central nervous system
norepinephrine release occurs with antagonism of central a2-adrenergic receptors.
Clinical Effects
Adverse effects of yohimbine after intravenous infusion include tachycardia, hypertension, diaphoresis,
lacrimation, mydriasis, salivation, nausea and vomiting, facial flushing, pallor of the hands and feet, anxiety,
and priapism.[20][34] In doses of 10 mg, yohimbine can induce manic symptoms in patients with bipolar
disorder.[54] Yohimbine in therapeutic doses can also cause bronchospasm and lupus-like syndrome.[43][61]
In overdose, yohimbine produces the adverse effects discussed earlier. In one case, a 38-year-old man with
insulin-dependent diabetes presented 2 hours after ingesting 350 mg of yohimbine with no symptoms and
was discharged. He presented 17 hours later confused, drowsy, hypothermic, and normotensive. The
electrocardiogram (ECG) showed atrial fibrillation with a ventricular rate of 150 beats/minute. He had
retrograde amnesia for the preceding 24 hours. The day after admission, the ECG showed normal sinus
rhythm.[66] In another reported overdose, a 62-year-old male with non–insulin-dependent diabetes mellitus
presented 2 hours after ingesting 200 mg of yohimbine with vodka. He had emesis and complained of
lightheadedness when standing. He was tachycardiac (106 beats/minute) and hypertensive (174/94 mm Hg)
and had a normal ECG. He was treated with activated charcoal, his vital signs normalized, and he was
discharged 19 hours after admission. [18] The third case of reported yohimbine overdose involved a 16-year-
old girl who ingested an estimated 250 mg of yohimbine powder. Symptoms were weakness, generalized
paresthesias, loss of coordination, dissociative state, severe headache associated with dizziness, and
tremors. Several hours later, she noted decreased hearing. She experienced nausea, diaphoresis, and
intermittent palpitations. On arrival in the emergency department, she was hypertensive, tachycardia,
tachypneic, pale, and diaphoretic. She was discharged after overnight observation.[47]


Altered mental status can result from toxicologic, metabolic, neurologic, or psychiatric causes. Obtaining a
history of events that preceded the onset of symptoms as well as a past medical history aids in eliminating
other causes for the altered mental status. Table 78–2 lists some common causes of mental status changes,
rhabdomyolysis, and hyperthermia—three clinical manifestations common to most drugs of abuse discussed
in this chapter.
Table 78-2 -- Common Causes of Mental Status Changes, Hyperthermia, and Rhabdomyolysis
Altered Mental Status Toxicologic Causes Other Causes
Alcohols Anoxia
Anticholinergics Electrolyte abnormalities
Antidepressants Head trauma
ß-Adrenergic receptor antagonists Heat stroke
Carbon monoxide Hepatic encephalopathy
Cholinergic agents Hyperthermia
Coma Opioids Hypothermia
Salicylates Hypoglycemia
Sedative hypnotics Hypothyroidism
Sympathomimetics Intracerebral hemorrhage
Meningitis
Trauma
Amphetamines Acute schizophrenia
Anticholinergics Hypoglycemia
Cocaine Hyperthermia
Ethanol withdrawal Organic brain disease
Delirium/hallucinations
GHB withdrawal Meningitis
Inhalant abuse Psychiatric disorders
Sedative-hypnotic withdrawal
Sympathomimetics
Amphetamines Cerebrovascular accidents
Altered Mental Status Toxicologic Causes Other Causes
Anticholinergics Heat stroke
Caffeine Infection
Cocaine
Dinitrophenol
Hyperthermia Lithium
Neuroleptics
Pentachlorophenol
Salicylates
Serotonin syndrome
Sympathomimetics
Amphetamines Compartment syndrome
Anticholinergics Electrocution
Antihistamines Exercise
Cocaine Genetic/immunologic disorders
Ethanol Heat stroke
Heroin Hypothermia
Rhabdomyolysis Isopropyl alcohol Hyperthermia
Neuroleptics Infections
PCP Ischemia
Salicylates Metabolic derangements
Seizures
Sepsis
Trauma and burns
GHB, gamma-hydroxybutyrate; PCP, phencyclidine.


LABORATORY STUDIES
Hypoglycemia or hyperglycemia can cause altered mental status; therefore, a bedside glucose
determination or serum level should be obtained in any patient presenting with altered mental status. An
ethanol level may confirm a coingestant or may be the sole explanation for the altered mental status.
Patients with extreme agitation, muscle rigidity, hyperthermia, or prolonged seizure activity are at risk for
rhabdomyolysis. Serum electrolyte levels, renal function, serum creatine kinase level, and calcium and
phosphorus levels should be monitored. A fivefold or greater increase in serum creatine kinase without
apparent injury is diagnostic of rhabdomyolysis. Patients with peak creatine kinase levels of greater than
20,000 U/L are at high risk for renal insufficiency.[6][35][60] Caution must be exercised in using a single result,
however, because the peak level may occur at a time other than when the sample was obtained.
Hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia may also be present.
A clue to myoglobinuria may be obtained by comparing the urine dipstick result to a microscopic analysis of
the urine. A heme-positive dipstick result with few or no red cells on microanalysis suggests myoglobinuria.
In severe cases, the urine may be cola colored. Urinary pH should also be determined. A urine pH of less
than 5.6 facilitates dissociation of myoglobin, which may produce acute renal failure.
Blood gas analysis may be indicated in patients with extreme agitation, hyperthermia, or suspected hypoxia,
or in those who are receiving intravenous sodium bicarbonate to prevent myoglobinuric renal failure. An
ECG should be obtained in any patient with suspected dysrhythmia or with hemodynamic instability.
Phencyclidine and LSD may can be detected in urine but are not typically part of a routine urine drug screen.
Urine drug screens may occasionally help to identify the actual substance used but rarely contribute to
patient management.


TREATMENT
Supportive care with attention to airway is the most important aspect of care ( Table 78–3 ). Concomitant
trauma may be present, and the patient should be carefully examined for injuries, with special consideration
given for occult cervical spine injuries and for intracranial trauma masquerading as severe drug intoxication.
A protocol should be established whereby physicians, nursing staff, and security personnel work together in
a coordinated fashion to (1) protect the staff and other patients from harm, (2) prevent the intoxicated patient
from injuring himself or herself, and (3) provide counseling or rehabilitation after the acute episode.
Table 78-3 -- Medical Management of the Patient Who Has Used Psychoactive Drugs
Provide supportive care with maintenance of airway.
General Use cardiac monitor, ECG, and IV access for (1) hemodynamically unstable patient; (2)
patient with suspected or known dysrhythmias.
Check for hypoglycemia and treat with D50W if present.
Coma/altered Administer naloxone, 2-mg IV bolus (0.4-mg IV bolus if opioid dependence suspected,
mental status unless patient has respiratory distress); can repeat prn. Be prepared for opioid withdrawal.
Administer thiamine, 100 mg IV.
Put patient in quiet room or area.
Administer benzodiazepines (lorazepam or diazepam).
Agitation Patient control with neuromuscular blockade, with endotracheal intubation and airway
support, may be indicated if cervical spine or other traumatic injuries are suspected in an
agitated, confused patient or when adequate trials of the aforementioned therapies fail to
control the patient’s agitation (rare).
Administer lorazepam.
Seizures
Administer phenobarbital, 10–20 mg/kg IV, if lorazepam is not effective.
Administer fluids.
Use external cooling techniques.
Hyperthermia *
Administer benzodiazepines: lorazepam or diazepam to control muscle hyperactivity and
shivering.
Administer benzodiazepines: lorazepam or diazepam should be tried first to decrease
agitation.
Hypertensive crisis
Sodium nitroprusside should be considered for severe hypertension that persists after
agitation is controlled.
Administer IV crystalloids to correct dehydration and maintain a urine output of 3–5
mL/kg/hr
Administer mannitol 0.5 g/k IV bolus for declining urine output.
Rhabdomyolysis
Maintain urine pH at 6.5 or greater with sodium bicarbonate bolus and infusion as needed.
Monitor for hyperkalemia, hyperphosphatemia, and hypocalcemia.
Monitor BUN and creatinine levels for the development of acute renal failure.
ECG, electrocardiogram; BUN, blood urea nitrogen.
* See Chapter 27 for advanced cooling techniques.
Activated charcoal may be of value when given within 1 to 2 hours for ingestion of jimson weed. Multiple
doses of activated charcoal may be efficacious for THC body packers or for PCP taken by any route
because it is excreted into the stomach.[50] Standard therapies for agitation, seizures, hyperthermia, and
rhabdomyolysis should be used. If it becomes necessary to physically restrain the patient, chemical
restraints in the form of benzodiazepines should be administered soon afterward. The patient who continues
to fight physical restraints is at risk for hyperthermia, rhabdomyolysis, dehydration, and metabolic acidosis. If
restraints are used, the patient should be monitored vigilantly for changes in respiratory status,
cardiovascular status, temperature, and recurrence of agitation.
Benzodiazepines used to control agitation may also control hypertension by reducing the central
sympathetic production. Extremely high blood pressure (>120 mm Hg diastolic) not responding to sedation
may be treated with vasodilators, such as sodium nitroprusside. Hypertension with reflex bradycardia
resulting from direct a1-adrenergic receptor stimulation from phenylpropanolamine, a frequent street
substitute for stimulants and PCP, is best treated with phentolamine.
Gamma-Hydroxybutyrate.
Naloxone and flumazenil have been unsuccessful in reversing GHB effects.[13][21][45] The respiratory
depression can be managed with supplemental oxygen and close monitoring of the patient’s respiratory
efforts, with endotracheal intubation for cases of significant hypoventilation.
Jimson Weed.
Severe agitation and delirium may be treated initially with benzodiazepines.[57] Physostigmine can be used
for continued severe agitation that is unresponsive to benzodiazepine therapy. Physostigmine is also
indicated for life-threatening conditions, such as severe hypertension, seizures, supraventricular
tachycardias, and hyperthermia, that are unresponsive to therapy. Complications of physostigmine include
seizures, bradycardia, and precipitation of a cholinergic crisis.
Yohimbine.
Clonidine has been used to treat hypertension associated with yohimbine overdose.[18] However, it should
be used with caution because of the potential for worsening hypertension from unopposed a1-adrenergic
receptor activity. ß-Adrenergic receptor antagonists should be avoided for the same reason.


DISPOSITION
Patients who experience coma because of GHB or its analogs can be discharged after they have been
awake and alert for 2 to 4 hours, have normal vital signs, and have no suspected ongoing drug absorption
from the gastrointestinal tract, even if initial endotracheal intubation was required. Patients presenting with
hypertension may be discharged if they have had moderate uncomplicated hypertension that is controlled
with sedation, normal vital signs after observation for 4 to 6 hours, a normal ECG, and a normal physical
examination. Patients experiencing a “bad trip” or hallucinations, with mild hypertension and tachycardia,
usually can be monitored in the emergency department until the effects of the drug subside. Patients
requiring admission should be placed in an area where close monitoring is available to prevent the patients
from harming themselves or other patients.
Patients experiencing seizures, severe hypertension, and rhabdomyolysis may require further evaluation
and monitoring, as deemed clinically necessary. All patients with moderate-to-severe hyperthermia that
resolves should be admitted for further evaluation and therapy. An intensive care unit admission is required
for life-threatening symptoms, such as hypertension requiring intravenous vasodilators, recurrent seizures,
ongoing hyperthermia, and rhabdomyolysis associated with potentially life-threatening electrolyte
abnormalities.


SEQUELAE
Flashbacks, also known as pseudohallucinations, can occur after the acute effects of the drug have
resolved. These pseudohallucinations can occur after one-time LSD use but are usually associated with
repeated use of the drug. During these recurrences, the patient has the sensations, feelings, and previous
hallucinations experienced during LSD use.[44] Their pathophysiologic mechanism is unknown. They can
occur many times a day and reportedly have continued 5 years or more after LSD use has stopped. Stress,
illness, or exercise and marijuana and alcohol use may precipitate flashbacks.[44]
Phencyclidine withdrawal symptoms of nervousness, anxiety, depression, and short-term memory loss may
occur and persist for months or years. Deaths have occurred with the use of GHB.


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65. Texas Department of Health Austin man’s death prompts TDH warning about new round of
bodybuilding products. Austin, TX, News Release, May 3, 1999.
66. Varkey S: Overdose of yohimbine. [Letter.] Br Med J 1992; 304:548.
67. Widler P, Mathys K, Brenneisen R, et al: Pharmacodynamics and pharmacokinetics of khat: A controlled
study. Clin Pharmacol Ther 1994; 55:556-562.
68. Wu TC, Tashkin DP, Djahed B, et al: Pulmonary hazards of smoking marijuana as compared with
tobacco. N Engl J Med 1988; 318:347-351.


Chapter 79 – Inhalants of Abuse
LEON M. GUSSOW
Essentials
• Clinical “intoxication” and ataxia in the absence of ethanol.
• Unexplained cardiac dysrhythmia, cardiac arrest, or neurotoxicity in an adolescent or young adult.
• Unexplained distal renal tubular acidosis (hyperchloremic metabolic acidosis with normal anion gap and
hypokalemia).
• Unexplained carbon monoxide toxicity, methemoglobinemia, or pancytopenia.
INTRODUCTION
Solvent sniffing began as an American epidemic among adolescent males in California in the 1950s and
then spread to the Midwest and East Coast over the next decade. Initially, the solvents themselves were
thought to be relatively nontoxic, and the occasional sudden death seen in abusers was attributed to
suffocation while inhaling solvent from a plastic bag.[32] However, in 1970, Bass reported 110 cases of
sudden sniffing death from the 1960s that were not associated with plastic bag suffocation.[3] These cases
involved toluene (model airplane glue), benzene, gasoline, trichloroethane (spot remover), and fluorocarbon
propellants. Typically, death occurred during an episode of sudden activity or stress that followed inhalation
abuse; precipitating activities included wrestling, running, and masturbation. Bass hypothesized that
hydrocarbon solvents sensitized myocardium to the effects of endogenous catecholamines, a mechanism
exacerbated by hypercarbia resulting from breathing into a bag.
Volatile substances of abuse (VSA) include aliphatic and aromatic hydrocarbons, halogenated
hydrocarbons, ethers, ketones, esters, alkyl nitrites, and anesthetic agents ( Table 79–1 ). The typical
inhalant abuser is a teenage male who is attracted to solvents because of their euphoric and hallucinogenic
properties and the fact that they are cheap, legal, and easily obtainable.[32]
Table 79-1 -- Volatile Substances of Abuse

Aliphatic hydrocarbons
n-Hexane
Methane
Ethane
Acetylene
Propane
Butane
Isopentane
Naphtha
Aromatic (cyclic) hydrocarbons
Benzene
Toluene
Xylene
Trichloroethylene
Trichloroethane
Methylene chloride
Fluorocarbons (Freon)
Perchloroethylene
Ketones
Acetone
Methyl-n-butyl ketone
Methylethyl ketone
Anesthetic agents
Ethers
Nitrous oxide
Alkyl nitrites
Amyl nitrite
Butyl nitrite
There are several techniques that solvent abusers use to increase the dose absorbed by inhalation.
“Sniffing” involves inhaling directly from an open container. “Huffing” refers to inhaling through a piece of
cloth soaked in solvent and held over the nose and mouth.[40] “Bagging” describes breathing vapor from a
plastic bag containing the solvent, resulting in exposure to very high concentrations of toxin. Some of these
techniques (especially “bagging”) cause hypercarbia and hypoxia, exacerbating hydrocarbon-induced
myocardial irritation.
VSA are often contained in easily obtainable commercial products ( Table 79–2 ). It is important to note that
commercial products often contain a variety of chemicals, the precise formulation of which may be changed
at any time by the manufacturer. When dealing with clinical exposure, it is important to identify the specific
product involved, and if possible to get a list of the constituents from the product label or the company.
Table 79-2 -- Volatile Substances of Abuse Commonly Found in Commercial Products

Glues and adhesives
Toluene
Acetone
n-Hexane
Benzene
Xylene
Trichloroethylene
Cleaning fluids
Benzene
Trichloroethylene
Trichloroethane
Typewriter correction fluid
Trichloroethane
Trichloroethylene
Perchloroethylene
Refrigerants
Fluorocarbons (Freon)
Shoe polish
Toluene
Chlorinated hydrocarbons
Room deodorizers
Amyl nitrite
Isobutyl nitrite
Butyl nitrite
Fuels
Gasoline
Aliphatic hydrocarbons
Alkyl nitrites
Ethers
Paints
Mineral spirits
Turpentine


Pharmacology
Solvents are fat-soluble; when inhaled, they are rapidly absorbed through the alveoli, readily cross cell
membranes, and quickly enter the central nervous system and other lipid-rich tissues. Some can also be
absorbed through intact skin.[49] Blood concentrations from inhalation exposure are determined by the
blood-air partition coefficient, which is different for each solvent.[49] Physical exertion will increase absorption
and therefore the blood concentration of some solvents. The major route of elimination of many inhaled
solvents is also through the lungs. Some solvents also undergo hepatic transformation into water-soluble or
toxic metabolites. For example, carbon tetrachloride is metabolized by cytochrome P-450–dependent mono-
oxygenase into the reactive trichloromethyl (CCl4) and trichloromethylperoxy (Cl3COO) free radicals.[28]
When the metabolites are water-soluble and available for renal excretion, they can often be detected in the
urine, allowing screening for solvent abuse. For example, benzene is excreted as phenol, toluene as
hippuric acid, xylene as methylhippuric acid, and trichloroethylene as trichloroacetic acid and
trichloroethanol.[49] Chloroform is metabolized into phosgene, and thus is potentially hepatotoxic.[28]
Pathophysiology
All VSA cause central nervous system (CNS) depression. Small straight-chain hydrocarbons (methane,
ethane, propane) are simple asphyxiants, producing CNS effects from hypoxia. Higher-molecular-weight
hydrocarbons, halogenated and aromatic compounds, and petroleum distillates directly affect the
CNS.[21][34][42] The precise mechanism by which acute abuse causes CNS effects is not known, but may
involve -aminobutyric acid (GABA) agonism or altered neuronal membrane function.[35] Chronic persistent
neurologic deficits in heavy long-term abusers are probably caused by the action of lipid-soluble neurotoxins
on neuronal membranes. Magnetic resonant imaging and histologic studies of the brains of chronic toluene
abusers have shown diffuse white matter degeneration, which appears to be irreversible. [14][15][42] n-Hexane
and methyl n-butyl ketone (MBK), which are constituents of some glues and are both metabolized to the
axonal neurotoxin 2,5-hexanedione, cause a peripheral neuropathy characterized by muscle weakness and
wasting, diminished deep tendon reflexes, decreased nerve conduction, and paresthesias.[26][34] Sural nerve
biopsy demonstrates axonal swelling, a finding absent in Guillain-Barré syndrome. It is a useful test in
differentiating between the two similar conditions.[26][34]
VSA are both cardiovascular and central respiratory depressants and also sensitize the myocardium to the
dysrhythmogenic effects of endogenous catecholamines. [10] The cardiac depressant effect of 1,1,1,-
trichloroethane (TCE) may be related to its inhibition of calcium mobilization during cardiac contraction.[20]
Dogs exposed to TCE by inhalation developed hypotension and decreased cardiac output, which were
reversed by administration of intravenous calcium.[19] White and Carlson found that trichloroethylene
increases the incidence of epinephrine-induced dysrhythmias in rabbits, an effect exacerbated by
ethanol.[51] Sudden unexpected death during inhalant abuse is thought to be caused predominantly by
ventricular fibrillation. This event most frequently follows abuse of halogenated hydrocarbons but has also
occurred with toluene.[27] Respiratory depression, hypoxia, hypercarbia, acidosis, hypokalemia, and
hypocalcemia all predispose to dysrhythmias. Toluene huffing has been associated with recurrent non-Q-
wave myocardial infarction, possibly related to vasospasm.[23]
With chronic abuse toluene impairs the ability of the distal renal tubule to excrete hydrogen ions, producing
classic type I distal renal tubular acidosis with a normal anion gap.[46] This can present with life-threatening
hypokalemia and muscle weakness. The acidification defect is reversible if continued exposure to toluene is
avoided. When used acutely, toluene can also produce a high anion-gap metabolic acidosis from
accumulation of its metabolites, benzoic acid and hippuric acid.[16] Proximal tubular dysfunction with
increased urinary excretion of amino acids, calcium, phosphate, glucose, and urate (Fanconi syndrome) has
been described in a chronic glue sniffer.[36]
Alkyl chlorides can cause hepatic necrosis and renal impairment through toxic intermediate metabolites.
Carbon tetrachloride is the best-known example. Benzene exposure causes bone marrow suppression and
aplastic anemia.


CLINICAL PRESENTATION ( Table79–3 )
The signs and symptoms of VSA are so varied, and affect so many different systems, that a high level of
suspicion is required to make the diagnosis. Occasionally, residue or odor from the abused substance may
be detectable on the patient or his clothing. Patients who have been sniffing paint often have paint around
their mouth, nose, and hands from huffing or bagging. Certainly, any adolescent who presents with
unexplained mental status changes, cerebellar findings, cardiac dysrhythmia, syncope, hypokalemia,
methemoglobinemia, carbon monoxide toxicity, or cardiac arrest should be evaluated for inhalation abuse. In
addition to specific toxic manifestations of the various VSA, patients may present with trauma caused by
drug-induced behavioral changes. Burn injuries are seen in youths who inhale gasoline, or indulge in the
practice of “fire breathing” (igniting exhaled butane vapor).
Table 79-3 -- Clinical Presentation of Inhalant Intoxication

Neurologic
Intoxication
Hallucinations
Ataxia, cerebellar dysfunction
Nystagmus
Headache
Lethargy
Seizures
Coma
Agitation
Cognitive dysfunction
Peripheral nervous system
Sensorimotor neuropathy
Cardiovascular
Supraventricular dysrhythmias
Hypotension
Sudden death
Gastrointestinal
Nausea and vomiting
Hematemesis
Abdominal pain
Pulmonary
Wheezing
Rales
Rhonchi
Electrolyte/acid-base
Hypokalemia
Metabolic acidosis
With increased anion gap
Without increased anion gap
Hypocalcemia
Hypophosphatemia
Renal
Hematuria
Sterile pyuria
Proteinuria
Muscular
Weakness
Rhabdomyolysis
Acute Toxicity
Central nervous system manifestations of acute VSA intoxication begin within seconds of exposure. Initially,
the patient may be hyperactive and appear drunk, with incoordination, slurred speech, and ataxia. Early
intoxication produces a sensation of euphoria. As symptoms progress, CNS depression with lethargy,
confusion, and impaired judgment may be seen, along with auditory or visual hallucinations. Severe
intoxication can cause seizures or coma.[1] Central respiratory depression may result in hypoxia and
hypercarbia, exacerbating cardiac irritability.
Cardiovascular effects of acute VSA intoxication include ventricular and supraventricular dysrhythmias, heart
block, tachycardia or bradycardia, and hypotension. Sudden death has most commonly been reported in
association with abuse of toluene and the halogenated hydrocarbons, but has also occurred after exposure
to non-Freon aerosol propellants (isobutane, n-butane, propane), benzene, and gasoline.[50] Clinical
experience and animal studies support Bass’s original suggestion that VSA sensitize myocardium to the
effects of endogenous catecholamines, predisposing to dysrhythmias.[3][19][20][51] Other causes of death in
these patients include asphyxia, aspiration, and airway obstruction caused by oropharyngeal burns from
aerosol sprays ( Fig. 2–1 in Chapter 2 ).
In addition to airway obstruction, other causes of respiratory compromise and hypoxia include central
respiratory depression, asphyxia, bronchospasm, and muscle weakness. Pneumonitis from intense
inhalation exposure, aspiration, or burn injury from fire breathing presents with wheezing, rales, rhonchi, and
infiltrates on chest radiograph. [8][31][47] Nausea and vomiting, hematemesis, and abdominal pain or
tenderness without peritoneal signs are common gastrointestinal complaints. Hepatic manifestations can
mistakenly be attributed to viral hepatitis but reverse rapidly with abstinence from VSA.[9] Trichloroethylene
inhalation causes acute renal injury along with hepatic necrosis. [2]
Chronic Toxicity
Chronic abusers can present with neurologic, gastrointestinal, or metabolic sequelae. Profound muscle
weakness with difficulty walking or even quadriparesis may reflect severe hypokalemia from toluene-induced
distal renal tubular acidosis.[5][46] Hypophosphatemia, hypocalcemia, metabolic acidosis with either a normal
or high anion gap, renal failure, and rhabdomyolysis may also be seen in this setting. Urinalysis may show
hematuria, sterile pyuria, and proteinuria.[36] One study found neurologic impairment in 13 of 20 (65 per
cent) chronic solvent abusers.[21] Findings included spastic motor neuropathy with hyperreflexia and clonus,
cognitive dysfunction ranging from mild impairment to disabling dementia, personality changes, decreased
sense of hearing and smell, and cerebellar dysfunction. Parkinsonism and optic neuropathy have also been
reported.[24][48] Magnetic resonance imaging in these patients may show widespread white matter disease.[7]
Gastrointestinal complaints in chronic VSA abusers include anorexia and weight loss. Hepatotoxicity has
been associated with chloroform, carbon tetrachloride, toluene, and trichloroethylene. [2][34][38] If hepatic
necrosis or fulminant hepatic necrosis occurs, the patient may present with tender hepatomegaly, jaundice,
elevated liver enzymes, and coagulopathy. [2][33]


Other causes of apparent intoxication (altered or decreased mental status) include hypoxia, hypoglycemia,
ethanol, toxic alcohols and glycols, opioids, benzodiazepines, and barbiturates. Ataxia, slurred speech,
muscle weakness, and agitation can be seen in phencyclidine toxicity. Mental status changes and cardiac
irritability can mimic overdose of caffeine, cocaine, or amphetamines. Any patient with altered mental status
should be evaluated for CNS trauma, infections, or sepsis ( Table 79–4 ).

Toxic alcohols
Amphetamines (“ice”)
Cocaine (“crack”)
Caffeine
Phencyclidine
Sedative-hypnotics
Carbon monoxide
CNS infection
CNS trauma
Sepsis
Hypoglycemia
Hypoxia


LABORATORY STUDIES
Laboratory tests useful in the initial evaluation of a known or suspected inhalant abuser include electrolytes,
blood urea nitrogen (BUN), creatinine, and urinalysis. Specific qualitative and quantitative tests for the
presence of solvents are not readily available at most hospitals. Unexpected abnormalities of electrolytes,
arterial blood gases, or ionized calcium (metabolic acidosis with increased or normal anion gap,
hypokalemia, hyperchloremia, or hypocalcemia) may suggest the diagnosis in a patient not suspected of
inhalation abuse. BUN and creatinine will detect renal damage. The best screening test for hepatic
involvement in the patient with apparent jaundice, hepatomegaly, or right upper quadrant pain is the urine
dipstick for bilirubin, which reflects increased direct bilirubin, a sensitive and specific marker for liver
disease.[6] A urine pH greater than 6.0 in the face of metabolic acidosis suggests distal renal tubular
dysfunction consistent with toluene exposure. Patients with chronic benzene exposure need a complete
blood count to detect aplastic anemia. Symptomatic patients should be placed on a cardiac monitor; EKG
may document ventricular dysrhythmias or conduction delays. Chest radiograph should be obtained if there
are any respiratory symptoms. Patients with muscle tenderness, myoglobinuria, or other evidence of
rhabdomyolysis should have creatine phosphokinase measured. Carboxyhemoglobin level should be
determined in a patient exposed to methylene chloride, and methemoglobin in a patient with cyanosis or
alkyl nitrite exposure. Any patient with unexplained altered mental status deserves a head computed
tomography scan.


TREATMENT
In general, there are no specific antidotes for toxicity from VSA (individual exceptions are discussed below
under Special Situations). The patient should be removed from the source of exposure. Symptomatic
patients should be given supplemental oxygen, and intravenous access should be secured. If intubation is
indicated, hyperventilation may increase pulmonary excretion of the toxin. Exposed skin, eyes, and mucous
membranes should be decontaminated with copious irrigation ( Table 79–5 ).
Table 79-5 -- Treatment of Inhalant Intoxication

Remove patient from source of exposure
Provide supplemental oxygen
Hyperventilate intubated patients
Decontaminate skin and eyes with copious irrigation as indicated
Avoid epinephrine and other vasopressors
Use benzodiazepines for sedation
Potassium, calcium, and phosphorus replacement, as indicated
100% O2 for carbon monoxide toxicity caused by methylene chloride
Methylene blue for symptomatic methemoglobinemia or levels > 30%
Use pressors and epinephrine cautiously, if at all, because they may precipitate dysrhythmias in sensitized
myocardium. Treat hypotension initially with normal saline, and maintain an adequate urine output (1–2
mL/kg/hr). Glucose is generally unnecessary and may exacerbate hypokalemia. Bronchospasm secondary
to aspiration can be treated with inhaled ß2-adrenergic receptor agonists; like pressors, they must be used
cautiously to avoid causing dysrhythmias. Corticosteroids and prophylactic antibiotics are not indicated.
Seizures or agitation should be treated aggressively with benzodiazepines to prevent excess catecholamine
stimulation.
If possible, determine the specific agent involved. The compositions of individual products often change over
time, and information can be obtained from the product container or from the manufacturer. Anticipate and
monitor for renal and hepatic toxicity, cardiac dysrhythmias, rhabdomyolysis, hypokalemia, hypocalcemia,
and hypophosphatemia.


DISPOSITION
Symptomatic patients with significant CNS depression, seizures, muscle weakness, dysrhythmias,
hypotension, or severe electrolyte abnormalities requiring treatment should be admitted. Indications for
intensive care unit admission or telemetry include the need for airway or ventilatory support, cardiac
dysrhythmia, significant hypokalemia or hypocalcemia, hypotension, coma, and seizures. Patients with
transient CNS depression can clear with observation and can be discharged from the emergency
department, preferably to the care of a competent friend or relative. Psychiatric evaluation and follow-up, as
well as referral to a substance abuse program, should be considered.


SEQUELAE
Neuropathy, muscle wasting, and weakness caused by chronic glue sniffing may persist.[34][44] Parkinsonism
and optic neuropathy have also been described.[24][48] Cerebellar dysfunction may improve if long-term
solvent abuse is discontinued, but can be persistent. [34] Long-term glue sniffing may produce irreversible
myocardial dysfunction, secondary to chronic myocarditis and fibrosis.[34]
Chronic toluene abusers can develop thinning and rupture of alveolar walls in a pattern similar to panacinar
emphysema, with elevated lung volumes on pulmonary function testing.[43] Goodpasture syndrome has been
associated with glue sniffing and TCE abuse.[4][37][41]
Renal and metabolic abnormalities caused by glue sniffing can improve with abstinence. In one report, a 27-
year-old woman was hospitalized with severe hyperchloremic metabolic acidosis, hypokalemia, and
hypocalcemia after chronic glue bagging.[36] All abnormalities reversed after 3 weeks of forced abstinence,
except for mild residual acidosis. Chronic toluene abuse has caused interstitial fibrosis, distal tubular
damage, and irreversible renal failure.
Hepatic sequelae of solvent abuse range from reversible centrilobular necrosis to fatal fulminant hepatic
failure.[2][33]


SPECIAL SITUATIONS
Typewriter Correction Fluid
Typewriter correction fluid (“white-out”) is an opaque liquid used to correct typing errors. Although
manufacturers have recently changed the formulation of some of these products, they still may contain the
halogenated hydrocarbons TCE, trichloroethylene, and perchloroethylene.[25] These compounds, also used
in industrial solvents and degreasers, cause cardiac dysrhythmias, seizures, and CNS depression.
Inhalation abuse of these products has been associated with sudden death, often occurring during strenuous
physical exertion. This scenario is consistent with a sudden cardiac dysrhythmia induced by the effect of
catecholamines on sensitized myocardium. Recently, mustard oil has been added to some typewriter
correction fluids as an irritant to prevent deliberate inhalation. In addition to the effects mentioned, both TCE
and perchloroethylene have been associated with massive hepatic necrosis. [17]
Gasoline
Gasoline is a mixture of alkanes, cycloalkanes, alkenes, and aromatic hydrocarbons.[39] The precise
composition will vary among different products. Medium-chain saturated hydrocarbons (4–8 carbon atoms)
are narcotics that can cause nausea, vomiting, and loss of consciousness. Alkenes are weak anesthetics.
Taking 15–20 breaths of gasoline vapor can produce intoxication lasting 5 to 6 hours. Signs and symptoms
include dizziness, incoordination, confusion, headache, euphoria, agitation, hallucinations, nystagmus, and
coma.[13] Sudden death has been reported, most likely from ventricular fibrillation. Benzene is present in
gasoline in concentrations up to 1.31 volume per cent, and may cause persistent encephalopathy and
aplastic anemia. Treatment of gasoline inhalation exposure is supportive. The lead toxicity from gasoline
sniffing seen in the past is no longer a major problem in the United States now that tetraethyl lead has been
removed from most gasoline.
Alkyl Nitrites
Alkyl nitrites (e.g., amyl, butyl, and isobutyl nitrite) are reactive agents capable of oxidizing ferrous iron in
hemoglobin (Fe2+ ) to the ferric state (Fe3+ ), producing methemoglobin (metHb). Ferric iron is not able to
carry oxygen and causes a relative functional anemia. In addition, metHb increases the affinity of
hemoglobin for oxygen, decreasing oxygen delivery to the tissues.
Alkyl nitrites, present in many products marketed as “room deodorizers,” are often inhaled during sexual
activity because of their alleged ability to enhance orgasm. They have been sold under such names as
Rush, Locker Room, Bolt, Climax, Satan’s Scent, Oz, Hardware, Bang, Mama Poppers, Hi Ball, Discoroma,
Joe Aroma, and Heart On.[12] Amyl nitrite, previously available in glass perles for use as a coronary
vasodilator, is now found primarily as a component of the cyanide antidote kit.
Alkyl nitrites are vasodilators causing hypotension, reflex tachycardia, and throbbing headache.[45] Effects
occur within 30 seconds of exposure and resolve within minutes. Clinically significant methemoglobinemia is
most commonly seen after ingestion of alkyl nitrites but can occur following inhalation.[18] The specific
antidote for methemoglobinemia, methylene blue, accelerates the reduction of metHb to hemoglobin through
an NADPH-metHb reductase pathway.[11] It is indicated for levels greater than 30 per cent, or for lower
levels in the presence of hypoxic symptoms. The dose is 1–2 mg/kg (0.1–0.2 mL/kg of 1 per cent solution)
intravenously over 5 minutes. The dose may be repeated in 1 or 2 hours, but the total cumulative dose
should not be greater than 7 mg/kg (0.7 mL/kg of 1 per cent solution). [11]
Methylene Chloride
Methylene chloride (CH2CI2), found in solvents and paint stripping products, is a highly lipid-soluble, volatile
compound that is taken up by and then slowly released from many body tissues after absorption through the
respiratory tract. It is found in some solvents and many paint stripping products. As it is released, methylene
chloride is metabolized to carbon monoxide and carbon dioxide by the liver.[22] Although the resulting
carboxyhemoglobin levels are usually modest, levels as high as 50 per cent have been reported.[29] Patients
with marginal cardiac or respiratory function may suffer clinically significant impairment of oxygen delivery to
vital organs. Unlike the situation with exposure to carbon monoxide gas, levels of carboxyhemoglobin may
increase up to 9 hours after exposure,[30] even after the victim is removed from the source of exposure and
started on oxygen therapy. In addition, the carboxyhemoglobin half-life will be several times greater than that
usually seen after direct carbon monoxide exposure.[22] Patients with increased carboxyhemoglobin levels
should be treated with 100 per cent normobaric oxygen until the level is less than 5 per cent. The role for
hyperbaric oxygen therapy, if any, in the treatment of carbon monoxide poisoning caused by methylene
chloride has not been elucidated. Methylene chloride itself also causes CNS depression.


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49. Waldron HA: Effects of organic solvents. Br J Hosp Med 1981; 26:645.
50. Wason S, Gibler WB, Hassan M: Ventricular tachycardia associated with non-Freon aerosol propellants.
JAMA 1986; 256:78.
51. White JF, Carlson GP: Epinephrine-induced cardiac arrhythmias in rabbits exposed to trichloroethylene:
Potentiation by ethanol. Toxicol Appl Pharmacol 1981; 60:466.


Chapter 80 – Carbon Monoxide
CHRISTIAN TOMASZEWSKI
Essentials
• Carbon monoxide source (combustion or methylene chloride exposure)
• Elevated carboxyhemoglobin (COHb) level (up to several hours post exposure)
• Flu-like symptoms (e.g., headache, nausea, dizziness)
• Altered mental status (cognitive deficits, confusion, coma)
• Syncope (with severe poisoning)
• Cardiac ischemia (with severe poisoning)
• Family members or coworkers with similar symptoms
INTRODUCTION
Carbon monoxide (CO) is the leading cause of death from poisoning in the United States. In a review of
death certificate data from 1979 to 1988, there were over 5,000 deaths each year from CO poisoning.[21]
These included intentional suicides as well as unintentional exposures from home heating, automobile
exhaust, and smoke inhalation. Although there appears to be increased public awareness of the CO
problem, there were still 2,581 U.S. deaths (14 per cent of total poisoning deaths) attributed to known CO
exposure in 1995, of which 436 were unintentional.[38] In addition to immediate mortality, it is estimated that
more than 10,000 people lose at least 1 day of work each year due to CO exposure.[106] Besides acute
morbidity, survivors are at risk for prolonged or delayed neurologic problems. Because of these issues, CO
poisoning is one of the most common and challenging toxic exposures the clinician must manage.
CO is so insidious because it is clear, odorless, and nonirritating. With a density of 0.968 relative to air, it
quickly diffuses to equilibrate with any indoor air space. CO naturally occurs as a byproduct of the
degradation of heme.[22] Extraneous sources include the combustion of any carbonaceous fuel, such as
gasoline, natural gas, kerosene, or oil. Automobile exhaust is responsible for over half of unintentional
deaths.[21] This number may decrease as older vehicles without catalytic converters, which reduce CO
emissions, are disposed.[70]
The key to the diagnosis of CO poisoning is a complete history regarding potential for exposure to any
combustion source, such as motor vehicles, heaters, and appliances that use carbon-based fuels. CO from
motor vehicle exhaust accounts for the most poisoning deaths in the U.S. caused by a single agent. [21][38]
With older vehicles, emissions are so great that there have been poisonings even outside the vehicle
compartment, such as in the back of pickup trucks, in garages with doors and windows open, or entrained
from a source outside the patient’s dwelling.[51][139] Heating and cooking sources of CO result in 500
unintentional deaths each year from the burning of oil, natural gas, kerosene, and charcoal.[21][27][41][50] Even
propane, which allegedly burns cleanly, has resulted in mass poisonings from the operation of indoor
powered vehicles such as forklifts and ice-resurfacers.[36][64] An open ventilated area does not guarantee
against CO poisoning, as has been seen in incidents involving boats and tractors.[3][65] A reliable rule in
winter for targeting COHb levels is to test any patient with flu-like symptoms who has been near gas
appliances or if there are cohabitants with similar symptoms.[55]
There are other sources of CO intoxication that may be overlooked. Smoke inhalation survivors are more
often than not subject to the deleterious effects of CO.[109] When combined with hydrogen cyanide toxicity,
another common fire intoxicant, both morbidity and mortality are greater than that predicted by CO alone.[5]


TOXICOKINETICS/PATHOPHYSIOLOGY
Toxicokinetics
Carbon monoxide is readily inhaled and absorbed at a rate proportional to respiratory exchange rate.
Probable the most accurate model for predicting COHb levels based on exposure history is the Coburn-
Forster-Kane (CFK) model.[24] Simplification of the original model results in an equation that allows one to
estimate the equilibrium level based on the CO exposure level in parts per million[127]:
This assumes the person is a normal-sized adult without anemia. In addition, one must keep in mind that
with exponential uptake it make take many hours (4–8) before the equilibrium value is approximated.
Endogenous production of COHb is negligible, accounting for only 2 per cent of total COHb.
Initially, CO is primarily confined to the blood compartment, with little change in oxygen extraction and
consumption by tissues.[48] The Haldane ratio, the affinity of CO versus oxygen for hemoglobin, is
approximately 200.[17][18] As COHb levels increase and time passes, up to 15 per cent of total CO stores can
distribute from the blood and be taken up by tissue stores, primarily by binding to myoglobin.[23]
Elimination of CO can be modeled mathematically as well using the CFK model.[24] Using this equation, the
human COHb half-life has been predicted to be 252 minutes and was measured at 249 and 320 minutes,
respectively, in two actual volunteer studies.[92][98] Although not proportional, increasing oxygen pressure
promotes more rapid CO elimination.[127] With 100 per cent oxygen at atmospheric pressure, half-lives were
47 to 80 minutes in the volunteer studies.[92][98] Two patient series showed half-lives of 74 and 131
minutes.[11][137]
Methylene chloride, a paint stripper, is metabolized to CO by the liver after inhalation or dermal
absorption.[114] The problem with this method of intoxication is that peak COHb levels may be delayed more
than 8 hours.[66] Deaths have resulted from this agent, with COHb levels as high as 50 per cent.
Pathophysiology
Carbon monoxide’s toxicity is attributable mainly to its ability to bind avidly to a variety of heme proteins.
Most notably, CO has an affinity for hemoglobin 200 to 250 times that of oxygen.[33] Adding further insult is
the fact that COHb shifts the oxyhemoglobin dissociation curve to the left, making oxygen less available to
cells.[126] Although COHb may cause the acute anoxic-type symptoms characteristic of poisoning, it does not
explain all manifestations of this intoxication. This is why COHb levels do not correlate with either acute
symptoms or final outcome.[85][89][112]
CO may further cause damage by binding to myoglobin, with an affinity approximately 60 times greater than
oxygen.[25] Animal studies show CO exposure produces myocardial impairment with subsequent
hypotension.[29] Carboxymyoglobin may explain the dysrhythmias and ischemia that can occur with mild
exposures, especially in patients with pre-existing heart disease.[4] Finally, CO can bind to cytochrome
oxidase, the enzyme responsible for allowing cells to utilize oxygen. Although not usually bound extensively,
this may be exaggerated under hypotensive or hypoxic conditions.[12] Cytochrome oxidase may be further
inactivated by nitric oxide release from platelets that then forms peroxynitrite, a strong oxidizing free
radical.[124]
The inactivation of cytochrome oxidase may be the initiating event for a cascade of processes that lead to
ischemic reperfusion injury and delayed neuronal cell death. The precipitating event is probably a
hypotensive episode, which in animal studies must accompany the initial poisoning to cause neuronal
damage.[45][91][117] This hypotensive event, clinically represented by syncope, results from a combination of
vasodilation, owing to nitric oxide release from platelets[124] and cyclic guanosine monophosphate[132]
activation, and myocardial depression from carboxymyoglobin.[26][39] During recovery from the initial injury,
white blood cells are attracted and adhere to the brain microvasculature.[120] These leukocytes release
proteases that convert xanthine dehydrogenase to xanthine oxidase, an enzyme that promotes the formation
of oxygen free radicals.[119] The end result of this ischemic reperfusion cascade is lipid peroxidation with
delayed neurologic damage of the brain.
Newer developments show that excitatory amino acids may amplify the central nervous system damage
from CO. After severe CO poisoning, there is an increase in glutamate in rat brains.[141] Glutamate is a
known excitatory amino acid that can damage neuronal cells by stimulating N-methyl- D-aspartate (NMDA)
receptors and causing intracellular calcium release.[19] Blockage of NMDA receptors can prevent both the
neuronal cell loss and amnesia that accompanies CO poisoning in a mouse model.[61]
One last putative mechanism for neuronal death from CO may involve apoptosis or programmed cell death.
This may be mediated through a combination of free radicals[130] and excitatory amino acids. [141] CO acts
both on the whole organism as well as on the cellular level to ultimately cause the most feared complication
of CO poisoning, namely, neuronal cell death. These hypothesized mechanisms are complex and not
completely understood. They are schematized based on our current knowledge as discussed earlier ( Fig.
80–1 ).
Figure 80-1 Possible mechanisms for carbon monoxide toxicity resulting in neurologic damage and delayed sequelae.


Acute Presentation
Acute symptoms can occur with exposures as low as 100 ppm for several hours. The U.S. Government
standard for exposure to CO prohibits exposure to more than 35 ppm, averaged over an 8-hour workday.[131]
There is also a ceiling limit of 200 ppm (measured over a 15-minute period). Just over 4 hours of exposure
to 100 ppm CO can result in COHb levels of over 10 per cent with symptoms.[98]
The most common initial symptoms are headache, nausea, and dizziness ( Table 80–1 ). In fact, CO
poisoning is most commonly misdiagnosed as influenza. Infants may present with only vomiting, eliciting a
diagnosis of gastroenteritis. In addition, patients may complain of malaise and fatigue and manifest
weakness, confusion, or ataxia. With more extensive exposures, patients have symptoms attributable to the
organs most sensitive to hypoxia, namely, the brain and heart. Syncope, coma, and seizures may result.
Patients with pre-existing heart disease are especially prone to palpitations, dyspnea, dysrhythmias, and
other manifestations of cardiac ischemia.[77]
Table 80-1 -- Clinical Presentation of Carbon Monoxide Poisoning

Signs Symptoms
Vomiting Headache
Ataxia Nausea
Confusion Dizziness
Syncope Weakness
Coma Chest pain
Seizures Dyspnea
Cardiac dysrhythmias Visual changes
Tachypnea
Myocardial ischemia
With severe exposure, other organ systems are susceptible to CO’s effects. Metabolic acidosis, due to
lactate formation from relative hypoxia, is generally considered a reliable marker of severe toxicity.[112]
Often, severe poisoning will result in some rhabdomyolysis, especially if the patient has been found
comatose.[134] The resulting myoglobinuria can lead to renal failure, but this can also develop from direct CO
toxicity in rare cases.[7] Although cherry-red coloration of the skin has been attributed to CO, this is in fact
usually only seen in the morgue.[87] Bullae may also result from either pressure necrosis or direct toxic
effects of CO on the epidermal-dermal junction.
Once it is established that the patient has symptoms consistent with CO exposure, history can be elicited.
CO exposure tends to be seasonal, with most exposures in the winter. Any patient with CO symptoms and
history of symptomatic cohabitants or gas burning appliances should elicit a COHb level. Any vehicle,
regardless of whether it burns gasoline or propane, can cause CO poisoning, even in a ventilated area.
Exacerbation or association of symptoms with vehicle use may be the only historical clue to CO poisoning,
especially in the summer. In survivors of fires, patients who were in enclosed spaces or unconscious are
especially susceptible to high COHb levels. Finally, the person with no obvious risk factors may be the victim
of delayed adverse effects from paint stripper use. Then there is always the rare exposure from entrainment
of CO into anesthesia circuits or compressed air for breathing in underwater hazardous situations.
Chronic Exposure
Occasionally, the health care worker will have to evaluate the patient who has suddenly discovered a faulty
furnace and now realized that he or she has sustained a prolonged exposure to low levels of CO. There are
no controlled data comparing neurologic outcome in patients with low level exposures with those without. Of
interest, Johnson and coworkers found that highway toll collectors, presumably due to chronic CO exposure,
had problems performing on parallel processing tasks.[63] Forklift workers, owing to incomplete combustion
of propane, tend to have intermittent problems with headache, nausea, and lightheadedness.[37] As late as 2
years after a more acute episode, this can lead to subjective complaints, such as paresthesias, headaches,
confusion, and movement and memory problems. In 1990, Ryan published a case of a woman who had 3
years of headache, depression, and confusion after long-term exposure to CO at 180 ppm from a faulty
furnace.[104] Formal testing of this patient showed permanent problems with verbal memory and learning, as
well as impaired immediate and delayed visual recall and poor retrieval under cued recall. These could not
be explained by depression alone. In vitro studies suggest that low levels of CO exposure could lead to the
liberation of nitric oxide–derived oxidants. [122] This may partially explain the accelerated atherosclerosis
attributed to tobacco smoking but still does not shed light on neurologic sequelae from chronic CO exposure.
One would expect such types of exposures to portend poor fetal outcomes. However, in one retrospective
case control study, there was no association of CO exposure in the last trimester with low birth weight.[1] In
conclusion, health care providers need to be vigilant for complaints that may be associated with chronic CO
exposure. This is not so important for acute treatment, especially if the patient has low levels of COHb with
minimal complaints, but for prevention of potential disasters from an unsafe home or work environment.


The differential diagnosis of an exposure to CO includes altered mental status from a variety of other gases (
Table 80–2 ). Any physical asphyxiant, such as natural gas (uncombusted), carbon dioxide, acetylene, or
helium, can cause temporary unconsciousness. These exposures tend not to cause the delayed neurologic
symptoms seen more commonly with CO. Irritant gases, such as formaldehyde, chloride, or nitrogen dioxide
tend to cause mucous membrane and pulmonary irritation with coughing and bronchospasm, effects not
seen with nonirritating CO. Although CO has been deemed a cellular asphyxiant by virtue of binding to
cytochrome oxidase, hydrogen cyanide and hydrogen sulfide are much more efficient inhibitors of this
enzyme. They are truly “knock-down” gases, causing loss of consciousness within minutes of exposure to
concentrations less than 1,000 ppm. In contrast, exposure of subjects to CO levels of 20,000 ppm for 3
minutes, followed by 232 ppm for 130 minutes has resulted in COHb levels of over 20 per cent without
discernible symptoms.[6]
Table 80-2 -- Differential Diagnosis of Carbon Monoxide Poisoning

Influenza
Gastroenteritis
Food poisoning
Cerebrovascular event
Asphyxia
Parkinsonism (delayed)
Sedative-hypnotic overdose
Hypothermia
Myxedema coma
The most common misdiagnosis is viral illness, such as influenza. Up to one fourth of patients with flu-like
symptoms (e.g., headache and dizziness) who present to emergency departments during the winter may
have COHb levels greater than 10 per cent.[32][54] Excessive vomiting, especially in infants, can lead to a
misdiagnosis of gastroenteritis or food poisoning. Stroke, with focal neurologic deficits, or myocardial
ischemia may be precipitated by CO exposure. Any overdose of a sedative-hypnotic agent, or simple
ethanol intoxication, can confuse the neurologic assessment in a victim of potential CO intoxication by virtue
of the accompanying altered mental status and ataxia.
The differential diagnosis for delayed sequelae from CO can include a variety of disorders, predominantly
neurologic ones. One of the most devastating events from CO are cognitive and movement disorders,
including choreoathetosis and parkinsonism, which can present days to weeks after the initial poisoning. [74]
Toxin-induced parkinsonism, with damage to the globus pallidus, can also be due to manganese, carbon
disulfide, neuroleptics, and, rarely, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant of
illicit opioids. Damage to the putamen can accompany methanol poisoning, but the associated blindness is
peripheral rather than cortical, as has been seen rarely with CO. Blindness due to quinine is also peripheral.
Both cyanide and hydrogen sulfide can cause acute hypoxic-related syncope followed by delayed neurologic
sequelae and even parkinsonism. [102] Long-term cognitive problems can be attributed to chronic inhalation,
usually deliberately, of solvents such as toluene.[58]


Initial laboratory evaluation should be directed at immediate life threats that can accompany CO poisoning
and can be easily corrected with supportive care. An immediate bedside determination of blood glucose is
essential in patients with altered mental status. In severely ill patients, cardiac monitoring should be initiated
and an electrocardiogram obtained to evaluate for cardiac ischemia. Because of the interference of COHb,
the pulse oximeter will greatly overestimate the percentage of saturated hemoglobin.[14] If there is any
concern about oxygenation in the presence of CO poisoning, an arterial blood gas study is essential. This
test can accurately assess oxygenation and confirm the presence of metabolic acidosis from lactate, a
marker for serious CO toxicity and worse prognosis.[112]
Carboxyhemoglobin Levels
The most important laboratory study for confirmation of CO poisoning is the COHb level. Normal levels are
less than 5 per cent in nonsmokers and can be as high as 12 per cent in two pack-per-day smokers.[113]
Although serious toxicity is often associated with levels over 25 per cent, patients may present comatose
with levels approaching zero, especially if they have received prolonged treatment with oxygen. Both this
and differences in “soaking,” defined as duration of exposure, make COHb levels unreliable in gauging
symptoms or predicting outcome. Therefore, such levels only confirm poisoning. Current studies looking at
total dissolved CO in the blood may better approximate tissue levels and therefore better correlate with
symptoms and outcome. [75]
Traditionally, COHb levels are performed on a co-oximeter with arterial blood, but venous blood has been
shown to be just as accurate, particularly when looking at levels less than 20 per cent.[129] Of note, samples
appear to be stable for at least 5 days, making field samples, drawn in heparinized tubes, valid for COHb
determination.[8] Breath sampling techniques with bedside monitors are available; however, ethanol, an all
too common confounder, will cross-react with the assay to produce erroneously high levels.[69]
Other Tests
Other laboratory tests may be useful, depending on the severity of symptom. Electrolytes will confirm
metabolic acidosis as well measure blood glucose. Any unconscious CO victim is susceptible to
rhabdomyolysis, and a screening creatine kinase test may be useful.[108]
Most CO patients do not require neuroimaging for altered mental status. If done for other reasons, computed
tomography of the brain may show low density changes in the globus pallidus and subcortical white matter
as early as 4 to 6 hours after severe poisoning ( Fig. 80–2 ).[83] These lesions are associated with a poor
clinical outcome.[100] Magnetic resonance imaging may be more useful because it is superior to computed
tomography in demonstrating CO injury.[59] Regardless of which neuroimaging modality is used, such tests
rarely dictate a change in treatment and are generally reserved for cases that fail to respond to initial
treatment or have an unclear diagnosis.
Figure 80-2 Computed tomographic scan of the brain showing globus pallidus lesions that are classic early signs after serious CO
poisoning.


TREATMENT
Initial treatment is directed at providing immediate oxygen to a patient who may be suffering from relative
hypoxia. A 100 per cent non-rebreather face mask should be used. In addition to promoting cellular
respiration, 100 per cent oxygen will reduce the elimination half-life of COHb from an average 4 to 5 hours to
1 to 2 hours.[75][86][92] Initial stabilization of the patient includes a blood glucose determination with correction
of hypoglycemia or hyperglycemia. Extremes of glucose should be avoided because of the potential to
exacerbate neuronal cell death.[94][97] Treatment with oxygen should continue until the patient is
asymptomatic, usually when COHb levels are less than 10 per cent.
Hyperbaric Oxygen
Scientific Rationale
In case of persistent severe symptoms or markers of severe toxicity, consideration should be given to
treatment with hyperbaric oxygen (HBO). Many researchers advocate HBO for definitive treatment of severe
symptomatic CO poisoning. The most obvious benefit of HBO is enhanced elimination of COHb, with a half-
life average of 20 minutes at 3 atmospheres absolute.[86][92][105] However, in reality most dissociation of
COHb occurs with administration of normal pressure oxygen before HBO treatment. Therefore, the real
benefit of HBO may be in regeneration of cytochrome oxidase and inhibition of leukocyte adherence to the
microvascular endothelium.[13][121][123] All this prevents the cascade of events that leads to ischemic
reperfusion injury, the process thought to be responsible for lipid peroxidation of the brain and delayed
neurologic sequelae.[118][121]
The consensus of animals studies, using the rat model, is that HBO reduces central nervous system
damage after CO poisoning. This is manifested by improved short-term outcome in locomotor activity and
survival.[62] Long-term outcome, performance on a maze at 1 week, was also improved by HBO.[128]
Unfortunately, both of these studies involved Levine-prepared (unilateral carotid occlusion) animals. The
beneficial effects of HBO in CO poisoning were corroborated, however, in a non-Levine model in which lipid
peroxidation of the brain from CO was prevented by early HBO treatment.[118]
Although basic animal studies support the benefits of HBO, there is a paucity of randomized clinical trials
with conflicting results. The most comprehensive randomized study comparing HBO to routine oxygen
treatment was performed by Raphael and colleagues in France. [101] In 343 patients who had no loss of
consciousness, the incidence of delayed neurologic sequelae was the same in both groups. Unfortunately,
flaws with this study included prolonged delays to treatment and failure to treat at optimal pressure. A later
study with similar mildly intoxicated patients avoided some of these flaws and demonstrated a decrease in
delayed neurologic sequelae from 23 per cent in oxygen controls to 0 per cent in the HBO group.[125] This
study has been criticized because of small sample size and lack of blinding. Several large well-designed
clinical trials with seriously ill CO patients are underway in this country and abroad.[79][136] The most recent
published trial showed that daily HBO (minimum three treatments) had no benefit over normal pressure
oxygen.[107] Unfortunately, no patient received timely HBO—the minimum time to treatment was 6.3 hours.
Also, less than half of the patients returned for 1-month follow-up. Thus, in light of Thom’s clinical and
animal work, HBO must still be considered a potential beneficial therapy, with little risk, for seriously
poisoned CO patients.
Indications
The scientific uncertainty and relative unavailability of HBO in some geographic areas makes establishing a
standard of care difficult. Nonetheless, examination of pre-existing literature allows the identification of
patients at high risk for delayed neurologic sequelae. These patients have the most to gain from HBO
therapy. Patients with a history of syncope are more likely to develop delayed neurologic sequelae.[20][40][82]
An episode of hypotension is necessary for neuronal damage to occur after CO poisoning in animals and is
consistent with the ischemic-reperfusion model of injury.[45][90] Patients with longer exposures, or “soaking”
periods, are at greater risk regardless of COHb levels. [9][135] A significant lactic acidosis may be a marker for
these prolonged exposures.[72][112] Ongoing cardiac ischemia has been touted as an indication for HBO
therapy after CO poisoning, but the efficacy of this treatment has not been prospectively evaluated.[2][35]
Patients with ongoing ischemia usually received HBO because of concomitant neurologic findings, and
isolated ischemia would probably benefit from routine cardiac treatment instead. This is definitely not an
indication for transport to another facility for HBO therapy. The ultimate marker of CO poisoning, COHb
level, is not reliable in predicting symptoms or final outcome.[78][85][89][101][112]
Neuropsychological Testing
Neuropsychological testing has traditionally had two roles in acute CO poisoning: (1) determining which
patients require HBO treatment and (2) establishing post-treatment baseline function, which can be
compared with follow-up testing for deterioration. A special neuropsychological battery of tests has been
developed for evaluating CO patients. The battery is altered by CO poisoning and improves with HBO
treatment.[81] However, it is not very sensitive or specific for CO poisoning.[103] More importantly, the battery
cannot predict patients at risk for delayed neurologic sequelae. It simply documents the temporary mental
impairment, which has also been seen in volunteers, associated with CO intoxication. [73][115]
This battery of tests can also establish baseline mental function in patients who have recovered from acute
CO poisoning. Such testing, usually done after oxygen or HBO treatment and before discharge, is more
appropriate for research documentation rather than treatment evaluation. At this writing, neuropsychological
testing in the acutely poisoned patient cannot be routinely recommended. Its predictive value has not been
established and, furthermore, the test is difficult to perform routinely in the average emergency department
because of multiple distractions, time constraints, and the presence of confounding co-intoxicants, such as
ethanol.[81][103] Currently, each patient should receive a bedside mini-mental status examination that
includes orientation and short-term memory as well as assessing gait for ataxia. Persistence of testing
deficits after several hours of routine oxygenation indicates a potential need for HBO therapy if the patient
does not already meet HBO criteria ( Table 80–3 ).
Table 80-3 -- Indications for Hyperbaric Oxygen (HBO) Treatment of Carbon Monoxide Poisoning *
Indications for HBO
Any loss of consciousness
Seizures, coma, altered mental status
Consider HBO in symptomatic patients with
Persistent neurologic symptoms
Pregnancy
Persistent cardiac ischemia
* All symptomatic patients should receive 100% oxygen.
Treatment Regimen
There are ways to optimize HBO treatment for CO poisoning. The first is that treatment should be performed
as early as possible. In the only clinical series that retrospectively examined this factor, both mortality and
delayed neurologic sequelae were substantially less in patients treated within 6 hours of discovery.[47] Two
recent controlled studies showed no benefit of HBO in poisoned patients when the average time to treatment
was 6 hours.[101] In contrast to these findings, a recent randomized trial showed a reduction in delayed
sequelae from 33 per cent to zero, when patients were treated within 6 hours with HBO as opposed to
routine oxygen.[125]
At this time there are no controlled studies or scientific rationale to commend more than just one HBO
treatment for any CO-poisoned patient regardless of clinical findings. Some hyperbaric experts advocate
repeated HBO treatments, especially in patients with persistent neurologic symptoms such as coma.[31]
Adding a second HBO treatment reduced delayed neurologic sequelae at 1 month from 55 to 18 per cent in
an uncontrolled retrospective series.[46] A prospective controlled study failed to confirm any benefit.[101]
Complications
Hyperbaric oxygenation is a low-risk procedure, and the only absolute contraindication is an unvented
pneumothorax.[110] The most common serious adverse effect is a seizure, which is usually short lived and
occurs in less than 2 per cent of cases.[52] The most common complication is barotrauma, usually
manifested as barotitis media and more rarely as a ruptured tympanic membrane or tension
pneumothorax.[60][110] Such problems can be foreseen. Any seriously ill patient, particularly one who has
had endotracheal intubation or central venous cannulation, warrants chest radiography before HBO.[110]
Either pseudoephedrine (60 mg orally) in awake patients or myringotomies in comatose patients is
advocated to help prevent middle ear barotrauma.[15]


DISPOSITION
Any patient with documented syncope or worse, such as seizures or coma, may benefit from an HBO
treatment (see Table 80–3 ). These patients are at the greatest risk of developing neurologic sequelae. Any
patient with altered mental status, especially if it persists after 2 to 4 hours of oxygen, should also be
considered as a treatment indication. Other clinical markers, such as acidosis, cardiac ischemia, or
abnormalities on neuropsychological testing cannot be used reliably as indications for HBO treatment
because of lack of studies.
Patients with abnormal vital signs or persistent neurologic symptoms after acute exposure require admission
for observation. If HBO treatment can be arranged early, usually within 6 hours of presentation, then transfer
to a facility with HBO capability should be considered for any patient who meets indications for HBO.
Patients usually experience cardiac or respiratory arrest before emergency department admission or during
initial resuscitation and therefore can usually be transferred safely without complications after initial
evaluation and stabilization.[110] Patients with mild symptoms and no loss of consciousness can be
discharged from the emergency department after symptoms resolve with oxygenation. Figure 80–3 outlines
a suggested algorithm for the management of symptomatic CO cases.
Figure 80-3 Suggested algorithm for the management of CO poisoning.
Other individuals inhabiting the same building or using the same transportation vehicle should be referred for
evaluation and treatment if symptomatic. More importantly, all involved individuals need to be warned of the
potential for further exposure and death. Local fire officials, utilities, or mechanics (in the case of motor
vehicles) can assist in the evaluation and correction of any suspected CO source. CO monitors are available
that may warn of exposures in homes with natural gas appliances or oil furnaces and in workplaces that use
propane or gasoline combustion engines indoors.[140]


SEQUELAE
Occasionally, after discharge, a patient who has been treated for symptomatic CO poisoning will return with
new or persistent symptoms. These sequelae typically involve the central nervous system. Patients may
recover from CO poisoning and appear fine, only to develop delayed neurologic sequelae 2 to 40 days after
the original exposure.[20][46][53][82][101][111] The incidence of such sequelae is as high as 40 per cent,
especially in patients who present after a syncopal episode and do not receive
treatment.[42][46][89][100][101][125] Review of such series shows that the most common sequelae are chronic
headaches and subtle problems with learning and memory ( Table 80–4 ). Neuroimaging studies will
occasionally demonstrate damage to the basal ganglia, white matter, globus pallidus, cerebellum, and
hippocampus.[59][71][83][88][90] These sequelae may persist months to years in many cases, although some
manifestations can spontaneously resolve. These sequelae cannot be reliably predicted or prevented.
Table 80-4 -- Manifestations of Delayed Neurologic Sequelae

Memory problems Cognitive deficits
Cognitive deficits Aphasia
Lack of concentration Apraxia
Lethargy Incontinence
Headache Dementia
Movement disorders Cortical blindness
Parkinsonism


SPECIAL SITUATIONS
Pregnancy
There are unique effects and treatment considerations with pregnant patients who are CO poisoned. In
general, more aggressive treatment of the poisoned pregnant patient is indicated. Additionally, CO exposure
can increase the incidence of stillbirths. CO is a known teratogen, with the potential to cause limb
malformation, cranial deformities, and limb disabilities.[16][68][133] Maternal COHb levels do not necessarily
reflect fetal levels, a fact that complicates treatment decisions. In primates, exposures insignificant to the
mother have led to intrauterine hypoxia, fetal brain injury, and death. [43][44] In humans, minor exposures
without loss of consciousness in pregnant mothers, especially prolonged exposures, have resulted in poor
fetal outcomes.[16][68] In one human case of fetal loss, the measured maternal peak COHb was 24 per cent,
but much higher levels were measured in fetal tissue at autopsy.[28] This discrepancy may be partly due to
slower CO absorption and elimination, predicted to be 3.5 times longer, in fetal circulation.[56][76]
Because of the prolonged elimination half-life of COHb in the fetus,[56][76] any symptomatic exposure should
be treated with 100 per cent oxygen for approximately five times the length of time it requires for maternal
symptoms to resolve and COHb levels to decrease below 5 per cent. Because of the potential for fetal
demise from CO and the favorable clinical experience with HBO in pregnancy, any sign of fetal demise,
regardless of the mother’s status, warrants a treatment with HBO. Finally, because of the concern for COHb
elimination in the fetus, it is much more efficient, and possibly efficacious, to use HBO on any pregnant
patient with a COHb greater than 15 per cent. The safety of HBO in pregnancy has been confirmed in animal
studies using therapeutic doses.[133] Multiple case reports of pregnant women treated with HBO for severe
CO poisoning have reported good fetal outcomes.[34][57][68][133]
Children
The relative susceptibility of pediatric patients to CO poisoning and neurologic sequelae is unclear. Under
the same conditions as adults, children may entrain greater CO because of greater minute ventilation rates.
However, no data suggest that the symptoms and outcome for children are markedly different than adults. In
fact, in one small pediatric series, every patient with a COHb level of 24 per cent and greater experienced
syncope.[30] In a retrospective series of 106 CO-poisoned children treated without HBO, the incidence of
neurologic sequelae was less than 10 per cent, with only three cases of delayed neurologic sequelae.[80]
Unfortunately, the study included many patients who did not appear to be intoxicated with CO and
comprehensive neuropsychological follow-up was not done. In an uncontrolled series, use of HBO was
associated with a reduction in delayed neurologic sequelae, which ranges as high as 25 to 29 per cent in
untreated patients.[30][67] Therefore, the same criteria for HBO treatment in adults should be used in children
as well. However, one may have to rely more on COHb levels (i.e., =25 per cent) as an indication for HBO
therapy, particularly in infants in whom history and neurologic findings are unreliable.
Delayed Presentation
Patients who present more than 6 hours after an acute exposure or with a history of chronic exposure may
not benefit from HBO therapy. At this time, routine HBO treatment of these patients is not recommended. In
Goulon’s series of 200 severe poisonings treated with HBO, those receiving HBO more than 6 hours after
exposure had an increased incidence of delayed sequelae (30 vs. 19 per cent) and mortality (30 vs. 14 per
cent).[47] Based on the physiologic mechanisms involved, it is unlikely that HBO will reverse the cascade of
events in progress several hours after an ischemic reperfusion injury. Anecdotal reports exist of successful
treatment days later[84]; however, these reports lack controls and may simply represent a temporary
salutatory effect of HBO or spontaneous resolution of delayed sequelae, which has been reported.[20][125]


EXPERIMENTAL THERAPIES
A variety of pharmacologic approaches for the treatment of CO poisoning have been investigated. These
studies are exciting because of the potential for discovering an “antidote” that can be administered early at
any hospital regardless of HBO availability. A promising intervention is insulin, which has demonstrated
neuroprotective activity after ischemia.[49] Hyperglycemia has been associated with worse neurologic
outcome after CO poisoning.[93][94][96] In rodent studies, insulin protects against the neurologic deficits
associated with CO poisoning in the presence of hyperglycemia.[138] Hyperglycemia should be quickly
treated with insulin, particularly in diabetic patients seriously poisoned by CO.
Another experimental approach is the use of antagonists of excitatory amino acids, such as glutamate, that
are responsible for neuronal damage after ischemia. Dizocilpine (MK-801), a specific blocker of the N-
methyl-D-aspartate receptor where glutamate specifically binds, shows some promising results. There is
decreased hippocampal damage, as well as less learning and memory deficits, in mice pretreated with
dizocilpine before CO poisoning. [61] Comparable results were obtained, with a reduction in mortality, with
ketamine treatment in rats poisoned with CO after unilateral carotid ligation.[95] Use of these drugs in CO
poisoning awaits regulatory approval, especially those newer products with less adverse side effects.
Hypothermia, a therapy touted early, does not improve outcome from CO poisoning. Animal studies show no
benefit and, in fact, suggest that this process leads to increased mortality.[99][116] Limiting free radical injury
has been attempted using allopurinol to prevent formation of xanthine oxidase. Rats show less xanthine
oxidase formation and subsequent lipid peroxidation of the brain when pretreated with allopurinol before CO
poisoning.[119] This intervention must be done before poisoning and therefore has no clinical utility at this
time.


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Chapter 81 – Smoke Inhalation
BRETT ROTH KENT R. OLSON
Essentials
• History of exposure to smoke or a fire in a closed space.
• Indications of thermal injury to airway include dyspnea and stridor, facial burns, or history of exposure to
steam.
• Highly soluble gases (ammonia, chlorine, sulfur dioxide) primarily cause upper airway chemical injury,
whereas insoluble gases (phosgene, nitrogen oxides) cause lower airway injury.
• Cyanide (CN), carbon monoxide (CO) poisoning, and methemoglobinemia are potential systemic
effects.
INTRODUCTION
There are approximately 4000 structural fire fatalities each year in the United States. According to the
Consumer Product Safety Commission, the proportion of these fatalities that are attributable to smoke
inhalation has been steadily increasing, to a high of 75 per cent in recent estimations.[50] Changes in coding
practice, greater progress in treating cutaneous burns, increased toxicity of fire smoke, or a combination of
these factors may explain this trend. The deadly effects of smoke inhalation are illustrated by several
infamous fires. The 1942 Coconut Grove Nightclub fire in Boston killed 491 persons, whereas 177 died in
the 1977 Beverly Hills Super Club fire in Kentucky.[11] Of 84 victims from the 1980 MGM Grand Hotel fire in
Las Vegas, only 5 died of burns and related trauma. The others were found on the upper floors of the hotel
in areas devoid of soot and remote from flames and heat, all victims of the inhalation of products of
combustion.[6][26]


PATHOPHYSIOLOGY
Standard definitions of smoke inhalation injury have ranged from a simple respiratory or pulmonary burn to
“smoke poisoning.”[8] Although these definitions emphasize key aspects of injury, they each identify only one
element in a complex process. Smoke is a mixed suspension of small particles in hot air and gas.[11] Its
composition depends not only on the material burned but also on the temperature of the process and the
concentration of oxygen available.[4][40] As many as 400 toxic compounds can be demonstrated in smoke
from house fires.[1] Polyvinyl chloride, which as a component of many plastics is ubiquitous in modern
households, generates 75 different toxic products of combustion. The most damaging of these are
hydrochloric acid and carbon monoxide (CO).[14] Smoke inhalation causes not only poisoning from these
toxins but also thermal burns from hot particles and gases and chemical injury from irritant gases and
vapors. Asphyxiation due to rapid consumption of oxygen by the fire may also occur. Pneumonitis, adult
respiratory distress syndrome (ARDS), and multisystem organ failure often complicate the clinical picture
over the course of days to weeks. Several excellent reviews of inhalational injury are available.[3][13][21][47][55]
Thermal Injury
Dry air has very poor heat-carrying capacity, so that heated dry air is usually cooled by contact with the
tissues of the upper airway before it reaches the bronchioles and alveoli.[7] Thermal burns from dry air are
therefore generally limited to the pharynx, epiglottis, and larynx. Severe thermal injury to the lower airway
occurs more often when the water vapor content of the inhaled air is high, because water increases the heat-
carrying capacity of air. Steam has approximately 4000 times the heat-carrying capacity of dry air. [58] Heated
particles of soot are also effective vehicles for the transport of heat to the lower airways.[52] Thermal injury to
the lower airway may also occur if the cough reflex is impaired by loss of consciousness or by severe burns
to the upper airway.[3] Laryngeal edema is the most common early manifestation of direct thermal injury to
the airway, typically developing within 1 hour and peaking by 8 to 12 hours. [3]
Chemical Injury
A chemical tracheobronchitis results when irritant gases come into contact with mucosal surfaces. With the
exception of poorly water-soluble agents (see discussion under Clinical Presentation), injury from chemical
irritants generally manifests itself within the first several hours after exposure. Laryngeal edema, stridor,
severe bronchospasm, or complete respiratory failure may develop.[3]
Highly water-soluble gases are more rapidly absorbed by the moist surfaces of the upper respiratory tract
and, unless exposure is overwhelming, usually only affect the upper airway.[21] Ammonia from nylon,
chlorine from polyvinyl chloride (PVC), sulfur dioxide from organic materials, and acrolein from burning wood
and acrylic are potent water-soluble gases that act as corrosive agents on the upper respiratory mucosa.
Gases with relatively low water solubility such as phosgene from plastics and oxides of nitrogen from wool
and rubber pass more readily into the lower respiratory tract, causing severe damage to the small airways,
the respiratory bronchioles, and alveoli. Inflammatory occlusion of terminal bronchioles and necrosis of the
endobronchial mucosa limit ventilation and render the airway and pulmonary parenchyma especially
susceptible to infection. Loss of surfactant, decreased pulmonary compliance, and destruction of alveoli may
lead to respiratory failure.[20]
Systemic Poisoning
Carbon monoxide is a deadly product of combustion and is reported to play a role in 50 per cent of all
immediate smoke inhalation deaths.[22] Formed from the burning of wood, coal, and other organic materials
in low-oxygen environments, CO has an affinity for hemoglobin more than 200 times greater than that of
oxygen.[17] It readily displaces oxygen from the hemoglobin molecule and also causes a leftward shift in the
oxygen-hemoglobin dissociation curve. It also binds competitively to cytochrome oxidase, impairing the
cellular utilization of oxygen. High CO levels result in fatal anoxia because of decreased delivery of oxygen
to the tissues and impairment of the ability of cells to use oxygen. A process of CO-mediated brain lipid
peroxidation has also been described and is believed to be associated with the delayed neurologic
deterioration seen in 4 to 40 per cent of victims.[54] Further discussion of CO poisoning can be found in
Chapter 80 .
The thermal decomposition of nitrogen-containing materials, whether natural (wool and silk) or synthetic
(polyurethane and polyacrylonitrile), can produce toxic levels of hydrogen cyanide.[2] Several reports
document the presence of CN in up to 90 per cent of smoke inhalation victims, and some believe that the
significance of CN poisoning in fire victims has been underestimated.[1][2][26][29][51] This seems possible
considering that no simple confirmatory test for CN intoxication is available and that many of the signs and
symptoms of CN intoxication overlap with those of CO poisoning. Metabolic acidosis is often attributed to
tissue anoxia, owing to oxygen deprivation or to the presence of CO.[26] CN potently inhibits cellular
respiration by blocking cytochrome oxidase. This results in severe metabolic acidosis.[39]
Several animal studies have shown that CN acts synergistically with CO to cause tissue hypoxia and
ischemic injury.[34][39] This is supported by studies of fire victims who died despite having blood levels of CO
and CN that are generally considered nontoxic.[2] The enhanced lethality is most likely the result of
synergistic inhibition of cytochrome oxidase and augmentation of the blockade of cellular capacity to use
oxygen.[39] This is further compounded by breathing ambient air depleted of oxygen and by hyperventilation
that increases inhalation of irritant gases and hot smoke.[60] A recent study has implicated significant
concentrations of volatile organic compounds, including benzene, toluene, and xylenes, in fire-related
death.[23a]
Other systemic toxins associated with smoke inhalation are described in Table 81–1 . In addition to its direct
toxic effects, smoke may also serve as a vehicle for vaporized toxins released from damaged storage
containers.[42] In one incident, several San Francisco firefighters developed methemoglobinemia after
inhaling vapors of butyl nitrite released during a warehouse fire.[56]
Table 81-1 -- Toxins Found in Fires

Found in/Product
Mechanism of Injury Clinical Findings/Presentation
of…
Systemic Poisons
Found in/Product
of…
Combustion of any Headache, nausea, vomiting, confusion, coma, seizures,
organic material: metabolic acidosis, dysrhythmias, death. Venous blood
Carbon monoxide (CO) *
wood, paper, fabrics, may appear bright red, and arterial blood PO 2 and pulse
etc. oximeter saturation are usually normal.
Symptoms are very similar to those with CO poisoning.
Carpets, upholstery,
Cyanide (HCN, CN) Mixed venous oxygen saturation may be greater than 90%
nylon
in severe poisonings.
Oxides of nitrogen Nitrocellulose Methemoglobinemia, lung injury
Simple Asphyxiants
Combustion of any
organic material: Respiratory acidosis, central nervous system depression,
Carbon dioxide (CO2)
wood, paper, fabric, hypoxic seizures, death
etc.
Leaks from heaters,
Propane/ethane/methane
stoves
Chemical Irritants
High Water Solubility
Persistent cough, stridor, throat pain, and eye irritation are
Acrylics, wood
Acrolein the most prominent findings. Pink frothy or blood-tinged
finishes, wall coverings
sputum can occur.
Diffuse airway injury, coagulation (HCl), or liquefaction
Organic sulfur-
Sulfur dioxide (SO2) (NH3) necrosis of mucous membranes occurs in severe
containing compounds
cases
Ammonia (NH3) Phenolics, nylon
Fabrics, polyvinyl
Hydrochloric acid (HCl) chloride, synthetic
polymers
Intermediate Water Solubility
Cleaning mixtures, As above, but with greater lower respiratory tract
Chlorine (Cl2)
polyvinyl chloride involvement
Insulation, foams, Asthma and delayed hypersensitivity pneumonitis are
Isocyanates
rubber adhesives reported with isocyanates
Low Water Solubility
Predominantly lower respiratory tract injury with delayed
Wool, silk, synthetic
Oxides of nitrogen † onset of hemoptysis, chest pain, and hypoxia due to
rubber, silo fires
pulmonary edema
Found in/Product
of…
Plastics, polyvinyl
Phosgene ‡ chloride, halogenated
hydrocarbons
Other
Cements, glues,
Volatile hydrocarbons Narcosis, psychosis, sudden death
lacquers, alcohols
Central nervous system depression, renal and bone
Glues, cement,
Aromatic hydrocarbons marrow toxicity. Loss of central nervous system white
toluene, benzene
matter (toluene)
Halogenated Solvents, Freon,
Central nervous system toxicity, myocardial sensitivity
hydrocarbons chloroform
Nickel, antimony,
Metal oxides Airway irritation, viral-like syndrome
copper
Delayed onset of severe upper and lower respiratory tract
Metal cleaners, glass
Hydrofluoric acid (HF) symptoms (see irritants). Massive inhalational exposure
etching, ceramics
can result in systemic HF toxicity
* Odorless and tasteless.
† Pungent odor.
‡ Smell of newly mown hay.


Airway Injury
Although no specific clinical findings are diagnostic of inhalation injury, the triad of (1) burns of the mouth
and nose; (2) singed nasal hairs; and (3) history of exposure to a closed space fire has been used classically
to predict serious airway injury. The absence of this triad does not, however, rule out serious airway injury. In
one study the history of an unconscious victim in a closed-space fire had the strongest correlation with
eventual pulmonary failure.[23]
Respiratory symptoms such as dyspnea, cough, hoarseness, and chest pain occurred inconsistently in 25 to
75 per cent of smoke inhalation victims with inhalation injury studied at large centers ( Table 81–2 ). The
expectoration of carbonaceous sputum, considered essential for diagnosis in a few early reports, is seen in
only 10 to 20 per cent of patients. It reflects the nature of the exposure but does not correlate with prognosis
or injury severity.[21] Facial burns alone have a positive predictive value of only 50 to 70 per cent.[43][61]
However, facial burns associated with large cutaneous burns reflect the inability to escape direct flame
and/or prolonged exposures, and they do correlate with severe upper airway edema, pulmonary edema, and
pneumonia. The presence of hoarseness, dysphonia, or dysphagia signals possible severe upper airway
injury. Stridor, which may not be present with quiet breathing, is a sign of critical airway or pharyngeal
edema and should alert the clinician to imminent airway obstruction and respiratory arrest.
Table 81-2 -- Physical Examination Findings in Patients with Inhalation Injury (N = 108) *
Finding %
Burn, face 65
Carbonaceous sputum 48
Soot, nose and mouth 44
Rales, rhonchi 23
Wheeze 31
Voice change 19
Corneal burn 19
Singed nasal vibrissae 11
Stridor 5
Dyspnea 3
Intraoral burn 2
From Clark WR, Bonaventura M, Myers W: Smoke inhalation and airway management at a regional burn unit:
1974–1983. I. Diagnosis and consequences of smoke inhalants. J Burn Care Rehabil 1989; 10:52–62.
* Fifteen per cent of patients had only one physical finding, 56% had three or more findings, and 32% had four or more findings.
Other signs of respiratory injury include tachypnea, the use of accessory muscles of respiration, crackles
reflecting severe lung parenchymal damage, and cyanosis, which is often masked by soot.[21]
Exposure to highly soluble irritant gases or mists such as hydrochloric acid or acrolein usually causes a
rapid onset of mucosal irritation and upper airway symptoms, including burning of the eyes and throat,
painful cough, and wheezing. Exposure to less soluble gases, such as phosgene, hydrofluoric acid, or
nitrogen dioxide may cause minimal upper airway irritation initially with progression to chemical pneumonitis
or noncardiogenic pulmonary edema over a 24-hour period.[49]
Systemic Poisoning
Patients with CO poisoning may complain of headache, dyspnea, dizziness, or nausea or may be found
unconscious or seizing. Tachypnea resulting from cellular hypoxia or metabolic acidosis may be present.
Hypotension and cardiac dysrhythmias can occur.[13] The classic “cherry red” skin coloration often looked for
in CO poisoning was observed in only 14 of 105 patients in one series. [32] Soot deposits in the mouth and/or
sputum have been shown to correlate with COHgb levels > 11 per cent with a sensitivity, specificity, and
negative predictive value of 93 per cent, 63 per cent, and 92 per cent, respectively.[4a] Thus the absence of
soot deposits makes significant carboxyhemoglobinemia less likely, but does not rule out significant CO
poisoning. The finding of bright red venous blood, or “arterialization” of retinal veins, which may also be seen
in CN poisoning, does suggest the diagnosis.[25][27] These clinical findings suggest severe poisoning.
Cyanosis is much more common, occurring in 40 per cent of patients with CO poisoning.[32] Unfortunately,
CN poisoning cannot be distinguished from CO poisoning on clinical examination.


The diagnosis of smoke inhalation injury is readily apparent from the setting in which the patient was found.
Thus, any difficulties in diagnosis consist of elucidating all the injuries and toxicities sustained during the
exposure.


LABORATORY/CLINICAL STUDIES
The diagnosis of inhalation injury from smoke inhalation is generally clinical. When present, the diagnosis
may be supported by abnormal arterial blood gas measurements, pulmonary function tests, or chest
radiography. Routine laboratory tests that may be helpful include arterial blood gas analysis, and
determination of CO, methemoglobin, and lactate levels. An electrocardiogram and a chest radiograph
should be obtained. Other tests and radiographs are dictated by clinical findings ( Table 81–3 ).
Table 81-3 -- Laboratory Observations in Patients with Inhalation Injury

No. Patients %
CO2 < 15 Mmol/L 64 59
CoHgb > 5% and < 20% 55 51
A-a > 100 mmHg 42 39
CoHgb > 20% 33 31
CoHgb, carboxyhemoglobin; A-a = alveolar-arterial gradient
Although they are sensitive for the diagnosis of injury to the lower respiratory tract, the routine use of
bronchoscopy and xenon lung scans is not recommended. The one critical exception to the predominantly
clinical evaluation of patients with direct inhalation injury is the use of direct laryngoscopic examination to
evaluate the patency of the upper airway.[11] The following section reviews specific monitoring modalities.
Pulse Oximetry
The routine use of bedside pulse oximetry to measure oxygen saturation is recommended to identify
hypoxia. Normal readings do not rule out injury because patients may hyperventilate to maintain normal
oxygenation. In addition, pulse oximetry cannot distinguish oxyhemoglobin from carboxyhemoglobin, so that
patients with severe CO poisoning may have normal readings. Pulse oximetry is also inaccurate in patients
with methemoglobinemia.[38] Patients with CN poisoning also have normal oxygen saturations because
oxyhemoglobin levels are normal in uncomplicated cases.
Arterial Blood Gases
Acidosis, hypoxia, and hypercarbia are easily detected when arterial blood gases are measured. Normal
arterial blood gases do not exclude significant injury, because the initial insult to the respiratory tract may not
immediately affect gas exchange.[35] A progressive increase in the alveolar-arterial oxygen gradient has
been found useful in predicting subsequent pulmonary dysfunction. In one study, the alveolar-arterial oxygen
gradient measured while breathing 100 per cent oxygen at 12 to 24 hours after injury was greater in patients
whose conditions subsequently deteriorated and further increased 48 to 72 hours after the injury.[28]
It is important to realize that blood gas machines normally measure only the oxygen dissolved in plasma,
which may be normal in the case of CO poisoning despite a severe reduction in the amount of oxygen
carried by hemoglobin. The direct measure of oxyhemoglobin and carboxyhemoglobin using a co-oximeter
is required to make the diagnosis of CO poisoning. Unfortunately, not all hospitals have access to this
instrument.
Lactic Acidosis
A French study that obtained blood samples of smoke inhalation victims at the scene found that a plasma
lactate concentration above 10 mmol/L was a sensitive indicator of CN intoxication independent of
hypoxemia.[2] In addition to hypoxemia and CN toxicity, other conditions that contribute to lactic acidosis
include CO poisoning,[5] shock, upper airway obstruction, and anemia.
Mixed Venous Oxygen Saturation
Studies in dogs have demonstrated a significant rise in venous oxygen saturation and a fall in the
arteriovenous oxygen difference within minutes of the administration of sodium cyanide.[41] Because CN
poisoning reduces cellular oxygen utilization, severe poisoning may be associated with elevated oxygen
saturation in the venous blood. Although blood from the pulmonary artery provides the most accurate
determination of venous oxygen saturation, markedly high venous oxygen saturation from a peripheral vein
has been reported in patients with CN overdose.[25] Although no controlled studies have been performed, if
a patient has a normal hemoglobin and cardiac output, a mixed venous oxygen saturation of greater than 90
per cent is strongly suggestive of CN poisoning.[25]
Portable CO Meter
Field detection of CO poisoning may be carried out using a portable CO meter that measures the
concentration of the gas in expired air. A conversion table estimates the probable carboxyhemoglobin
concentration. This device has proved useful in firefighters and has also been used in screening studies to
detect occult CO poisoning in the emergency department.[57]
Bronchoscopy
Bronchoscopy has been considered by some as the “gold standard” for defining inhalation injury. A study
involving 180 patients determined that bronchoscopy-proven inhalational injury was one of the strongest
predictive variables for the onset of adult respiratory distress syndrome and death.[31] Another study
involving 330 patients with inhalation injury showed that less-serious findings on bronchoscopy were
associated with better outcomes.[48] Despite these findings many clinicians do not recommend
bronchoscopy because it does not alter therapy.[8]
Transnasal Fiberoptic Laryngoscopy
Early direct visualization of the larynx should be done in any patient with a history of smoke inhalation and
respiratory signs or symptoms, including dyspnea, cough, hoarseness, stridor, tachypnea, wheezing, and
rhonchi. Laryngoscopy may be repeated serially and should be used as a guide to determine the need for
endotracheal intubation.
Chest Radiography
Chest radiography is insensitive for the demonstration of pulmonary damage ( Table 81–4 ). In one study, 92
per cent of patients with inhalation injury had a negative initial chest radiograph.[10]
Table 81-4 -- Imaging Observations in Patients with Inhalation Injury

Imaging Mode No. Patients % Positive False-Negative Rate (%)
Chest radiograph 106 8 92
Xenon-133 scan 44 86 14
Albumin scan 44 82 18
CT of chest 13 77 23
Other
Radionuclide xenon scans and pulmonary function tests are more sensitive than chest radiography in
determining pulmonary injury.[22][45] Unfortunately, these tests often cannot be performed in critically ill
patients, and false-positive results from xenon lung scans may occur in patients with pre-existing bronchitis,
bronchiectasis, asthma, or pneumonia.[3]


TREATMENT
Any patient who manifests objective signs of respiratory dysfunction or has a history of being burned in a
closed space should be assumed to have smoke inhalation injury. Early identification of risk factors for
inhalational injury ( Table 81–5 ) and aggressive supportive care with early endotracheal intubation when
indicated help to avoid common pitfalls ( Table 81–6 ).
Table 81-5 -- Predictors of Inhalation Injury

Exposure in a closed space
Entrapment or a history of exposure >10 minutes
History of using ethanol *
Disabled
Unconscious
Other person(s) death
Known inhaled toxin
* Implicated in up to 40% of residential fires.
Table 81-6 -- Common Pitfalls in the Management of Inhalation Injury

Failure to appreciate the potential for rapid airway deterioration *
Failure to obtain important historical information about exposure to systemic toxins
Failure to administer available antidotes
Failure to stabilize before sending to a hyperbaric chamber
Failure to recognize associated trauma (cervical spine, abdominal injury)
Failure to decontaminate (remove clothes, irrigate eyes)
Failure to assess for underlying medical conditions (myocardial infarction, hypoglycemia, stroke, seizures)
* Relative indications for early intubation include central nervous system depression, visible burns or edema of oropharynx, stridor, full-
thickness circumferential burns to neck, and full-thickness burns to lips and nose.
Initial Therapy
High flow supplemental oxygen using a tight-fitting nonrebreather mask or through an endotracheal tube is
indicated pending complete patient evaluation. Specific antidotal therapy for CN poisoning is not necessary
if significant recovery has occurred before the patient reaches medical attention. Extensive decontamination
of the skin and eyes should be performed in patients with cutaneous exposure to hazardous materials, with
adequate precautions to protect the medical staff.
Patients with suspected CO poisoning or methemoglobinemia should have arterial blood gases checked
with a co-oximeter ( Figs. 81–1 and 81–2 ). Cardiac monitoring with continuous pulse oximetry is considered
essential for all symptomatic patients. Associated medical conditions such as hypoglycemia, acute
myocardial infarction, a postictal state, or traumatic injuries should be identified. Crystalloid fluid
resuscitation should proceed as needed for patients with cutaneous burns.[9] Central venous monitoring is
advised in complicated cases.
Figure 81-1 Airway assessment.
Figure 81-2 Evaluation and treatment of systemic toxins.
Early Endotracheal Intubation
Intubation of the trachea with mechanical ventilation should be considered in any patient with a history of
smoke inhalation and respiratory signs and symptoms. Relative indications for early intubation include
central nervous system depression, visible burns or edema of the oropharynx, full-thickness circumferential
burns to the neck, stridor, and full-thickness burns to the lips and nose. Delays may result in progression of
edema that makes orotracheal intubation difficult or impossible.[15][33][59] Fiberoptic transnasal laryngoscopy
may be used in stable patients to more precisely define the extent of upper airway injury and to help guide
the decision to intubate.[11] Mild to moderate bronchospasm without evidence of upper airway obstruction
often responds to aerosolized bronchodilators and does not necessarily require endotracheal intubation.[47]
Corticosteroids
Because of the intense inflammatory response to smoke seen in pathologic specimens and experimental
models, anti-inflammatory therapy with corticosteroids has been advised. Although corticosteroids have
shown benefit in some patients with nitrogen dioxide exposure,[53] there is no evidence to support their
routine use in patients with acute smoke inhalation injury.[21] Among victims of the Las Vegas MGM Grand
Hotel fire, no differences in outcomes could be discerned between patients who had received corticosteroids
compared with those who had not.[46] Corticosteroids may be helpful in patients with pre-existing asthma or
other reversible bronchospastic conditions.
Antidotes
Systemic poisoning should be treated with available antidotes. Initially, CO poisoning is treated with 100 per
cent oxygen. Hyperbaric oxygen therapy may be indicated in selected patients with elevated CO levels,
pregnant patients, or those with significant clinical toxicity.[12][18][36][37] See Chapter 80 for a more detailed
discussion.
Treatment of suggested CN poisoning in patients with smoke inhalation is problematic because the nitrites
found in the antidote kit may cause serious side effects.[19][24] Nitrites are vasodilators that can produce
hypotension, especially in hypovolemic patients. Methemoglobinemia formed by nitrite-induced oxidation of
hemoglobin can worsen hypoxemia in patients with parenchymal injury or CO poisoning. Fortunately,
sodium thiosulfate, the other component of the Lilly Cyanide Antidote kit, is an effective antidote when used
alone. The adult dose is 50 mL (12.5 g) (pediatric dose is 1.65 mL/kg of a 25 per cent solution) intravenously
at a rate of 3 to 5 mL/min, with readministration within 1 hour if symptoms reappear or persist.
Hydroxycobalamin (vitamin B12a) is an effective CN antidote that acts like a chelating agent. It combines with
CN to form cyanocobalamin (vitamin B12), which is nontoxic and renally excreted. It is used for the treatment
of CN poisoning in Europe in a dose of up to 100 mg/kg.[1] In the United States, hydroxycobalamin is
available in only 1-mg/mL concentrations, which would require the administration of several liters of this
antidote to deliver a comparable dose.
The question of who should receive therapy with thiosulfate is frequently raised. Given the lack of a rapidly
available laboratory test for CN and the risks of not treating CN poisoning, treatment should proceed based
on a history of a closed-space fire involving synthetic materials (upholstery or plastics) and the presence of
severe, persistent metabolic acidosis. Prior recommendations have ranged from treatment if hydrogen
cyanide was detected with special gas detectors to treatment for any unconscious patient with hypoxia when
diagnostic tools are unavailable.[44] We agree with the American College of Emergency Physicians who
have recommended empirical treatment of CN toxicity in the setting of persistent metabolic acidosis. [16] This
is based on studies showing that metabolic acidosis from CO poisoning clears rapidly with oxygen
administration and knowledge that the lactic acidosis from traumatic injuries will clear with treatment of
associated shock.[1] An elevated carboxyhemoglobin level has been shown to correlate with elevated CN
levels and may also help to guide therapy.[1][2]
Methemoglobinemia has been reported in smoke inhalation victims.[56] Methemoglobinemia with a level
greater than 20 to 30 per cent or evidence of serious symptoms such as dyspnea, altered mental status, or
metabolic acidosis can be treated with intravenous injection of methylene blue, 1 to 2 mg/kg (0.1–0.2 mL/kg
of a 1 per cent solution).[30] Failure to respond to methylene blue may be due to deficiency of glucose-6
phosphate dehydrogenase, hereditary NADPH methemoglobin reductase deficiency, or the presence of
sulfhemoglobinemia.[30]
Hospital Therapy
Bronchopulmonary lavage and physiotherapy may be indicated to help clear debris from the lower airway.
Therapeutic bronchoscopy is used when moderate to severe atelectasis is unresponsive to conventional
chest physiotherapy.[21] Empirical antibiotics specific for Staphylococcus aureus and Pseudomonas
aeruginosa are indicated when evidence of infection exists. Sensitivities of blood and sputum cultures
should guide the choice of antibiotics once analysis is complete. Prophylaxis with parenteral antibiotics is not
recommended.[47]
Experimental Treatments
Investigational agents such as surfactant, neurodepressors, superoxide dismutases, catalase, glutathione

reductases, allopurinol, ibuprofen, deferoxamine, vitamin E, and other antioxidant agents have theoretical
appeal but cannot be recommended at this time.[21]


DISPOSITION
Patients with a brief, mild exposure to smoke who have no evidence of upper airway compromise, altered
mental status, or elevated CO level may be discharged if they remain asymptomatic during a short
observation period. If an exposure to phosgene or oxides of nitrogen is suspected, a 24-hour period of
observation is recommended, owing to the delayed onset of symptoms. A low threshold for admission and
observation is warranted in most cases (see Figs. 81–1 and 81–2 ).


SEQUELAE
Tracheal stenosis, chronic bronchitis, bronchiolitis obliterans, irritant-induced asthma, bronchiectasis, and
permanent hypoxic brain injury are potential complications.


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Med 1995; 10:117-127.
46. Robinson NB, Hudson LD, Riem M, et al: Steroid therapy following isolated smoke inhalation injury. J
Trauma 1982; 22:876-879.
47. Ruddy RM: Smoke inhalation injury. Pediatr Clin North Am 1994; 41:317-336.
48. Rue LWd, Cioffi WG, Mason AD, et al: Improved survival of burned patients with inhalation injury. Arch
Surg 1993; 128:772-778.discussion 778–780.
49. Schwartz D: Acute inhalational injury. Occup Med 1987; 2:297-318.
50. Shusterman DJ: Clinical smoke inhalation injury: Systemic effects. Occup Med 1993; 8:469-503.
51. Silverman SH, Purdue GF, Hunt JL, Bost RO: Cyanide toxicity in burned patients. J
Trauma 1988; 28:171-176.
52. Stone J, Hazlett R, Johnson J: The transport of hydrogen chloride by soot from burning polyvinyl
chloride. J Fire Flammability 1973; 4:42-51.
53. Summer W, Haponik E: Inhalation of irritant gases. Clin Chest Med 1981; 2:273-287.
54. Thom S: Experimental carbon monoxide–mediated brain lipid peroxidation and the effects of oxygen
therapy [abstract]. Ann Emerg Med 1988; 5:403.
55. Thom SR: Smoke inhalation. Emerg Med Clin North Am 1989; 7:371-387.
56. Tong T: The role of regional medical poison control in hazardous material accidents.
In: Sullivan JJ, Krieger GR, ed. Hazardous Materials Toxicology: Clinical Principles of Environmental Health,
Baltimore: Williams & Wilkins; 1992:396-401.
57. Vreman HJ, Baxter LM, Stone RT, Stevenson DK: Evaluation of a fully automated end-tidal carbon
monoxide instrument for breath analysis. Clin Chem 1996; 42:50-56.
58. Walker J, Wells RE: Heat and water exchange in the respiratory tract. Am J Med 1961; 30:259.
59. Wanner A, Cutchavaree A: Early recognition of upper airway obstruction following smoke inhalation.
Am Rev Respir Dis 1973; 108:1421-1423.
60. Weiss SM, Lakshminarayan S: Acute inhalation injury. Clin Chest Med 1994; 15:103-116.
61. Wroblewski DA, Bower GC: The significance of facial burns in acute smoke inhalation. Crit Care
Med 1979; 7:335-338.


Chapter 82 – Inhalation: Gases with Immediate Toxicity
ALAN L. WEINER MARC J. BAYER
Essentials
• Rapid development of mucosal (eyes, nose, and throat) irritation occurs after the inhalation of an irritant
gas with moderate to high water solubility, such as ammonia or chlorine.
• Cardiovascular collapse or loss of consciousness in an enclosed space should raise the possibility of
simple asphyxiation.
INTRODUCTION
The discussion in this chapter is on gases that produce immediate toxicity on inhalation. Sources of these
gases vary. For example, ammonia can be found in most homes, in dilute concentrations (5–10 per cent),
where it is used as a cleaning and bleaching agent. Industrial strength ammonia (25–30 per cent) is used in
the production of fertilizers, dyes, and plastics.[19] Industrial uses of chlorine include bleaching fabrics and
disinfecting water or sewage. [9] Industrial accidents after chlorine gas leaks account for many toxic
exposures. Household and recreational exposures can also occur from swimming pool accidents.[6]
Gases with immediate toxicity can be divided into (1) irritants (ammonia, chlorine), (2) simple asphyxiants,
and (3) chemical asphyxiants such as carbon monoxide, hydrogen cyanide, and hydrogen sulfide. The
chemical asphyxiants are discussed in separate chapters. Multiple gases may be inhaled simultaneously, as
with smoke inhalation. Some of these gases will produce symptoms immediately, whereas others are
characterized by a latent period before symptoms occur. The potential for delayed deterioration in these
patients must always be considered. Gases presenting primarily with delayed toxicity are discussed in
Chapter 83 .


PATHOPHYSIOLOGY
The injuries produced by the inhalation of toxic gases are due primarily to two mechanisms: local pulmonary
damage and systemic hypoxia. Local pulmonary damage is caused by the irritant gases, whereas hypoxia is
caused by the asphyxiant gases. Several agents, such as hydrogen sulfide, can cause toxicity by both
mechanisms. The irritant gases dissolve in the mucosa lining the respiratory tract and impair respiratory
function through several mechanisms, including oxidation, desiccation, and through the formation of an acid
or a base. The water solubility of the gas determines the site in the respiratory tract where it dissolves and,
subsequently, the symptoms that it produces.
Irritants
Highly water-soluble gases ( Table 82–1 ), such as ammonia, dissolve quickly in the mucous membranes of
the eyes, throat, and upper airway, producing immediate symptoms.[15] The injuries produced by ammonia
range from mild edema and erythema to full-thickness tissue burns and complete obstruction of the upper
airway.[4][7][19] Sulfur dioxide and formaldehyde combine with water to form sulfuric acid and formic acid.
Hydrogen chloride produces damage by forming hydrochloric acid on contact with mucosal water. In a
similar fashion, chloramine releases ammonia and hypochlorous acid. The mixing of household cleaners,
such as ammonia, with a hypochlorite bleach can produce chloramine gas.[11] In contrast, hydrogen fluoride
depletes intracellular and extracellular calcium stores, resulting in cell death. Possible toxic mechanisms of
acrolein include oxygen free radical production and sulfhydryl binding, resulting in protein damage.
Table 82-1 -- Gases Presenting with Immediate Toxicity

Irritants Asphyxiants
High Water Solubility Intermediate Water Solubility Simple Chemical
Ammonia Chlorine Nitrogen Carbon monoxide
Sulfur dioxide Methane Hydrogen cyanide
Hydrogen fluoride Carbon dioxide Hydrogen sulfide
Formaldehyde Argon Oxides of nitrogen
Acrolein Helium
Chloramine Ethane
Hydrogen chloride Hydrogen
Acetylene
Butane
Neon
Propane
Xenon
Chlorine gas is of intermediate water solubility and may produce damage to both the upper and lower
airways.[5] Chlorine reacts with water to form hydrochloric and hydrochlorous acids. Hydrochlorous acid
quickly degenerates into hydrochloric acid and oxygen free radicals, which disrupt cellular proteins. [5]
Depending on the duration and concentration of the exposure, the entire respiratory tract can be affected.
Mild exposures result in superficial inflammatory changes of the upper and lower airways. More severe
exposures lead to bronchial epithelial sloughing, ulcerative tracheobronchitis, and pulmonary edema.[9]
Simple Asphyxiants
Simple asphyxiants (see Table 82–1 ) are nonpoisonous inert gases that displace oxygen, typically when
concentrations increase in an enclosed space.[3][10] As exposure increases, the percentage of oxygen in the
atmosphere decreases, causing increasing hypoxia. Sudden and complete cessation of respiratory and
cardiac activity can occur. Most of these gases are colorless and odorless and thus are not easily detected.
Chemical asphyxiants (see Table 82–1 ) interfere with oxygen utilization at the cellular level and use the
lung as a port of entry into the body to produce toxic effects. These are discussed in other chapters.


Irritant gases with high water solubility ( Table 82–2 ) produce symptoms immediately after inhalation. The
clinical effects depend on the concentration of the gas, the duration of the exposure, other inhaled toxins,
and the premorbid condition of the victim. In mild cases, the patient will display tearing and conjunctival
hyperemia, as well as burning of the mucous membranes of the mouth and throat.[4] More significant
exposures are characterized by full-thickness burns of the upper airway and nasal passages.[4][19]
Symptoms of respiratory distress such as stridor, wheezing, and tachypnea can occur. The most severe
exposures present with acute narrowing of the upper airway.[7] The patient displays marked stridor, drooling,
a changed voice, and severe dyspnea. Because symptoms occur at very low concentrations, the vast
majority of patients leave the exposure site before more severe symptoms can occur. Patients who are
immediately exposed to high concentrations or who are trapped in an enclosed space may become severely
affected and die quickly.[1]
Table 82-2 -- Clinical Presentation of Gases with Immediate Toxicity

Classification Signs and Symptoms
Irritants
Burning of eyes, nose, and throat
High water solubility Dyspnea, wheezing, and cough
Potential for upper airway obstruction with stridor and hoarseness
Upper and lower tract involvement, including mucosal irritation, bronchospasm, and
Intermediate water dyspnea
solubility
Potential for pulmonary edema, possibly delayed for hours after exposure
At low concentrations, nonspecific symptoms such as headache, nausea,
confusion, and dyspnea
Asphyxiants
At higher concentrations, possible seizures, syncope, and dysrhythmias
Eventually, coma and cardiovascular collapse
Gases of intermediate water solubility, such as chlorine, may produce symptoms of both upper and lower
respiratory tract injury. In addition to the manifestations of mucous membrane irritation described earlier,
chlorine also has the potential to induce inflammatory changes in the lower airways. Bronchospasm,
pneumonia, and pulmonary edema can occur, depending on the concentration of the gas and the duration of
the exposure. Several cases of delayed pulmonary edema after exposure to chlorine gas have been
reported.[5][9]
Presentation of common asphyxia is similar to that of hypoxia from any other source. The organs most
dependent on oxygen, such as the brain and heart, are the most readily affected. Myocardial ischemia and
resulting myocardial infarction, dysrhythmias, and hypertension can occur and be followed by cardiac
arrest.[8][10] Except in patients with pre-existing cardiac and pulmonary disease, symptoms may be difficult to
detect with oxygen saturation greater than 90 per cent. Tachypnea, tachycardia, and decreased alertness
become evident at 85 per cent saturation. At oxygen saturations less than 60 to 70 per cent patients may
become helpless and unable to seek assistance.


Patients often present with a history of having smelled a particular odor or with irritation, but the exact toxic
inhalant may be unknown. Patients with burning eyes, mucous membrane irritation, and bronchospasm may
occasionally be mislabeled as having reactive airway disease or asthma. However, in most cases, the
individuals exposed include many who do not have a prior history of asthma. See Table 82–3 for differential
diagnoses to consider.
Table 82-3 -- Differential Diagnosis of Irritant Gas Exposure

Inhalation
Capsaicin
Isocyanates
Lacrimators (e.g., chloroacetone, chloroacetophenone, chloropicrin)
Nitrogen dioxide
Other
Asthma
Reactive airways disease
Congestive heart disease
Pulmonary edema, non–inhalation related
Because simple asphyxiants cause hypoxia, all causes of decreased level of consciousness and myocardial
ischemia must be considered in the differential diagnosis. However, if the cause is a simple asphyxiant the
patient should rapidly improve with supplemental oxygen. Most patients who succumb to simple asphyxia
are found unconscious in a small, closed space, such as a mine or at the bottom of a sewer shaft.[2][13][17]


LABORATORY STUDIES
Laboratory studies should never delay management of life-threatening airway or cardiovascular

compromise. Early studies should focus on assessing the patient’s respiratory function.[13] A blood gas
analysis is helpful in severe cases or when patients do not rapidly improve. It provides readily available
information about the patient’s oxygenation, ventilation, and acid-base status and can confirm a hypoxic
patient, although most will have improved before arrival at the hospital. Pulse oximetry should not be relied
on, because the sensor may not truly measure the oxygen content in the setting of a chemical asphyxiant.
Frequently, the initial chest radiograph will appear normal, even in patients who are obviously ill.[12][13] A
normal chest radiograph in the first 24 hours after injury should not lull the physician into a false sense of
security. Masanes and colleagues found that only 15 per cent of biopsy-proven inhalation injuries produced
abnormalities on the initial chest radiograph.[12] A normal chest radiograph may evolve during the first 24
hours to show evidence of diffuse injury and pulmonary edema. Follow-up radiographs can be helpful in
detecting delayed pulmonary disease after toxic inhalation. The differential diagnosis of pulmonary edema
after inhalation should include the adult respiratory distress syndrome, aspiration, volume overload, and
cardiogenic shock.
The carboxyhemoglobin level should be checked if carbon monoxide exposure is possible. Blood cyanide
levels take hours to days to return and are not of acute clinical benefit but may be helpful retrospectively to
confirm a diagnosis. In the setting of a toxic inhalation and elevated lactic acid, carbon monoxide and
cyanide should be suspected.
Other studies include a pregnancy test in women of childbearing age and an electrocardiogram, together
with cardiac enzyme analysis, in patients complaining of chest pain or shortness of breath after having
inhaled systemic toxins. As always, any comatose patient should have a quick fingerstick glucose
determination to rule out hypoglycemia.


TREATMENT
The patient who is suspected of having inhaled a toxic gas requires rapid assessment and should be
assumed to be critically ill. An initial survey of the patient’s airway, breathing, and circulation will immediately
identify any life-threatening injuries. Resuscitative efforts should proceed simultaneously with the primary
survey. Once life-threatening injury has been ruled out, a more thorough history and physical examination
can be carried out. The treatment of gases that are immediately toxic is summarized in Table 82–4 .
Table 82-4 -- Treatment of Gases Presenting as Immediate Toxicity

1. Supportive care (for all cases)
a. Removal from the source
b. Oxygen
c. Cardiac monitor, intravenous access
d. Rapid assessment of airway, breathing, and circulation
e. Nebulized ß2 agonists (e.g., albuterol, for bronchospasm)
f. Consider nebulized 3.75% bicarbonate for chlorine
g. Further treatment for respiratory failure or pulmonary edema can include CPAP, BiPAP, endotracheal
intubation, PEEP
2. Decontamination (for irritant gases)
a. Removal of all contaminated clothing
b. Irrigation of skin if symptomatic
c. Irrigation and examination of the eyes if symptomatic
3. Protect rescuers and coworkers
a. Skin protection
b. Self-contained breathing apparatus as used by firefighters
CPAP, continuous positive airway pressure; BiPAP, bilateral positive airway pressure; PEEP, positive end-
expiratory pressure.
Life-threatening airway compromise may be present when the patient presents to the hospital or may
develop suddenly after a period of relative quiet.[12][13] Early intubation should be considered whenever there
is stridor, second- or third-degree burns to the neck or throat, or central nervous system depression.
Delaying intubation in a patient with upper airway injury only allows time for edema to progress. To prevent
hypoxia, all patients should be placed on 100 per cent oxygen through a tight-fitting non-rebreathing face
mask. In the intubated patient, positive end-expiratory pressure (PEEP) should be used to further improve
oxygenation. Continuous positive airway pressure and bilateral positive airway pressure (BiPAP) can be
used in the nonintubated patient. Fluids should be restricted early on unless the patient is clearly
hypovolemic, because excessive hydration contributes to further airway edema.
Many of the respiratory irritants will cause air flow obstruction through bronchospasm or through edema
formation within the wall of the respiratory mucosa. Inhaled ß2 agonists, such as albuterol, are considered
useful for the relief of bronchospasm after a toxic inhalation, although no prospective studies have validated
their efficacy.[13] Nebulized sodium bicarbonate (3.75 per cent solution) has been shown to improve
oxygenation after chlorine exposure in human case reports, but routine use is not yet recommended.[18]
Aminophylline is of dubious benefit in relieving acute air flow obstruction and carries with it significant side
effects. Corticosteroids, although a mainstay of asthma therapy, have not been proven to be of benefit after
a toxic inhalation.[14] Routine antibiotics are not recommended except in cases of documented pneumonia
or lower airway injury.
As early as possible after arrival, decontamination of any remaining toxins from the patient’s skin and eyes
should be undertaken. Care should be taken to ensure that health care workers are not exposed to any
chemicals still present on the patient’s skin or clothes. The patient’s eyes should be irrigated and also
stained with fluorescein to detect any corneal burns. Irrigation of the eyes should continue until the patient is
more comfortable and the pH of the corneal fornices is at or near neutrality.


DISPOSITION
Patients with mild exposures, who have no evidence of airway compromise, and who have not been
exposed to a gas having known delayed complications can be discharged after a period of several hours of
observation in the emergency department.[16] Any patient who was unconscious at the scene or who has
developed anything more than minor symptoms should be admitted for inpatient observation.[2][16] Many
inhaled gases are known to produce rapid clinical deterioration several hours after the inhalation (see
Chapter 83 ). In any patient in whom airway compromise is present or cannot be ruled out, admission to an
intensive care unit is advised so that rapid airway control can be achieved if necessary. All patients who
have suffered a toxic inhalation require outpatient follow-up after hospital discharge, because many of these
agents will have chronic effects on the respiratory tract or the central nervous system.[2][4][17]


SEQUELAE
Complications can include tracheobronchitis with secondary infections, lower airway hemorrhage, bronchial
hypersensitivity, and reactive airway dysfunction syndrome.


SPECIAL SITUATIONS
Pregnant women, by virtue of their higher metabolic demands, are at especially high risk of suffering
complications after a toxic inhalation.[16] The best way to protect the fetus is to prevent maternal hypoxia and
hypotension. As in other patients, ensuring a patent airway and supplying 100 per cent oxygen early in the
course is the key to a favorable outcome.
Children are also at high risk of complications as a result of their high metabolic demands. As in pregnant
women, aggressive treatment is warranted in children to minimize acute mortality and to prevent delayed
morbidity.


REFERENCES
1. Allan AR, Blackmore RC, Toseland PA: A chloroform inhalation fatality. Med Sci Law 1988; 28:120-
122.
2. Birky MM, Clarke FB: Inhalation of toxic products from fires. Bull NY Acad Med 1981; 57:997-1013.
3. Byard RW, Wilson GW: Death scene gas analysis in suspected methane asphyxia. Am J Forensic Med
Pathol 1993; 13:69-71.
4. Close LG, Caitlin FI, Cohn AM: Acute and chronic effects of ammonia burns on the respiratory tract.
Arch Otolaryngol 1980; 106:151-158.
5. Das R, Blanc PD: Chlorine gas exposure and the lung: A review. Toxicol Indust Health 1993; 9:439-
445.
6. Decker WJ: Chlorine poisoning at the swimming pool revisited: Anatomy of two minidisasters. Vet Hum
Toxicol 1988; 30:584-585.
7. Flury KE, Dines DE, Todarte JR, et al: Airway obstruction due to inhalation of ammonia. Mayo Clin
Proc 1983; 58:389-393.
8. Hag MZ, Hameli AZ: A death involving asphyxiation from propane inhalation. J Forensic
Sci 1980; 25:25-28.
9. Hedges JR, Morrisey WL: Acute chlorine gas exposure. JACEP 1979; 8:59-63.
10. Jawan B, Lee JH: Cardiac arrest caused by incorrectly filled oxygen cylinder: A case report. Br J
Anaesth 1990; 64:749-751.
11. Jones FL: Chlorine poisoning from mixing household cleaners. JAMA 1972; 222:1312.
12. Masanes MJ, Legendre C, Lioret N, et al: Fiberoptic bronchoscopy for the early diagnosis of subglottic
inhalation injury. J Trauma 1994; 36:59-67.
13. Mellins RB, Park S: Respiratory complications of smoke inhalation in victims of fire. J
Pediatr 1975; 82:1-7.
14. Nieman GF, Clark WR, Hakim T: Methylprednisolone does not protect the lungs from inhalation injury.
Burns 1991; 17:384-390.
15. Raabe OG: Physical properties of aerosols affecting inhalation toxicology.

In: Sanders CL, Cross FT, Dagle G, et al ed. Pulmonary Toxicology of Respirable Particles, Springfield,
VA: National Technical Information Service, U.S. Department of Commerce; 1980.
16. Rorison DG, McPherson SJ: Acute toxic inhalations. Emerg Med Clin North Am 1992; 10:409-435.
17. Terazawa K, Takatori T, Tomii S, et al: Methane asphyxia. CDAL mine accident investigation of
distribution of gas. Am J Forensic Med Pathol 1985; 6:211-214.
18. Vinsel PJ: Treatment of acute chlorine gas inhalation with nebulized sodium bicarbonate. J Emerg
Med 1990; 8:327-329.
19. Walton M: Industrial ammonia gassing. Br J Ind Med 1973; 30:78-86.


Chapter 83 – Inhalation: Gases with Delayed Toxicity
DAVID M. COSENTINO MEGAN C. COSENTINO MARC J. BAYER
Exposure to toxic inhalants may cause a vast array of clinical sequelae. These effects on the human body
can result in both acute and delayed symptoms. Many factors contribute to the resultant clinical scenario,
including exposure type, duration, concentration, degree of ventilation, and underlying
pulmonary/cardiovascular disease. The discussion in this chapter focuses on toxic inhalants that typically
cause delayed symptoms more often than immediate symptoms. These inhalants include phosgene,
nitrogen dioxide, isocyanates, zinc chloride, arsine, acrolein, and ethylene oxide, all of which are gases with
relatively low water solubility, which limits immediate dissolution on contact with moist mucous membranes.
PHOSGENE
Essentials
• Common exposures include welding and combustion of household products.
• Pulmonary, eye, and skin irritation may take up to 24 hours to manifest.
• Delayed effects include noncardiogenic pulmonary edema occurring minutes to 72 hours after
exposure.
Introduction
Phosgene, also known as carbonyl chloride, is a synthetic, colorless, irritant gas that is heavier than air and
has a somewhat musty odor. It developed a worldwide reputation during World War I, when it was used in
chemical warfare and accounted for approximately 80 per cent of the 100,000 gas-induced casualties.[7][16]
Today, phosgene gas most commonly arises from welding and the combustion of volatile substances,
including organochloride compounds (i.e., polyvinyl or methylene chloride) and isocyanates. These
substances are found commonly in many household products, such as solvents, paint removers, dry
cleaning fluids, home and office furnishings, floor coverings, and electrical insulation.
Pathophysiology
Because of its poor water solubility, inhaled phosgene gas is transported deeply into the lungs where it
slowly hydrolyzes to form hydrochloric acid and carbon dioxide over a few minutes to more than 24 hours.
This reaction and the subsequent extent of pulmonary damage depend on exposure concentration and
duration. Animal data suggest the pulmonary damage may be caused, in part, by lipooxygenase-dependent
arachidonate mediators.[23] The damage to the basal lamina of the pulmonary capillary bed permits the
development of leakage through the endothelial cell layer leading to increased permeability, with resultant
noncardiogenic pulmonary edema[35][59] manifested primarily by leakage of fluid, protein, and neutrophils.[19]
Phosgene can also bind to cellular enzymes, causing hepatic and renal necrosis.[14]
Concentrations of as little as 3 to 5 parts per million (ppm) can cause acute, mild irritant symptoms.
Exposure to 25 ppm, even for short periods of time, is extremely dangerous and can be fatal. Exposure to 50
ppm is usually rapidly fatal without appropriate medical intervention.[52]
Signs and symptoms of acute phosgene gas exposure include irritation to the eyes, skin, and respiratory and
gastrointestinal systems and are dependent on exposure concentration and duration. A patient presenting to
the emergency department after an acute exposure may complain of a burning sensation in the eyes, cough,
dyspnea, and a dry or burning throat with subsequent thirst, nausea, and vomiting. On examination, the
patient may have tachycardia, tachypnea, irritant conjunctivitis, excessive lacrimation, dermal burns, and/or
cough ( Table 83–1 ).
Table 83-1 -- Clinical Presentation of Phosgene Exposure

Acute
Ocular: burning sensation, conjunctivitis, excessive lacrimation, corneal damage (with liquid exposure)
Dermal: burns after direct contact with liquefied phosgene
Respiratory: cough ± sputum, hemoptysis, dyspnea, chest discomfort, pneumonitis
Gastrointestinal: dryness/burning of throat, thirst, nausea, vomiting
Delayed
Pulmonary edema and its sequelae, including severe dyspnea, productive cough, hemoptysis, hypovolemia,
hemoconcentration, hypotension, adult respiratory distress syndrome, and death
Infectious pneumonitis
In addition to the acute irritant symptoms, noncardiogenic pulmonary edema can develop within minutes to
up to 72 hours later. This pulmonary edema may be accompanied by hypovolemia with hemoconcentration,
hypotension, and progressive respiratory distress. These patients may present with shortness of breath,
cough, chest pain, dehydration, or increasing lethargy. Physical examination may reveal tachypnea,
pulmonary rales, cyanosis, tachycardia, hypotension, dry oral mucosa, orthostasis, and other signs of
hypovolemia (see Table 83–1 ). Rarely, adult respiratory distress syndrome can lead to death. These
delayed symptoms are usually preceded by a relatively asymptomatic period, the length of which is thought
to be inversely proportional to the severity of the initial symptoms. Rarely, infectious pneumonitis can
develop 3 to 5 weeks after exposure. Mortality is rare, but, if it does occur, usually does so within 24 to 48
hours.
The differential diagnosis of phosgene exposure is presented in Table 83–2 .
Table 83-2 -- Differential Diagnosis of Phosgene Exposure

Noxious gas exposure, including phosgene, nitrogen oxides, chlorine, ammonia, and sulfur dioxide
Asthma
Upper respiratory tract infection (viral vs. bacterial)
Pneumonia
Adult respiratory distress syndrome
Laboratory Studies
There are no specific laboratory tests for phosgene gas; however, pulmonary status should be monitored.
Tests include a chest radiograph, bedside pulse oximetry, arterial blood gas analysis if dictated by the
patient’s condition, and volume status assessment. The chest radiograph may be normal or may show signs
of pulmonary edema, with enlargement of the hilar areas being the earliest finding, or ill-defined patchy
infiltrates.[13]
Treatment
Treatment consists of decontamination and pulmonary support. The patient should be removed from the
exposed environment and stripped of all clothing. Exposed skin or eyes should be irrigated with tepid water.
With direct skin contact, one should perform a thorough rinse and wash with soap and water.
Hypoxia should be treated initially with oxygen; continued hypoxia may require intubation with positive end-
expiratory pressure (PEEP). Noncardiogenic pulmonary edema should be managed with continuous positive
airway pressure in nonintubated patients and PEEP in intubated patients. Intravascular volume status should
be carefully monitored. However, diuretics are not useful for noncardiogenic pulmonary edema. If necessary,
fluid status should be monitored through a central line or Swan-Ganz catheter. Antibiotics should be
reserved for clinical evidence of pneumonia or bronchitis.
Specific treatments studied include the use of colchicine, hexamethylenetetramine (HMT), and N-
acetylcysteine (NAC). Colchicine may prevent the neutrophil migration across capillaries that contributes to
pulmonary edema. HMT was once considered a specific antidote for acute phosgene exposure, and NAC is
thought to “trap” phosgene and convert it to a less harmful metabolite. There are, however, no good in vivo
studies that demonstrate reduction of morbidity and mortality with the administration of colchicine, HMT, or
NAC.[14][19][47][48]
Disposition
Because of the risk of delayed noncardiogenic pulmonary edema, patients should be monitored and
observed for a minimum of 24 hours after phosgene gas exposure, especially if there are multiple irritant
symptoms or any evidence of instability, including tachycardia, tachypnea, hypotension, hypoxemia,
orthostasis, cyanosis, or pulmonary rales. Infectious pneumonitis may develop as a secondary complication.


NITROGEN DIOXIDE
Essentials
• Sources include ice surfacing machines, agricultural silos, welding, nitrocellulose combustion, and dye
and fertilizer manufacture.
• Acute symptoms include:
• Asphyxiation and bronchospasm (acute)
• Noncardiogenic pulmonary edema (can be delayed)
• Bronchiolitis obliterans can develop subacutely.
Introduction
Nitrogen dioxide is relatively water insoluble and heavier than air, with many properties and clinical sequelae
similar to phosgene. It is a mild irritant with a reddish-brown to copper color. A 1929 fire in a radiology
department with 125 deaths remains the largest catastrophe involving nitrogen dioxide, as well as carbon
monoxide and chlorine.[15] Today the most common sources of indoor nitrogen dioxide are stoves (gas and
wood), pilot lights, fireplaces, heaters (kerosene and gas-fueled), and engines, including Zamboni machines
used to resurface ice skating rinks. Nitrogen dioxide is also an outdoor air pollutant.[26][51] “Silo gas”
develops when green plants are stored in silos for the winter feeding of livestock. During storage, nitrates
present in the plants are oxidized to various nitrogen oxides, with peak levels occurring the first 10 to 14
days of storage. A worker entering a poorly ventilated silo and exposed to these nitrogen oxides may
develop silo filler’s disease.[21] Additional sources include fumes from nitrocellulose (contained in radiology
films), bed mattresses, torch welding, accidents with nitric acid, dye and fertilizer manufacturing, and
detonation of explosives.
Pathophysiology
Nitrogen dioxide causes minimal to mild irritation of the upper airways and passes deep into the lung,
exerting its primary toxicity on the terminal bronchioles and alveoli. Subsequent oxidative damage to the
pulmonary tissues leads to free radical formation. These free radicals cause damage by oxidizing amino
acids present in tissue proteins.[1] In addition, nitrogen dioxide reacts with water to form nitrous and nitric
acids. These acids produce alveolar and endothelial cell damage, leading to noncardiogenic pulmonary
edema. Inflammatory cell exudate may also occur. This exudate, along with regenerating epithelial cells,
intraluminal debris, and fibroblast proliferation, can lead to the development of bronchiolitis obliterans 2 to 6
weeks after the exposure.
Clinical effects depend on the concentration and duration of exposure as well as underlying respiratory
disease. The odor of nitrogen dioxide is detected at 1 to 3 ppm and causes minimal membrane irritation at
13 ppm. Concentrations of 50 to 150 ppm may produce only mild to moderate irritant symptoms, allowing
people to remain in the offending environment for prolonged periods. The lack of severe irritation can prove
fatal because the LD50 of nitrogen dioxide is 174 ppm for 1 hour.
Acute symptoms are due to the irritant and asphyxiant properties of nitrogen dioxide and usually occur after
a latent phase of several hours. These symptoms may persist for 1 to 2 weeks and are listed in Table 83–3 .
Patients may develop hypotension. The etiology of this hypotension may be multifactorial, including a direct
effect of nitrates on blood vessels, loss of intravascular fluid into the pulmonary parenchyma, metabolic
acidosis, and methemoglobinemia. Symptoms may resolve after the irritant symptoms with no subsequent
sequelae for some patients.
Table 83-3 -- Clinical Presentation of Nitrogen Dioxide Exposure

Acute Phase
Mucosal irritation (including eyes), conjunctivitis, nausea, vomiting, headache, sore throat, dyspnea, cough, and
wheezing
Vertigo, pleuritic chest pain, tachycardia, and diaphoresis
Hypoxemia, methemoglobinemia, metabolic acidosis
Delayed Phase (3 to 36 Hours)
Fever, tachypnea, dyspnea, rales, cyanosis, tachycardia, hypotension
Hypoxemia, perihilar infiltrates/pulmonary edema via chest radiograph
Subacute Phase (2 to 6 Weeks)
Fever, chills, cough, chest tightness, dyspnea, rales, wheezes, hypotension, confusion
Hypoxemia
Other patients progress to a delayed phase usually within 3 to 36 hours but reportedly as late as 10 days.[24]
One study demonstrated development of the delayed phase in 5 of 23 subjects; some progressed to this
phase after minimal initial symptoms. [30] Symptoms of the second phase (see Table 83–3 ) are due to
noncardiogenic pulmonary edema with both restrictive and obstructive ventilatory defects. Infectious or
chemical pneumonitis can develop during or after this phase. Patients may subsequently become
asymptomatic or, after a 2- to 6-week asymptomatic period with clearing of the chest radiograph, progress to
phase three. This subacute phase is characterized by bronchitis, bronchiolitis, or bronchiolitis obliterans and
can be fatal. The risk of developing bronchiolitis obliterans correlates with the presence of the delayed-
phase symptoms. If no delayed phase develops, the patient is unlikely to progress to the subacute phase.
The differential diagnosis of nitrogen dioxide exposure is given in Table 83–4 .

Table 83-4 -- Differential Diagnosis of Nitrogen Dioxide Exposure
Allergic lung disease secondary to molds (e.g., farmer’s lung)
Exposure to other noxious gases (e.g., phosgene)
Asthma
Pneumonia
Postinfectious bronchiolitis
Bronchiectasis
Miliary tuberculosis
Viral influenza
Laboratory Studies
There are no specific diagnostic tests for nitrogen dioxide. Assessment of respiratory function in
symptomatic patients can include pulse oximetry, arterial blood gas analysis with a methemoglobin level if
methemoglobinemia is suspected, and a chest radiograph. In addition, one should assess and follow
pulmonary functions. Expected results are noted in Table 83–3 .
Treatment
Treatment should focus on decontamination and pulmonary supportive care as needed. The patient should
be removed from the exposed environment and stripped of all clothing with thorough irrigation of exposed
eyes and skin.
Oxygen should be administered and noncardiogenic pulmonary edema managed as with phosgene gas
exposure.
Bronchodilators and glucocorticosteroids are useful treatments for bronchospasm. High-dose oral
corticosteroids (40–80 mg/d), over 8 weeks, are useful in the treatment of ongoing symptoms, as well as in
the prevention of delayed and subacute phases of nitrogen dioxide toxicity.[30][60] They are also indicated for
bronchiolitis obliterans.
Because of the high risk for infection, sputum cultures should be obtained with antibiotics initiated to cover
community-acquired organisms at the first sign of infection.
Severe acid-base abnormalities should be treated. If significant methemoglobinemia develops, methylene

blue is administered intravenously at a dose of 1 to 2 mg/kg.[43] Hypotension should be carefully treated with
intravenous crystalloids because of intrapulmonary fluid accumulation.
Disposition
Because of the risk of delayed noncardiogenic pulmonary edema, even asymptomatic patients with a normal
chest radiograph should be admitted for close observation for a minimum of 48 to 72 hours.[43][54] Patients
should be monitored as outpatients for 2 to 3 months because of the risk of progression to the subacute
phase.[43][54]


ISOCYANATES
Essentials
• The most common site of exposure is in the workplace. These agents are also produced from
combustion of insulation and household furnishings.
• There is acute irritation of the eyes, nose, throat, respiratory tract, and gastrointestinal system.
• Exposure to these substances is a common cause of occupational asthma.
Introduction
The isocyanates are used primarily in the production of fibers, building insulation, household upholstery,
polyurethane coatings, and elastomers. In addition, they are increasingly used for automobile replacement
materials. Exposures result from combustion or vaporization of any of the previously mentioned products,
with most cases occurring in the working environment. Toluene diisocyanate is the most frequently occurring
isocyanate; however, methyl isocyanate is the most notorious and was responsible for over 2000 deaths in
the Bhopal, India, tragedy of 1984.[16]
Pathophysiology
The isocyanates are highly reactive chemical compounds because they all contain an N=C=O group that
readily reacts with hydrogen ions to form urethanes.
Isocyanates are strong mucous membrane irritants and potent pulmonary sensitizers that can readily induce
reactive airway disease in up to 5 per cent of exposed individuals.[24] Isocyanates are thought to induce
bronchospasm by both nonspecific and direct pharmacologic means.[4] Toluene diisocyanate has been
shown to interfere with cholinergic and adrenergic mechanisms of the bronchial mucosa.[57]
Toluene diisocyanate produces a detectable odor at 0.02 to 0.005 ppm. Irritant symptoms occur at levels of
0.005 to 0.1 ppm. Sensitized individuals will develop bronchospastic symptoms at levels as low as 0.02
ppm.[8]
Exposure to isocyanates acutely produces mucous membrane irritation of the eyes, nose, throat, and
gastrointestinal tract. Patients also may present with neurologic complaints, including headache, insomnia,
euphoria, ataxia, anxiety, depression, and paranoia. These symptoms may persist for several weeks.
Respiratory symptoms may result in occupational asthma or chronic obstructive pulmonary disease. There is
not yet an established way to predict who will go on to develop these disease states. Delayed
noncardiogenic pulmonary edema and adult respiratory distress syndrome (ARDS) have also been reported.
Permanent personality changes, memory deficits, irritability, and depression have been reported after
exposure to high doses of toluene diisocyanate ( Table 83–5 ).[38]
Table 83-5 -- Clinical Presentation of Isocyanate Exposure

Acute Irritant Effects
Eyes: conjunctivitis, lacrimation, photophobia, corneal damage, and lid edema
Gastrointestinal: nausea, vomiting, and abdominal pain
Respiratory: cough ± sputum, burning chest pain, dyspnea, wheeze, and choking sensation
Neurologic: headache, insomnia, euphoria, ataxia, anxiety, depression, and paranoia
Delayed/Chronic Effects
Neurologic sequelae including memory deficits, irritability, personality changes, and depression
The differential diagnosis of isocyanate exposure is presented in Table 83–6 .
Table 83-6 -- Differential Diagnosis of Isocyanate Exposure

Noxious inhalational exposures, including phosgene, nitrogen oxides, chlorine, ammonia, sulfur dioxide,
sodium hydroxide, acids (glacial acetic, sulfuric, hydrochloric), ozone, smoke inhalation
Asthma (including occupational)
Reactive airway dysfunction syndrome
Laboratory Studies
There are no specific diagnostic tests for isocyanate exposure. Pulse oximetry, arterial blood gas analysis,
and chest radiograph may be appropriate.
Residual effects should be monitored with pulmonary function tests, looking for an obstructive pattern
consistent with asthma. Spirometry before and after work can indicate if occupational asthma is involved,
which is possible with ongoing isocyanate gas exposure.
Treatment
Initial treatment should be centered around decontamination and pulmonary supportive care, including
removal from the offending environment. Humidified supplemental oxygen with assisted ventilation should
be administered as needed. Initial and delayed bronchospasm should respond to inhaled bronchodilators
and/or corticosteroids as needed. Management of pulmonary edema should follow the same guidelines
discussed earlier under phosgene exposure.
The eyes should be copiously irrigated if the patient is symptomatic. In the presence of a corneal abrasion,
mydriatics, topical antibiotics, and analgesics should be used.
Disposition
Patients who develop asthma can be managed as outpatients with standard asthma medication. If there is
an occupational association, the worker should be transferred from the source of exposure. All patients who
develop asthma should be followed regularly with serial pulmonary function monitoring and bronchial
reactivity testing.[9]
Patients with neurologic sequelae should be followed with serial neuropsychiatric testing.


ZINC CHLORIDE
Essentials
• Individuals at risk include military personnel, rubber and textile workers, dental cement workers, and
embalmers.
• Initial symptoms are caused by irritant effects on the respiratory tract, skin, eyes, and mucous
membranes.
• Delayed effects include ARDS, pulmonary fibrosis, bronchiolitis obliterans, and hyperactive airway
disease.
Introduction
Zinc chloride is a corrosive heavy metal salt. It is the most toxic form of zinc, and fatalities have been
reported from inhalation of fumes. It is produced by the combustion of soldering flux, dry battery cells, oil
refining, dentist’s cement, and various objects used in taxidermy. This places rubber and textile workers,
dental cement workers, and embalmers at risk for exposure. Zinc chloride is the primary component of
fumes emitted from smoke ammunition bombs (hexite) and has caused serious pulmonary injury among
soldiers exposed to these bombs. [28]
Pathophysiology
Because of the immediate formation of hydrochloric acid and zinc oxychloride, zinc chloride is caustic and
burns the skin, eyes, and mucous membranes on contact. In addition, zinc chloride particles measuring 0.1
µm are deposited along the transbronchial tree as far as the respiratory bronchioles.[6][44] Subsequently,
laryngeal, tracheal, and bronchial mucosal edema and ulceration may occur, resulting in pneumonitis. Zinc
chloride fumes also injure the lower airways, leading to increased permeability of the alveolocapillary
membrane. This initially results in interstitial and alveolar edema, which may be followed by fibrosis of the
interstitium, alveolar obliteration (bronchiolitis obliterans), beginning 3 to 4 days after initial exposure, and,
finally, subpleural emphysematous blebs.[40] Inflammation and fibrosis of the pulmonary parenchyma can
lead to fatal and nonfatal ARDS. Proliferation of fibroblasts may also cause vaso-occlusion of pulmonary
vasculature, which contributes to the development of acute pulmonary hypertension. The delayed effects are
thought to be from persistent high plasma levels of the zinc salt. [29] Exposure has been found to cause
“asthma” and “alveolitis-like” interstitial lung disease, which may also progress to fibrosis.[49][58]
If exposure occurs in open spaces where particles may deliquesce in a humid atmosphere, zinc chloride can
be harmless. The only serious or fatal injuries reported have been due to inhalation of hexite smoke in an
enclosed space.[29]
On inhalation of zinc chloride, its caustic properties will cause immediate cough and dyspnea. Those who
are exposed to moderate doses complain of dyspnea, retrosternal chest pain, stridor, rhinitis, and
lacrimation. Many present with copious sputum production and some with hemoptysis. An early and
persistent rise in core temperature often results from the release of cytokines from inflammatory cells.[29]
Delayed-onset symptoms are of particular concern with exposure to zinc chloride. In cases of mild toxicity,
initial symptoms of upper airway irritation may be followed by dyspnea during exercise ( Table 83–7 ).
Table 83-7 -- Clinical Presentation of Zinc Chloride Exposure

Acute Effects
Lacrimation and rhinitis
Stridor
Cough ± sputum, dyspnea, hemoptysis, and retrosternal chest pain
Chemical pneumonitis
Metal fume fever
Delayed/Chronic Effects
Noncardiogenic pulmonary edema, pulmonary fibrosis, bronchiolitis obliterans
Cor pulmonale and right ventricular hypertrophy
A number of disorders should be considered in the differential diagnosis of zinc chloride exposure ( Table
83–8 ).
Table 83-8 -- Differential Diagnosis of Zinc Chloride Exposure

Exposure to other noxious gases
Allergic lung disease of other causes
Asthma
Pneumonia (viral or bacterial)
Miliary tuberculosis
Adult respiratory distress syndrome, other causes
Laboratory Studies
There are no specific tests for zinc chloride, but pulmonary status should be evaluated as appropriate.
Appropriate tests may include a chest radiograph, pulse oximetry, and arterial blood gas analysis. Long-term
effects should be monitored with pulmonary function testing.
Plasma and urinary zinc levels can be obtained and followed in all symptomatic patients.
Treatment
Initial treatment includes removal from the offending environment and removal of the patient’s clothes.
Exposed skin, eyes, or mucous membranes should be irrigated.
Oxygen is given as necessary, and pulmonary edema is managed as in phosgene gas exposure. Special
attention is required for patients who develop pulmonary infiltrates after the initial upper airway symptoms,
because they are at risk for the development of infections from community-acquired organisms as well as
ARDS.
Any patient who develops pulmonary infiltrates should be followed with serial plasma zinc levels.
Nonsteroidal anti-inflammatory drugs will increase urinary excretion of zinc in the first week of therapy.
However, use beyond this time frame produces a decrease in zinc excretion.[17] For those patients in whom
massive exposure is suspected, N-acetylcysteine may be administered early either in nebulized or
intravenous form (see Chapter 29 for a discussion of intravenous N-acetylcysteine). However, this treatment
continues to be experimental.[28] It functions as a free radical scavenger. Treatment with an antifibrotic agent
such as L-3,4-dehydroproline (DHP) may retard the increase of collagen production, although its efficacy is
unproven.[28]
Disposition
Patients exposed to a large amount of zinc chloride gas should be admitted and observed for the
development of pulmonary edema and ARDS. Those individuals experiencing minimal irritant symptoms
after a known or suspected low level exposure can be discharged home. However, they should be followed
as outpatients because of the risk of developing asthma.
Sequelae
In the case of serious injury with progression to ARDS, there may be advanced pulmonary fibrosis,
increased pulmonary vascular resistance, acute cor pulmonale, and right ventricular hypertrophy.[29][40]
After chronic exposure to zinc chloride, occupational asthma may result. Documented cases have shown
work-related decreases in lung performance and prolonged bronchial hyperresponsiveness after removal
from the environment. The deterioration in pulmonary function has been attributed to an allergic or
hypersensitivity-mediated reaction rather than an irritant mechanism.[58] Pulmonary function tests
demonstrate an obstructive picture with decreased FEV1 and vital capacity consistent with asthma.


ARSINE
Essentials
• Exposures occur predominantly in the microelectronics industry, but also with metal refining, soldering,
and galvanizing.
• Latent period between exposure and symptoms may last 1 to 24 hours.
• Hemolysis and acute renal failure may be present on initial presentation.
• Other effects include cardiac conduction disturbances and neurologic damage.
Introduction
Arsine, also known as arsenous hydride (AsH3), is a colorless gas with a slight garlic odor that is
nonirritating to mucosal tissue. It is produced when metals containing arsenic react with acid. First identified
in 1775, it is the most toxic form of arsenic. Lewisite is an arsine derivative that has been used as a poison in
gaseous warfare. Today it continues to pose serious industrial and community hazards.
Metal refining, galvanizing, and soldering have been implicated as sources of arsine emission and
poisoning, but the use of arsine is greatest and most vital in the microelectronics industry. Semiconductors
are processed in the manufacture of computer chips, requiring etching of gallium arsenide with acids. Arsine
gas is transported in metal cylinders by truck or railroad. One cylinder spilled in a microelectric plant would
deliver a lethal dose to all workers. The loss of a cylinder in transport could result in hundreds of fatalities in
the community.[24]
Pathophysiology
Arsine inhalation produces a hemolytic anemia that is unique and fulminant. The mechanism of red blood
cell toxicity is speculative. Current proposals suggest arsine induces oxidative damage and red cell lysis with
evidence of Heinz bodies, elevated methemoglobin, and decreased levels of glutathione. Arsine’s affinity for
sulfhydryl groups disrupts red cell integrity by depleting glutathione levels, causing protein denaturation. In
addition, arsine exerts oxidative stress on ferrous heme, resulting in red cell lysis.[5] Osmotic hemolysis
ensues, with a resultant characteristic peripheral smear containing fragmented and ghost cells. Patients
have normal serum iron values and normal bone marrow morphology without significant alteration[5] in
platelets or white blood cells.[36]
Nephrotoxicity also occurs. Massive hemolysis releases hemoglobin, which may precipitate in the form of
As-hemoglobin complexes in nephrons. Further impairment results from a decrease in renal perfusion that is
inversely proportional to the degree of hemolysis.[45] In addition, arsine may be directly toxic to renal
tissues.[31][42] Untreated arsine poisoning exerts continuous damage to renal tissue manifested by a
prolonged anuric period (>20 days) and irreversible damage to tubular cells.
Cardiac effects may present as conduction disturbances most likely related to hyperkalemia produced by
persistent and massive hemolysis. Pulmonary edema may arise as a potentially fatal complication of cardiac
insufficiency. Arsine may also exert direct toxicity on myocardial tissue, accounting for cases of cardiac
failure of greater severity than would be expected from the degree of hemolysis.[3]
Immune function may be affected. In a dose-dependent manner, arsine decreases T-killer and natural killer
cell function without altering host response to viral and tumor challenges. [24]
Arsine may also damage the central and peripheral nervous systems by an unknown mechanism.
Teratogenicity has been a concern, given the known effects of arsenic, but no developmental toxicity
occurred in pregnant rats and mice exposed to arsine at hematopoietically toxic concentrations.[41]
Exposure to arsine in concentrations of 5 to 9 ppm for 1 hour will produce significant decreases in
hematocrit in animal models.[46] Concentrations of 3 to 10 ppm for several hours have produced minimal
symptoms, whereas exposure to 16 to 300 ppm for 30 to 60 minutes is extremely dangerous.[10] The current
threshold limit value for arsine is an 8-hour time-weighted average of 0.05 ppm.
Acute Toxicity
Toxic arsine exposure classically presents as abdominal pain, hemolysis, and renal failure after a latent
period lasting from 1 to 24 hours. Initial constitutional symptoms include malaise, headache, chills,
dizziness, and weakness. Nausea and vomiting may accompany abdominal pain. Hematuria may present as
complaints of dark red urine 4 to 6 hours after inhalation. Jaundice secondary to hemolysis appears 24 to 48
hours after exposure and is often associated with hepatosplenomegaly. A decreasing urinary output signals
early acute renal failure, and patients may develop oliguria or anuria before the third day after arsine
exposure.
Physical examination often reveals fever, tachycardia, tachypnea, jaundice, sweat with garlic odor, keratosis,
hair loss, coryza, abdominal tenderness, abdominal rigidity, and hepatosplenomegaly. Mees’ lines, which
are transverse white striae of the fingernails, may appear 2 to 3 weeks after exposure.
Because arsine is a pancytotoxin with demonstrable effects on every mammalian organ, delayed
complications can vary. Central nervous system effects depend on exposure dosage and duration. In
addition to headache, confusion, and lethargy, individuals may present acutely with agitation, disorientation,
and hallucinations, which may persist after the recovery of other organ systems. Peripheral neuropathy
typically presents as a delayed-onset complication with focal anesthesia or paresthesias of extremities.
Patients may also develop symptoms consistent with cardiac dysrhythmias or myocardial failure.
Chronic Toxicity
Chronic exposure to arsine produces a dose-dependent anemia and other signs and symptoms, including
headache, nausea, vomiting, perforated nasal septum, hoarseness, dyspnea, icterus, and paresthesias of
the extremities. No renal damage occurs with chronic exposure ( Table 83–9 ).
Table 83-9 -- Clinical Presentation of Arsine Gas Exposure

Acute (Latent Period 1–24 Hours)
Fever, malaise, headache, dizziness, weakness, hair loss, sweat with garlic odor, abdominal pain with or
without nausea and vomiting, and paresthesias or numbness
Intravascular hemolysis
Hematuria, oliguria, or anuria associated with acute renal failure
Delayed
Jaundice (24 to 48 hr) associated with hepatosplenomegaly
Oliguria or anuria
Cardiac failure with or without pulmonary edema
Mees’ lines (2 to 3 wk)
Table 83–10 lists those disorders that should be considered when diagnosing arsine exposure.
Table 83-10 -- Differential Diagnosis of Arsine Exposure

Acute renal failure of other causes
Hemolytic anemia of other causes
Thrombotic thrombocytopenic purpura
Viral syndrome
Peripheral neuropathy
Liver or biliary disease
Laboratory Studies
A complete blood cell count with peripheral smear should be obtained. The hemolytic anemia of acute arsine
toxicity can produce hemoglobin values below 10 6 g/dL, low red blood cell counts (<1 × 10/mL), and
methemoglobinemia. White blood cell and platelet counts should be within normal range. The peripheral
smear is remarkable for ghost cells (circular red cell membranes with an area of central clearing), basophilic
stippling, fragments, anisocytosis, and poikilocytosis. Neither a Coombs’ test nor bone marrow aspirate is
routinely warranted, but both may help confirm the diagnosis. The hemolytic anemia is Coombs’ test
negative, and bone marrow examination demonstrates a hyperplastic response of erythroid precursors.
Serum total bilirubin may be elevated with an elevated indirect (unconjugated) fraction because of
hemolysis.
The urine can appear pink to red secondary to free hemoglobin, red blood cells, and sometimes tubular
casts containing erythrocytes and hemoglobin. Albuminuria may also be present. Serum chemistries may
reveal elevated blood urea nitrogen and creatinine levels, with either a prerenal or renal ratio. The serum
potassium level is usually elevated because of hemolysis and decreasing renal function, and the lactate
dehydrogenase value may be mildly increased.
Electrocardiographic findings can include high peaked T waves, nonspecific ST-T wave changes, and
various degrees of heart block and asystole. If any abnormality is present or cardiac toxicity is suspected, a
chest radiograph should be obtained to evaluate for pulmonary edema.
Individuals chronically exposed to arsine gas may demonstrate a mild elevation in serum total bilirubin, low
hemoglobin value with reticulocytosis, and an appreciable quantity of urinary arsenic.
Treatment
Treatment includes initial decontamination with removal from the environment as well as removal of clothing.
In addition, copious irrigation of the skin with warm tepid water or saline should be performed. Stabilization
should occur simultaneously with airway management, oxygen administration, intravenous crystalloids, and
cardiac monitoring.
The goal of further intervention should be to stop the ongoing hemolysis and restore or compensate for lost
renal function. When free hemoglobin levels exceed 1.5 g/dL and exposure to high levels of arsine is
suspected, exchange transfusion may be indicated. This is the only therapy that will remove the arsine-
reticulocyte complexes. Hemodialysis will treat acute renal failure. Supportive care should include monitoring
of potassium levels and urine output. Life-threatening hyperkalemia can be treated with intravenous calcium,
sodium bicarbonate, insulin, and glucose, and with oral or rectal sodium polystyrene sulfonate. Urine flow of
at least 2 mL/hr/kg should be maintained in patients with evidence of hemolysis. Acidic urine is alkalinized
with sodium bicarbonate.
Chelation therapy does not prevent or reduce hemolysis, and current data do not indicate a beneficial effect
of dimercaprol (British Anti-Lewisite [BAL] compound) in improving long-term sequelae of arsine poisoning.
Therefore, BAL should not be used.
Disposition
Because of the risk of developing hemolysis and acute renal failure, patients who are significantly exposed
to arsine gas should be admitted for observation and supportive care for a minimum of 24 to 48 hours.
These individuals should also be monitored for possible long-term sequelae of arsine toxicity.


ACROLEIN
Essentials
• This gas is produced from combustion of resins, herbicides, perfumes, plastics, textiles, and sewage
treatment products.
• Acute irritant effects to the eyes, respiratory tract, and skin usually limit exposure.
• Delayed effects include noncardiogenic pulmonary edema, pneumonitis, bronchitis, and bronchiectasis.
Introduction
Acrolein is a volatile, insoluble, unsaturated aldehyde gas that is highly irritating to the upper airways and
eyes. It is the most toxic among the aliphatic aldehydes and was used during World War I as a poison
contained in hand grenades. Acrolein is produced by the combustion of cotton, wood, and lipids and is a
ubiquitous air pollutant generated in house fires, cigarette smoke, automotive emissions, and burning of
vegetable oil. Commercially, acrolein is used in the manufacture of pharmaceuticals, resins, food
supplements, herbicides, perfumes, plastics, sewage treatment, and textiles and as a consumer odor-
warning signal in methylene refrigerators.
Pathophysiology
Acrolein directly irritates mucosal membranes of the conjunctiva, nasal passages, and upper airways. It
binds sulfhydryl groups and impairs enzyme function and depletes glutathione. In the nasal turbinates,
acrolein induces exfoliation, erosion, necrosis, and metaplasia of the squamous epithelium. Acrolein impairs
ciliary function in upper airway mucosa, which may allow bacterial invasion and a pneumonitis 3 to 5 days
after exposure.
In the lower respiratory tract, acrolein activates c-fibers and irritant receptors and induces
bronchoconstriction.[37] Acrolein also impairs a1-proteinase inhibitor, which may be a possible mechanism
for postexposure emphysematous lesions.[18] Fibrin deposits in alveoli and congestion of bronchial vessels
marks the development of widespread pulmonary edema, which may be delayed 2 to 4 hours after low-dose
inhalation. Individual case reports of acrolein toxicity have documented obstruction of bronchioles secondary
to massive cellular desquamation of the mucosa and development of diffuse bronchiectasis up to 9 months
after inhalation.[25][39]
The odor of acrolein gas is pungent, acrid, and detectable at concentrations below 0.16 ppm. The irritation
threshold in humans ranges from 0.25 to 0.5 ppm. The threshold limit value of 0.1 ppm is sufficient to
minimize but not to prevent local irritant effects. Thus, exposure to dangerous quantities is usually avoided in
industrial settings owing to the irritant effect. However, there are documented cases of toxic inhalation
occurring in very young children from domestic accidents.[20][39]
Acrolein vapor may produce burning sensation of the eyes, photosensitivity, and mild to profuse lacrimation
depending on the concentration and duration of exposure. Itching and irritation of exposed skin has also
been reported. A burning sensation of the nose and throat is often noted before the onset of cough and
dyspnea. Acute tracheobronchitis characterized by cough, sore throat, chest pain, and lightheadedness can
occur. Nausea, vomiting, diarrhea, and altered consciousness may be present. Symptoms may progress to
respiratory distress and failure with tachypnea, cyanosis, and chest pain.
Delayed-onset pulmonary complications are rare but likely to follow inhalation of high concentrations of
acrolein. Noncardiogenic pulmonary edema can occur within a few hours, and chemical pneumonitis may
develop 3 to 5 days after inhalation. Bronchitis, tracheobronchitis, and bronchiectasis have also been
reported as late as 9 months after exposure to high concentrations of acrolein ( Table 83–11 ).[2]
Table 83-11 -- Clinical Presentation of Acrolein Exposure

Acute Phase
Eyes: burning sensation, photosensitivity, lacrimation
Skin: irritation, pruritus
Respiratory: burning sensation of nose or throat, cough, dyspnea, chest pain
Gastrointestinal: nausea, vomiting, diarrhea
Neurologic: lightheadedness, altered mental status
Delayed Phase
Pulmonary edema (few hours)
Chemical pneumonitis (3 to 5 days)
Bronchitis, tracheobronchitis, bronchiectasis (up to 9 months later)
The differential diagnosis of acrolein exposure is provided in Table 83–12 .
Table 83-12 -- Differential Diagnosis of Acrolein Exposure

Noxious gas stimuli
Upper respiratory tract infection
Pneumonia
Bronchiectasis of other causes
.
Laboratory Studies
There are no specific tests for acrolein exposure. Pulse oximetry and arterial blood gas analysis may reveal
hypoxemia and respiratory acidosis. Chest radiography may demonstrate pulmonary edema within 2 to 6
hours after exposure or pneumonitis up to 5 days later.
Treatment
Initial treatment consists of decontamination and pulmonary support similar to that discussed for phosgene.
Glucocorticosteroids, such as oral prednisone in a quick tapering dose, should be administered as well as
analgesics, as needed for relief of symptoms.[2] Even if respiratory distress is not present on initial
examination, subsequent treatment with glucocorticosteroids is recommended. Vasoconstrictive
ophthalmologic preparations may be used to relieve conjunctival irritation.
Disposition
Patients suspected of having high-dose exposure should be observed in hospital for 24 hours for delayed
pulmonary edema and managed as just discussed. Patients who have suffered a low-dose exposure can be
discharged home with strict instructions to return if they develop any symptoms consistent with pulmonary
edema or pneumonitis.


ETHYLENE OXIDE
Essentials
• The most common industrial source is the commercial sterilization of medical supplies.
• Household exposure sources include antifreeze and detergents.
• Acute effects include irritant symptoms and neurologic sequelae.
• Delayed effects include asthma, pulmonary edema, adverse outcomes of pregnancy, and
carcinogenesis.
Introduction
Ethylene oxide is widely used for the production of ethylene glycol, nonionic surfactants, ethanolamines, and
glycol ethers. It is a principal intermediate in the manufacture of polyester resins, automotive antifreeze, and
household and industrial detergents. Ethylene oxide has been used as a fumigant and insecticide for food,
clothing, and bedding. Approximately 270,000 workers in the United States are exposed to ethylene oxide
regularly, with the highest exposure rate found among hospital workers and personnel who sterilize heat-
sensitive medical and scientific supplies and pharmaceuticals.[56]
Pathophysiology
Ethylene oxide is a highly reactive epoxide and cytotoxic alkylating agent. It reacts directly and irreversibly
with sulfhydryl, amino, carboxyl, and hydroxyl groups of proteins and with nucleic acids. Chromosomal
aberrations and sister chromatid exchanges have been described in lymphocytes of exposed
individuals.[7][16] Multiple studies have reported an increased incidence of lymphatic and hematopoietic
cancer, including lymphatic leukemia and non-Hodgkin’s lymphoma among sterilant workers and chemical
manufacturers exposed to ethylene oxide.[32][55][56]
Adverse pregnancy outcome may be associated with ethylene oxide exposure. One study reported an
increased rate of spontaneous abortion among pregnant hospital sterilization workers.[27] Degeneration of
Sertoli cells, deformation of germ cells, and tubule atrophy in testicular biopsy samples have been found in
male rodents experimentally exposed to ethylene oxide.[34] However, these changes have not been found in
humans.
In addition to the mutagenic, teratogenic, and potential carcinogenic effects, adverse effects occur acutely in
lungs and neuromuscular units. Ethylene oxide is directly cytotoxic to pulmonary epithelial cells. [53] This
destruction is accompanied by subepithelial fibrosis with minimal inflammation potentially resulting in
pulmonary fibrosis. Biopsy of skeletal muscle in animal models reveals atrophy and fatty infiltration. In
humans, various neurologic sequelae have been described.[22]
Ethylene oxide–induced IgE antibodies have been documented in sensitized dialysis patients using sterilized
dialyzers and may induce degranulation of basophils.[50] This sensitization reaction is thought to modulate
the allergic and anaphylactoid sequelae that occasionally arise.
The Occupational Safety and Health Administration has set the 8-hour time-weighted standard of exposure
at 50 ppm. However, the threshold odor level of ethylene oxide, 700 ppm, far exceeds the level for
inhalational toxicity. Thus, routine proper monitoring in the workplace is essential to avoid exposure to toxic
doses of ethylene oxide.
Ethylene oxide at a level of 200 ppm irritates the skin and mucous membranes of the upper airway. Skin
lesions typically develop several hours after exposure and may resemble scalded skin with bullous lesions,
erythema, edema, and vesicles. Contact dermatitis due to sensitization has also been described as a result
of repeated exposure to dressings containing ethylene oxide residue.[33]
Ethylene oxide may also induce conjunctivitis and lens opacification. Anterior and posterior subcapsular
bilateral cataracts have been described in operators of medical sterilizers. Lens opacity, increased corneal
thickness, and decreased visual acuity have been associated with both massive and chronic exposures to
low concentrations of ethylene oxide. [11]
Respiratory tract irritation and neurologic impairment present acutely after brief exposure to levels greater
than 1000 ppm. Irritant symptoms include hoarseness, cough, chest pain, dyspnea, and wheeze. A profound
central nervous system depressant effect similar to that of ethanol can occur. Headache, nausea with
recurrent vomiting, disorientation, decreased consciousness, dysarthria, loss of coordination, muscular
weakness, sleeplessness, and seizures may occur after acute exposure. A sensory and motor
polyneuropathy has been documented in case reports of exposed workers.[22] Neurologic sequelae from
ethylene oxide toxicity usually resolve completely within hours after exposure ( Table 83–13 ).
Table 83-13 -- Clinical Presentation of Ethylene Oxide Exposure

Acute
Eyes: conjunctivitis
Respiratory: hoarseness, cough, chest pain, dyspnea, wheeze
Anaphylactic reaction
Neurologic: headache, nausea, vomiting, disorientation, decreased level of consciousness, dysarthria, loss of
coordination, seizures. Sensory and motor polyneuropathy (transient).
Delayed
Carcinogenesis
Spontaneous abortion
Scalded skin with bullous lesions, erythema, edema, and vesicles
Cataracts
Asthma
Table 83–14 lists those disorders that should be considered in the differential diagnosis of ethylene oxide
exposure.
Table 83-14 -- Differential Diagnosis of Ethylene Oxide Gas Exposure

Noxious gas exposure
Anaphylaxis, other etiologies
Alcohol/sedative-hypnotic drugs
Neuropathies of other etiologies
Asthma
Contact dermatitis/allergic skin reaction
Laboratory Studies
There are no specific laboratory tests for ethylene oxide exposure. If pulmonary toxicity is suspected,
laboratory workup and monitoring should be performed as with nitrogen dioxide.
After acute exposure, pulmonary function tests often indicate bronchial obstruction and hyperreactivity. In
cases of occupational asthma, a decrease in FVC, FEV1, and FEF27–75 with a normal DLCO, may persist as
late as 1 year after injury.[12] Nerve conduction studies may be abnormal with a decreased amplitude of
muscle action potential, decreased conduction velocity, and data consistent with a degenerative axonal
neuropathy. These tests are not routinely indicated.
Treatment
Initial treatment consists of cessation of exposure, removal of the patient’s clothing, and decontamination of
skin and mucous membranes. Further therapy includes oxygen, maintenance of a secure airway, and
intravenous crystalloids as deemed necessary. Bronchospasm may be treated with an inhaled ß2-adrenergic
agonist and glucocorticosteroids.
Disposition
Patients exposed to ethylene oxide can be discharged if signs of respiratory distress or neurologic toxicity
are not present. These patients should be monitored on a close outpatient basis for reactive airway disease,
potential complications of pregnancy, and possible development of malignancy.
Patients with respiratory distress or neurologic toxicity should be admitted for further treatment until
symptoms resolve.
Sequelae
Delayed-onset effects depend on irritant effects and mutagenic potential. A nonimmunologic asthma may
develop after acute exposure to high concentrations. Symptoms include cough, shortness of breath, and
wheeze, which may persist despite removal from the setting. Other delayed-onset sequelae include
pulmonary edema and cancer of the lymphatic and hematopoietic systems.


TREATMENT
The general treatment strategy is summarized in Table 83–15 . The first priorities are to safeguard rescuers
and prevent worsening of the patient’s condition. As soon as possible, the airway and breathing should be
stabilized. Decontamination, further support, and definitive treatment should follow.
Table 83-15 -- Treatment of Toxicity from Inhalation Gases

I. General Measures
A. Remove patient from exposure
B. Airway management
1. Oxygen
2. Endotracheal intubation for respiratory insufficiency or airway protection
3. Bronchospasm
a. Inhaled ß2-adrenergic agonists
b. Glucocorticosteroids (intravenous or oral)
4. Noncardiogenic pulmonary edema
a. Continuous positive airway pressure or bilateral positive airway pressure (not intubated)
b. Positive end-expiratory pressure (intubated)
c. Meticulous intravenous crystalloid administration
d. Antibiotics only for infection
II. Decontamination
A. Dermal
1. Remove clothing
2. Wash skin with copious soap and water
B. Ocular
1. Irrigation with normal saline
III. Specific Therapies
A. Nitrogen dioxide
1. Treat methemoglobinemia with 0.1 to 0.2 mL/kg (1–2 mg/kg) of 1% methylene blue IV
B. Isocyanates
1. Treat corneal abrasions with mydriatics, topical antibiotics, eye patch as needed, analgesics
C. Zinc chloride
1. Nonsteroidal anti-inflammatory drugs to increase zinc elimination (week 1 only)
2. N-Acetylcysteine inhaled or intravenous (experimental) *
D. Arsine
1. Treat hemolysis
a. Intravenous crystalloids to maintain urine output at a rate of 1 to 2 mL/kg/hr
b. Intravenous sodium bicarbonate to alkalinize acidic urine
c. Packed red blood cells as needed
d. Exchange transfusion
e. Treat hyperkalemia as needed with intravenous calcium, sodium bicarbonate, insulin and dextrose, sodium
polystyrene sulfonate
f. Hemodialysis for acute renal failure
* See Chapter 29 for a discussion of intravenous N-acetylcysteine.


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11. Deschamps D, Leport M, Laurent AM, et al: Toxicity of ethylene oxide on the lens and on leukocytes: An
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12. Deschamps D, Rosenberg N, Soler P, et al: Persistent asthma after accidental exposure to ethylene
oxide. Br J Ind Med 1992; 49:523-525.
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14. Diller WF: The methenamine misunderstanding in the therapy of phosgene poisoning. Arch
Toxicol 1980; 46:199-206.
15. Easton WH: Smoke and fire gases. Ind Med 1942; 11:466-468.
16. Eckert WG: Mass deaths by gas or chemical poisoning: A historical perspective. Am J Forensic Med
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17. Elling H, Kiilerich S, Sabro J, et al: Influence of a non-steroid antirheumatic drug on serum and urinary
zinc in healthy volunteers. Scand J Rheumatol 1980; 9:161.
18. Gan JC, Ansari GA: Plausible mechanism of inactivation of plasma alpha 1-proteinase inhibitor by
acrolein. Cancer Res 1988; 55:419-422.
19. Ghio AJ, Kennedy TP, Hatch GE, et al: Reduction of neutrophil influx diminishes lung injury and
mortality following phosgene inhalation. J Appl Physiol 1991; 71:657-665.
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21. Grayson RR: Silage gas poisoning: Nitrogen dioxide pneumonia, a new disease in agricultural workers.
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23. Guo Y-L, Kennedy TP, Michael JR, et al: Mechanism of phosgene-induced lung toxicity: Role of
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24. Haddad LM, Winchester JF: Clinical Management of Poisoning and Drug Overdose. 2nd ed.
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25. Hales CA, Barkin P, Jung W, et al: Bronchial artery ligation modifies pulmonary edema after exposure to
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26. Hedberg K, Hedberg CW, Iber C, et al: An outbreak of nitrogen dioxide induced respiratory illness
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29. Homma S, Jones R, Qvist J, et al: Pulmonary vascular lesions in the adult respiratory distress syndrome
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32. International Agency for Research on Cancer : Geneva, World Health Organization, 1994.
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electron microscopic studies. Toxicol Pathol 1992; 20:32-43.
35. Kennedy TP, Michael JR, Hoidal JR, et al: Dibutyryl cAMP, aminophylline, and beta-adrenergic agonists
protest against pulmonary edema caused by phosgene. J Appl Physiol 1989; 67:2542-2552.
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response in mice. Fundam Appl Toxicol 1985; 5:499-505.
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50. Rumpf KW, Seubert S, Seubert A, et al: Association of ethylene-oxide–induced IgE antibodies with
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60. Yockey CC, Eden BM, Byrd RB: The McConnell missile accident. JAMA 1980; 244:1221-1223.


Chapter 84 – Lacrimating Agents: Tear Gases and Pepper Spray
LEON M. GUSSOW
Essentials
• Incapacitating blepharospasm, copious tearing, conjunctivitis
• Upper respiratory and oropharyngeal irritation
• Skin pain and burning, erythema, allergic contact dermatitis
• Delayed chemical pneumonitis and pulmonary edema
INTRODUCTION
The use of irritating vapors in warfare goes back to the time of the ancient Greeks, who burned tar, pitch,
and sulfur to produce smoke that caused eye pain and choking when directed at enemies. This technique,
used in the war between the Athenians and the Spartans, was later refined by Leonardo da Vinci and
others.[1][13] The age of modern riot control agents began in 1869, when 1-chloroacetophenone (CN) was
discovered in Germany.[15] A newer agent, o-chlorobenzylidenemalononitrile (CS), was named after the
English chemists Carson and Stoughton, who first manufactured it in the 1950s.
The lacrimating agents commonly used today are readily dispersed and easily decontaminated. Symptoms
usually resolve rapidly when the victim is removed from the source of exposure.


PATHOPHYSIOLOGY
CS and CN are highly reactive alkylating agents that attack sulfhydryl groups on crucial enzymes and
coenzymes.[4] Dogs exposed to small airborne doses of CS develop hypertension and tachycardia, possibly
mediated by a thalamic reflex; those exposed to higher doses recover from the initial reaction and then
develop respiratory distress and die 48 to 70 hours later.[4] Pathologic examination of the lungs of these
animals reveals pulmonary edema, hemorrhage, and atelectasis. This suggests a decrease in lung
surfactant activity.[4] Although lacrimators cause tissue injury by inhibiting specific enzymes, pain and
irritation of skin and eyes can occur in the absence of detectable tissue injury. These symptoms may be
mediated by increased generation of bradykinin. CS has been shown to increase conversion of
bradykininogen to bradykinin in the dog.[4]
An autopsy of a 29-year-old man who suddenly developed fatal respiratory compromise 12 hours after
exposure to high-dose CN in an enclosed space showed pulmonary edema and intra-alveolar hemorrhage.
The entire respiratory tract was edematous and covered with frothy pale fluid. Histopathologic examination
revealed diffuse superficial acute necrosis of respiratory mucosa with pseudomembrane formation,
inflammation and desquamation of bronchiolar epithelium, and early bronchopneumonia.[26]
CS is more effective than CN in causing lacrimation and other disabling symptoms, but it is safer and causes
less systemic and ocular toxicity.[13] Corneal injuries caused by lacrimators usually heal rapidly by
regeneration from adjacent epithelial cells. No permanent scarring occurs if structures under the epithelium
are not affected. Injury to deeper layers may result in conjunctival edema, necrosis, and sloughing. An
inflammatory reaction, ulceration, and revascularization may occur, leading to corneal opacification, iritis,
and intraocular hemorrhage.[16] In addition, increased intraocular pressure secondary to exposure may
cause acute glaucoma.[1]
Although each CS molecule contains two cyanide groups, it has been estimated that even if all the CS
absorbed during a 1-minute exposure to 10 mg/m3 was metabolized to cyanide, the amount produced would
be less than that contained in 2 puffs of a cigarette.[30]


Within seconds of exposure, lacrimators typically cause burning eye pain and irritation, uncontrollable
blepharospasm, copious tearing, palpebral edema, and conjunctivitis ( Table 84–1 ).[1] Moving the victim into
fresh air brings immediate relief, which is usually complete within 15 to 30 minutes.[1] Upper respiratory and
oropharyngeal symptoms include nasal irritation, rhinorrhea, sore throat, burning sensation of the tongue,
and increased salivation.[1][13] Lacrimators can exacerbate underlying asthma or bronchitis, producing chest
tightness, dyspnea, and wheezing. Prisoners exposed repeatedly to high doses of CN for prolonged periods
of time developed laryngotracheobronchitis, with wheezing and rhonchi (sometimes delayed), fever, and
purulent sputum. Chest radiographs in these patients were clear.[27]
Table 84-1 -- Clinical Presentation of Exposure to Lacrimating Agents

Sudden onset of tearing, blepharospasm
Nasal and oral mucosal burning
Skin erythema and pain
Other manifestations: tachycardia, transient hypertension, photophobia, headache, nausea, vomiting,
abdominal pain
Rapid improvement after removal from exposure
Exacerbation of reversible airway disease
After inhalation of the lacrimating agents, bronchospasm and laryngospasm may occur after a delay of 24 to
36 hours.[29] Other delayed pulmonary sequelae include pneumonia, pulmonary edema, and chemical
pneumonitis.[1][13][18][29] A 4-month-old boy developed signs of pneumonia 1 day after being exposed to CS
for 2 to 3 hours in an enclosed home; he recovered after prolonged treatment with corticosteroids,
antibiotics, and supplemental oxygen.[18] Chronic reactive airways dysfunction has been reported after
exposure to tear gas. A 21-year-old healthy woman without a history of respiratory problems was exposed to
CS for 5 to 10 minutes. She developed a chronic cough, wheezing, and dyspnea on exertion that were still
present 2 years after exposure, despite treatment with inhaled ß-adrenergic receptor agonists and both
inhaled and systemic corticosteroids.[12]
Lacrimators are also primary skin irritants, producing immediate erythema and discomfort.[20][24] Prolonged
exposure can cause first- and second-degree burns.[27] Mild dermal irritation after tear gas exposure usually
abates rapidly without treatment. More severe primary contact dermatitis may produce persistent pain,
erythema, and desquamation. This may be followed after several days by an allergic hypersensitivity
reaction with a pruritic, vesicular, scaling rash and require treatment with topical corticosteroid ointment.[21]
In studies with CN, removing the agent from the skin within 1 minute of application prevented the
hypersensitivity reaction.[21] Often, symptoms occur on repeat contact with the agent in a victim who had no
reaction to earlier exposures. [9][14][20][24][27]
Other signs and symptoms that can result from exposure to lacrimators include tachycardia and transient
hypertension (which may be significant in patients with cardiac disease), photophobia, headache, abdominal
pain, nausea, and vomiting.[13] In addition, traumatic injury may occur from the explosive discharge of the
agent itself or secondary to crowd panic and mass riot. Despite the dramatic symptoms they produce, in
general these agents have low systemic toxicity and rarely cause long-term morbidity or mortality unless the
victims are exposed to high concentrations in an enclosed space from which they are unable to escape.


SPECIFIC AGENTS
1-Chloroacetophenone (CN)
CN is a lipid-soluble white crystalline powder that is often released by explosive aerosolization.[1][11][17][27] It

is also the active ingredient in the irritant spray mace. CN is a more effective dermal irritant than CS and
more readily produces first- and second-degree burns and vesiculation after exposure. [11][26] The effect of
CN on the skin is more pronounced if the area is moist. CN produces more morbidity and systemic toxicity
than does CS and has been associated with at least six reported deaths.[2][26][27] In addition, CN seems to
be directly toxic to sensory neurons, possibly because its actions on sulfhydryl groups denature important
enzymes associated with sensory activity.[23]
o-Chlorobenzylidenemalononitrile (CS)
Although CS is less toxic systemically than CN and associated with fewer chronic sequelae, it is 10 times as
effective (per equivalent weight) as an ocular and upper respiratory tract irritant. [13] CS has largely replaced
CN in use in the United States and Great Britain. It is a white crystalline solid that is only sparingly soluble in
water.[13][22] The effects of CS are exacerbated in hot humid weather and in subjects who are
hyperventilating.[13][22] High-dose exposure to CS has been associated with heart failure, hepatocellular
damage, and death. [13] Ingestion of CS has caused severe gastroenteritis and perforation of the
gastrointestinal tract.[13] Although each molecule of CS contains two cyanide groups, the amount of cyanide
released after inhalation exposure is negligible.[30] Like CN, CS can cause allergic contact dermatitis.
Dibenz(b.f.)-1,4-oxazepine (CR)
CR, a powerful stimulant of sensory nerve endings in skin and mucosa, is a very effective skin irritant.
Symptoms resolve rapidly once the victim is removed from exposure, but dermal irritation can recur up to 24
hours later if the affected area is washed or moistened. CR does not seem to produce vesiculation.[10]
Mace
Mace (methylchloroform chloroacetophenone) is a mixture of CN (approximately 0.9 per cent) with methyl
chloroform (5 per cent), 1,1,2-trichloro-1,2,2-trifluroethane (Freon 113, 70–80 per cent), and a combination
of various hydrocarbons resembling kerosene (4 per cent).[6][19][21][23] It is used by police and military
organizations and is also found in personal protection spray devices. It causes immediate intense eye pain,
skin discomfort, and respiratory distress; it can also cause second-degree dermal burns. Exposure has been
associated with transient memory loss, confusion, and dysequilibrium, all symptoms consistent with
methylchloroform toxicity.[23]
Capsaicin
Capsaicin (oil of cayenne pepper), a fat-soluble phenol, is the active ingredient in some personal protection
or “anti-mugger” sprays. It activates peripheral sensory nerve endings, an effect mediated by substance
P,[28] and causes pain and burning on contact with skin, followed by desensitization.[3] Inhalation causes
cough in both normal and asthmatic subjects and a transient increase in airway resistance. These changes
resolve within seconds of stopping exposure. [3][8] Recently, two deaths of persons in custody have been
associated with the use of pepper spray by law enforcement officers.[25]


There are a number of chemicals that can cause symptoms of extreme irritation to the mucosa and
respiratory tract, as well as to exposed skin ( Table 84–2 ). These include caustics, especially if they have
direct contact with skin, and gases such as chlorine or phosgene. Hydrogen sulfide at low concentrations
smells like rotten eggs and can be very irritating, but at high concentrations it can cause rapid loss of
consciousness and sudden death. Nitrogen mustard and other chemical warfare agents can also be very
irritating and give delayed symptoms.
Table 84-2 -- Differential Diagnosis of Exposure to Lacrimating Agents

Chemical warfare agents
Nitrogen mustards
Caustic chemicals
Acids
Alkalis
Gases
Chlorine
Chloramine
Ammonia (industrial)
Phosgene
Organophosphates
Hydrogen sulfide
Organophosphates, used in chemical warfare or for agriculture, give similar symptoms of tearing,
bronchorrhea, and increased salivation. Typically, organophosphates will have the feel and odor of a
petroleum product.
Usually, exposure to lacrimating agents will be apparent from the history and situation. Often, victims are
brought in by law enforcement agents or present after a civil disturbance. If exposure was brief, the
symptoms may already be improving spontaneously. Although in individual cases the exact chemical
composition of the lacrimating agent involved is frequently unknown, management is fortunately similar for
all agents.


LABORATORY STUDIES
Victims with persistent or recurrent respiratory symptoms should have a chest radiograph and arterial blood
gas analysis. Because absorbed CS is metabolized to cyanide in peripheral tissues, some authors suggest
that a thiocyanate level be considered in cases of extreme exposure or ingestion.[13] Others point out that
even if all inhaled CS is metabolized to cyanide, the total amount generated would be negligible. [30]
Although studies of rats exposed to intraperitoneal or aerosolized inhaled CS indicate rapid transformation of
the agent to cyanide,[7] there is no evidence that this is clinically significant, and these levels are not
recommended.


TREATMENT
The most important immediate intervention is to move the exposed victim into fresh air. In most cases,
symptoms from low-dose exposure (blepharospasm, blepharoconjunctivitis, eye pain) resolve quickly once
exposure is terminated. All clothing should be removed and sealed in plastic bags. Heavy rubber gloves
should be worn when handling contaminated clothing; CS and CR are especially liable to spread and affect
rescue workers during decontamination. Respiratory protection (properly fitted gas masks) should be worn if
necessary ( Table 84–3 ).
Table 84-3 -- Treatment of Exposure to Tear Gas

1. Remove victim from source of exposure. Protect rescuers with heavy rubber gloves and respiratory isolation.
2. Monitor for respiratory compromise. Airway management as appropriate.
3. Irrigate contaminated skin with copious amounts of water and mild soap. Seal contaminated clothing in
plastic bags.
4. Irrigate eyes with water or normal saline. Perform fluorescein examination of cornea to detect abrasion.
5. Treat respiratory symptoms with humidified oxygen and inhaled ß-adrenergic agonists.
6. Observe victims with significant high-dose exposure for delayed pulmonary edema or bronchospasm.
Victims should be assessed immediately for airway compromise, laryngospasm, and exacerbation of asthma
or chronic obstructive pulmonary disease. Patients with respiratory symptoms should receive supplemental
humidified oxygen; bronchodilators (inhaled ß-adrenergic receptor agonists) can be used to treat wheezing
or bronchospasm.
Exposed skin and eyes are decontaminated. The skin can be washed with mild soap and water, although
contact with moisture may temporarily increase skin irritation and burning caused by CS.[13] Showering is
effective, but runoff from the hair may cause secondary eye contamination.[1] It has been suggested that
decomposition of individual agents can be facilitated by using a 5 per cent solution of sodium bicarbonate
(for CN) or 5 to 10 per cent sodium carbonate (for CS).[5] Persistent contact dermatitis can be treated with
corticosteroid ointment.
For ocular exposure and symptoms, irrigation is done abundantly with water or normal saline. Victims should
be reassured that permanent eye damage will not occur. The cornea is examined with fluorescein and a slit
lamp to detect corneal abrasion. Persistent eye discomfort can be treated with oral analgesics and
cycloplegics to prevent pain from ciliary spasm. Home use of topical anesthetics is not recommended for
fear of impairing epithelial regeneration and slowing healing.[16] Usually, further treatment after
decontamination is unnecessary. If the victim was exposed to explosive injury during dispersal of the agent,
explosive eye trauma or retained foreign bodies should be considered.[15]


DISPOSITION
Patients with systemic symptoms requiring treatment should be admitted to the hospital. Indications for
admission to an intensive care unit include the need for airway or ventilatory support. Victims with significant
respiratory symptoms or severe exposure (high doses in an enclosed space) should be observed for several
days to monitor for delayed pulmonary edema and respiratory compromise.[13] Asymptomatic patients and
those with treated ocular exposures can be discharged, preferably to the care of a competent friend or
relative.


SEQUELAE
In most situations, ocular symptoms caused by tear gas exposure resolve within 15 to 30 minutes of
removing the victim from the source of exposure. Even when partial or complete loss of corneal epithelium
occurs, healing is usually rapid. [16] However, persistent—sometimes permanent—eye problems have
followed more intense contact. Severe injury usually results from close range attacks, often with concomitant
blast injury and/or retained foreign bodies. Ophthalmologic injuries that have been reported in such cases
include severe conjunctival congestion with edema, corneal abrasion, necrosis and ulceration, complete
corneal opacification and vascularization with loss of vision, decreased corneal sensitivity, iritis, deformity of
the anterior chamber filtration angle leading to increased intraocular pressure and glaucoma, and
cataracts.[1][15][16][17][23] Pathologic studies of eyes with tear gas injuries that required enucleation showed
intense suppurative necrotizing keratitis, coagulative necrosis, suppurative iridocyclitis, formation of
retrocorneal membranes, and anterior chamber deformities. [16]


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18. Park S, Giammona ST: Toxic effects of tear gas on an infant following prolonged exposure. Am J Dis
Child 1972; 123:245.
19. Pearlman AL: Chemical weapons on the home front. N Engl J Med 1969; 281:442.
20. Penneys NS: Contact dermatitis to chloroacetophenone. Fed Proc 1971; 30:96.
21. Penneys NS, Isreal RM, Indgin SM: Contact dermatitis due to 1-chloroacetophenone and chemical
mace. N Engl J Med 1969; 281:413.
22. Punte CL, Owens EJ, Gutentag PJ: Exposures to ortho-chlorobenzylidene malononitrile: Controlled
human exposures. Arch Environ Health 1963; 6:72.
23. Rose L: Mace, a dangerous police weapon. Presented before the 3rd Congress of the European Society
of Ophthalmology, Amsterdam, 1968. Ophthalmol Additamentum 1969; 158:448-454.
24. Rothberg S: Skin sensitization potential of the riot control agents BBC, DM, CN and CS in guinea pigs.
Mil Med 1970; 135:552.
25. Steffee CH, Lantz PE, Flannagan LM, et al: Oleoresin capsicum (pepper) spray and “in-custody
deaths.”. Am J Forensic Med Pathol 1995; 16:185-192.
26. Stein AA, Kirwan WE: Chloracetophenone (tear gas) poisoning: A clinicopathologic report. J Forens
Sci 1964; 9:374.
27. Thorburn KM: Injuries after use of the lacrimatory agent chloroacetophenone in a confined space. Arch
Environ Health 1982; 37:182.
28. Tominack RL, Spyker DA: Capsicum and capsaicin—a review: Case report of the use of hot peppers in
child abuse. Clin Toxicol 1987; 25:591.
29. Vaca FE, Myers JH, Langdorf M: Delayed pulmonary edema and bronchospasm after accidental
lacrimator exposure. Am J Emerg Med 1996; 14:402.
30. Verdict A: Verdict on CS [editorial]. BMJ 1971; 3:722.


Uncited reference
Winograd HL: Acute croup in an older child: An unusual toxic origin. Clin Pediatr 1977; 16:884.


Chapter 85 – Metal Fume Fever
BETH A. BAKER
Essentials
• Symptoms typically occur 3 to 12 hours after welding or other operations in which metals are heated.
• Prodrome includes a sweet or metallic taste and nasal and throat irritation.
• Flulike symptoms such as nonproductive cough, dyspnea, fever, malaise, myalgias, and shaking chills
occur.
• Symptoms are worse the first day of the work week and resolve on weekends and nights.
• Symptoms peak in 18 hours and resolve spontaneously within 1 to 2 days.
INTRODUCTION
Metal fume fever is a self-limiting acute illness that occurs with exposure to metal oxides. The symptoms
closely resemble influenza. Symptoms may occur after welding, smelting, or galvanizing operations,
particularly if these operations are done in poorly ventilated areas. Over 1000 cases are reported in the
United States to regional poison control centers every year.[25] A metal fume fever due to zinc oxide was first
described in metal guilders by Patissier in 1822.[34] Drinker published a series of articles in 1927 that clearly
explained the clinical features and etiologic agents that cause metal fume fever. [12] Other names for metal
fume fever include Monday morning fever, welders’ ague, zinc chills, brass chills, brazier’s disease, brass
founders’ ague, foundry fever, spelters’ shakes, the smothers, smelters’ chills, and copper fever.
Workers at high risk for developing metal fume fever include those involved in zinc smelting, welding of zinc
or galvanized iron, brass foundry work, bronzing, galvanizing, copper rolling, forging, casting, manganese-
bronze welding and brazing, chrome welders, brass solderers, molten metal fabricators, metal grinders, and
manufacturers of steel alloys.[15][30] Workers near furnaces that melt metals are also susceptible.[15]
Welders are particularly at risk. Welding involves joining metals by heating the metals to the temperature
required to produce coalescence or joining of the metals.[11] Ross found that 31 per cent of welders aged 20
to 59 years had a history of metal fume fever.[38] Depending on the welding process, ventilation type, and
degree of enclosure, the concentration of welding fumes may range from less than 5 to over 100
mg/mm3.[11]
Metal fume fever is most commonly associated with zinc fumes but also occurs with magnesium, brass, and
copper fumes. Other metals that may cause metal fume fever include those from aluminum, antimony,
arsenic, cadmium, cobalt, chromium, iron, lead, manganese, nickel, selenium, silver, and tin.[15][36]
Zinc oxide is readily volatilized at low temperatures. Zinc fumes that result from heating a galvanized coating
to above 930°F are the most common cause of metal fume fever.[13][14] These fumes have produced metal
fume fever in both human volunteers and animals. Large amounts of zinc oxide particles in the range of 0.2
to 1 µm are also produced in smelting and in welding on galvanized metal.[15] Although it is often cited that
only “freshly formed” zinc oxide fumes can result in metal fume fever, there have been case reports of metal
fume fever developing after exposure to “mature” zinc dust or powder.[5][35] It is also possible that workers
may develop symptoms even at workplaces where the zinc oxide threshold limit value (TLV) is not
exceeded. A study by Gordon and associates showed human subjects (with no prior welding exposure), rats,
and guinea pigs that were exposed at the current TLV exposure limit of 5 mg/m3 of zinc oxide for 2 hours
developed one or more classic symptoms of metal fume fever.[19]
The only other metal that has been shown to cause metal fume fever experimentally is magnesium.[12]
Several cases of metal fume fever developing in workers exposed to brass (contains 90 per cent copper)
have been reported, including a series by Armstrong and colleagues describing 26 workers who became
symptomatic after cutting “brass” pipes.[4] There is one case report of metal fume fever among
ferrochromium smelters, but beyond those reports and the previously cited data on zinc, magnesium,
copper, and brass the other metals have minimal or no clinical or experimental evidence of causing metal
fume fever in humans. [8]


PATHOPHYSIOLOGY
Fumes are small, solid particles formed by vaporization of metal with subsequent condensation.[11] Metal
fume fever occurs after inhalation of oxidized particles from 0.05 to 1 µm in diameter that are formed when
these metals are heated to their melting point in an oxidizing environment. [45] Particles less than 1 µm in
diameter have a high probability of being deposited in the terminal bronchioles and alveoli.[39]
The etiology of metal fume fever remains unknown, although numerous hypotheses have been postulated
since the early 1900s.
One theory is that fumes may cause a direct toxic effect on the respiratory tract with resultant chemotaxis of
leukocytes and macrophages and release of pyrogens and chemotactic factors.[8][9] Blanc and associates
demonstrated a dose-dependent increase in polymorphonuclear leukocytes by bronchoalveolar lavage 22
hours after exposure of welders to zinc welding fumes.[7] A follow-up study supported the pathophysiologic
role of cytokines known to be associated with inflammation or fever.[9] Twenty-three human volunteers
subjected to a welding challenge exposure showed dose-dependent increases in tumor necrosis factor,
interleukin-6, and interleukin-8 in bronchoalveolar samples. There was no significant increase in interleukin-
1 concentrations,[9] as had been theorized. The latency of at least 6 hours between exposure and metal
fume fever response may be due to the time required to synthesize and release tumor necrosis factor and
interleukins.[8]
Fumes from metals such as zinc may cause a mixed cellular infiltrate and modify lung proteins.[2] The metal
oxides involved in metal fume fever may be directly cytotoxic to cells in the respiratory tract or to bacteria
colonizing the airways, causing release of “foreign proteins” that generate the symptoms of metal fume
fever.[24] Guinea pigs exposed to zinc oxide fumes at 5 mg/m3 (the current recommended TLV) for 3 hours
per day for 6 days showed pulmonary interstitial thickening due to inflammation and a mixed cellular infiltrate
(macrophages, lymphocytes, neutrophils, and pulmonary fibroblasts).[22] Lung volumes in this study (total
lung capacity [TLC], vital capacity [VC], and functional residual capacity [FRC]) were significantly
decreased.[22]
A delayed immunologic, hypersensitivity reaction may be responsible for metal fume fever. Farrell
demonstrated immediate and late-phase reactions characterized by urticaria and angioedema in a metal
fume fever patient, suggesting hypersensitivity that possibly was mediated by a delayed IgE reaction.[14] The
inhaled particles may cause respiratory tract tissue inflammation and release of histamine or histamine-like
substances.[28] An antigen complex consisting of the oxide particles and the damaged tissue then leads to
formation of antibodies that can cause an allergic reaction on re-exposure.[28] Against this theory is the fact
that metal fume fever can occur without a prior sensitizing exposure. [15][45]
Another study demonstrated accumulation of zinc particles in pulmonary macrophages and postulated these
particles may, in turn, result in metal fume fever symptoms and ultimately pulmonary fibrosis.[29]
Finally, metal fume fever has been postulated to be a form of hypersensitivity pneumonitis. However, Malo
and colleagues, in a case of zinc fume fever, were unable to detect any specific IgG antibodies that
commonly occur with hypersensitivity pneumonitis. [26]


A history of exposure to metal fumes at work, particularly in operations involving heating of metals shown to
cause metal fume fever, is the key to diagnosis, because there is no pathognomonic constellation of signs
and symptoms. The chemical makeup of the base metal, welding rods or electrode, and filler or flux can be
obtained from material safety data sheets (MSDS). Alternatively, the outer surface of the electrode or filler
metal is often stamped with an American Welding Society classification number that can be used to identify
the exact ingredients.[39]
A prodrome consisting of a metallic or sweet taste and throat irritation may occur soon after exposure. The
median time between fume exposure and onset of other symptoms is 5 hours, with patients typically
presenting within 3 to 12 hours after exposure. Patients often present after they have left work, in the late
afternoon or early evening. Signs and symptoms mimic a viral, “flulike” illness ( Table 85–1 ). Fever in the
range of 38°C to 39°C may peak within 10 to 12 hours after exposure, and sinus tachycardia may be
present.
Table 85-1 -- Clinical Presentation of Metal Fume Fever

Prodrome (may occur soon after exposure to heated metal fumes)
Nasal and throat irritation
Sweet or metallic taste in mouth
Signs and symptoms (occur 3 to 12 hours after fume exposure)
Headache Chest tightness
Chills Nasal irritation
Myalgia Dry mouth
Cough Lethargy
Dyspnea Sweating
Nausea Diaphoresis
Fever Vomiting
A review of 20 previous studies of metal fume fever revealed the most frequent symptoms to be chills (98
per cent), headache (69 per cent), myalgia (61 per cent), cough (59 per cent), dyspnea (38 per cent), and
nausea (20 per cent).[7] Physical examination findings in 15 of those studies included fever (90 per cent),
tachypnea (17 per cent), and rales (33 per cent).[8] In another series of 26 workers who developed metal
fume fever after cutting brass pipes with electric cutting torches, the most common symptoms were fever (96
per cent), dyspnea (88 per cent), chills (81 per cent), headache (81 per cent), nausea (73 per cent), myalgia
(73 per cent), cough (65 per cent), shortness of breath (65 per cent), metallic or sweet taste in mouth (54 per
cent), and vomiting (31 per cent).[4] Other nonspecific symptoms included nonproductive cough, dry throat,
rigors, fevers, malaise, sweating, fatigue, muscle and joint aches, and shortness of breath without wheezing.
Physical examination findings were present in only 8 of the 26 symptomatic workers and consisted of rales
or wheezing.[4] Twenty-five of the 26 symptomatic workers had spent more than 1 hour working in the poorly
ventilated condenser cutting the brass pipes.[4]
Complete recovery usually occurs within 24 to 48 hours with no permanent lung damage. Some patients
may have recurrent episodes without major physiologic damage.[15] Workers with continuous metal fume
exposure will develop a tachyphylaxis or tolerance with short-term immunity during the workweek. This
tolerance disappears over the weekend.
There is one case report by Shusterman and Nel of myocardial and skeletal muscle injury occurring with
metal fume fever.[41] Pulmonary edema, bronchospasm, and pneumonitis are more common with cadmium
fume exposure. At least one fatality due to acute respiratory failure has been described in a worker exposed
to sheet metal and cadmium fumes.[17]


The most frequently described acute occupational respiratory illness in welders is metal fume fever,[39] and
clues to its diagnosis include typically mild to moderate “flulike” symptoms that spontaneously resolve in 1 to
2 days without sequelae. Welders may also develop nonoccupational related respiratory tract illnesses, such
as acute airway irritation, acute bronchitis, influenza, pneumonia, or pulmonary embolus ( Table 85–2 ).[1][39]
Table 85-2 -- Differential Diagnosis of Metal Fume Fever: Nonoccupational Causes

Influenza or acute viral syndrome
Acute bronchitis
Pneumonia
Malaria
Septicemia
Other infectious processes
Pulmonary embolus
Other occupational exposures may produce symptoms similar to those of metal fume fever ( Table 85–3 ).
Welders who present with pulmonary infiltrates or hypoxia may have chemical pneumonitis induced by
fumes from nitrogen dioxide, ozone, phosgene, or cadmium.[8] Cadmium, in particular, may present as
bilateral pulmonary infiltrates, pulmonary edema, hemorrhage, and a restrictive pattern on pulmonary
function testing.[39] The chemical pneumonitis or pulmonary edema may also be delayed.[6] Acute cadmium
toxicity typically presents as bilateral pulmonary infiltrates and respiratory symptoms that persist longer than
24 to 48 hours. These patients complain of severe shortness of breath and have findings of pulmonary
edema. Although patients are often labeled as having cadmium fume fever, a more accurate description
would be a cadmium or toxic pneumonitis.[3][8]
Table 85-3 -- Differential Diagnosis of Metal Fume Fever: Occupational Causes

Pulmonary Abnormal Clinical
Disease Onset Treatment
Exposure Laboratory Course
Metal fume fever Metal oxides 3–12 hours after CXR—usually Supportive; Usually
of zinc, exposure; no normal; WBC may remove from resolves within
magnesium, sensitizing be elevated exposure 24–48 hours
copper, exposure needed without
brass, etc. sequelae
Pulmonary Abnormal Clinical
Disease Onset Treatment
Exposure Laboratory Course
3–10 hours after Usually no
Pyrolysis
exposure; CXR and laboratory sequelae; may
Polymer fume products of
associated with studies usually Supportive cause
fever fluorinated
contaminated normal interstitial
polymers
cigarette smoking fibrosis
Organic dusts
Pulmonary
(e.g., animal, 4–8 hours after CXR—normal or
Allergic alveolitis Supportive; fibrosis,
avian, fungi, exposure; requires bilateral infiltrates;
(hypersensitivity corticosteroids if especially with
bacterial, prior sensitizing positive antibodies
pneumonitis) severe repeated
plant exposure precipitans testing
exposures
proteins)
Hours to days; CXR—bilateral Supportive;
Often lasts
onset of pulmonary infiltrates, oxygen,
Cadmium more than
Cadmium edema up to 24 pulmonary edema; corticosteroids,
pneumonitis 24–48 hours;
hours after PFTs—restrictive bronchodilators if
may be fatal
exposure pattern severe
Organic
dusts, Supportive;
Minutes to hours; May see
colophony CXR usually normal; corticosteroids,
Occupational requires prior persistent
zinc, PFTs—obstructive bronchodilators,
asthma sensitizing bronchial
chromium, pattern theophylline if
exposure hyperreactivity
nickel, severe
vanadium
Pulmonary
Cobalt,
Hard metal Months to years of CXR—pulmonary fibrosis;
tungsten Supportive
disease chronic exposure infiltrates occupational
carbide
asthma
Lung
CXR—mimics granulomas
Beryllium lung Acute—minutes to sarcoidosis; positive Supportive; and
Beryllium
disease hours lymphocyte corticosteroids granulomas in
transformation test other organ
systems
Chronic—months
to years
Smoke, Interstitial
CXR—bilateral Supportive;
Chemical ozone, fibrosis;
24–48 hours infiltrates, oxygen,
pneumonitis cadmium, restrictive lung
pulmonary edema bronchodilators
others disease
CXR, chest radiograph; WBC, white blood cell count; PFTs, pulmonary function tests.
Hypersensitivity pneumonitis is typically due to inhaled organic dusts such as plant proteins, animal proteins,
thermophilic actinomycetes, fungi, or micro-organisms. Certain metals such as zinc, beryllium, and “hard
metal” may also cause hypersensitivity pneumonitis.
Smoke generated by military grenades and smoke pots may contain hydrochloric acid and zinc oxychloride,
which, when inhaled, produce a chemical pneumonitis associated with a relapse of pulmonary symptoms
after a 24- to 48-hour delay.[13]
Polymer fume fever can mimic metal fume fever. It occurs when pyrolysis products of fluorinated polymers
are inhaled, with the majority of cases reported due to inhalation of smoke from cigarettes contaminated with
the polymers.[40][46] These pyrolysis products are produced by routine combustion of tetrafluoroethylene
(TFE) resins such as polytetrafluoroethylene (PTFE) or Fluon, Teflon, and polyvinyl fluoride, methylene
chloride, and polyurethane.[39]
Occupational asthma can develop after exposure to colophony (pine resin) and aminoethylethanolamine,
which are used in soldering. [39] Malo and Cartier described two cases of occupational asthma in welders
exposed to zinc and chromium fumes.[27] Chromium and nickel are potent sensitizers and may cause
dermatitis or asthma. Acute exposure to nickel vapor may result in pulmonary edema.


LABORATORY STUDIES
Laboratory studies are often normal and are indicated only for severe symptoms or to rule out infection or
other pulmonary problems. The most common abnormality is a leukocytosis of 12,000 to 16,000 cells/mm3
with elevated band neutrophils. In one study, 21 of 24 patients had white blood cell counts greater than
10,000/mm3.[4] The leukocytosis may persist up to 12 hours after the patient defervesces.[30] Erythrocyte
sedimentation rate may also be increased. An elevated lactate dehydrogenase level (primarily LDH3, or lung
component) is occasionally seen.[4]
Chest Radiography
The chest radiograph is usually normal,[8] although it may show a diffuse increase in bronchovascular
markings.[23][29] A study of Gdansk shipyard workers found normal chest radiographs in 24 of 29 workers
with metal fume fever, whereas 5 had increased vascular markings or round opacities.[21][23] Transient
bilateral, multiple, discrete lung opacities 3 to 4 mm in diameter were found in a worker exposed to zinc
fumes.[23] Malo and associates also described diffuse pulmonary opacities in a worker who sprayed heated
zinc.[26]
Arterial Oxygen Monitoring/Pulmonary Function Testing
Bedside pulse oximetry is a noninvasive method for evaluating hypoxia in patients with mild to moderate
respiratory symptoms. Arterial blood gas measurement should be reserved for patients with severe
respiratory symptoms; it may show normal or decreased arterial PO 2. Pulmonary function testing may be
normal or show a decreased VC and decreased DLCO (diffusing capacity of the lung for carbon
monoxide).[23][44] A study of 14 welders exposed to zinc welding fumes showed minimal changes in
pulmonary function (forced expiratory volume in 1 second [FEV1], FVC, TLC, DLCO) and airway reactivity by
methacholine challenge.[7] Vogelmeier and associates, however, described a patient with recurrent metal
fume fever with a 60 per cent fall in DLCO and a 40 per cent decrease in VC.[44] The VC was maximally
depressed at 6 hours and normalized by 24 hours.[44] More rarely, pulmonary function studies may show an
obstructive pattern.[3]
Malo and associates demonstrated a significant reduction in FEV1 and FVC 4 to 6 hours after zinc oxide
fume inhalational challenge in a worker who had previously had zinc fume fever.[26]
Metal Testing
In most cases, urine or serum metal levels correlate poorly with symptom severity and are not indicated.[30]
Five of 12 workers exposed to zinc and copper fumes had urine copper levels elevated at greater than 0.05
mg/L whereas all of the urine zinc levels were normal.[4] Most other studies and case histories reported
normal zinc levels in workers with metal fume fever, with only four cases reporting elevated zinc
levels.[16][32][37][42][43]


TREATMENT
Supportive therapy is the mainstay of treatment with use of oxygen, intravenous fluids and analgesics. Other
therapies are dictated by symptoms ( Table 85–4 ). Glucocorticosteroids may be warranted in patients with
severe symptoms or interstitial infiltrates on a chest radiograph,[10] but their efficacy has not been rigorously
evaluated.
Table 85-4 -- Treatment of Metal Fume Fever

Supportive care
Antacids for gastrointestinal symptoms
Corticosteroids for severe symptoms or pulmonary interstitial infiltrates
Bronchodilators if wheezing
Minimize future exposure to the causative metal fumes
Job site evaluation
Optimize ventilation
Consider respirator if ventilation cannot be improved
Antacids may alleviate gastrointestinal symptoms such as nausea, vomiting, and abdominal pain.[33]
Although milk has been used anecdotally as a treatment since the 1800s, its efficacy has never been
studied.[8]
Workplace Intervention
Preventing or minimizing subsequent exposures to causative metal fumes is essential. The welder’s
worksite needs to be evaluated with regard to ventilation, respiratory protection, and individual work
practices. Recommending good workplace ventilation is vital to reduce the risk of repetitive episodes. Local
exhaust ventilation is the most effective method for reducing fume concentrations[39] and is essential for
welding in a confined space. Reliance on general exhaust ventilation may not be adequate.[11] If ventilation
cannot be optimized, then respiratory protection may be a good alternative. [8] The respirator selected for use
by the worker must be capable of filtering out the specific metal fumes. Whereas the welder’s shield offers
some respiratory protection it is designed to protect the worker from sparks and light, not fumes.[39] Fume
concentrations inside a welding helmet are typically one fifth to one tenth the ambient air concentrations.[18]
Individual work practices can have a significant impact on metal fume exposure; in one NIOSH study the
TLVs for total welding fumes were routinely exceeded.[31] A study showed fume concentrations to be highest
if welding was done in an enclosed space with no ventilation and lowest if welding was done in a semi-
enclosed space with good ventilation. More than any other factor the degree of confinement determined
welding fume concentrations.[18] Workers who weld or flame cut zinc-coated metals or zinc-containing
metals are at particular risk for metal fume fever.[9] Welding on metal pieces with metallic coatings may be
particularly hazardous.[11]


DISPOSITION
Most patients with metal fume fever do not require hospitalization. Patients with mild respiratory distress may
be evaluated and discharged home unless testing or observation reveals worrisome findings or worsening
symptoms. These patients should be cautioned to return for respiratory distress or worsening symptoms.
Patients with moderate or severe pulmonary distress should be observed in hospital for 24 to 48 hours and
discharged when their respiratory status is considered stable. As discussed earlier, the work environment
should be assessed for adequate ventilation and exhaust of metal fumes.


SEQUELAE
In general, symptoms resolve spontaneously within 1 to 2 days with no sequelae. However, persistent
bronchitis, asthma, and respiratory changes have been described in zinc and cobalt production workers. [38]
One case had persistent disabling “pneumonopathy” after recurrent metal fume fever.[20]
Occupational asthma has been reported in two solderers with a history of metal fume fever who processed
galvanized metal.[27] One of these two workers also presented with fever and leukocytosis consistent with
either metal fume fever or hypersensitivity pneumonitis. Bronchial hyperresponsiveness to histamine
challenge was positive in one worker and borderline in the other worker.[27]
Some workers with metal fume fever who are severely affected or who find their symptoms unacceptable
may seek alternative employment. However, many workers may continue to work and suffer recurrent
episodes of metal fume fever with minimal long-term sequelae.


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13. Evans EH: Casualties following exposure to zinc chloride smoke. Lancet 1945; 2:368.
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National Institute of Occupational Safety and Health, Cincinnati, OH.
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33. Papp JP: Metal fume fever. Postgrad Med 1968; 43:160-163.
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35. Rohrs LC: Metal fume fever from inhaling zinc oxide. Arch Intern Med 1957; 100:44-48.
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40. Shusterman D: Prolonged fever associated with inhalation of multiple pyrolysis products. Ann Emerg
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46. Wegman DH, Peters JM: Polymer fume fever and cigarette smoking. Ann Intern Med 1974; 82:55-57.


Chapter 86 – Cyanide
KATHLEEN A. DELANEY
Essentials
• Rapid onset of central nervous system (CNS) and cardiovascular symptoms
• Rapid onset of lactic acidosis
• Normal measured arterial O2 saturation
• Decreased AVO2 difference
• Improvement with empirical treatment
• Confirmation by serum or erythrocyte cyanide levels
INTRODUCTION
Cyanide is a powerful cellular poison. A highly reactive compound of carbon and nitrogen, it is an essential
component of many important synthetic reactions and industrial processes and is commonly encountered in
laboratories and industry. It is also a product of normal metabolism and occurs naturally in many plant
products, including tobacco. Because exposure to cyanide in nature is unavoidable, most living organisms
have evolved ways to detoxify cyanide. When these natural detoxification mechanisms are overwhelmed,
serious poisoning may occur.
Poisoning most often occurs through ingestion of cyanide salts or inhalation of hydrogen cyanide gas,
although poisoning after skin exposure to concentrated salt solutions has also been observed.[3][26] Cyanide
poisoning is also caused by the ingestion of agents that are metabolized to cyanide such as organonitrile-
containing solvents[11][32][37] and naturally occurring cyanogenic glycosides such as amygdalin (from
Laetrile) and linamarin found in certain nuts, plants, and fruit pits. [6][10][21] Iatrogenic poisoning may follow
the infusion of degraded sodium nitroprusside, which is 44 per cent cyanide by weight.[15] Smoke from
burning nitrogen-containing polymers such as vinyl, polyurethane, or silk may contain large amounts of
cyanide gas, resulting in cyanide toxicity as a complication of smoke inhalation.[5][31][33]


TOXICOLOGY/PATHOPHYSIOLOGY
Toxicology
Cyanide is rapidly absorbed by the respiratory tract and mucous membranes and more slowly by the
gastrointestinal tract and the skin. It rapidly distributes into red blood cells and tissues. Detoxification occurs
through the combination of cyanide with sulfur to form thiocyanate. This may occur enzymatically through
reactions catalyzed by rhodanese or ß-mercaptopyruvate-cyanide sulfur transferase or nonenzymatically by
combining a sulfane-albumin complex with cyanide.[3][51] The thiocyanate is eliminated renally, with an
elimination half-life of 2.5 days in patients with normal renal function.[44]
Pathophysiology
Cyanide has a high affinity for metals, forming complexes with metallic cations at the catalytic sites of
several important enzymes and inhibiting their function.[3][53][54] The most severe, life-threatening clinical
effects are caused by binding to the ferric (+3) iron of mitochondrial cytochrome oxidase (cytochrome a-a3) (
Fig. 86–1 ). Cytochrome a-a3 mediates the transfer of electrons to molecular oxygen, the final step in
oxidative phosphorylation. Blockade of this enzyme disrupts the ability of the cell to use oxygen, resulting in
tissue anoxia, increased anaerobic metabolism, and the rapid development of lactic acidosis.[51] This iron-
cyanide complex is labile and readily disrupted, making detoxification possible through natural biochemical
mechanisms or with antidotal therapy. The binding of cyanide to other metal-containing enzymes interferes
with glycogen and lipid metabolism, effects that are less clinically evident owing to the dramatic impact of the
effect of cyanide on aerobic cellular respiration. [3][47][53][54]
Figure 86-1 Cyanide inhibits oxidative phosphorylation at cytochrome a-a3 to block the final step, which reduces oxygen to water.
Other toxins that inhibit this step include hydrogen sulfide, carbon monoxide, azide, and formic acid.


Recognition of Cyanide Toxicity
The History
The greatest challenge to the physician is the timely recognition of the possibility of cyanide poisoning in a
critically ill patient. A carefully focused history may suggest the possibility of exposure to cyanide. Cyanide is
readily available to suicidal persons who work in laboratories, the electroplating industry, or jewelry
shops.[52] In industrial poisonings, the diagnosis may be suggested by the patient’s job or work site. A history
of the use of alternative therapies by a cancer patient, the recent ingestion of an unidentified solvent, or
smoke inhalation during a fire may also indicate the possibility of cyanide. The patient who is a victim of
homicidal cyanide poisoning usually arrives with no historical clues.
Physiologic Manifestations of Toxicity
The severity of symptoms from cyanide is independent of the source and depends on the actual amount and
rate of cyanide exposure ( Table 86–1 ). Patients who are significantly poisoned with cyanide have
physiologic manifestations that suggest severe hypoxia, such as metabolic acidosis, bradycardia, dyspnea,
and CNS disturbances. However, a pulse oximetry reading is usually normal and patients are not cyanotic
unless pulmonary edema is present or apnea has occurred.[19][48] Severe lactic acidosis is an important
clue. CNS manifestations range from initial anxiety to agitation, seizures, and coma. Cardiac effects include
sinus tachycardia, followed by bradycardia that can progress to asystole. Ventricular tachycardia and
ventricular fibrillation are less common.[25][30] The rapid onset of symptoms and rapid deterioration are
important clues.
Table 86-1 -- Dose-Dependent (Mild Severe) Signs and Symptoms of Acute Cyanide Toxicity
Headache
Drowsiness
Dizziness
Seizures
Coma
Pulmonary
Dyspnea
Tachypnea
Apnea
Hypertension
Tachycardia
Hypotension
Bradycardia
Asystole
Cardiovascular collapse
Other Effects (After Oral Ingestion)
Burning of the tongue and mucous membranes
Gastrointestinal irritation
Smell of bitter almonds
Inhalation Exposure to Hydrogen Cyanide Gas
The onset of symptoms is virtually immediate after inhalation of cyanide gas. The severity of the symptoms
depends predominantly on the ambient concentration of the gas. After several hours of exposure to an
atmospheric concentration of less than 50 ppm, patients develop feelings of anxiety, restlessness, shortness
of breath, palpitations, and headache. Recovery may be rapid when exposure is terminated, although
prolonged exposure even at low levels may be fatal. Atmospheric concentrations of 100 ppm lead to death
after approximately 30 minutes. Higher levels cause a rapid onset of tachycardia, dyspnea, syncope, and
seizures. These symptoms may also resolve quickly after termination of exposure. In severe cases,
bradycardia develops and may progress to asystole. Coma and cardiovascular collapse can occur
immediately when concentrations of hydrogen cyanide gas are greater than 270 ppm.[22][25][40]
Toxicity of Ingested Cyanide Salts
Symptoms begin within minutes after the ingestion of cyanide salts. Cyanide salts are caustic, and oral
burns may develop after ingestion. The smell of bitter almonds may also be present. Ingestion of only 50 mg
has caused death in adults, whereas survival of much larger ingestions has been reported with aggressive
supportive care and the use of antidotes. The median oral lethal dose of the potassium or sodium salt of
cyanide in an untreated adult is 140 to 250 mg.[24]
Organic Nitriles and Cyanogenic Glycosides
Symptoms are delayed after the ingestion of compounds that require metabolic activation. Cyanogenic
glycosides such as amygdalin, found in apricot pits and bitter almonds, are hydrolyzed in the small intestine,
resulting in the release of cyanide several hours after ingestion.[45] As might be expected, amygdalin is not
toxic when given intravenously.[42][44] Acetonitrile, found in some solvent products marketed as artificial nail
removers, requires oxidation by hepatic enzymes before the release of cyanide. Prolonged latencies of up to
24 hours before death have been reported after ingestion of these solvents.[9][11][32][37] Ingested solvents
should be carefully identified to prevent the accidental discharge of a patient who has taken a compound
with delayed toxicity.[11][32]
Chronic Cyanide Poisoning
Whether or not there are significant clinical effects from chronic low-level cyanide exposure is controversial.
Cassava, a plant that contains the cyanogenic glycoside linamarin, is a significant source of carbohydrate in
many developing countries. Epidemiologic studies have suggested that some endemic problems such as
vitamin B 12 deficiency, goiter, and certain demyelinating diseases may be due to the chronic ingestion of
linamarin.[26][55] Chronic cyanide exposure in the workplace has been associated with an increased
incidence of vitamin B12 deficiency and thyroid disease.[8] An epidemiologic survey prompted by a high
incidence of optic neuropathy in Cuba showed that poorly nourished smokers were at greatest risk and
implicated an etiologic association between elevated levels of cyanide normally found in cigarette smoke
and dietary deficiency of the natural cyanide scavengers, vitamin B12 and ß carotene.[14]
Nitroprusside Infusions
The deterioration of sodium nitroprusside in aqueous solutions results in the release of cyanide.[2][15][43][50]
Toxicity from nitroprusside is discussed in Chapter 47 .


The differential diagnosis of cyanide poisoning must be considered in the setting in which it occurred ( Table
86–2 ). Inhalational exposures leading to severe acidosis include those of toxic gases such as carbon
monoxide and hydrogen sulfide. Carbon monoxide is generated by the incomplete combustion of organic
fuels, in the setting of a fire, or after exposure in a closed space to faulty gas-powered heaters or gasoline-
powered engines. Hydrogen sulfide is a cellular poison found in a number of occupational settings where
organic decomposition occurs, such as sewers, septic tanks, fertilizer manufacturing and use, and petroleum
refining. The odor of “rotten eggs” may be discernible.
Table 86-2 -- Differential Diagnosis of Cyanide Poisoning

Inhalation exposure with rapid deterioration and acidosis
Hydrogen sulfide
Carbon monoxide
Simple asphyxiants
Unknown ingestion with mental status alteration and acidosis
Sodium azide
Salicylates
Iron
Beta-adrenergic receptor antagonists (with seizures)
Cocaine (with agitation or seizures)
Isoniazid (with seizures)
Toxic alcohols
Metformin/phenformin
Sodium nitroprusside infusion
Sepsis (acidosis, decreased AVO 2 difference)
Thiocyanate toxicity (encephalopathy)
The differential diagnosis of anion gap metabolic acidosis in patients with suspected ingestions includes
toxic alcohols such as methanol and ethylene glycol and therapeutic drugs such as phenformin and
metformin. Salicylates and iron also cause metabolic acidosis in association with altered mental status. The
time course of deterioration after poisoning with these agents is slower than that which occurs after the
ingestion of cyanide salts, although cyanogenic compounds may present a similar picture. Severe poisoning
with isoniazid, ß-adrenergic receptor antagonists, and cocaine can be associated with seizures and
significant lactic acidosis. In cocaine poisoning and phencyclidine poisoning, intense muscular activity alone
may be associated with significant lactic acidosis, even in the absence of seizures. In the absence of a
history of use or abuse, these may be difficult to distinguish from cyanide poisoning. However, unlike
cyanide, the lactic acidosis associated with these agents begins to resolve spontaneously when the seizures
or muscle hyperactivity are controlled. Sodium azide, an agent used in many hospital chemistry laboratories,
is a cellular toxin similar to cyanide.[1] When a history of toxic exposure is uncertain, the diagnosis of
ketoacidosis, lactic acidosis of any etiology (sepsis, status epilepticus, shock), and uremia must be
considered. When a patient is in the intensive care unit on a nitroprusside infusion, the diagnosis of
thiocyanate toxicity should be considered if the patient becomes encephalopathic. This is not associated
with lactic acidosis nor with an alteration of the AVO2 difference. Sepsis may also cause encephalopathy, an
elevated anion gap, and a decreasing AVO 2 difference.[15]


LABORATORY STUDIES
Routine Studies
Readily available laboratory studies that may be useful to support the emergent diagnosis of acute cyanide
poisoning include an electrocardiogram (EKG), arterial blood gas analysis (looking for acidosis and the
absence of hypoxia), a co-oximeter measurement of carboxyhemoglobin and per cent oxygen saturation,
and determination of serum lactate and serum electrolyte levels ( Table 86–3 ). As noted earlier, the EKG
demonstration of sinus tachycardia or bradycardia is nonspecific but consistent with cyanide toxicity. The
demonstration of severe acidemia on arterial blood gas assessment,[46] an elevated lactate level, and an
increased anion gap is also consistent. The PO 2, pulse oximetry, and the measured oxygen saturation of
hemoglobin are expected to be normal unless aspiration, apnea, or pulmonary edema is present.
Table 86-3 -- Anticipated Laboratory Abnormalities in Cyanide Poisoning

Test Result Cause
Serum electrolytes Elevated anion gap Lactic acidosis from increased anaerobic
metabolism
Arterial blood gas Metabolic acidosis As above
Normal PO 2
Measured % O2 saturation Normal *
Arterial-central venous O 2
Decreased Decreased tissue O2 utilization
difference
Serum cyanide level
Toxic > 0.5 mg/L
Fatal > 3.0 mg/L
Erythrocyte cyanide level
< 1.9 µM/L (50
Normal
µg/L)
Fatal > 40 µM/L (1 mg/L)
Whole blood cyanide level Not useful
* Carbon monoxide and methemoglobinemia significantly increase the oxygen saturation gap, which is the difference between the calculated
O 2 saturation and the co-oximeter measured O2 saturation. Neither cyanide nor hydrogen sulfide significantly alters this gap.
In a victim of smoke inhalation or other suspected inhalational exposure, measurement by co-oximeter of the
carboxyhemoglobin level is essential. Although the PO2 measured on an arterial blood gas analysis is
normal in uncomplicated poisoning with cyanide, hydrogen sulfide, or carbon monoxide, the per cent oxygen
saturation of hemoglobin measured on the co-oximeter is lowered by the presence of carboxyhemoglobin in
the patient with carbon monoxide poisoning but is normal in the patient poisoned with cyanide or with
hydrogen sulfide. When bedside pulse oximetry is done, all three of these agents may produce normal
readings as carboxyhemoglobin absorbs light at the same wavelength as oxyhemoglobin.[17][48]
Confirmatory Tests
Laboratory confirmation of cyanide poisoning is always a retrospective event. The diagnosis must be
considered and treatment administered long before any laboratory could perform definitive tests. Cyanide
can be measured in erythrocytes, where it is concentrated, or in serum. Because of this concentration of
cyanide in erythrocytes, serum cyanide levels are lower than erythrocyte levels in all cases. Whole blood
cyanide levels are not useful. [15]
Normal erythrocyte cyanide levels are less than 1.9 µM/L (50 µg/L), whereas death from cyanide is
associated with erythrocyte levels greater than 40 µM/L (1 mg/L). [15] Toxicity is seen with serum cyanide
levels ranging from 0.5 mg/L (anxiety, confusion, tachypnea) to more than 3 mg/L (apnea, cardiovascular
collapse).[25][30]
The Arteriovenous Oxygen (AVO2) Difference
Because cyanide does not affect the oxygen-carrying capacity of hemoglobin, sufficient oxygen is available
to tissues but cannot be used.[16][53][54] This results in decreased tissue extraction of oxygen, increased
venous oxygen, and a decrease in the AVO 2 difference. Use of this measurement to rapidly diagnose
cyanide poisoning is not feasible, however. The most accurate estimation of the AVO2 difference requires
the placement of a Swan-Ganz catheter for pulmonary artery sampling, an impractical procedure for
emergent diagnosis. The determination of the AVO 2 difference is most useful in the invasively monitored
patient in the intensive care unit who is on a nitroprusside infusion and has suggested cyanide toxicity.
Measurement of the oxygen saturation of peripheral venous blood has been recommended as a diagnostic
test.[24] However, the range of normal values for peripheral venous oxygen saturation and the effects of
oxygen administration on these values have not been well studied, and little useful information is likely to be
gained by this measurement.[56] “Arterialization” of veins on funduscopic examination has been described as
a clinical manifestation of increased venous PO 2.[24][29]


TREATMENT
Treatment is to monitor, establish intravenous access, and administer 100 per cent oxygen by mask to all
patients with suggested exposure to cyanide. Gastric lavage is indicated in patients with recent cyanide
ingestion but should not take priority over resuscitation of the symptomatic patient. Ipecac is absolutely
contraindicated owing to the expected rapid onset of symptoms. Activated charcoal binds small amounts of
cyanide and may decrease the significance of an ingestion. It should be administered at a dose of 1 g/kg.[34]
The Taylor Cyanide Antidote Kit
Although many patients have survived cyanide poisoning with supportive care alone, the use of specific
antidotes has salvaged severely poisoned patients. Sodium nitrite and sodium thiosulfate are the antidotes
available in the United States. These are contained in the Taylor Cyanide Antidote Kit, which also contains
an ampule of amyl nitrite for inhalation.
For the patient known or strongly suspected to be poisoned with cyanide, sodium nitrite and sodium
thiosulfate are administered according to the regimens outlined in Table 86–4 .Therapy should be rapidly
initiated in the symptomatic patient. Because of the toxicity of sodium nitrite, an asymptomatic patient should
never be treated. Patients with inhalational exposures do not require specific antidotal therapy if significant
recovery has occurred before reaching medical attention. Patients with moderate symptoms may be closely
observed for more serious signs before the initiation of treatment.
The amyl nitrite capsule contained in the Taylor Cyanide Antidote Kit is included as a means to initiate
therapy when intravenous access has not been obtained or when treatment is initiated by nonmedical
persons in the prehospital setting. It is not necessary to administer the amyl nitrite when intravenous sodium
nitrite can be given. For symptomatic cyanide poisoning, the dose of sodium nitrite in adults is 300 mg,
followed by 12.5 g of sodium thiosulfate. Children should receive 0.33 mL/kg of 10 per cent sodium nitrite
and 1.65 mL/kg of 25 per cent sodium thiosulfate. The pediatric dosage of sodium nitrite should be lowered
if anemia is known to be present.[7]
Therapy with these agents is based on studies published by Chen in the 1930s.[12] Traditionally, nitrites are
thought to be therapeutic because of their capacity to form methemoglobin, which binds avidly to cyanide.
Although nitrites are clearly efficacious in the treatment of cyanide poisoning, the mechanism of this effect
has been brought into question by the low amounts and slow rate of methemoglobin production observed in
humans compared with the rapidity of response to sodium nitrite administration. [4][28][53][54] Levels of
methemoglobin production in successfully treated patients range from 2 to 10 per cent,[20][28][31] far from the
25 per cent or higher recommended as a goal in the older literature.[12] In addition, agents such as dimethyl-
4-aminophenol that form methemoglobin much more rapidly do not appear to work any faster than sodium
nitrite.[54] The mechanism of the beneficial effect of sodium nitrite remains elusive.[54]
The major side effect of nitrite administration is hypotension related to its vasodilatory effects. [4][33][38]
Significant methemoglobinemia
Table 86-4 -- Treatment of Cyanide Poisoning
Adults
100% Oxygen
Sodium nitrite: 10 mL IV (10 mL ampule 3% NaNO 2 = 300 mg) *
Sodium thiosulfate: 50 mL IV (50 mL ampule 25% Na2S2O3 = 12.5 g) *
Children
100% Oxygen
IV sodium nitrite and sodium thiosulfate:
Hb (g/100 mL) 3% NaNO2 (mL/kg) † 25% Na2S2O3 (mL/kg)
7 0.19 1.65
8 0.22 1.65
9 0.25 1.65
10 0.27 1.65
11 0.30 1.65
12 0.33 * 1.65
13 0.36 1.65
14 0.39 1.65
Monitor methemoglobin to keep level less than 30%.
* Repeat once at one-half dose if symptoms persist.
† From recommendations by Berlin.[7]
as a consequence of nitrite administration occurs more commonly in other species than in humans,[4] although
severe methemoglobinemia resulted in the death of a child who received sodium nitrite for an asymptomatic
cyanide ingestion.[8]
Practically, sodium thiosulfate is given after the administration of sodium nitrite, although it may be initiated
as soon as sodium nitrate therapy is started. The combined therapeutic effects of these two agents, as
determined by the LD50 for cyanide in animal studies, are greater than their additive effects, demonstrating
synergism. Sodium thiosulfate increases the detoxification rate of cyanide by donating a sulfur molecule to
the enzyme rhodanese, which catalyzes the formation of less toxic thiocyanate, which is then excreted in the
urine.[4][12][22][27][38]
Anecdotal reports suggest that sodium thiosulfate may be effective as a sole therapy in human cyanide
poisoning, although data are limited.[12][38] This is an important issue because sodium thiosulfate has very
limited toxicity when compared with sodium nitrite and is safer when used for empirical therapy when the
diagnosis is not clear.[27][53] The administration of sodium nitrite to victims of smoke inhalation suspected of
having cyanide poisoning raises concerns when concomitant carbon monoxide poisoning is present,
because the formation of methemoglobin may further decrease the oxygen-carrying capacity of the blood.[33]
In animal studies, synergism of 100 per cent oxygen with sodium thiosulfate and with the sodium thiosulfate-
nitrite combination has been demonstrated in the treatment of cyanide poisoning. This occurs despite the
fact that cyanide blocks oxygen utilization. This enhancement of the efficacy of thiosulfate and sodium nitrite
by oxygen is unexplained. It may be due to an effect of oxygen on the binding of cyanide to cytochrome
oxidase or on the capacity of nitrite to form methemoglobin. Hyperbaric oxygen does not offer any additional
benefit over the administration of 100 per cent oxygen in animal models of cyanide poisoning.[35][52][53]
Anecdotal reports of severely poisoned patients who survived with hyperbaric treatment in addition to
standard therapy exist,[18][36] but no human studies evaluating its efficacy have been performed. The patient
with both carbon monoxide and cyanide poisoning will reasonably be expected to benefit from hyperbaric
oxygen therapy.[33][41]
Other Cyanide Antidotes
The toxicity of the nitrites has led to a search for safer, efficacious therapies. Cobalt compounds have a high
affinity for cyanide, and dicobalt edetate is widely used to treat cyanide poisoning in the United Kingdom.[39]
Although an effective antidote, it has significant toxicity, especially when cyanide is not present, limiting its
use as an empirical therapeutic agent. [38] Hydroxycobalamin (vitamin B12a) reverses cyanide toxicity in
animal models and has been used to protect patients on prolonged nitroprusside infusions.[13][57] In the
concentrations currently available in the United States, infusions of large volumes of hydroxycobalamin are
required, which limits its usefulness.[23] When hydroxycobalamin is administered alone, cyanide is held in
the form of cyanocobalamin. However, when combined with sodium thiosulfate, the cyanide appears in the
form of thiocyanate. Concurrent administration of thiosulfate is thought to “recycle” the hydroxycobalamin
binding and may reduce the amount of hydroxycobalamin required to detoxify a given dose of cyanide. This
effect has been termed antidotal synergy.[23]
4-Dimethylaminophenol (DMAP) produces a rapid methemoglobinemia and is used in Germany. It is not

more effective than sodium nitrite despite the production of more significant methemoglobinemia. Although it
does not cause the same degree of hypotension as sodium nitrite, it has been associated with renal failure
in experimental animals. Unlike dicobalt edetate, it does not have greater side effects in the absence of
cyanide. In practice, most of these agents are used in combination with sodium thiosulfate.[38][53][54]
Decisions to Treat Empirically: The Case of the “Unknown”
The decision to administer the sodium nitrite-thiosulfate antidote is straightforward in the case of a
comatose, acidemic patient with a history of cyanide exposure. Hypotension is not a contraindication to the
use of sodium nitrite in these patients.
More difficult management decisions arise in patients with smoke inhalation who have an elevated carbon
monoxide level as well as suspected cyanide exposure and in patients who are comatose and acidemic in
whom a history of exposure is absent.
In one study of smoke inhalation victims, Baud and colleagues demonstrated a significant correlation
between toxic cyanide levels (>40 µM/L) and plasma lactate levels greater than 10 mM/L that was
independent of the carbon monoxide concentration.[5] The administration of sodium nitrite to patients with
elevated carbon monoxide levels is potentially dangerous because of the postulated detrimental impact of
methemoglobin formation on the oxygen-carrying capacity of hemoglobin.[41] A limited clinical study of seven
patients with both carbon monoxide and cyanide poisoning demonstrated methemoglobin levels maximally
elevated to 13 per cent 1 hour after treatment with sodium nitrite. Because of the rapid clearance of
carboxyhemoglobin none of these patients had a total decrease in their oxygen-carrying capacity of greater
than 21 per cent. However, none of these patients had initial carbon monoxide levels greater than 38 per
cent.[31]
Administration of sodium thiosulfate alone to victims of smoke inhalation when concomitant cyanide
poisoning is suspected remains the safest intervention. When a high carboxyhemoglobin level is the sole
deterrent to the use of sodium nitrite, it may be safely administered in the hyperbaric chamber.[33] In all
cases when empirical treatment is considered, the safest therapy is the administration of 100 per cent
oxygen and sodium thiosulfate.
The physician should consider empirical treatment of cyanide poisoning in the patient with unexplained
severe lactic acidosis, coma, bradycardia, and normal oxygenation, especially if the onset of symptoms and
deterioration was rapid. Other antidotal therapies, including naloxone, glucose, fomepizole (for suspected
methanol or ethylene glycol poisoning), or vitamin B 6 (for suspected isoniazid ingestion with intractable
seizures), should also be considered depending on the clinical scenario. In the absence of hypotension and
a significantly elevated carboxyhemoglobin level, sodium nitrite may be administered in addition to sodium
thiosulfate if the diagnosis of cyanide poisoning is strongly entertained.


DISPOSITION
All patients with symptomatic cyanide poisoning require admission to an intensive care unit until complete
resolution of the metabolic acidosis occurs. Patients with inhalational exposure who are asymptomatic in the
emergency department do not require admission. Patients with ingestion of a cyanide salt who remain
asymptomatic during a 4-hour period of observation do not require medical admission. Asymptomatic
patients who have ingested cyanogenic glycosides or organonitriles require a minimum of 24 hours of
inpatient observation for the development of symptoms. All suicidal patients should undergo psychiatric
evaluation.


SEQUELAE
The long-term effects of acute cyanide poisoning are related to anoxic CNS and myocardial injury. Like
patients with severe hypoxia, with or without cardiac arrest, patients who are resuscitated quickly may suffer
no adverse effects whereas others sustain permanent CNS or myocardial injury. These injuries are usually
clinically evident in the postresuscitation period.
Chronic exposure to low levels of cyanide may be associated with thyroid disorders and vitamin B12
deficiency. Irreversible optic neuropathy has also been attributed to chronic cyanide exposure. These effects
are epidemiologic associations and are debated.


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to a lethal oral dose of potassium cyanide. Ann Emerg Med 1988; 17:595-598.
35. Litovitz T: The use of oxygen in the treatment of acute cyanide poisoning.
In: Ballantyne B, Marrs TC, ed. Clinical and Experimental Toxicology of Cyanide, Bristol,
England: Wright; 1987:467-472.
36. Litovitz TL, Larkin RF, Myers RAM: Cyanide poisoning treated with hyperbaric oxygen. Am J Emerg
Med 1983; 1:94-101.
37. Losek JD, Rock AL, Boldt RR: Cyanide poisoning from a cosmetic nail remover.
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38. Marrs TC: The choice of cyanide antidotes. In: Ballantyne B, Marrs TC, ed. Clinical and Experimental
39. Nagler J, Provost RA, Parizel G: Hydrogen cyanide poisoning: Treatment with cobalt EDTA. J Occup
Med 1978; 20:414-416.
40. Peden NR, Taha A, McSorley PD, et al: Industrial exposure to hydrogen cyanide: Implications for
treatment. BMJ 1986; 293:538.
41. Perrone J, Hoffman RS: Use of sodium nitrite needs further investigation. Ann Emerg
Med 1994; 24:539-540.
42. Rauws AG, Olling M, Timmerman A: The pharmacokinetics of amygdalin. Arch Toxicol 1982; 49:311.
43. Schulz V, Gross R, Patsch T, et al: Cyanide toxicity of sodium nitroprusside in the therapeutic use with
and without sodium thiosulfate. Klin Wochenschr 1982; 60:1393-1400.
44. Schulz V, Bonn R, Kindler J: Kinetics of elimination of thiocynate in 7 healthy subjects and 8 subjects
with renal failure. Klin Wochenschr 1979; 57:243-247.
45. Shragg TA, Albertson TE, Fisher Jr CJ: Cyanide poisoning after bitter almond ingestion. West J
Med 1982; 136:65-69.
46. Shusterman D, Hargis C: Surrogate laboratory measures of cyanide intoxication. [Letter]. Ann Emerg
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J 1989; 65:923-925.
48. Van Heijst AN, Douze JM, Van Kesteren RG, et al: Therapeutic problems in cyanide poisoning. Clin
Toxicol 1987; 25:383-398.
50. Vesey CJ, Batistoni GA: The determination and stability of sodium nitroprusside in aqueous solutions.
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51. Vogel SN: Lactic acidosis in acute cyanide poisoning. In: Ballantyne B, Marrs TC, ed. Clinical and
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Uncited reference
Vegfors M, Lennmarken C: Carboxyhaemoglobinaemia and pulse oximetry. Br J Anaesth 1991; 66:625-

626.


Chapter 87 – Hydrogen Sulfide
JERROLD B. LEIKIN
Essentials
• Sulfur (“rotten egg”) odor
• Metabolic (lactic) acidosis
• Ocular, pulmonary, or mucosal irritation
• Dyspnea, headache, dizziness
• Rapid “knockdown” effect
INTRODUCTION
Hydrogen sulfide (H2S) ranks with carbon monoxide and cyanide in terms of potent, systemic inhalation
toxins.[12] Otherwise known as sulfur hydride, “sewer gas,” “sour gas,” or “stink damp,” it is a colorless,
flammable gas with a sweet taste that is heavier than air (specific gravity = 1.2 g/L) and is usually
encountered in situations in which there is bacterial decomposition of protein or putrefaction (fishing vessels,
livestock, liquid manure). It occurs naturally in volcano or subterranean emissions.[7][8][35] Other toxic gases
associated with putrefaction include methane, ammonia, and carbon dioxide.[35] Humans produce and emit
about 3 mg daily of hydrogen sulfide.[30] Whereas car exhaust may contain as much as 7 ppm of hydrogen
sulfide (especially in cold weather), automobiles typically emit less than 0.1 ppm, which is then diluted in the
atmosphere and not thought to be a significant source of atmospheric hydrogen sulfide. Most atmospheric
emissions emanate from paper mills, tanneries, waste disposal ponds, sewage treatment plants, geothermal
energy sources, or coke ovens. [23] Occupations at risk for exposure to hydrogen sulfide and occupational
standards are listed in Table 87–1 . It has been estimated that as many as 125,000 workers in the United
States may be exposed to hydrogen sulfide, and it is one of the leading causes of sudden death in the
workplace.[21][35] Unlike carbon monoxide or cyanide, there are no reported cases of suicides involving
hydrogen sulfide.
Table 87-1 -- Occupations at Risk for Exposure to Hydrogen Sulfide

Agriculture (liquid manure systems)
Fishing
Brewers
Leather industry (tanning)
Glue making
Rubber vulcanization
Geologists
Nuclear reactor technicians (heavy water production)
Natural gas/petroleum/oil exploration, refining, or transport *
Felt/artificial silk production
Abattoirs
Chemist (purification and preparation of phosphorus barium sulfur/sesquisulfide carbonate; organic sulfur)
Sulfur dye production (brown, black, blue)
Sugar beet factory
Lithography
Fertilizer production
Sausage production
Industrial paper plants (Kraft process)
Coal/lead/gypsum/sulfur mining
Sewer construction
Well/tunnel digging
Septic tank cleaning/industrial waste disposal
Caisson work
Metal smelting
Roofing asphalt
Pesticide production
Rayon production (viscose process)
Occupational Standards
Workplace Standards
10 TLV–TWA (threshold limit values–time-weighted average)
15 STEL (short-term exposure limits)
300 IDLH (immediately detrimental to life and health)
Short-Term Inhalation Limits
200 10 minutes
100 30 minutes
50 60 minutes
* Largest source of occupational exposure.


Pharmacokinetics
Percutaneous absorption of hydrogen sulfide gas does not occur. The primary route of absorption is through
the lungs; and because hydrogen sulfide is relatively insoluble in water, it can pass efficiently through the
respiratory tract. At concentrations of 50 to 600 ppm it causes an irritant effect on the distal and smallest
airways, resulting in diffuse alveolar damage. Thus, it is well absorbed and distributed throughout the
pulmonary circulation. Hydrogen sulfide does not bioaccumulate. Detoxification primarily occurs within 1
hour through oxidative mechanisms to thiosulfate and reversal of the inhibition of cellular respiration, with
subsequent renal elimination. Minor amounts of hydrogen sulfide may enter the muscles, whereupon a
similar process involves transformation by oxymyoglobin.[4] Pulmonary elimination as dissolved H 2S is
believed to be minimal.
Pathophysiology
Hydrogen sulfide is quite lipid soluble and crosses biologic membranes easily.[20] It causes cellular hypoxia
by means of binding to the ferric form of iron in cytochrome oxidase a3, thus inhibiting mitochondrial electron
transport and reducing cellular uptake of oxygen, resulting in anaerobic metabolism and lactic acidosis ( Fig.
87–1 ). Therefore, tissues with high oxygen demands are most susceptible to hydrogen sulfide poisoning.
Hydrogen sulfide may affect the central nervous system directly by mechanisms other than anoxia.
Increased concentrations of brain stem neurotransmitters (alanine, aspartate, -aminobutyric acid, serotonin,
dopamine, epinephrine, norepinephrine, glutamate, glutamine, glycine, and taurine) have been described in
animal studies after exposure to hydrogen sulfide.[20] Electrophysiologic data suggest that hydrogen sulfide
induces neuronal depolarization, possibly through direct inhibition of adenosine triphosphate (ATP)
Figure 87-1 Methemoglobin (MetHb) attracts hydrogen sulfide (H2S) from cytochrome oxidase, forming sulfmethemoglobin (SH
MetHb). This results in reactivation of aerobic metabolism and subsequent rapid detoxification of sulfmethemoglobin by oxidation and
renal elimination.
Hydrogen sulfide may affect the central nervous system directly by mechanisms other than anoxia.
Increased concentrations of brain stem neurotransmitters (alanine, aspartate, -aminobutyric acid, serotonin,
dopamine, epinephrine, norepinephrine, glutamate, glutamine, glycine, and taurine) have been described in
animal studies after exposure to hydrogen sulfide.[20] Electrophysiologic data suggest that hydrogen sulfide
induces neuronal depolarization, possibly through direct inhibition of adenosine triphosphate (ATP)
production or increased conductance of the potassium channel and inhibition of the sodium/potassium
ATPase activity.[20] Although human data are lacking, based on rodent studies it appears that chronic
exposure to low levels of hydrogen sulfide (20–75 ppm) can depress fetal neurotransmitter content and
cerebellar Purkinje cells. Thus, hydrogen sulfide may cause a reversible encephalopathy in a neonate.[10][20]
The hydrogen sulfide anion (HS-) can form a complex with reduced hemoglobin known as
sulfmethemoglobin (as differentiated from sulfhemoglobin) and is similar to cyanmethemoglobin; however,
measurement of this entity is not clinically useful.


Hydrogen sulfide is about as toxic and acts as rapidly as hydrogen cyanide, within seconds at high
exposure. To some extent, there is a dose-effect relationship ( Table 87–2 ), with mucosal irritation occurring
at concentrations over 50 ppm.[20] Signs of mucosal irritation include ocular pain, keratitis (“gas eye,”
“spinner’s eye,” or “sore eye”), photophobia, cough, sore throat, blepharospasm, nausea, and vomiting.[16]
Prolonged exposure can cause corneal ulceration, which can progress to corneal scarring and permanent
visual impairment.[20] Although the characteristic rotten egg or sulfur odor can occur at levels below 1 ppm
(higher threshold levels for older individuals), olfactory fatigue can occur after 10 minutes at concentrations
of approximately 100 ppm and even faster at higher concentrations.[20]
Table 87-2 -- Clinical Presentation of Hydrogen Sulfide Exposure: Dose–Effect Relationship

ppm Response
0.05 Taste threshold
0.005 to 0.25 Odor threshold
5 to 10 Odor is obvious; muscle fatigability may result
50 to 150 Ocular irritation
80 to 100 Mild symptoms (nausea, vomiting, salivation, lacrimation)
100 to 150 Sore throat, cough, olfactory nerve paralysis in 3 to 15 minutes, fatal to birds and guinea pigs
150 to 300 Blepharospasm, blurred vision
250 to 500 Pulmonary edema/bronchopneumonia
50 to 500 Respiratory irritant
500 Headache, dizziness, central nervous system depression within ½ hour
800 to 1000 Lethal level, coma or respiratory arrest within ½ hour
Over 1000 One single breath can cause coma or respiratory arrest
Low level (about 10 ppm) exposure appears to have little effect on cardiac or pulmonary function; increase in
muscle lactate and reduced oxygen uptake have been noted in muscles of exercising humans during low
level exposure, thus demonstrating an inhibition of muscular aerobic metabolism and increasing muscle
fatigue.[4][5][6]
Systemic signs of cellular anoxia can occur at concentrations over 250 ppm with the central nervous system
and cardiovascular system being primary target organs. Dyspnea (incidence as high as 23 per cent), cough,
tachypnea, and chest pain are common initial complaints and can progress to pulmonary edema.[27]
Headache, dizziness, lethargy, irritability, confusion, nystagmus (horizontal or vertical), and delirium may
also be noted, followed by a toxic encephalopathy, anoxic seizures, and coma with prolonged exposure at
concentrations over 500 ppm. Associated cardiovascular changes include hypotension, tachycardia,
myocardial depression, and cardiac dysrhythmias, with subendocardial myocardial infarction also being
described.[18][30] As with any cellular asphyxiant, a type A lactic acidosis can occur.
At levels over 1000 ppm, sudden death can occur from direct respiratory depression and respiratory
paralysis. Individuals may have associated traumatic injuries from falls or accidents as a result of their
sudden neurologic impairment from the exposure.[2] As many as 5 per cent of victims may be dead on arrival
at the hospital.


Differential diagnostic entities are listed in Table 87–3 . Because the sulfuric odor of hydrogen sulfide can be
detected at relatively very low concentrations before it is harmful, this unpleasant odor may be a stimulus for
the development of epidemic mass hysteria.[15][17][18] Chronic exposure can result in diarrhea, weakness,
abdominal pain, conjunctivitis, nausea, vomiting, weight loss, dizziness, and headache. These symptoms
may be confused with plumbism or subacute carbon monoxide intoxication.[20] Purple and blue discoloration
of pennies and the edges of dimes may provide early clues to H 2S exposure.[11]
Table 87-3 -- Differential Diagnosis of Hydrogen Sulfide Exposure

Inhalation Toxin
Simple asphyxiant (i.e., methane, propane)
Carbon monoxide
Hydrogen cyanide
Organic solvents
Methylene chloride
Nickel carbonyl
Ammonia
Nitrogen oxides
Formaldehyde
Polyvinyl chloride
Carbon dioxide
Carbon disulfide
Carbonyl sulfide (may be endogenously converted to H2S)
Other Entities
Hyperventilation syndrome
Foodborne/waterborne infection
Epidemic hysteria
Low oxygen concentration in the environment
Other Causes of “Rotten Egg” Odor
Disulfiram
Mercaptans
Sulfur compounds (i.e., sulfur dioxide)
Carbon disulfide (“rotten cabbage” odor)
Trimethylamine (“rotten fish” odor)
Chronic Exposure
Lead
Carbon monoxide (subacute: concentrations probably under 150 ppm)


LABORATORY STUDIES
Laboratory analysis of the toxic patient is not specific for hydrogen sulfide. The metabolic acidosis may also
be seen after exposure to other toxic inhalants (e.g., carbon monoxide or cyanide), and chest radiographs
and electrocardiograms will not be diagnostic. Arterial blood gases may[28] or may not demonstrate an
oxygen saturation gap (calculated oxygen saturation minus measured oxygen saturation = 5 per cent
difference).[24] Although it has not been formally studied, pulse oximetry may overestimate oxygen saturation
in a patient exposed to hydrogen sulfide and thus may not be useful. There is no clinical benefit in obtaining
sulfmethemoglobin levels. Postmortem blood sulfide ion levels in victims of hydrogen sulfide exposure range
from 0.92 to 3.75 mg/L (normal sulfide concentration in whole blood is under 0.05 mg/L).[3][14] Direct
hydrogen sulfide atmospheric measurements can be assayed by a calorimetric method using continuous
infrared spectroscopy; a gas diffusion denuder can remove sulfur dioxide or hydrogen sulfide.[9][15]


TREATMENT
Prehospital
As with virtually every other toxic inhalant, safe evacuation of the patient with appropriate airway
management and prompt administration of high flow humidified oxygen should be performed ( Table 87–4 ).
Rescuers must proceed especially cautiously in the hydrogen sulfide environment. In an enclosed
environment, self-contained breathing apparatus and special chemical protective clothing are required with
safety harnesses and outside observers.[7] Rescuers can also become victims during administration of
mouth-to-mouth resuscitation efforts.
Table 87-4 -- Treatment Plan for Hydrogen Sulfide Exposure

100% Humidified oxygen
Copious irrigation with saline or water for ocular exposure
Methemoglobin induction (should be initiated within minutes):
Inhalation of amyl nitrite (30 seconds per minute for 5 minutes)
Intravenous sodium nitrite (3% solution: 10 mL in adults, or 0.33 mL/kg in children who are not anemic)
Crystalloid infusion for hypotension
Intravenous sodium bicarbonate (1 to 2 mEq/kg) for refractory acidosis
Benzodiazepines or barbiturates for seizures
Consider hyperbaric oxygen for neurologic abnormalities, acidosis, or pulmonary edema
Antidote
The production of methemoglobin will result in competitive binding of the hydrogen sulfide anion to form the
nontoxic sulfmethemoglobin compound. Inhalation of amyl nitrite ampules (30 seconds per minute for 5
minutes), or preferably intravenous administration of sodium nitrite, is used to produce methemoglobin. Both
drugs are components of the cyanide antidote kit. The dosage of sodium nitrite (3 per cent solution) is 10 mL
(300 mg) at a rate of 2.5 to 5 mL/min in adults and 0.33 mL/kg (10 mg/kg) up to 10 mL in children, but lower
if the patient is anemic; it is administered intravenously over 15 to 20 minutes. It is the primary
pharmacologic treatment of the severely toxic patient, although there are no case-control studies on its
efficacy.[25] Because hydrogen sulfide does not accumulate and is detoxified very rapidly, this antidote
needs to be started within minutes and given over a short time period (under 1 hour) for maximum benefit.
There is probably minimal benefit from the antidote if the patient has already shown clinical improvement.
Prolonged therapy is not necessary. Unlike cyanide poisoning, the enzyme rhodanese is not involved in
hydrogen sulfide metabolism, so that sodium thiosulfate is not useful.[19]
Supportive Therapies
Further advanced life support measures are dictated by the patient’s clinical condition. Supportive therapy
consists of crystalloid infusions with vasopressors (dopamine or norepinephrine) for treatment of
hypotension and benzodiazepines for seizure control with barbiturates and possibly general anesthesia and
neuromuscular paralysis for refractory seizures. Intravenous sodium bicarbonate (1 to 2 mEq/kg) should be
used to treat acidosis with a serum pH under 7.2 that is not responsive to the previously mentioned
treatment modalities.
Other Therapies
Hyperbaric oxygen (at 2 to 3 ATA) has been used in several cases and should be considered in the
neurologically compromised or acidemic patient refractory to conventional therapy.[1][19][22][29][31][34] Patients
exhibiting pulmonary edema may also benefit from this modality. The mechanism proposed entails
competitive binding by oxygen with sulfide for cytochrome binding while enhancing catalytic oxidation of
sulfide.[29] As with nitrite therapy, it needs to be instituted promptly.[1]
Exchange blood transfusion can be considered in severely affected infants, although this modality has not
been studied.
Ocular Treatment
Ocular treatment should consist of copious irrigation with saline or water for 15 to 30 minutes.
Keratoconjunctivitis can be treated with a brief-acting cycloplegic agent, antibiotic ointment, and eye
patching. Because spontaneous epithelial healing usually occurs, prolonged administration of local ocular
anesthetics can retard this process and should be avoided.


DISPOSITION
Any symptomatic patient should be admitted to the hospital for observation for 24 to 48 hours. Asymptomatic
patients may be discharged after 6- to 8-hour observation after exposure. Patients who were initially
unconscious should be re-examined within 1 week to monitor for any delayed neurologic sequelae.[12]


SEQUELAE
Although complete recovery after prompt resuscitation and return of the patient to a normal mental status
within 4 hours usually occurs, long-term neurologic sequelae such as retrograde amnesia, cerebellar ataxia,
sensorineural hearing loss (at 2000 Hz), intention tremor, and spasticity have been described.[26][33]
Noncardiogenic pulmonary edema may be delayed for up to 3 days after exposure. Hydrogen sulfide does
not appear to be carcinogenic or mutagenic.[20]


REFERENCES
1. Al-Mahasneh QM, Cohle SD, Haas E: Lack of response to hyperbaric oxygen in a fatal case of hydrogen
sulfide poisoning: A case report. Vet Hum Toxicol 1989; 31:353.
2. Arnold IM, Dufresne RM, Alleyne BC, et al: Health implications of occupational exposures to hydrogen
sulfide. J Occup Med 1985; 27:373-376.
3. In: Baselt RC, Cravey RH, ed. Disposition of Toxic Drugs and Chemicals in Man, 4th ed. Foster City,
4. Bhambhani Y, Burnham R, Snydmiller G, MacLean I: Effects of 10 ppm hydrogen sulfide inhalation in

exercising men and women: Cardiovascular, metabolic and biochemical responses. J Occup Environ
Med 1997; 39(2):122-129.
5. Bhambhani Y, Burnham R, Snydmiller G, et al: Effects of 10 ppm hydrogen sulfide inhalation on

pulmonary function in healthy men and women. J Occup Environ Med 1996; 38:1012-1078.
6. Bhambhani Y, Burnham R, Snydmiller G, et al: Effects of 5 ppm hydrogen sulfide inhalation on

biochemical properties of skeletal muscle in exercising men and women. Am Ind Hyg Assoc
J 1996; 57:464-468.
7. Centers for Disease Control : Fatalities attributed to entering manure waste pits—Minnesota—1992.
MMWR 1993; 42:325-332.
8. Centers for Disease Control : Occupational fatality following exposure to hydrogen sulfide—Nebraska.
MMWR 1986; 35:533-535.
9. Cobourn WG, Husar RB, Husar JD: Continuous in-site monitoring of ambient particulate sulfur using
flame photometry and thermal analysis. Atmos Environ 1978; 12:89.
10. Gaitonde UB, Sellar RJ: Long-term exposure to hydrogen sulfide producing subacute encephalopathy in
a child. BMJ 1987; 294:614.
11. Graeme KA, Wallace KL, Curry SC, et al: Hydrogen sulfide–induced changes in coin appearance.
[Abstract]. J Toxicol Clin Toxicol 1998; 36:469-470.
12. Hartman DE (ed): Hydrogen sulfide. In Neuropsychological Toxicology: Identification and Assessment
of Human Neurotoxic Syndromes, 2nd ed. New York, Plenum Press, pp 395–397.
14. Jappinen P, Tenhunen R: Hydrogen sulphide poisoning: Blood sulphide concentration and changes in
haem metabolism. Br J Ind Med 1990; 47:283-285.
15. Landrigan PJ, Miller B: The Arjenyattah epidemic: Home interview data and toxicological analysis.
Lancet 1983; 2:1474-1476.
16. Luck J, Kaye SB: An unrecognized form of hydrogen sulfide keratoconjunctivitis. Br J Ind
Med 1989; 46:748-749.
17. Modan B, Tirosh M, Weissenberg E, et al: The Arjenyattah epidemic: A mass phenomenon: Spread and
triggering factors. Lancet 1983; 2:1472-1474.
18. Mofenson HC. Hydrogen sulfide in Poisindex System. Rumack BH, Hess AJ, Gelman CR (eds).
Englewood, CO, Micromedex, vol 88; edition expires May 31, 1996.
19. Ravizza AG, Carugo D, Cerchiari EC: The treatment of hydrogen sulfide intoxication, oxygen vs. nitrites.
Vet Hum Toxicol 1982; 24(4):241-243.
20. Reiffenstein RJ, Hulbert WC, Roth SH: Toxicology of hydrogen sulfide. Ann Rev Pharmacol
Toxicol 1992; 32:109-134.
21. Sittig M: Handbook of Toxic and Hazardous Chemicals and Carcinogens. 2nd ed. Park Ridge,
NJ, Noyes Publications, 1985.
22. Smilkstein MJ, Bronstein AC, Pickett HM, et al: Hyperbaric oxygen therapy for severe hydrogen sulfide
23. Smith RP: The sulfur cycle and reducing-type air pollution. In: Smith RP, ed. A primer of environmental
toxicology, Philadelphia: Lea & Febiger; 1992:151-170.
24. Smith RP, Gosselin RE: Hydrogen sulfide poisoning. J Occup Med 1979; 21:93.
25. Stine RJ, Slowsberg B, Beacham BE: Hydrogen sulfide intoxication: A case report and discussion of
treatment. Ann Intern Med 1976; 85:756-758.
26. Synder JW, Safir EF, Summerville GP, et al: Occupational fatality and persistent neurological sequelae
after mass exposure to hydrogen sulfide. Am J Emerg Med 1995; 13:199-203.
27. Tanaka S, Fujimoto S, Tamagaki Y, et al: Bronchial injury and pulmonary edema caused by hydrogen
sulfide poisoning. Am J Emerg Med 1999; 17:427-429.
28. Thoman M: Sewer gas: Hydrogen sulfide intoxication. Clin Toxicol 1969; 2:383-386.
29. Tomaszewski CA, Thom SR: Use of hyperbaric oxygen in toxicology. Emerg Med Clin North
Am 1994; 12:445-446.
30. Vathenen AS, Emberton P, Wales JM: Hydrogen sulphide poisoning in a factory worker.
Lancet 1988; 1:305.
31. Vicas I, Fortin S, Uptigrove OJ, et al: Hydrogen sulfide exposure treated with hyperbaric oxygen. Vet
33. Wasch HH, Estrin WJ, Yip P, et al: Prolongation of the P-300 latency associated with hydrogen sulfide
exposure. Arch Neurol 1989; 46:902-904.
34. Whitcraft DD, Baily TD, Hart GB: Hydrogen sulfide poisoning treated with hyperbaric oxygen. J Emerg
Med 1985; 3:23-25.
35. Zenz C, Cordasco EM: Hydrogen sulfide. In: Zenz C, Dickerson OB, Horvath Jr EP, ed. Occupational
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Hoffman RS: Hydrogen sulfide. Emerg Med 1995; 27(7):45.
Wang TC: A study of bioeffluents in a college classroom. ASHRAE Trans 1975; 81(part 1):32-44.


Chapter 88 – Arsenic
DANIEL HRYHORCZUK JANET ENG
Essentials
• Acute toxicity: gastroenteritis, cardiovascular instability, encephalopathy, seizures, acute respiratory
distress syndrome, renal failure
• Chronic toxicity: personality changes, fatigue, sensorimotor peripheral neuropathy, pancytopenia,
dermal keratoses, cancers
• Bioassays: 24-hour urine arsenic, hair and nail arsenic
INTRODUCTION
Arsenic is a metalloid with a complex chemistry and an infamous criminal history. It is the 20th most
abundant element in the Earth’s crust and forms various trivalent and pentavalent inorganic and organic
compounds. It has been a favorite of poisoners for centuries and is widely recognized by the public for its
toxicity.[3][10][13][58] Despite its infamous reputation, it is used in many industrial settings, is used as a
chemotherapeutic agent, and is a common, although unessential, component of our daily diet.
Environmental sources of arsenic range from underground aquifers to volcanoes. Natural contamination of
underground aquifers whose water was used for drinking resulted in a large-scale epidemic of poisoning in
India and Bangladesh.[60][70] However, the major source of environmental arsenic for the general population
in the United States is food. The average intake of arsenic in the United States population is 50 µg per day.
Seafood and shellfish contain the highest concentrations of arsenic in the form of organic arsenic
(arsenobetaine), which is considered nontoxic.[6] Other dietary sources of arsenic include meats, grains, and
drinking water. At this writing, the United States Environmental Protection Agency has recommended
decreasing the standard for arsenic in drinking water from 50 ppb to 5 ppb. Potential nontoxic dietary
sources should always be considered when the results of arsenic bioassays are interpreted.
Historically, famous epidemics of arsenic poisoning included the “British beer-poisoning epidemic,” which
affected thousands of British beer drinkers at the turn of the century. The source of the epidemic was traced
to arsenic contamination of sulfuric acid that was used to make glucose.[38] In 1955, 12,000 Japanese
infants were poisoned with infant formula contaminated with arsenic. In 1972 and 1973, chronic arsenic
intoxication in Singapore was traced to contamination of sin lak, an antiasthmatic herbal preparation.[71]
More recently, mass arsenic poisoning occurred with deliberate contamination of food at a festival in Japan.
Arsenic has also been found as an occasional contaminant of illegally produced liquor, or “moonshine.”
Uses of arsenic have varied through history. The most common current use is as a wood preservative in
combination with copper and chromium. Burning of arsenic-treated wood has resulted in local poisoning
outbreaks.[55] Arsenic is a byproduct of primary smelting operations that, if uncontrolled, can release huge
amounts of arsenic into the environment. Arsenic has been used in agriculture as an insecticide, herbicide,
algicide, and growth stimulant. It has also been used as an ant and rat poison. In the past, it was available
as Terro Ant Poison; today, it is available in Grant’s Ant Killer, which contains 0.46 per cent arsenic trioxide.
Other uses for arsenic include the electronics industry, glass clarification, and medicinal applications.
Arsenic has been used in the treatment of syphilis,[74] yaws, amebic dysentery, and trypanosomiasis.[31a] It
had been used in Fowler’s solution (1% potassium arsenite). Today, it can be found as a homeopathic
remedy in some health food stores.
This chapter focuses on the toxicity of inorganic arsenic.


Toxicokinetics.
Inorganic arsenic is readily absorbed through the gastrointestinal and respiratory routes. Dermal absorption
is minimal unless the arsenic is present in a lipid-soluble vehicle or the skin integrity is damaged, but
significant absorption can occur through mucous membranes. Once absorbed, arsenic can change valence:
arsenites can be oxidized to arsenates, and vice versa. The volume of distribution is 0.21 L/kg. Distribution
from the central compartment is rapid, with 90 per cent being eliminated from the blood with a half-life of 2
hours. The remainder is eliminated more slowly over a period of days to weeks.[48] Arsenic can cross the
blood-brain barrier and is stored in liver, kidney, heart, lung, and muscle. Arsenite is methylated in the liver
to form methylarsonic acid, followed by dimethylarsinic acid. Renal elimination is the primary route of
excretion for these metabolites plus any unchanged arsenic. Maximal urinary excretion occurs in the first
week after exposure, but continued excretion can occur for weeks to months. Depending on the time course
of testing, blood and urine arsenic levels may fall below the concentrations considered toxic. Thus, the
clinician must consider the onset of symptoms in relation to time of testing when interpreting blood and urine
arsenic levels. Arsenic is also eliminated in bile, and small amounts are eliminated in saliva, sweat, and milk.
Arsenic binds to keratin and is also present in hair, nails, and skin. Levels in hair and nails may be more
reliable when the potential for remote exposure is being assessed. Again, individual factors, such as hair
and nail growth (0.4 mm/d for hair, 0.1 mm/d for nails) and hair and nail cutting, must be considered when
interpreting test results.
Pathophysiology.
The toxicity of inorganic arsenic varies with valence. Trivalent arsenic is more toxic than pentavalent arsenic.
Trivalent arsenic (arsenite) inhibits the pyruvate dehydrogenase complex by preventing the regeneration of
lipoamide, a substance necessary for the conversion of pyruvate to acetyl coenzyme A. Arsenite also
interferes with the alpha-ketoglutarate dehydrogenase complex in the Krebs cycle. The result of both
mechanisms is a decrease in adenosine triphosphate production. Arsenic5+ (arsenate) is similar to
phosphate both chemically and structurally. Arsenate substitutes for inorganic phosphate during the
production of adenosine triphosphate. An adenosine diphosphate–arsenate complex also forms that
uncouples oxidative phosphorylation. Patients with glutathione deficiency, such as long-term ethanol
abusers and malnourished patients, may be at higher risk for developing adverse effects because reduced
glutathione is necessary for methylation. Arsenic inhibits both monothiol and dithiol enzymes.
Arsenic is a direct gastrointestinal irritant that causes necrosis and ulceration before it is completely
absorbed. Arsenic also causes venodilation and directly alters capillary membrane permeability.


The clinical presentation of arsenic intoxication depends on the route, dose, and timing of exposure. The
authors reviewed 37 reported cases (63 patients) of arsenic intoxication that illustrate the spectrum of clinical
presentation, depending on whether exposure is acute, subacute, or chronic. * Duration of exposure was
classified as acute (up to 7 days), subacute (1 week to 1 month), and chronic (1 month to years).
* References 1a , 2 , 3 , 4 , 10 , 13 , 14 , 18 , 20 , 21 , 22 , 24 , 25 , 27 , 30 , 32 , 34 , 35 , 39 , 40 , 43 , 45 , 47 , 49 , 52 , 54 , 55 , 62 , 63 , 65 , 68 ,
72 , 73 , 74 , 75 and 77 .
Acute Toxicity.
The classic presentation of acute arsenic intoxication is described as dysphagia associated with a metallic
taste. This is followed by nausea, vomiting, abdominal pain, and “rice water” diarrhea within several hours of
ingestion. Cardiovascular collapse can occur as a result of vasodilation, myocardial dysfunction, and
intravascular volume depletion. Electrocardiographic findings may include nonspecific T wave changes[74]
and prolonged QTc interval.[25] Seizures and coma may occur after a massive ingestion, followed by
encephalopathy days later. The encephalopathy may result from cerebral edema followed by
microhemorrhages and areas of necrosis.[15][66] Acute tubular necrosis may occur after a large ingestion.
Peripheral neuropathy may present within 3 weeks of ingestion.
Our review of 27 acute poisoning cases reveals that gastrointestinal symptoms occur most commonly, with
vomiting (74%), nausea (63%), abdominal pain (59%), and diarrhea (59%) being reported ( Table 88–1 ).
Cardiac involvement and hypotension occurred in 37 per cent of cases. Cardiac findings included left bundle
branch block,[54] systolic ejection murmur and rub,[77] ventricular fibrillation,[43] and prolonged QT
interval.[3][24][30] Renal insufficiency and peripheral neuropathy each occurred in one third of the cases. The
peripheral neuropathy presented more commonly as paresthesias than as muscle atrophy or loss of deep
tendon reflexes. Skin findings were uncommon in acute poisoning; Mees lines and hyperpigmentation were
reported in only 7 per cent of cases, whereas hyperkeratoses were reported in 4 per cent of cases. Coma
and seizures were rare.
Table 88-1 -- Signs and Symptoms of Acute Arsenic Toxicity

Manifestation Occurrence (%)
Vomiting 74
Nausea 63
Abdominal pain 59
Diarrhea 59
General weakness 41
Cardiac involvement 37
Hypotension 37
Peripheral neuropathy 37
Renal insufficiency 33
Irritability 30
Anemia 26
Confusion 19
Mees lines 11
Basophilic stippling 7
Pigmentation changes 7
Dysphagia 4
Headache 4
Keratosis 4
SubacuteToxicity.
Subacute poisoning has features of both acute and chronic toxicity. Gastrointestinal symptoms are common:
vomiting (79%), diarrhea (47%), and abdominal pain (21%) ( Table 88–2 ). Peripheral neuropathy was seen
in 58 per cent of cases, and cardiac involvement was reported in 32 per cent. Electrocardiographic
abnormalities included prolongation of QTc interval, torsades de pointes,[2][24][62] and ventricular
fibrillation.[68] Anemia was more common (37%) than in acute poisoning, with basophilic stippling reported in
11 per cent of cases. Mees lines were seen in 42 per cent of the cases. Renal insufficiency was reported in
only 11 per cent of cases.
Table 88-2 -- Signs and Symptoms of Subacute Arsenic Toxicity

Vomiting 79
General weakness 63
Nausea 63
Diarrhea 47
Mees lines 42
Anemia 37
Cardiac (e.g., dysrhythmias, hypotension) 32
Confusion 26
Abdominal pain 21
Irritability 11
Keratosis 11
Renal insufficiency 11
Headache 5
Hemolysis 5
Chronic Toxicity.
Chronic arsenic poisoning can develop insidiously, and the diagnosis can be difficult. The classic description
of chronic arsenic poisoning includes peripheral neuropathy accompanied by dermal changes. In Kelynack’s
series,[38] patients complained of weakness and pain in the limbs. They described sensations of pins and
needles, numbness, and dysesthesias. Their patients had darkened skin, which was often mistaken for dirt
that could not be washed away. The skin also had small areas with hypopigmentation, which later became
known as “rain drop” lesions. Dermal manifestations included hyperkeratoses, brittle nails, and Mees lines.
Gastrointestinal symptoms were infrequent, and constipation was more common than diarrhea.
In our review of these and other cases, peripheral neuropathy was the most common complication, reported
in 87 per cent of the cases ( Table 88–3 ). Sensory symptoms were more common than motor, with
paraesthesias reported in 93 per cent of cases, general weakness in 40 per cent, and muscle atrophy in 7
per cent. A history of diarrhea was still common, reported in 73 per cent of cases. Skin changes were
common, including hyperkeratoses (60%), Mees lines (60%), and pigmentation changes (13%). Central
nervous system symptoms were more common than in acute and subacute toxicities, with 73 per cent of
patients reporting headache and 33 per cent reporting confusion.
Table 88-3 -- Signs and Symptoms of Chronic Arsenic Toxicity

Diarrhea 73
Headache 73
Keratosis 73
Alopecia 60
Mees lines 60
General weakness 40
Confusion 33
Nausea 20
Vomiting 20
Irritability 13
Abdominal pain 7
Anemia 7
Dysphagia 7
Systemic occupational poisoning is rarely seen in industry. More often, workers experience direct irritating
effects from respiratory exposure to arsenic dust. Symptoms include hoarseness, nasal septal perforation,
and upper respiratory tract disease. Systemic toxic manifestations can include peripheral neuropathy,
anemia, skin changes, and other organ system involvement observed through other routes of exposure.
Inorganic arsenic is a recognized human carcinogen, primarily of the respiratory tract and skin (International
Agency for Research on Cancer group 1 and U.S. Environmental Protection Agency group A).


A list of conditions and other toxins to be considered in the differential diagnosis of arsenic toxicity is
contained in Table 88–4 .
Table 88-4 -- Differential Diagnosis of Arsenic Poisoning

Thallium poisoning
Guillain-Barré syndrome *
Alcoholic polyneuropathy
Diabetic neuropathy
Acute porphyria
Lead poisoning
Viral influenza
Toxin-induced hemolysis
Arsine
Stibine
* Arsenic toxicity causes a symmetrical sensory motor axonopathy injury. Guillain-Barré (infectious neuronitis) produces cranial nerve lesions,
whereas arsenic is associated with more prominent sensory manifestations and more severe weakness of the distal extremities.


LABORATORY STUDIES
Arsenic levels are measured by atomic absorption spectrophotometry and can be obtained from blood,
urine, hair, and nail samples. Blood levels are not considered to be a reliable measure for chronic low-level
arsenic toxicity, because arsenic is detectable only for 2 to 4 hours after ingestion.[50] Serum levels of
arsenic in nonexposed persons are less than 3 µg/dL. [17] Urinary levels of arsenic are considered to be the
most accurate indicator of recent exposure, and urinary arsenic levels peak 1 to 2 days after acute
exposure. The presence of organic arsenobetaine after ingestion of certain seafoods may cause an
elevation of urinary arsenic levels.[6] Inorganic and organic arsenic can be fractionated by a cation-exchange
cartridge, and this fractionation should be requested whenever elevation of arsenic levels by seafood
ingestion is suspected. Normal urine levels of arsenic in an unexposed person should be less than 25 µg per
24 hours or 10 to 30 µg per liter of urine.[1] Urinary levels of inorganic arsenic, both trivalent and pentavalent,
peak within 10 hours and normalize approximately 20 to 30 hours after ingestion. Levels of urinary
methylarsonic acid and dimethylarsinic acid peak within 40 to 50 hours after ingestion and normalize
approximately 6 to 20 days after ingestion.[5a][48][71a] Elevated arsenic levels in hair and nails indicate past
exposure to arsenic; these levels can remain elevated for 6 to 12 months until the growth and removal
process results in removal of contaminated hair and nails. Normal arsenic levels for nails and hair are less
than 1.0 µg/g.[17] External contamination of hair by arsenic may cause falsely elevated levels; therefore,
analysis of pubic hair should be considered.
Abdominal radiographs may be helpful initially after an acute ingestion because inorganic arsenic is
radiopaque. The rapid absorption of arsenic may limit the usefulness of later radiographs. Several qualitative
tests can assist in rapid diagnosis. The Gutzeit test detects urinary levels as low as 1 µg per milliliter of urine
and is conducted as follows: (1) 5 mL of urine is placed in a test tube, (2) several drops of sulfuric acid and
several granules of zinc are added, and (3) the test tube is covered with filter paper that has been wetted
with two drops of silver nitrate solution. Brown or black discoloration of the filter paper is considered a
positive result.[31] The Reinsch test can be used to screen for arsenic in gastric contents. This test is
sensitive but not specific for arsenic, because it can cross-react with antimony and bismuth. Ten milliliters of
gastric contents is placed in a flask. Ten milliliters of 2-N-hydrochloric acid and a 0.5-cm2piece of copper foil
are added. The mixture is boiled for 5 minutes. Black staining of the copper foil is considered a positive
result.
One should also obtain a complete blood count with peripheral smear, a chemistry panel, and an
electrocardiogram, looking for the presence of anemia, basophilic stippling, leukopenia, renal insufficiency,
and prolongation of the QTc interval. Those findings may be useful indicators of arsenic toxicity but may not
always be present.


TREATMENT
General supportive care should be instituted during the initial treatment of the acutely poisoned patient (
Table 88–5 ). If the patient presents shortly after ingestion, gastric decontamination with orogastric lavage
may be indicated, although its efficacy may be limited because of the rapid gastrointestinal absorption of
arsenic. Activated charcoal should not be used unless coingestants are suspected, because arsenic does
not adsorb to activated charcoal. Intravenous crystalloids should be infused to maintain intravascular volume
in the event of circulatory collapse. All patients should be placed on a cardiac monitor and evaluated for
cardiac dysrhythmias or evidence of conduction abnormalities. In the event of renal failure, hemodialysis
should be instituted. Hemodialysis has been reported to eliminate arsenic at clearance rates of 76
mm/min[72] and 87 mL/mm.[23]
Table 88-5 -- Treatment of Arsenic Poisoning

Supportive care
Acute toxicity: monitor for dysrhythmias, hypotension, seizures
Restrict food and drink from outside hospital
GI decontamination (if radiopaque material is seen on abdominal radiograph):
Whole-bowel irrigation until radiopaque material clears on radiograph
Continuous nasogastric suction to interrupt enterogastric recirculation
Chelation therapy:
Institute for elevated blood or urinary arsenic levels * or if poisoning is suspected in acutely ill patient
Chelation therapy †
BAL 3–5 mg/kg IM every 4 hours
DMSA, 10 mg/kg PO tid for 5 days, then bid
Hemodialysis—institute for renal failure
BAL, British antilewisite; GI, gastrointestinal; DMSA, 2,3-dimercaptosuccinic acid.
* Assumes that elevated levels are not due to contamination from arsenobetaine or other arsenical species found in foods.
† Continue chelation until the urinary arsenic level is <50 µg/L per 24 hours. DMSA can be substituted for BAL when patient can tolerate an
oral chelator.
Chelation.
Therapy should be initiated if arsenic toxicity is suspected. Chelators available in the United States include
2,3-dimercaptopropanol (BAL, British antilewisite), 2,3-dimercaptosuccinic acid (DMSA), and D-
penicillamine. BAL was developed during World War II because of concern about poisoning from lewisite, a
toxic dichlorovinyl arsine vesicant used as a form of chemical warfare.[56] BAL was to be used as a topical
agent, but fortunately, it was never needed to treat lewisite chemical warfare. BAL was first used clinically for
the treatment of arsenical dermatitis caused by diphenylamine chlorasine and an organoarsenical
antisyphilitic agent.[44]
British antilewisite is a lipid-soluble dithiol chelator formulated in peanut oil to prevent its oxidation. Because
of the peanut oil, it can be administered only as a deep intramuscular injection. BAL binds to arsenic to form
a BAL-thioarsenite compound, which is readily eliminated. Several studies have evaluated the efficacy of
BAL for the treatment of arsenic. Heyman and colleagues[33] showed that BAL was not effective in treating
the neuropathy associated with arsenic poisoning, possibly because the treatment was not instituted until 4
to 6 weeks after ingestion. Jenkins[36] demonstrated that neuropathy could be prevented if BAL therapy was
instituted within hours of ingestion. Potential side effects from BAL include elevated blood pressure,
tachycardia, nausea, vomiting, headache, burning sensation of the lips, coma, and seizures. These side
effects are more commonly seen with increased dosages of BAL.[76] BAL also chelates other essential
metals, such as copper. The recommended dose of BAL is 3 to 5 mg/kg every 4 hours until the urinary
arsenic level is less than 50 µg/L per 24 hours.[26] Concern exists that BAL may redistribute arsenic into the
brain.[67] However, the clinical relevance of this remains unknown, and BAL may be superior to the water-
soluble chelators DMSA and 2,3-dimercaptopropanesulphonate sodium in removing arsenic not located in
the extracellular space.[51]
2,3-Dimercaptosuccinic acid, a derivative of dimercaprol, is a polar substance that can be administered

orally and is well tolerated. It chelates extracellular but not intracellular arsenic. The dimercaptan-arsenic
complex is water soluble, resulting in the renal excretion of arsenic.[29][46] DMSA is as effective as BAL in
decreasing the concentration of arsenic in the liver, kidneys, spleen, and brain of mice poisoned with arsenic
trioxide.[2][65a] DMSA produced greater urinary and fecal elimination of arsenic than BAL.[28] Lenz and
associates[42] published a case report of a patient who was treated with DMSA and survived arsenic
poisoning after an attempted suicide. The optimal dosing of DMSA is unknown. Some experts follow the
treatment guidelines established for lead. The initial regimen is 10 mg/kg per dose every 8 hours for 5 days,
followed by every 12 hours for 14 days or until the urine arsenic is less than 50 µg/L per 24 hours. DMSA
appears to have no effect on zinc, iron, calcium, or magnesium elimination.[29]
D-Penicillamineis an oral monothiol chelator that is not as effective as dimercaprol or DMSA.

Recommended doses of D-penicillamine are 100 mg/kg per day (maximum, 1 g/d), given in divided doses
every 6 hours before meals for 5 days. A 3- to 5-day period should pass before therapy is reinstituted,[57] if
repeat treatment is necessary. Chelation therapy should continue until urinary arsenic levels are less than 50
µg/L per 24 hours. Side effects of D-penicillamine include rashes, leukopenia, eosinophilia,
thrombocytopenia, and nephrotoxicity. [42] Given the superior efficacy of DMSA, which can also be
administered orally, D-penicillamine should not be used unless DMSA is unavailable.


DISPOSITION
Patients displaying symptoms of acute arsenic toxicity should be admitted to the hospital for supportive care
and chelation therapy. All suicidal patients require a psychiatric evaluation when they are medically stable. If
homicidal intent is a concern, the appropriate law enforcement authorities should be notified. The patient
should also be prohibited from ingesting items brought from outside the hospital. Long-term physical therapy
and rehabilitation may be necessary for those experiencing neurologic sequelae. Full resolution of
neurologic symptoms and muscle weakness may not occur.


SEQUELAE
Persistent peripheral neuropathy with partial to full recovery occurring over months to years has been
reported.[8] Recovery from encephalopathy is less likely.[15]


SPECIFIC SITUATIONS
Liver disease has been associated with chronic poisoning from arsenic, because of its direct hepatotoxicity
leading to hepatic necrosis. Anasarca and ascites have been associated with arsenic toxicity. Chronic
arsenic poisoning producing hepatitis and portal cirrhosis have been reported with use of Fowler’s solution
and contaminated beer.[69] Franklin and colleagues[16] described two patients taking Fowler’s solution for
myelogenous leukemia and dermatitis herpetiformis who experienced abdominal distention. A liver biopsy in
one patient showed evidence of acute and chronic parenchymal liver disease with increased periportal
fibrosis extending interlobularly. The second patient had evidence of hepatomegaly and was diagnosed with
arsenical cirrhosis. Datta and colleagues[9] described nine patients with idiopathic portal hypertension and
elevated arsenic levels in the liver. Liver biopsies showed evidence of cellular infiltration of the periportal
region and evidence of portal fibrosis. There was also evidence of increased portal vein pressure. The exact
mechanism of idiopathic portal hypertension is unclear but may be narrowing of the portal vein, as
demonstrated on intrahepatic venogram.[5] Angiosarcoma has also been associated with long-term arsenic
exposure; however, this occurrence is rare.[12][37][61]
Blackfoot disease (Wu Chiao Ping), which is endemic to areas of Taiwan, is associated with chronic
poisoning from arsenic in the artesian water supply. It is characterized by small-vessel peripheral vascular
disease. Symptoms include numbness and tingling in the feet and toes, intermittent claudication, and finally,
progression to gangrene. The disease is not influenced by smoking; blackfoot disease may be due to zinc
deficiency in the person with chronic arsenic poisoning.[11]
Lung (adenocarcinoma and oat cell cancer) and skin cancers have been linked to long-term arsenic
exposure; bladder cancer may be linked as well. Arsenic is classified as a definite human carcinogen by the
International Agency for Research on Cancer and the National Toxicology Program.[64]


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Chapter 89 – Lead
MICHAEL J. KOSNETT
Essentials
• Multisystemic signs and symptoms include headache (in severe cases encephalopathy), abdominal
pain, anemia, and, less commonly, gout, motor neuropathy, and renal insufficiency.
• Subclinical effects in children include neurocognitive deficits, growth retardation, and developmental
delay.
• Laboratory tests may show anemia and basophilic stippling; definitive diagnosis is made by elevated
blood lead concentration.
INTRODUCTION
Metals have been mined for nearly 10,000 years, and lead poisoning is among the oldest of all occupational
diseases. Although the hazards of lead exposure have been recognized since classical times, lead
intoxication remains the most common metal poisoning encountered today. This situation is due in part to
the widespread presence of lead-containing products in industrial and residential settings, and to the
insidious, nonspecific, multisystemic findings that often characterize lead toxicity.
Lead is a soft, malleable metal that is obtained by the primary smelting and refining of natural ores or by the
common practice of recycling and secondary smelting of scrap lead products. Approximately 70 per cent of
current lead use occurs in storage batteries, an application that is likely to continue for many years. Lead is
also used in the production of solder for electrical devices, automobile radiators, and other applications; the
formulation of metal alloys, including certain steel, bronze, and brass alloys; and the manufacture of pipes,
weights, cable sheathing, radiation shielding, and ammunition. Lead compounds may be added as
pigments, stabilizers, or binders in paints, ceramics, glass, plastic, and mortar. Organolead compounds,
such as tetraethyl lead or tetramethyl lead, are still used as antiknock additives in certain gasolines,
particularly in developing countries.
Although the use of lead in residential housepaint has been curtailed since the 1970s, lead is still used in
certain industrial coatings and paints, where its anticorrosion properties are valued. Lead that remains in the
old surface or subsurface paint of older buildings and residences continues to be a source of contemporary
exposure, particularly during the sanding, sand-blasting, scraping, torching, welding, or pipe cutting that may
accompany renovation or demolition. The frequent hand-to-mouth activity of children renders them
vulnerable to ingestion of lead that may be present in paint chips; or in the soil around older homes,
roadways, certain industrial sites, or mine tailings; or in lead foreign bodies such as lead fishing weights. In
addition, the presence of lead dust on adults’ workclothes or footware may translocate lead to the home
environment of the child. Adults and children may ingest lead transferred to food or beverages from lead-
glazed ceramics, pewterware, lead-soldered electrical coils used to heat food or water, and lead-soldered
cans. Craftwork and avocational sources of lead exposure include lead came or solder in stained glass
artwork, lead glazes in ceramics and enamels, target shooting at indoor pistol ranges, and melting and
casting of lead for bullets, fishing weights, and toys. Certain folk medicines (such as the Mexican remedies
azarcon or greta) and cosmetics (surma or kohl in Asia, and certain over-the-counter hair dyes in North
America) may contain substantial quantities of lead. The deliberate ingestion of soil or clay by adults and
children, a folk tradition in certain communities, may result in elevated lead exposure.


TOXICOKINETICS AND PATHOPHYSIOLOGY
Toxicokinetics
Inorganic lead compounds may be absorbed through the respiratory and gastrointestinal tracts. The rate and
extent of absorption depend in part on particle size and composition: in general, absorption will vary directly
with solubility and inversely with particle size. Inhalation of lead fume or fine particulate results in rapid and
extensive pulmonary absorption, which is the major, though not exclusive, route of lead exposure in industry.
In nonindustrial settings, lead ingestion is the primary route, particularly for young children, whose
gastrointestinal absorption of approximately 45 to 50 per cent exceeds the adult absorption of approximately
10 to 15 per cent.[74] In both adults and children, gastrointestinal absorption of lead may be increased by iron
deficiency,[132]low dietary calcium, and ingestion on an empty stomach.[54][104] In this regard, it is of historical
interest to note that some nineteenth century lead industries attempted to reduce the incidence of lead
intoxication by serving workers a meal rich in milk and other dairy products immediately prior to the
workshift. Percutaneous absorption is minimal for inorganic lead compounds, but alkyl (organo) lead
compounds are well absorbed by the dermal route.
Following absorption, lead is extensively bound to circulating erythrocytes (generally over 99 per cent of
blood lead) and is distributed via the blood to soft tissues, the subperiosteal surface of bone, and eventually
the bone matrix. Lead crosses the placenta and the blood-brain barrier, although uptake into the central
nervous system (CNS) may be slower than it is for other organs. The clearance of lead from the body follows
a multicompartment kinetic model, composed predominantly of a fast compartment in the blood and soft
tissues (half-life of 1–2 months), and slower compartments in the skeleton (half-lives of years to decades) (
Fig. 89–1 ). Absorbed lead is excreted primarily (more than 90 per cent) via the urine, with lesser amounts
excreted in the bile, skin, hair, nails, sweat, and breast milk. The fraction of absorbed lead that is not quickly
excreted, possibly as much as half of all absorbed lead, is ultimately redistributed and incorporated in bone,
the site of greater than 90 per cent of the body lead burden in adults. Slow release of bone lead stores in the
course of normal bone turnover and remodeling redistributes lead back to the blood and soft tissues. Rapid
and extensive redistribution of lead from the bone to soft tissues in pathologic states, such, as
immobilization, osteoporosis, or hyperthyroidism, has resulted in the appearance of symptomatic lead
intoxication.[43][120] In the past decade, pharmacologically based pharmacokinetic models have been
developed to predict the temporal relationship between external lead exposure, endogenous redistribution,
and tissue lead content.[74][94]
Figure 89-1 Decline of the blood lead level (PbB, units of micromoles per liter, logarithmic scale) after the end of 10 years of
occupational exposure for a 49-year-old ex–lead worker. When fitted to a two-compartment exponential model, the half-life of the first
compartment was 39 days, and that of the second compartment was 4.2 years. (R2 = 0.98). (From Schutz A, Skerfving S, Ranstam J,
et al: Kinetics of lead in blood after the end of occupational exposure. Scand J Work Environ Health 1987b; 13:221.)
Pathophysiology
Lead interferes with several aspects of cellular metabolism in tissues throughout the body, resulting in
multisystemic effects. The pathophysiology of lead toxicity is complex and varies depending on the pattern
of dose, the target organ, and the developmental stage of the subject. Many findings suggest that the
multifaceted effects of lead on calcium metabolism play a fundamental role in the actions of lead at low
dose.[13][102] Lead can disturb calcium metabolism by substituting for this essential cation as an intracellular
second messenger, or by altering the distribution of calcium in subcellular compartments. Protein kinase C,
a calcium-dependent enzyme involved in the phosphorylation of regulatory proteins involved in multiple
cellular processes, is activated by lead at intracellular concentrations as low as 10 -10 M. Such
concentrations may occur at blood lead concentrations of 5 to 10 µg/dL.[131] Lead binds more avidly than
calcium to calmodulin, a key calcium-binding regulatory protein. Lead inhibits Na+,K+-ATPase, which may in
turn contribute to lead-associated increases in intracellular calcium.[124] These and other effects of lead on
cellular calcium biochemistry have substantial impacts on neurotransmission and vascular tone that, in turn,
may contribute to lead-related health effects such as neurotoxicity and hypertension.
Lead interferes with biosynthesis of heme, a metalloprotein that is required not only for the production of
hemoglobin, but also for cytochromes involved in cellular energy production, and microsomal mixed function
oxidases involved in biotransformation of endogenous and xenobiotic substances.[42] Lead inhibition of the
heme biosynthesis enzyme delta aminolevulinic acid dehydratase (ALAD) may be detectable at blood lead
concentrations as low as 10 µg/dL; however, this enzyme is not a rate-limiting step in the overall pathway,
and there are no clear clinical correlates to this particular low-dose effect.[103] Lead interferes with the
mobilization and intracellular transfer of iron to protoporphyrin IX via a process other than in vivo inhibition of
ferrochelatase.[72][73][109] Erythrocyte protoporphyrins, such as zinc protoporphyrin, are increased as a result.
Other mechanisms of lead toxicity are thought to exist. Lead has high affinity for binding to proteins,
including enzymes, which contain vicinal thiol groups, or accessible carboxyl groups.[42] Recent studies
demonstrate that relatively low levels of lead increase reactive oxygen species,[45] a process that may have
multiple pathogenic implications. Lead-induced elaboration of lead-binding proteins, a potential protective
mechanism for some adverse effects, may have secondary, deleterious effects resulting from intranuclear
translocation of the metal.[38][42]


Acute Toxicity
Acute symptomatic lead toxicity is relatively rare, but may follow accidental ingestion of large amounts (gram
quantities) of lead or high exposure to lead aerosols from activities such as sandblasting or torch cutting of
lead-containing surfaces. A key diagnostic feature in both acute and chronic lead poisoning is the presence
of multisystemic signs and symptoms, reflecting the diffuse cellular toxicity of the metal. In the case of acute
intoxication, usually in association with blood lead concentrations in excess of 80 µg/dL, the patient may
present with crampy abdominal pain, with or without neurologic or constitutional complaints ranging from
headache and malaise to overt encephalopathy (see next paragraph). The abdominal pain, referred to in its
severe form as lead colic, is characterized by paroxysmal bouts of pain in a rigid, retracted abdomen. During
each bout there may be a characteristic slowing of the pulse. Pressure applied to the abdomen may
somewhat relieve the pain. Both acute and chronic forms of lead intoxication are classically associated with
constipation; however, diarrhea may sometimes occur.
Table 89-1 -- Clinical Presentation of Lead Toxicity *

System Acute Toxicity Chronic Toxicity
Fatigue, malaise Fatigue, malaise
Headache Irritability, depressed mood
Encephalopathy (delirium, ataxia, seizures, stupor,
Decreased libido
coma)
Central nervous Impaired neuropsychological
system function
Headache
Tremor
Encephalopathy (delirium, ataxia,
seizures, stupor, coma)
Peripheral nervous
Motor weakness
system
Anorexia Anorexia
Nausea Nausea
Gastrointestinal Crampy abdominal pain Constipation
Transaminase elevation Weight loss
Crampy abdominal pain
System Acute Toxicity Chronic Toxicity
Anemia (hypochromic; microcytic
Anemia (esp. hemolytic)
Blood (heme) or normocytic)
Basophilic stippling Basophilic stippling
Pediatric Fanconi-like syndrome (aminoaciduria,
Chronic renal insufficiency
glucosuria, hypophosphatemia, hyperphosphaturia)
Renal
Interstitial nephritis
Low-grade proteinuria
Myalgias, arthralgias Myalgias, arthralgias
Rheumatologic
Gout
Cardiovascular Hypertension
Reproductive Spontaneous abortion Oligospermia
* Findings are dose-dependent; multiple findings within a system are listed in approximate order of appearance.
Overt lead encephalopathy may have an acute clinical presentation, but it is more commonly preceded by
several weeks of prodromal complaints, including increasing irritability, fatigue, headache, anorexia, and
sleep disturbance. There may then ensue the abrupt onset of encephalopathy characterized variably by
confusion, hallucinations, ataxia, seizures, stupor, and coma.[136] The blood lead concentration in overt
encephalopathy in adults is almost always in excess of 100 µg/dL, and occasional cases may present with
blood lead concentrations of several hundred micrograms per deciliter.
Chronic Toxicity
Chronic lead toxicity, a far more common clinical presentation, is also characterized by multisystemic signs
and symptoms. Adults with chronic lead exposure resulting in blood lead concentrations in the range of
25–60 µg/dL may experience some of the nonspecific constitutional complaints cited in the previous
paragraph, i.e., irritability, fatigue, headache, anorexia, sleep disturbance, and depressed mood. Libido may
be diminished. Controlled clinical studies of workers with blood lead concentrations in the range of 30–60
µg/dL have detected subclinical impairment on measures of visual-motor dexterity and reaction
time.[49][82][125] This impairment has been attributed to a combination of central and peripheral neurotoxic
effects,[126] the latter also demonstrable as subclinical slowing of motor nerve conduction velocity. [35][119]
Individuals with markedly elevated blood lead concentrations (e.g., over 80–100 µg/dL) on a chronic basis
may experience the insidious onset of weight loss and cachexia.
Overt neurotoxic effects of lead are usually not detectable on physical examination until a patient has had
months to years of blood lead concentrations greater than 60–80 µg/dL. In some cases the earliest
manifestation may be a tremor of the hands, sometimes also affecting the head, lips, or tongue, that can
mimic the tremor associated with chronic mercury exposure.[61] A classic finding, associated with more
extensive exposure, is weakness and atrophy of the peripheral muscles, particularly the extensors of the
fingers and wrists (“wrist drop”). However, patterns in which the predominant presentation is peripheral
motor weakness involving the shoulder girdle have also been described.[51] Disturbances in balance have
been reported.[79] Infrequently, cranial nerve abnormalities, including optic atrophy, have been described in
severely lead-intoxicated patients with incipient or overt encephalopathy.[51][86][92]
In individuals with poor dental hygiene and prolonged high-dose lead exposure, the reaction of circulating
lead with sulfur ions released by oral microbial activity may cause the deposition of dark deposits of lead
sulfide at the interface of the teeth and gums.[16] The resulting gingival “lead line” is occasionally an
important clue to the presence of high lead exposure, but it has low sensitivity as a clinical finding.
Prolonged high-dose exposure to lead (i.e., blood lead concentrations above 80 µg/dL for years), has been
associated with an increased risk of chronic renal insufficiency, on rare occasions progressing to frank renal
failure. The underlying renal disease is one of interstitial and peritubular fibrosis.[28] Short of overt renal
disease, high lead exposures have correlated with increases in serum creatinine and blood urea
nitrogen.[52][77] The impact of chronic, lower level lead exposure on renal function is uncertain. Among a
cohort of retired lead smelter workers with several decades of blood lead concentration averaging between
30 and 60 µg/dL, multiple tests of renal function, including plasma creatinine, creatinine clearance, urinary
albumin, urinary ß-2-microglobulin, and urinary N-acetylglucosaminidase (NAG), were similar to values
found in an unexposed reference population.[39] Some reports of active lead exposed workers have detected
an association between average blood lead concentrations in the range of 40–50 µg/dL and urinary
excretion of NAG and low-molecular-weight proteins[97] or renal prostaglandin production.[18] However, the
reversibility of these effects, or their clinical significance, is not known. In a recent longitudinal study of 459
adult men with predominantly environmental lead exposure and a mean blood lead concentration of 9.9
µg/dL, blood lead concentration was correlated with serum creatinine, and the age-related increase in serum
creatinine was accelerated in the quartile with the highest blood lead.[67]
Lead-induced chronic renal insufficiency has been associated with decreased renal clearance of uric acid,
resulting in an increased risk of gouty arthritis (often called saturnine gout).[7][29] Serum creatinine in such
cases may be only moderately elevated (e.g., less than 3 mg/dL); however, hypertension is common.[88][137]
Clinical features of the joint involvement in episodes of saturnine gout are similar to those in primary gout.
Even in the absence of gout or other overt signs of inflammation, individuals with blood lead concentrations
in excess of 40–50 µg/dL may complain of arthralgias or myalgias[30][41]; however, the pathophysiology of
these lead-related symptoms is not understood.
A growing body of experimental and epidemiologic data implicates lead exposure as a cause of increased
blood pressure. Although the variance in blood pressure attributable to lead in human population studies is
generally low, on the order of 1–10 per cent, the status of hypertension as a major risk factor for
cardiovascular, renovascular, and cerebrovascular disease underlies the potential public health benefit of
reducing lead exposure. As recently described in a meta-analysis,[117] more than 15 epidemiologic studies
conducted in the past 15 years have demonstrated a relatively consistent, statistically robust association
between increased blood lead concentrations and increased systolic blood pressure. This effect is present at
relatively low levels of lead exposure, such that a decrease in blood lead concentration from 10–5 µg/dL in
adult males is associated with a decrease in systolic blood pressure of 1.25 mmHg (95 per cent confidence
interval 0.87–1.63 mmHg).[117] Another meta-analysis[124] had similar findings. Hu et al.[59] recently reported
that bone lead concentration, a biomarker of long-term lead exposure that is assessed noninvasively by K x-
ray fluorescence (see later discussion), is positively associated with a risk of hypertension. In their study of
590 men aged 48–92 years with predominantly nonoccupational lead exposure and a mean blood lead
concentration of 6.3 µg/dL, the most significant factors related to the occurrence of hypertension were body
mass index, family history of hypertension, and tibia lead concentration.[59] Experimental data demonstrating
an effect of lead on intracellular stores of calcium, the “second messenger” for vascular smooth muscle
contraction, lend biologic plausability to the pressor effect of lead.[99]
Lead has been associated with adverse reproductive effects in both males and females. In a recent study of
male lead smelter workers, participants with blood lead concentrations greater than 40 µg/dL (mean 47.3
µg/dL) exhibited evidence of decreased sperm counts and sperm concentration.[1] Similar suppressive
effects on sperm count have been reported in battery workers with a mean blood lead concentration of 61
µg/dL. There were no abnormalities in hypothalamic-pituitary sex hormones, suggesting a direct toxic effect
of lead on sperm production or transport.[5]
The tendency for high-dose occupational lead exposure to increase the likelihood of female infertility and
stillbirth was recognized by the late nineteenth and early twentieth centuries,[51] and lead compounds were
once used as abortifacients.[50] In a recent prospective study of the effect of lower level environmental lead
exposure on pregnancy outcome, the rate of spontaneous abortion in females residing near a smelter (mean
mid-pregnancy blood lead concentration of 15.9 µg/dL) was not statistically different from that of females
residing 25 miles away (mean midpregnancy blood lead concentration of 5.2 µg/dL).[89] Studies examining
the risk of low-level environmental lead exposure (i.e., blood lead concentrations in range of 10–30 µg/dL),
for preterm delivery and low birth weight have yielded inconsistent results. [2][10] A recent study of mothers
and full-term infants in Mexico City found that a higher lead concentration in maternal bone, but not in cord
blood (7.1 ± 3.5 µg/dL), was associated with decreased birth weight.[46]
Unique Pediatric Features
Although pediatric lead intoxication shares many of the multisystemic findings of adult lead intoxication, a
few distinguishing features merit comment. As chronic childhood blood lead concentrations increase above
50–70 µg/dL, overt, albeit nonspecific, symptoms may emerge, including decrease in play activity, lethargy,
anorexia, sporadic vomiting, intermittent abdominal pain, and constipation.[21][130] At high levels of lead
exposure, e.g., with blood lead levels above 80–100 µg/dL, children appear to be more susceptible than
adults to the development of overt lead encephalopathy (delirium, ataxia, seizures, stupor, or coma). This
may be a consequence of increased capillary permeability and diminished capacity for protective
sequestration of lead by astroglia in the immature brain.[44][128]
The developing nervous system of the fetus and young child is considered the most susceptible target organ
in human lead neurotoxicity. In cross-sectional and prospective studies, early lead exposure has been
associated with an adverse effect on neurocognitive function that has no apparent low-dose threshold.[116]
Recent meta-analyses of epidemiologic studies have found an increase of blood lead of 10–20 µg/dL to be
associated with a decrease of approximately two full points in IQ. [116][101] The effect of lead on intellectual
function is considerably less than that of other factors such as socioeconomic status and maternal IQ,[6] and
the impact of low-level lead exposure on intelligence in any given individual may not be discernible.
Nevertheless, the public health significance of low-level lead exposure may be considerable. Because
intelligence is normally distributed, a 5 per cent downward shift in a population with a mean IQ of 105 may
result in a doubling of the number of children with IQ scores below 80. Based on these concerns, the U.S.
Centers for Disease Control acted in 1991 to define a childhood blood lead concentration of 10 µg/dL as a
level of concern.[21]
In addition to deficits in cognitive function, childhood lead exposure has been associated with an increased
incidence of behavioral problems, particularly attentional impairment, aggressiveness, and
delinquency.[90][118] Increasing blood lead concentration has been associated with elevated hearing
thresholds in children, raising the interesting possibility that subtle hearing loss may contribute to lead-
associated learning disabilities.[114]
Overt plumbism has been associated with diminished growth and stature in children since the early twentieth
century, when Nye and others in Australia described stunted growth as a characteristic of childhood
poisoning from lead based paint.[92] A cross-sectional analysis of NHANES II data on 2695 children 7 years
of age found blood lead concentrations across a range of 4–35 µg/dL to be statistically correlated with a
child’s height, weight, and chest circumference, controlling for age, race, sex, and nutritional status.[113] A
recent longitudinal study of chronic lead exposure and physical growth in 58 white children found that lead in
the dentin of shed deciduous teeth at a mean age of 7.4 ± 0.6 years was positively associated with body
mass index at age 20.5 ± 0.7 years. The authors suggested that chronic lead exposure in childhood may
result in obesity that persists into adulthood.[66]
Diagnosis
Although many of the signs and symptoms of lead intoxication in adults and children are nonspecific, the
very fact that plumbism characteristically presents with a constellation of multisystemic findings may provide
a useful clue to the diagnosis. At moderate to high doses in adults, the complaints of headache, myalgias,
and neuropsychological/constitutional disturbance, such as anorexia, sleep disturbance, irritability, and
fatigue, are frequent symptoms, as is the laboratory finding of anemia (see discussion under Laboratory
Studies). With high lead exposure, additional classic findings of crampy abdominal pain, nausea,
constipation, motor neuropathy, tremor, gout, renal insufficiency, or rarely, convulsions, may add to the
clinical picture. Basophilic stippling of erythrocytes, or hyperpigmentation at the gingival margin, are
relatively insensitive findings, but may add considerable specificity to the clinical presentation. Lead
encephalopathy should be considered in any child who presents with delirium or seizures, and chronic lead
poisoning should be considered in the differential diagnosis of any child with neurocognitive deficits,
attentional impairment, or developmental delay. Although the final diagnosis of lead intoxication should be
confirmed by a sufficient elevation in blood lead concentration, treatment for severe intoxication (see under
Treatment) should not be delayed for the one or more days often needed to obtain laboratory results.
Wide variability among individuals in clinical response is a hallmark of lead intoxication. Patients may differ
considerably in the level of lead exposure associated with the onset of symptoms, as well as in the specific
pattern of symptoms that are displayed. Some adult patients may exhibit overt constitutional symptoms (e.g.,
fatigue, sleep disturbance, anorexia) with blood lead concentrations in the range of 40–50 µg/dL, and others
with blood lead concentrations over 80 µg/dL may be entirely asymptomatic. Some patients with markedly
elevated blood lead concentrations may develop lead encephalopathy in the absence of antecedent
gastrointestinal symptoms, whereas others may complain of lead colic without any apparent change in
mental status. The biologic basis for this interindividual variability is not well understood; however, it may in
part be a consequence of differential expression of endogenous lead-binding proteins. Several such
proteins, isolated in the brain, liver, kidney, and erythrocytes of several mammals, including man,[25][42]
appear to avidly bind and sequester lead. This may reduce lead-induced interference with enzymes and
other cell functions.
Polymorphisms in the intra-erythrocyte enzyme a-ALAD may also influence the in vivo distribution of lead
among skeletal and soft-tissue compartments. [122][134] The overall extent to which variability in lead binding
influences lead toxicity is not clear, and it is possible that the protection of some target organs or intracellular
sites may occur at the expense of others.


DIFFERENTIAL DIAGNOSIS ( Table 89–2 )
In clinical practice, the differential diagnosis in adults includes a flu-like, viral illness that, like lead poisoning,
often presents with headache, myalgias, fatigue, anorexia, nausea, and crampy abdominal pain.
Accompanying symptoms of fever or diarrhea are more suggestive of an infectious process; however, fever
is sometimes seen in incipient lead encephalopathy, and diarrhea can sometimes follow lead ingestion. The
abdominal pain that characterizes “lead colic” has sometimes been mistaken for appendicitis, pelvic
inflammatory disease, peptic ulcer, renal colic, or biliary colic. Lead-induced encephalopathy may share
many of the clinical features of acute encephalopathies from infectious agents. The predilection of lead to
produce cerebellar edema, particularly in children, may result in head computed tomography (CT) or
magnetic resonance imaging (MRI) suggestive of a cerebellar tumor.[96] Other pathologic processes that
produce multisystem findings may enter into the initial differential diagnosis, including collagen-vascular
disease (e.g., fatigue, myalgias, anemia); gastrointestinal neoplasms or ulcers (abdominal pain, anemia,
weight loss), acute intermittent porphyria (abdominal pain, anemia, mental status changes), Reye syndrome
(acute encephalopathy and hepatitis), and paraneoplastic syndromes. These can usually be readily
excluded by further evaluation. When the diagnosis of lead poisoning is initially missed, it is frequently the
result of a failure to take a detailed occupational and environmental history.
Table 89-2 -- Differential Diagnosis of Lead Toxicity

Flu-like, viral illness Collagen vascular disease
Appendicitis, pelvic inflammatory disease, renal or biliary colic, peptic ulcer Gastrointestinal neoplasm
Infectious encephalitis Paraneoplastic syndromes
Reye syndrome
Depression


LABORATORY STUDIES
Blood Lead
The whole blood lead concentration is the single most useful laboratory test. The relationship between blood
lead concentration and clinical effects generally has been based on levels that result from subacute or
ongoing chronic lead exposure, and not on transiently high values that may occur immediately after acute
exposure. In the United States, blood lead concentration is less than 5 µg/dL in populations without
occupational or specific environmental exposure.[20] A value greater than 10 µg/dL should definitely alert the
clinician to a probable history of past or ongoing lead exposure above background levels.
Although the whole blood lead concentration reflects the amount of lead in circulation at the time of the test,
it is not a reliable indicator of the magnitude of current or past exposure. The blood lead pool, containing
approximately 1 per cent of a typical total body lead burden, reflects input from external exposure as well as
the release of lead stored in endogenous tissues, particularly in the skeleton. The pattern of decline in blood
lead concentration following reduction or cessation of exogenous exposure will vary, depending on the
magnitude of body lead burden. It is a frequent misconception that because the blood lead pool represents a
pharmacokinetic compartment with a half-life of 1–2 months, the observed blood lead concentration reflects
recent external exposure. On the contrary, in patients with high bone lead burdens, redistribution of lead
from bone may elevate blood lead for years after external exposure ceases.[57][111] The interpretation of a
single blood lead test therefore will be enhanced by inquiring whether the patient’s exposure was (1) recent
or remote, (2) short-term or long-term, and (3) high intensity or low intensity.
Protoporphyrins
Additional laboratory tests can augment the exposure information derived from the history and the whole
blood lead concentration. Elevations in erythrocyte protoporphyrin (EP) or zinc protoporphyrin (ZPP) (a
subset of EP) may reflect lead-induced inhibition of heme synthesis. Erythrocyte heme synthesis occurs in
developing cells within the marrow and not in mature, circulating erythrocytes. Because mature erythrocytes
have a normal turnover time of approximately 120 days, an increase in EP or ZPP outside the normal
reference range usually lags behind the onset of an elevation of blood lead by 2 to 6 weeks. Accordingly, a
high blood lead concentration in the presence of a normal EP or ZPP suggests very recent exposure. An
elevated EP or ZPP in the presence of an elevated blood lead concentration suggests that exposure
occurred more than 2 weeks ago, provided that the patient does not have another medical condition that can
also elevate ZPP, such as iron deficiency or anemia of chronic inflammatory disease.[53] Protoporphyrin
levels are not sensitive to low levels of lead in blood (less than 30 µg/dL), and are no longer used as a
screening test for low level exposure. However, they remain a component of OSHA-mandated biologic
monitoring for lead in the workplace.
Urinary Lead
Urine lead concentration increases and decreases more rapidly than that of blood lead in response to
changes in lead exposure. Tests that quantify the urinary excretion of lead following a single dose of a
chelating agent such as calcium disodium EDTA (often called “chelation challenge tests”) have sometimes
been advocated as a measure of total body lead burden with diagnostic or prognostic significance. However,
evidence supporting use of these challenge tests is weak. Recent studies have demonstrated that chelation
challenge tests may not reflect the major body burden of lead found in bone.[69][111][127] At the current time,
there are few data to indicate that chelation challenge tests reliably reflect either remote or long-term
cumulative lead exposure, or that their results can identify individuals who may derive a therapeutic benefit
from chelation.
X-Ray Fluorescence
Noninvasive in vivo (K shell) x-ray fluorescence measurement of the concentration of lead in bone (KXRF) is
finding increasing utility as a biomarker of long-term, cumulative lead exposure. In cohorts with occupational
lead exposure, tibial bone lead concentration has been highly correlated (r ˜ 0.8) with cumulative lead
exposure calculated from subjects’ blood lead records.[108] In a population with predominantly background
environmental lead exposure, tibial lead concentration has been highly correlated with age, probably a
reflection of relatively higher environmental lead exposure in years past.[70] For most of the adverse health
effects attributed to lead in adults, such as neuropsychological dysfunction, nephropathy, and hypertension,
the extent of exposure associated with the onset of disease has yet to be determined. The availability of
KXRF as a quantitative biomarker of cumulative lead exposure may facilitate clinical investigation of these
dose-response relationships.
Apart from epidemiologic studies, KXRF measurements of lead in bone may have clinical value as an
adjunct to biologic monitoring of lead in the blood of individual workers undergoing medical surveillance. For
example, if a worker’s blood lead concentration fails to substantially decline after industrial hygiene
measures are instituted, is this because the measures are not providing adequate protection, or is it because
the individual’s bone lead burden is high, and the blood lead concentration reflects remote, rather than
current, levels of exposure? KXRF measurements of lead in bone might help to address this question,
particularly for workers in occupations such as construction work, where historical data on lead exposure
may never have been collected. In patients with slightly elevated blood lead concentrations and medical
conditions consistent with high-dose lead exposure, such as renal insufficiency, bone lead measurements
might confirm significant past exposure.[133]
Complete Blood Count
Measurement of the complete blood count (CBC), in combination with direct microscopic inspection of the
peripheral blood smear, is an important laboratory study in patients with known or suspected lead exposure.
Lead may produce an anemia by shortening red blood cell survival[55] and by inhibiting heme synthesis.[72]
Although hemolysis may be seen after acute or subacute high-dose exposure,[19] the more common pattern
is a slowly developing, hypochromic anemia with normocytic or microcytic indices, the latter a possible
consequence of coexistent iron deficiency.[26] Lead-associated anemia in adults generally emerges with
blood lead concentrations in excess of 50–60 µg/dL,[76] although one study found delayed hematopoietic
regenerative capacity following voluntary blood donation in a cohort of lead workers with mean blood lead
concentration of 42 µg/dL.[47] In children, blood lead concentrations in excess of 25 µg/dL have been
associated with an increased prevalence of anemia.[115]
Basophilic stippling of erythrocytes, visible on inspection of the peripheral blood smear, may provide a clue
to the existence of lead intoxication. Basophilic stippling has sometimes been reported within 3–4 days of an
acute high-dose exposure[65][129] and may precede the appearance of anemia.[9] However, the stippling, an
aggregation of ribosomal fragments thought to be a consequence of lead-induced inhibition of pyrimidine-5'-
nucleotidase or cellular ribonucleases, is not a sensitive finding. It is also not specific for lead, and may be
seen in other hematologic conditions, including arsenic poisoning, benzene exposure, thalassemia, and
certain malignancies. Reticulocytosis, which may accompany lead-induced anemia,[95] is likewise neither a
sensitive nor specific finding.
Renal Function Tests
Standard markers of renal function, such as BUN, serum creatinine, and urinalysis, should be examined.
However, their sensitivity for detection of early or mid-stage lead nephropathy is low. The urinalysis may be
unremarkable, or may reveal minor changes such as 1 to 2 + proteinuria in lead workers with significant
elevations in blood urea nitrogen (BUN),[77] or in lead-exposed patients with biopsy evidence of interstitial
nephritis.[88] Unfortunately, biomarkers of early renal dysfunction, such as low-molecular-weight proteins
(e.g., retinol-binding protein) or lysozomal enzymes (urinary N-acetylglucosaminidase), have not shown
consistent utility in surveillance for incipient lead nephropathy. A Fanconi-like syndrome with aminoaciduria,
glucosuria, and hypophosphatemia with relative hyperphosphaturia appears rarely in children with high-
dose, acute lead poisoning, but is not a feature of chronic lead nephropathy in adults.[23][28]
Other Tests
Mild to moderate elevation in liver transaminases may occur in severe lead intoxication,[19][95] and the very
rare patient with lead-related acute hemolysis may present with elevated bilirubin and jaundice.[8][19][51][63]
Elevated serum urate may be seen in patients with saturnine gout. Lumbar puncture performed in patients
with lead encephalopathy characteristically reveals an elevated opening pressure, and increased
cerebrospinal fluid (CSF) protein.[136] The CSF white blood cell (WBC) count may be normal or slightly
elevated (e.g., 5 to 15 WBC/hpf). Head CT imaging in the patient with lead encephalopathy may reveal
symmetrically narrowed ventricles and effacement of the cerebral gyri consistent with diffuse cerebral
edema. Other head CT findings may include edema-related compression of the fourth ventricle and
obstructive hydrocephalus[96][121] or asymmetric compression of a lateral ventricle.[60]
In young children with a history of severe lead intoxication, plain radiographs may reveal thick, hyperdense,
transverse linear opacities at the metaphyseal ends of the long bones. Known as “lead lines,” the opacities
are not deposits of lead, but, rather, hyperdense deposits of calcium that accumulate owing to lead-induced
inhibition of calcified cartilage resorption. Lead lines are most often seen in children aged 2–6 years of age.
Sachs[110] indicated that lead lines appear in children who have had a blood lead concentration in excess of
70–80 µg/dL. However, in a series of 104 children with lead lines, the blood lead concentration was 49 ±
17.3 µg/dL at the time of diagnosis.[14] Initially formed at the metaphyseal plate, discrete line(s) may migrate
toward the diaphysis as the lead level declines and the child grows. Lead lines will not persist, nor first
develop, into late childhood or beyond. Because lead lines do not occur with low or moderate lead exposure
and because their absence does not rule out recent high dose lead exposure, long bone radiography is not
recommended as a screen for lead intoxication. However, the presence of lead lines may contribute to the
suspected diagnosis, and should prompt investigation for lead exposure when noted as an incidental finding.
In cases of suspected or occult lead ingestion, abdominal radiographs may reveal radiopacities consistent
with the presence of lead compounds or objects in the gastrointestinal tract. However, finely suspended or
highly soluble lead compounds may not be visible on abdominal radiographs, and a negative radiograph
alone should not be relied upon to exclude ingestion or to withhold gut decontamination. Retained lead
bullets or solid lead fragments are usually well visualized on plain radiographs.


TREATMENT
Optimal treatment of lead intoxication combines decontamination, supportive care, and judicious use of
chelating agents ( Table 89–3 ).
Table 89-3 -- Treatment of Lead Toxicity

I. Decontamination
A. Consider whole bowel irrigation (WBI) for inorganic lead compounds; administer activated charcoal after
recent ingestion of organolead compounds
B. Consider surgical or endoscopic removal of solitary lead objects in GI tract not removed by WBI and with
evidence of ongoing lead absorption
C. Consider surgical removal of lead bullets, shrapnel, or pellets located in or adjacent to synovial space, or in
other locations with evidence of ongoing lead absorption
II. Supportive care
Encephalopathy
A. Normalize elevated intracranial pressure secondary to cerebral edema
1. Mannitol (20–25% solution) 0.25–1.0 g/kg IV bolus; can repeat
2. Hyperventilation to PaCO2 30–35 mmHg
3. Consider dexamethasone (10 mg IV)
4. Monitor fluid status to avoid overhydration
5. Severe cases—consider invasive hemodynamic and intracranial pressure monitoring
B. Maintain urine output of 1–2 mL/kg/hr
C. Consider transfusion of packed red blood cells if hematocrit < 30
D. Treat seizures
1. Benzodiazepines, e.g., lorazepam or diazepam Adults: lorazepam 1–2 mg IV or diazepam 5 mg IV: repeat
as necessary Children: lorazepam 0.05–0.1 mg/kg IV or diazepam 0.1–0.3 mg/kg IV; repeat as necessary
2. Phenobarbital Adults and children: loading dose, 10–20 mg/kg IV at rate of 50 mg/min
Other symptoms—outpatients
A. Treat joint pain of saturnine gout with colchicine or NSAIDs
B. Antidepressant medication as indicated for behavioral effects
C. Consider referral to physical therapy and/or cognitive rehabilitative therapy for treatment of significant
neurotoxic sequelae
III. Chelation
A. Encephalopathy
CaNa2-EDTA: 30 mg/kg/24 hr (pediatric 1500 mg/m 2/24 hr via continuous IV infusion (diluted to 2–4 mg/mL
in 5% dextrose or normal saline), to maximum duration of 5 days
Note: Some clinicians initiate treatment with a single dose of dimercaprol (BAL) 3–5 mg/kg IM, followed in 4
hr by concomitant administration of CaNa2-EDTA and dimercaprol (3–5 mg/kg IM q 4–6 hr for up to 3 days)
B. Symptomatic lead intoxication without encephalopathy
Succimer 10 mg/kg PO TID for 5 days, followed by 10 mg/kg PO BID for 14 days; consider repeat courses as
necessary (see text)
or
CaNa2-EDTA 20–30 mg/kg/24 hr (pediatric 1000–1500 mg/m2/24 hr) via continuous IV infusion (diluted to 2
to 4 mg/mL in 5% dextrose or normal saline)
Note: Succimer is preferable in patients without major gastrointestinal symptomatology (e.g., lead colic)
C. Asymptomatic children with elevated blood lead concentrations
The Centers for Disease Control and Prevention recommend chelation for all children with blood lead
concentrations at or above 45 µg/dL; administer oral succimer 10 mg/kg PO TID for 5 days, followed by 10
mg/kg PO BID for 14 days; consider repeat courses as necessary (see text)
There is no consensus regarding the value of chelation at lower levels
D. Asymptomatic adults
Consider succimer chelation (see dosage above) for asymptomatic adults with markedly elevated blood lead
concentrations (e.g., > 80 to 100 µg/dL)
IV. Adjunctive measures
A. Identify and prevent/mitigate all sources of lead exposure
B. Assure adequate nutrition (particularly with respect to dietary iron and calcium)
C. Plan follow-up blood lead testing
Decontamination
Seemingly small amounts of lead products (such as a single paint chip, a sip of a lead containing glaze, a
lead pellet) may contain hundreds of milligrams of lead. In cases of known or suspected lead ingestion, gut
decontamination is prudent. The adsorbancy of lead compounds to activated charcoal in a clinical setting
has not been been determined. However, the administration of a single dose of activated charcoal would be
reasonable soon after ingestion of organolead compounds but would be of uncertain value following
inorganic lead ingestion. Other approaches to gut decontamination, such as cathartics or whole bowel
irrigation, have been reported[107][129] and merit consideration, but their efficacy is also unproved. Absorption
of lead from liquid ceramic glazes has produced symptomatic intoxication within days,[107][129] and retention
and dissolution of solid lead objects have resulted in symptomatic illness[34] or death[62] within weeks. If solid
lead objects are not passed per rectum within 2 days, blood lead measurements should be followed, and
endoscopic or surgical removal should be considered.[80] Skin decontamination to prevent direct absorption
is essential only in dermal exposure to organolead exposure, but is recommended in inorganic lead
exposure to reduce the risk of ingestion from hand-to-mouth contact.
Retention of lead-containing bullets, shrapnel, or pellets following a gunshot injury poses a well-documented
risk of lead intoxication that may appear after a latency period ranging from weeks to decades.[78] The onset
of significant lead absorption in such cases is often associated with migration of the lead object into or
adjacent to a joint space, where the actions of synovial fluid and mechanical wear promote dissolution.[83] If
surgical removal of lead fragments following a gunshot wound is deferred, then periodic monitoring for
particle migration or systemic lead absorption should be done during the ensuing year. The yield of
subsequent monitoring in the absence of symptoms cannot be predicted. However, affected patients should
be counseled regarding the signs and symptoms of lead toxicity and the potential for its development years
into the future.
Supportive Care
Lead encephalopathy represents a medical emergency requiring intensive care management. In addition to
decontamination, there are three immediate therapeutic goals: (1) normalization of elevated intracranial
pressure; (2) maintenance of urine output adequate to permit lead excretion; and (3) control of seizures with
anticonvulsants. Increased intracranial pressure may be emergently managed by bolus administration of
intravenous mannitol (0.25–1.0 g/kg as a 20–25 per cent solution), and by passive hyperventilation targeted
to a PaCO2 of 30–35 mmHg.[22] Because the pathophysiology of lead encephalopathy involves cerebral
capillary leak, there is theoretical benefit to the administration of glucocorticosteroids, such as
dexamethasone. Careful attention to fluid status is essential, and in critical cases invasive hemodynamic
monitoring and intracranial pressure monitoring may be necessary. Because lead is excreted predominantly
by the kidney, fluid status should be optimized to maintain urine output in the range of 1–2 mL/kg/hr. In
patients without intravascular volume depletion, fluids should be minimized, and urine output augmented as
necessary with loop diuretics, or the adjunctive action of mannitol. Overhydration, which may increase
intracranial pressure, should be avoided. If seizures occur, benzodiazepines such as diazepam or
lorazepam, possibly supplemented by phenobarbital, are the anticonvulsants of choice.
In the severely symptomatic patient with a hematocrit less than 30 and blood lead concentrations in excess
of 100 µg/dL, there is theoretical benefit to the transfusion of packed red blood cells. The plasma fraction of
lead, normally less than 1 per cent of blood lead, increases at a supralinear rate as blood lead
concentrations reach high levels or the hematocrit substantially declines.[32][84] This plasma fraction may
have the greatest capacity to cross cell membranes and enter key target organs such as the brain.
Transfusion of packed red blood cells may be beneficial by decreasing the plasma fraction in the
encephalopathic, anemic patient. This hypothetical premise is supported by anecdotal clinical observations,
but has not been the subject of systematic study.
Supportive care for the patient with mild to moderate signs or symptoms of lead intoxication follows standard
nonspecific measures. The joint pain of saturnine gout may respond to colchicine or nonsteroidal anti-
inflammatory drugs (NSAIDs). However, NSAIDs should be used cautiously in patients with decreased renal
function. Additional long-term measures are discussed further below (see discussion under Disposition).
Chelation
Several types of chelating agents may be used to decrease blood lead concentration and increase urinary
lead excretion. This mobilization is achieved when the agent, or the product of its in vivo biotransformation,
binds to the lead atoms. There are currently no placebo controlled, randomized clinical trials that
satisfactorily demonstrate that lead chelation improves therapeutic outcome. [68] The Treatment of Lead in
Children (TLC) study, a multicenter randomized trial of chelation in children with blood lead concentrations
between 25 and 44 µg/dL launched in 1994, may soon offer guidance on the value of chelation in low to
moderate level pediatric exposures. In patients with high blood lead concentrations, empiric use of chelation
has been advocated as a means to accelerate removal of lead from the body, or to possibly avert the onset
or progression of encephalopathy, a clinical endpoint associated with the risk of death or permanent
neurologic sequelae.
In patients with lead encephalopathy, calcium disodium edetate, also referred to as calcium EDTA, should
be administered at a dose of 30 mg/kg/24 hours (pediatric dose 1500 mg/m2/24 hours) by continuous slow
intravenous infusion. Under the trade name Versenate, calcium EDTA is supplied in 5-mL ampules (200
mg/mL), which should be diluted to 2–4 mg/mL in saline or 5 per cent dextrose solution for intravenous
administration. Although the intramuscular route has sometimes been advocated as a means to reduce
administered fluid volume in patients with increased intracranial pressure, the small volume needed to
deliver the intravenous dose, 20–40 mL/hour in an adult, carries minimal risk and assures complete and
rapid uptake. Some clinicians advocate initiating chelation in lead encephalopathy with a single dose of
dimercaprol (British anti-Lewisite, or BAL), 4–5 mg/kg in a deep IM injection (pediatric dose 75 mg/m2),
followed in 4 hours by the calcium EDTA infusion.[100] Dimercaprol is then repeated every 4 hours, in
conjunction with the calcium EDTA infusion, for 3–5 days.
The use of dimercaprol in conjunction with calcium EDTA is based largely on a study in children with lead
encephalopathy that found a more rapid rate of blood lead decline in patients given the combination, rather
than calcium EDTA alone.[24] More recently, a single bolus dose of calcium EDTA was found to redistribute
lead to the CNS in a rat model.[27] However, dimercaprol itself has drawbacks. As a single agent, it has
actually worsened the outcome of experimental lead poisoning.[40] In a study in rats, a single dose of
dimercaprol was ineffective in decreasing brain lead content.[4] Dimercaprol is associated with a high
incidence of adverse effects, including hypertension, nausea, vomiting, and pain at the injection sites, which
may be particularly undesirable in the encephalopathic patient. In adults with lead encephalopathy
accompanied by massive blood lead concentrations, continuous infusion of calcium EDTA alone, without
dimercaprol, has been performed without complication.[33][71] In a retrospective study comparing the efficacy
of dimercaprol plus calcium EDTA versus calcium EDTA alone in hospitalized, nonencephalopathic children
with blood lead concentrations between 50 and 60 µg/dL, no advantages of the combined regimen in lead
elimination were apparent.[93] However, the addition of dimercaprol to calcium EDTA was associated with a
markedly increased incidence of vomiting. Another retrospective study[11] found that combined therapy with
succimer and EDTA offered comparable blood lead reductions, with less side effects, than combined
therapy with dimercaprol and EDTA in children with blood lead levels less than 70 µg/dL. A direct
comparison of combined therapy with monotherapy was not performed.
The duration of parenteral treatment with calcium EDTA is limited to 5 days, largely to diminish the risk of
nephrotoxicity sometimes seen with prolonged dosing.[37][87][105] After 5 days, or sooner in alert patients with
a functioning gastrointestinal tract, calcium EDTA therapy may be replaced by treatment with the oral
chelating agent succimer (dimercaptosuccinic acid, or DMSA). Succimer, a water-soluble analog of
dimercaprol, is given at a dose of 10 mg/kg every 8 hours for 5 days, followed by 10 mg/kg every 12 hours
for 2 weeks. Succimer is generally well tolerated, although allergic skin rashes, mild reversible elevations in
serum transaminases, and mild to moderate neutropenia have occasionally been noted. Oral succimer is
comparable to parenteral calcium EDTA in reducing blood lead concentration.[48] In overtly symptomatic
adults without encephalopathy (generally at blood lead concentrations above 60–80 µg/dL) or in
nonencephalopathic children with blood lead concentrations above 45 µg/dL, EDTA may be avoided and
chelation may be initiated with oral succimer. However parenteral calcium EDTA may be preferable if the
patient has severe gastrointestinal toxicity (such as lead colic).
Once chelation is begun, it is prudent to repeat blood lead measurements within 24–48 hours to confirm that
levels are declining. The failure to observe a significant decline (e.g., greater than or equal to 20 per cent
within 48 hours) should suggest several possibilities: ongoing occult external exposure; significant lead
retention in the gastrointestinal tract or in a joint space; renal insufficiency; or noncompliance. Although a 24-
hour urine collection for lead and creatinine during the first day of chelation may provide assurance that the
anticipated urinary lead clearance has occurred, the quantitative urinary value is primarily of academic
interest and seldom adds management information to that derived from the more convenient blood lead test.
There is some evidence to suggest that succimer is a “pro-drug” that must form in vivo adducts with cysteine
in order for effective chelation to occur.[3][81] A small clinical study of succimer’s pharmacokinetics suggested
that lead-poisoned children may clear the drug at a slower rate than occurs in lead-poisoned adults. [31]
Polymorphisms in ALAD genotype may also influence the urinary excretion of lead following administration
of DMSA.[112] The clinician should be alert to the possibility that an occasional patient may have a
phenotypic or medical characteristic that results in altered drug metabolism and decreased lead clearance.
The need for repeat courses of oral chelation with succimer depends on the post-treatment blood lead
concentration and the patient’s symptoms. In some individuals with high body lead burdens, redistribution of
lead from bone to soft tissues following cessation of chelation may result in a “rebound” of blood lead
concentration to within 20 per cent of pretreatment values. An interval of 2 or more weeks may be necessary
to determine the extent of rebound that may occur. The endpoint of chelation is empiric. The U.S. Centers
for Disease Control have recommended that all children with blood lead concentrations in excess of 45
µg/dL should undergo chelation. [21] Even in the absence of controlled data on drug-induced clinical
improvement, this decision is rational because the blood lead reduction achieved by chelation provides a
margin of safety below the levels associated with development of encephalopathy. Therefore, a second
course of succimer is indicated in children whose blood lead concentration rebounds to a blood lead
concentration greater than 45 µg/dL, and the same approach may also apply to adults with recurrent or
persistent symptoms. The occasional patient with a high body lead burden will have a blood lead
concentration that persistently rebounds to the range of 30–40 µg/dL despite multiple courses of chelation,
suggesting that more than three or four chelation courses offer diminishing therapeutic yield.
A recent human study suggests that succimer given orally may cause a small increase in the gastrointestinal
absorption of lead present in the gastrointestinal tract.[123] In animal models, parenteral calcium EDTA and
parenteral succimer have also increased the absorption of ingested lead, although an increase in lead
excretion averted a net increase in whole body lead retention.[64] These findings underscore the need to
decontaminate the gut of retained lead particles, and to assiduously eliminate ongoing lead exposure,
whenever chelation is undertaken.
There are few data or consensus to guide the use of chelation in asymptomatic adults. Generally, chelation
is reserved for adults with significant signs and symptoms of lead toxicity, and asymptomatic patients with
high blood lead concentration, even those approaching 80–100 µg/dL, may be removed from exposure and
carefully followed without chelation. Adults with blood lead concentrations in excess of 100 µg/dL will usually
warrant chelation, either because they harbor significant symptoms, or because serious CNS symptoms may
possibly emerge following a latency period.[71]


DISPOSITION
Hospital admission is indicated for all patients with acute lead encephalopathy or lead colic. Because of the
risk of incipient encephalopathy, hospitalization is advisable for all children with blood lead concentrations in
excess of 70 µg/dL, or for nonencephalopathic, colic-free adults with massively elevated blood lead
concentrations (i.e., greater than 150 µg/dL).
The majority of symptomatic lead intoxications in adults occur as a consequence of workplace exposure. In
the United States, OSHA regulations pertaining to lead are among the most comprehensive of all workplace
health and safety standards, and provide for employer-funded medical surveillance, periodic blood lead
monitoring, and medical removal protection. [56] The latter provision mandates that lead workers retain full
salary, benefits, and seniority if they are removed from workplace lead exposure because of elevated blood
lead concentrations, adverse health effects, or other health concerns (such as pregnancy). Under the
general industry standard, medical removal is required for a single blood lead test in excess of 60 µg/dL, or if
the average of the past three measurements exceeds 50 µg/dL, provided that the last was not less than 40
µg/dL. In the newer construction standard, medical removal is required for a single blood lead level above 50
µg/dL. Under both standards, return to work requires that two consecutive blood lead concentration tests
measure 40 µg/dL or less. Although these parameters, established in the late 1970s, are specified in the
OSHA standards, these same standards explicitly empower physicians to restrict workplace lead exposure
at lower blood lead concentrations if warranted by an employee’s medical condition. In view of the decline in
background levels of blood lead, and recent information regarding the potential hazards of low-level lead
exposure, it may now be both feasible and prudent for employers to maintain their workers’ blood lead
concentrations below 20 µg/dL. When a medical examination or removal determination is made by a
physician selected by the employer, the standard allows for the employee to request and obtain a second
medical opinion at the employer’s expense. Full text of the federal OSHA lead standard for general industry
is available on the OSHA Internet website at http://www.osha-slc.gov/OshStd-data/1910_1025.html .
The clinician should be alert to the possibility that lead exposure or intoxication in any one adult or child may
serve as a sentinel health event for lead exposure to other individuals sharing that person’s environment.
Lead-exposed workers may bring lead home on workclothes and boots or in vehicles, potentially exposing
other family members, particularly young children.[85][98] Blood lead testing of the young children of lead-
intoxicated workers, or the young siblings or playmates of lead-intoxicated children, is an important public
health measure.


SEQUELAE
Although it has been recognized for decades that severe lead poisoning in children, either with or without
encephalopathy, carries a risk of prolonged neurocognitive and neurobehavioral sequelae,[15][17] only
recently have the long-term effects of lower level exposure been studied. In an 11-year follow-up study,
neurobehavioral function at age 18 was inversely associated with the lead content of teeth shed at the ages
of 6 to 7.[91] Young adults with a childhood dentin lead level over 20 ppm had a sevenfold increased risk of
dropping out of high school, and a sixfold increased risk of a reading disability, compared to young adults
with childhood dentin lead below 10 ppm. Based on testing of a subsample, the mean blood lead
concentration in the high dentin lead group at the onset of the study measured 34 µg/dL, and none were
overtly symptomatic. Recently, a larger but otherwise comparable 10-year follow-up study in New Zealand
children reported similar findings.[36] A 50-year follow-up study of children with symptomatic childhood
plumbism revealed evidence of decreased cognitive function and occupational attainment,[135] as well a
relative risk of 7.0 for the development of hypertension.[58]
The likelihood that elevated childhood lead exposure carries a risk of long-lasting health impairment
emphasizes the vital role of primary prevention. However, secondary prevention is also important, and the
clinician evaluating a child with lead intoxication should avoid discharging the patient into the same
environment that resulted in the initial exposure. Most state health departments, and many local and county
public health agencies, have programs specifically dedicated to the prevention of childhood lead poisoning
that can serve as resources for case management, parental education, environmental lead testing, and
residential lead containment or decontamination. Because dietary factors such as iron deficiency and low-
calcium diets may contribute to increased lead absorption, the provision of adequate childhood nutrition
constitutes a secondary approach to diminishing the lead hazard from low-level, non-point sources.
Although they have not been subject to detailed longitudinal study, adults with overt plumbism, including
encephalopathy, will generally experience considerable improvement in symptoms following removal from
lead exposure and decline in blood lead concentration. Recovery of some aspects of neurocognitive and
neurobehavioral function may lag behind the decline in blood lead, either because of slower removal of lead
from the CNS[44] or because of the nature of the underlying neurotoxic injury. Depending on the magnitude
of the lead intoxication, full recovery may sometimes take up to a year or more, and the occasional elderly
patient will have persistent cognitive deficits. A formal neuropsychological evaluation may be helpful in
assessing the magnitude of lead-related cognitive impairment. Antidepressant medication may help to
reduce the impact of lead on mood. Active involvement in programs of physical and occupational therapy
may hasten the recovery from central and peripheral neurotoxic injury.
The interstitial fibrosis of chronic lead nephropathy is unlikely to be reversible, and may be subject to
progression over time. Long-term follow-up with nonspecific dietary and pharmacologic interventions merits
consideration, but has not been studied in lead nephropathy patients.


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Chapter 90 – Mercury
WILLIAM K. CHIANG
Essentials
• Tremor
• Erethism—irritability, excitability, decreased concentration, hallucinations
• Stomatitis, gingivitis, excessive salivation
• Renal dysfunction
INTRODUCTION
Mercury, the only metal in a liquid state at room temperature, has a long and fascinating history of both uses
and toxicities. The history of mercury can be traced back several thousand years, when cinnabar (mercuric
sulfide) was used in prehistoric cave drawings. Mercury was used as a medicine over 2000 years ago in
India, China, and Asia Minor. In the Middle Ages, the medicinal use of mercury was widely accepted,
particularly for the treatment of syphilis. In the eighteenth and nineteenth centuries, the application of
mercury in the dawn of modern medicine included the treatment of syphilis, as diuretic agents (mercurial
diuretics), and as antiseptic agents.
Mercury toxicities from both medicinal uses and occupational causes have been recognized and described
since the Middle Ages.[19][30] The phrase “a night with Venus followed by a life with Mercury” described the
toxic effects of mercury for the treatment of syphilis. Of the many modern epidemics of mercury toxicities,
the most notorious epidemics included the Minamata disease from methyl mercury in Japan,[36] acrodynia
from calomel (mercuric chloride) teething powder,[44] erethism in the hatting industry (the “mad hatter
syndrome” from mercuric nitrate),[34][46] overdoses from mercuric bichloride antiseptic agents, [40] and toxicity
from organic mercury-treated grain seeds in Iraq (methyl mercury).[7][12] Despite all these epidemics,
mercury exposures and toxicities persist.[3][13][25][38][42][43]


TOXICOKINETICS AND PATHOPHYSIOLOGY
Toxicokinetics
The primary route of exposure to elemental mercury is through inhalation of the vapors. Elemental mercury
is readily absorbed by the alveoli. Much of the mercury in the blood is oxidized into the inorganic Hg2+ form,
which is then absorbed by different tissues.[15] Inorganic mercury, particularly mercuric bichloride, is
extremely corrosive to the gastrointestinal tract, and approximately 7–15 per cent may be absorbed through
the damaged mucosa. Inorganic mercury accumulates in the proximal renal tubules, where it predisposes to
acute renal failure.[20] Inorganic mercury is primarily eliminated via in the feces and the urine with an
approximate half-life of 40–60 days. Organic mercury is readily absorbed from the gastrointestinal tract (up
to 90–95 per cent). However, the long-chain organic mercury compounds are converted rapidly into the
inorganic forms and behave like inorganic mercury. The short-chain alkyl mercurials such as methyl and
ethyl mercury are stable. They penetrate all tissues, including the blood-brain barrier, and cause direct CNS
toxicity and congenital CNS toxicity from in utero exposure. They are eliminated in the feces after acetylation
or conjugation in the liver. The significant hepatoenteric circulation may be responsible for the prolonged
half-life of 70 days. [15]
Pathophysiology
Mercury is a general protoplasmic toxin. The pathophysiology of mercury toxicity is directly related to its
covalent binding to sulfhydryl groups of different cellular enzymes in the microsomes and the mitochondria,
interrupting cellular metabolism and function. Mercury also has an affinity to bind to carboxyl, amide, amine,
and phosphoryl groups of enzymes, which contributes to its toxicity.[20] The most vulnerable organ is the
central nervous system (CNS), but the renal system and the pulmonary system are also susceptible to
toxicity. More specific mechanisms for CNS toxicity are postulated to include effects on calcium
homeostasis, membrane functions, protein synthesis, phosphorylation-dephosphorylation, and the
generation of free radicals.[41]
Toxicities and clinical manifestations are related to a number of factors: the form of the mercury, the route,
the concentration, and the duration of the exposure. There are three different forms of mercury: elemental,
inorganic (mercurous, Hg+, and mercuric, Hg2+ ), and organic. There are numerous sources for potential
mercury exposures ( Table 90–1 ). With elemental mercury, absorption occurs via inhalation of the vapor,
which passes the alveoli readily and can be absorbed into the tissues and the CNS. Elemental mercury is
mostly oxidized into inorganic mercury (Hg2+ ) in the tissue and red blood cells by catalase enzymes. The
mercuric salts are then eliminated in the feces and the urine.[15] Despite its relatively low vapor pressure at
room temperature (0.002 mmHg), even a small accidental spill of elemental mercury also can achieve
significantly toxic air concentration in an enclosed environment (saturation of 18 mg/m3).
Table 90-1 -- Potential Sources of Mercury Exposure

Elemental Inorganic Organic
Batteries Acetaldehyde production Bactericides
Elemental Inorganic Organic
Barometers Cosmetics Embalming processes
Calibration instruments Disinfectants Farmers
Ceramics Dyes Fungicides
Chloralkali production Explosives Insecticide manufacturing
Dental procedures Fur processing Paper manufacturing
Electroplating Herbal medicines Seafoods
Fluorescent lights Leather tanning Seed dressing
Gold and silver extraction Mercury vapor lamps Wood preservatives
Mining Paints
Paints Stool fixatives
Paper pulp manufacturing Taxidermy
Photography Vinyl chloride production
Thermometers
Traditional remedies


Elemental Mercury
The two organs most vulnerable to elemental mercury inhalation are the lungs and the brain; the blood-brain
barrier is readily penetrated. Elemental mercury ingestion is considered benign because systemic absorption
is unlikely. [15] The exceptions are in patients with intestinal problems such as diverticulosis, fistula formation,
or obstruction, where mercury may be trapped or retained in the gastrointestinal tract for a prolonged period
of time. This allows bacteria to convert the elemental form into organic mercury which can be systemically
absorbed.[11][31] Aspiration of elemental mercury, however, may cause a severe pneumonitis and even result
in respiratory failure.[18] Subcutaneous injections of elementary mercury may also allow continuous
absorption leading to chronic toxicity. [48] Similarly, intravenous injection can lead to sequestrations in the
lungs causing both acute and chronic toxicity.
Table 90-2 -- Clinical Presentation of Mercury Poisoning

Type of Mercury
Organ System Elemental Inorganic Organic
Neurologic Tremor Chronic inorganic mercury Tremor
toxicity is similar to chronic
elemental mercury toxicity
Encephalopathy * Paresthesias
Erethism: shyness, emotional lability,
nervousness, insomnia, memory Erethism
problems, inability to concentrate
Peripheral neuropathy Dysarthria
Dysarthria Ataxia
Tunnel vision
Hearing impairment
Spasticity
Encephalopathy
Congenital neuro
encephalopathy:
Mental retardation
Micrognathia
Microcephaly
Blindness
Type of Mercury
Organ System Elemental Inorganic Organic
Chorea
Vomiting
Hematemesis
Gastrointestinal Abdominal pain
Intestinal perforation
Proctitis/colitis
Renal Proteinuria Acute renal failure
Cardiopulmonary Pneumonitis Cardiovascular collapse
Allergic dermatitis
Cheilitis
Dermal Gingivitis
Stomatitis
Excessive salivation
Acrodynia
Rash with desquamation of
hands/feet
Other Diaphoresis
Fever
Splenomegaly
Irritability, hypotonia
* Acute elemental mercury inhalation.
Acute Toxicity
Acute toxicity from elementary mercury vapor may be quite consequential. Concentrated elemental mercury
vapor exposure can cause acute bronchitis, bronchiolitis, and pneumonitis. Clinical manifestations may
include cough, fever and chills, dyspnea, metallic taste, and headaches. Severe cases may progress into
hypoxia and respiratory failure.[24] Acute encephalopathy and seizures may develop from concentrated
exposures. Elementary mercury aspiration[18] and intravenous injections can lead to a severe pneumonitis
and embolization of the pulmonary vasculature,[17] respectively; both conditions may lead to hypoxia. With
sufficient systemic absorption, acute renal toxicity manifested by proteinuria, nephrotic syndrome, and acute
renal failure may occur.[15]
Chronic Toxicity
With prolonged or chronic exposure, the classic features of mercury toxicity are frequently encountered:
tremors (intentional fine tremors with coarse shakes), oral cavity lesions (gingivitis, stomatitis, cheilitis), rash,
salivation, headaches, diaphoresis, and erethism. Erethism is a constellation of signs and symptoms,
including shyness, emotional lability, nervousness, insomnia, memory problems, and inability to concentrate.
Peripheral sensorimotor neuropathy, dysarthria, and parkinsonian symptoms are frequently associated with
chronic elementary mercury toxicity.[15]
Inorganic Mercury
Acute Toxicity
Inorganic mercury ingestion should be considered extremely serious and potentially life-threatening.
Previously, mercuric bichloride (tablets) was commonly used as a disinfectant and was readily available.
Numerous fatalities were reported in suicidal ingestions.[40] Because of the corrosive effects of inorganic
mercury, nausea and vomiting are almost universal in significant ingestions. Abdominal pain and
hematemesis from esophageal and gastric erosions are common. Acute oliguric or anuric renal failure
rapidly ensues in these patients. Shock with cardiovascular collapse is the primary cause of death.[40][47]
Chronic Toxicity
The chronic manifestations of inorganic mercury toxicity are similar to those of chronic elemental mercury
toxicity. These manifestations were documented in the hatting and furring industry, where the primary route
of exposure was from the inhalation of mercuric nitrate used for the limping of furs. The symptoms
documented included tremor, stomatitis, gingivitis, sensory and motor deficits, peripheral vision loss, and
erethism. [34] Renal dysfunction has also been documented, particularly proteinuria and nephrotic
syndrome.[15] Although the full spectrum of chronic inorganic toxicity is less commonly seen in the modern
workplace, subclinical peripheral nerve conduction and neuropsychiatric abnormalities have been
documented in workers.[37][39]
Organic Mercury
The clinical toxicity from organic mercury differs depending on whether exposure was to short-chain or long-
chain compounds. The long-chain compounds such as phenyl mercury and methoxyethyl mercury cause
toxicity similar to that seen in chronic inorganic mercury toxicity. The classic short-chain compounds include
methyl mercury, the etiologic agent for Minamata disease, and ethyl mercury. Short-chain organic mercury is
readily absorbed from the gastrointestinal tract and penetrates the CNS. The toxicity from short-chain
organic mercury is limited to the CNS except at the highest doses.[15] The symptoms of organic mercury
toxicity consist of tremor; ataxia; dysarthria; paresthesias of the hands, feet, and mouth; visual field
constriction; erethism; and spasticity.[12][22][23][32]
Prenatal methyl mercury exposure has much more diffuse and widespread effects than exposure in adults.
First, methyl mercury readily crosses the placenta and achieves a higher level in the cord blood than in the
maternal circulation. Second, methyl mercury inhibits brain cell division and migration, perhaps related to its
effects on the polymerization of microtubules.[16] Prenatal exposure to methyl mercury can result in severe
congenital abnormalities such as micrognathia and neuroencephalopathy (microcephaly, mental retardation,
blindness, and symmetric motor deficits).[23] It was the vivid images of the affected children taken by
photojournalists Eugene and Ailene Smith that brought worldwide attention to focus on the Minamata Bay
tragedy.[36]
Pediatric Issues
Acrodynia, also known as “pink disease,” and initially described in 1920, is characterized by pink, swollen
hands and feet; desquamation; evanescent rashes; and burning and pain of the extremities in young
children. Other associated symptoms included photophobia, hypotonia, insomnia, and apathy alternating
with irritability. During the 1930s and 1940s, over 500 children died from pink disease in England and Wales
alone. This entity was linked to the use of calomel teething powder. [44] Acrodynia has been rarely described
in older children and adults. With the discontinuation of calomel teething powder, acrodynia is extremely
uncommon now. There are occasional reports of acrodynia from other forms of mercury exposures, such as
exposures to elemental mercury vapors and organic mercury (dermal absorption from diapers contaminated
with phenyl mercury and respiratory absorption from phenyl mercuric acetate in latex paint).[8][34] Although it
is most often postulated that the etiology of this syndrome is an idiosyncratic hypersensitivity reaction to
mercury because of the lack of correlation with mercury levels, many of the symptoms resemble recognized
mercury poisoning.


Toxicity from other elements and compounds may mimic mercury poisoning ( Table 90–3 ).
Table 90-3 -- Toxin Differential Diagnosis

Toxin Effects
Arsenic/thallium Acute: nausea, vomiting, abdominal pain, diarrhea, peripheral sensory and motor deficits
Manganese Apathy, confusion, labile affect, parkinsonism
Lithium Tremor, hyperreflexia, lethargy, confusion, coma
Carbon disulfide Peripheral neuropathy, cranial nerve deficits, neuropsychiatric changes, parkinsonism
Bismuth Stomatitis, black spots in the oral mucosa, myoclonus, encephalopathy
Acute arsenic poisoning can resemble inorganic mercury toxicity, with nausea, vomiting, abdominal pain,
and profuse cholera-like diarrhea. More significant symptoms include hypotension, cardiac dysrhythmia, and
coma. Chronic toxicity from arsenic causes both peripheral sensory and motor deficits. Hyperkeratotic
dermatitis and Mee’s lines in the fingernails may be seen in some patients with chronic arsenic toxicity.
Lithium toxicity presents with mental status changes ranging from lethargy to coma, tremor, increased
muscle tone, and hyperreflexia. Acute lithium poisoning is most commonly associated with nausea and
vomiting.
Chronic manganese toxicity is associated with progressive personality, cognitive, and neurologic changes,
such as apathy, confusion, labile affect, hallucinations, and difficulty with speech and fine motor movements.
Many of the features are also similar to parkinsonism, such as tremor, lack of facial expression, muscle
rigidity, and gait disturbance. Anatomic damage can be seen in the globus pallidus and striatum. Almost all
manganese exposures are occupational related, usually from manganese mining and steel processing.
Acute exposure to carbon disulfide is associated with mucous membrane irritation and altered mental status.
Chronic toxicity is associated with peripheral neuropathies, cranial nerve dysfunction, neuropsychiatric
changes, and parkinsonism. Accelerated atherosclerosis is also associated with carbon disulfide exposure,
leading to coronary heart disease and retinopathy.
Bismuth toxicity usually results from repeated exposures and occasionally from large acute ingestions.
Toxicity may manifest as stomatitis, salivation, black discoloration of the mucosa and gums, renal
dysfunction, myoclonus, ataxia, and encephalopathy.
Kawasaki syndrome should always be considered in any child with the presumptive diagnosis of acrodynia.
The principal symptoms consist of fever (for more than 5 days), conjunctivitis, erythema of the lips and
tongue, and erythema of the palms of the hands and the soles of the feet followed by desquamation of the
skin, diffuse polymorphous rash, and cervical lymphadenopathy. Associated symptoms may include
arthralgias, abdominal pain, uveitis, aseptic meningitis, and cardiovascular changes.


LABORATORY STUDIES
Laboratory evaluation of mercury toxicity should include a complete blood count, serum electrolytes, renal
function tests, and urinalysis. Although only the renal function tests and urinalysis are expected to be
abnormal in mercury toxicity (elevated creatinine and proteinuria), other laboratory studies may be helpful to
differentiate other etiologies. For acute ingestion of inorganic mercury, blood type and cross should be
performed because of potential gastrointestinal tract hemorrhage and perforation. Because mercury is
radiopaque, appropriate radiographs can detect recent mercury exposure. Abdominal radiographs can
demonstrate mercury in the gastrointestinal tract. A chest radiograph may demonstrate aspirated mercury, or
mercury sequestered in the heart and lungs from intravenous mercury injection. Soft-tissue radiographs can
show mercury injected subcutaneously.
Blood and urine assays for mercury are used to detect mercury exposures. However, the interpretation of
mercury levels must take into consideration the type and the duration of the exposure. Different
methodologies are available, and cold vapor atomic absorption spectrometry is a common, reliable
method.[15] Both whole blood and 24-hour urine mercury levels can detect inorganic mercury and elemental
mercury exposure. Whole blood assays can detect recent exposures. The 24-hour urine mercury
concentration may reflect both recent exposure and continued renal elimination of tissue burden. A spot
urine level test can be used for emergency evaluation, but a 24-hour urine collection should be arranged as
soon as possible. Normal blood concentration is less than 10–20 µg/L and urine concentration is less than
20 µg/L; however, the correlation between mercury levels and toxicity varies considerably. In general, a
blood level greater than 35 µg/L or a urine level greater than 100 µg/L will necessitate therapy. To monitor
organic mercury exposure, whole blood analysis should be used because organic mercury is concentrated in
the erythrocytes.[15] Because mercury levels are not readily available, empirical therapy should be instituted
in patients suspected to have significant acute exposure or symptoms of toxicity.
Other types of diagnostic tests have been used to monitor mercury exposure, usually in occupational
settings. Elevation of N-acetylglucosaminidase (NAG) and ß-galactosidase (lysosomal enzymes in the renal
tubular cells) can be used as sensitive but nonspecific detectors for mercury toxicity in patients with chronic
inorganic mercury exposure. X-ray fluorescence technique can detect mercury in the wrist and temporal
bones. Hair analysis for mercury can detect past exposure but is not routinely used because of the potential
for environmental contamination.[15]


TREATMENT
Decontamination
Gastrointestinal decontamination should be implemented for recent acute inorganic and organic mercury
ingestions because of significant systemic absorption and potential toxicity. In patients with numerous
vomiting episodes, the need for additional decontamination must be individualized, depending on the
amount and the time of the ingestion and the symptoms. Despite the corrosiveness of inorganic mercury and
the potential risk for perforation, the benefit of gastrointestinal decontamination still outweighs the risk.
Lavage with a small orogastric or nasogastric tube using milk or egg white, sources of sulfhydryl groups,
may be adequate for liquid or powder forms of mercury. Whole bowel irrigation with polyethylene glycol
should be considered for any significant mercury ingestion. The need for whole bowel irrigation and the
duration and effectiveness of the procedure may be determined by examining abdominal radiographs for
radiopaque material. For accidental elemental mercury ingestion, decontamination is not necessary because
systemic absorption does not occur in normal gastrointestinal tracts. In patients with intestinal obstruction or
ileus, elemental mercury from ruptured Cantor tubes or similar devices should be removed by suction.
Similarly, mercury injected subcutaneously should be removed surgically to prevent systemic absorption.
Chelation
The primary treatment involves chelation to remove mercury from the body. All chelating agents for mercury
contain sulfhydryl groups, which bind mercury. Dimercaprol (BAL) and d-penicillamine have previously been
the primary chelators, but the newer water-soluble BAL derivatives, meso-2,3-dimercaptosuccinic acid
(DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS), are more effective. They are the chelators of
choice for all forms of mercury in patients with normal renal functions ( Table 90–4 ).[1][10][14][16][35] DMSA is
available in the United States, but DMPS has not been approved by the FDA despite extensive international
experience.[14][16] The dose of DMSA is 10 mg/kg orally, three times per day for 5 days, then twice daily for
14 days. Duration of therapy should be guided by blood or urine levels and should be continued until the 24-
hour urine mercury level is less than 20 µg/L in cases of elemental and inorganic mercury poisoning or until
the blood mercury level measures less than 20 µg/L in cases of organic mercury toxicity. These
measurements may be prolonged in some patients. Ideally, repeat courses should be separated by a 2-
week “drug holiday.”
Table 90-4 -- Treatment Essentials for Mercury Poisoning

Decontamination
Lavage early (within 2 hr) for ingestion of inorganic and organic mercury
Consider adding milk or egg white in the lavage fluid
Whole bowel irrigation when mercury is identifiable in the abdominal radiograph
Chelation
Initiate based on the likelihood of exposure
Do not delay, pending levels, for acute exposure
1. Initial therapy:
Meso-2,3-dimercaptosuccinic acid (DMSA) for all forms of mercury toxicity
10 mg/kg/dose, tid po for 5 days, then bid for 14 days
2 week hiatus recommended for repeated cycles
or
dimercaprol (BAL) for inorganic and elemental mercury toxicity *
3–5 mg/kg IM, q 4 h for 2 days, then 2.5–3 mg/kg IM q 6 h for 2 days, then 2.5–3 mg/kg IM 12 hours, for 1–3
days
consider switching to an oral agent (DMSA or d-penicillamine) when more prolonged therapy is required
2. Alternative therapy:
d-Penicillamine † for inorganic and elemental mercury toxicity
adults: 250 mg qid, po, for 1–2 weeks
children: 20–30 mg/kg/d in 4 divided doses (maximum 250 mg/dose)
for adults and children, repeat course of treatment should be separated by 3–5 days
End point for chelation should be guided by symptoms and mercury levels, e.g., stop chelation when urine
mercury level measured 1 week after chelation remains in the normal range, less than 20 µg/L
* Ineffective against organic mercury toxicity; may increase the CNS mercury levels.
† d-Penicillamine is contraindicated in renal failure because elimination is exclusively via the kidneys.
BAL should be used in patients with renal dysfunction because approximately 50 per cent is excreted in the
bile. However, BAL is not recommended for organic mercury toxicity because of animal studies
demonstrating an increase in CNS mercury level due to redistribution by BAL.[9][28] BAL is constituted in
peanut oil and can be given only by intramuscular injection. In patients with renal failure, extracorporeal
regional complexing hemodialysis has also effectively removed mercury. In cases of poisoning with
inorganic and organic mercury, patients were hemodialyzed while DMSA was infused into the arterial line;
effective removal of the DMSA-mercury complex was then achieved.[4][27] Alternative oral chelation
therapies include d-penicillamine and N-acetylpenicillamine, the latter not yet approved for use in the United
States. They are monothiol compounds and are less effective than the dithiol agents DMSA, DMPS, and
BAL.


DISPOSITION
With the advent of DMSA, patients with chronic mercury toxicity without life-threatening symptoms can be
treated as outpatients. Accidental elemental mercury ingestion in a patient with a normal gastrointestinal
tract can also be safely managed in the outpatient setting. Hospitalization is warranted when potential life-
threatening toxicity or significant short-term morbidity is anticipated. These indications include patients with
acute inorganic or organic mercury ingestions, encephalopathy, shock, or acute renal failure, and acute
pneumonitis from elemental mercury inhalation. Hospitalization for toxicity assessment and stabilization may
also be required for patients who inject subcutaneous or intravenous mercury. Long-term follow-up is
necessary for all patients with mercury toxicity or elevated mercury levels because tissue elimination and
chelation therapy may be prolonged, and neurologic toxicity may be delayed.


SEQUELAE
Acute sequelae from mercury exposures may be quite significant, particularly with inorganic and organic
mercury. Inorganic mercury can result in acute renal failure, gastric and esophageal erosion or perforation,
cardiovascular collapse, and death. Acute organic mercury toxicity primarily affects the CNS resulting in
confusion, seizures, coma, and death. In 1971–1972, grain seeds treated with organic mercury and
distributed for consumption caused 459 deaths in Iraq.[12] Elemental mercury, when inhaled in large
amounts or aspirated, may cause a significant pneumonitis that may progress to respiratory failure.
Chronic sequelae can result from exposure to all forms of mercury, and particularly from chronic exposures.
These symptoms predominantly reflect CNS toxicity and include tremor, personality changes, erethism,
parkinsonism, and dementia. Stomatitis and peripheral neuropathy can also persist. Prenatal organic
mercury exposure produces severe neuroencephalopathy. Significant elemental mercury inhalation or
aspiration can lead to pulmonary fibrosis. Because many of these chronic sequelae are irreversible,
emphasis should be placed on prevention and early chelation of mercury exposures.


REFERENCES
1. Aaseth J, Friedheim EAH: Treatment of methyl mercury poisoning in mice with 2,3-dimercaptosuccinic
acid and other complexing thiols. Acta Pharmacol Toxicol 1978; 42:248.
3. Agocs MM, Etzel RA, Parrish RG, et al: Mercury exposure from interior latex paint. N Engl J
Med 1990; 323:1096.
4. Al-Abbasi AH, Kostyniak PJ, Clarkson TW: An extracorporeal complexing hemodialysis system for the
treatment of methylmercury poisoning. III. Clinical applications. J Pharmacol Exp Ther 1979; 207:249.
7. Amin-Zaki L, Majeed MA, Clarkson TW, et al: Methylmercury poisoning in Iraqi children: Clinical
observation over the years. Br Med J 1978; 1:610.
8. Aronow R, Cubbage C, Wierner R, et al: Mercury exposure from interior latex paint—Michigan.
MMWR 1990; 39:125.
9. Berlin M, Rylander R: Increased brain uptake of mercury induced by 2,3-dimercaptopropanol (BAL) in

mice exposed to phenylmercuric acetate. J Pharmacol Exp Ther 1964; 146:236.
10. Bluhm RE, Bobbitt RG, Welch LW, et al: Elemental mercury vapour toxicity, treatment, and prognosis
after acute, intensive exposure in chloralkali plant workers. I: History, neuropsychological findings and
chelator effects. Hum Exp Toxicol 1992; 11:201.
11. Bredfeldt JE, Moeller DD: Systemic mercury intoxication following rupture of a Miller-Abbott tube. Am J
Gastroenterol 1978; 69:478.
12. Bakir F, Damluji SF, Amin-Zaki L, et al: Methylmercury poisoning in Iraq. Science 1973; 181:230.
13. Branches FJP, Erickson TB, Aks SE, et al: The price of gold: Mercury exposure in the Amazonian rain
forest. Clin Toxicol 1993; 31:295.
14. Campbell JR, Clarkson TW: The therapeutic use of 2,3-dimercaptopropane-1-sulfonate in two cases of
inorganic mercury poisoning. JAMA 1986; 256:3127.
15. Canady R, Rabe CS, Gan K: Toxicological Profile for Mercury, Atlanta: Department of Public Health
Service; 1994:66-259.
16. Clarkson TW, Magos L, Cox C, et al: Tests of efficacy of antidotes for removal of methylmercury in
human poisoning during the Iraq outbreak. J Pharmacol Exp Ther 1981; 218:74.
17. Celli B, Khan MA: Mercury embolization of the lung. N Engl J Med 1976; 295:883.
18. Dzau VJ, Szabo S, Chang YC: Aspiration of metallic mercury. A 22-year follow-up.
JAMA 1977; 238:1531.
19. Goldwater LJ: Mercury. A History of Quicksilver. Baltimore, York Press, 1972.
20. Goyer RA: Toxic effects of metals. In: Amdur MO, Doull J, Klaasen CD, ed. Casarett and Doull’s
Toxicology. The Basic Science of Poisons, 4th ed. New York: Pergamon Press; 1991:646-651.
22. Hunter D, Bonford RR, Russell DS: Poisoning by methylmercury compounds. Q J Med 1940; 9:193.
23. Igata A: Epidemiological and clinical features of Minamata disease. Environ Res 1993; 63:157.
24. Jung RC, Aaronson J: Death following inhalation of mercury vapor at home. West J
Med 1980; 132:539.
25. Kang-Yum E, Oransky SH: Chinese patent medicine as a potential source of mercury poisoning. Vet
Human Toxicol 1992; 34:235.
27. Kostyniak PJ, Greizerstein HB, Goldstein J, et al: Extracorporeal regional complexing haemodialysis
treatment of acute inorganic mercury intoxication. Hum Toxicol 1990; 9:137.
28. Magos L: The effects of dimercaptosuccinic acid on the excretion and distribution of mercury in rats and
mice treated with mercuric chloride and methylmercury chloride. Br J Pharmacol 1976; 56:479.
30. Maurissen JPJ: History of mercury and mercurialism. NY State J Med 1981; 81:1902.
31. Mayer O, Cantor MD: Mercury lost in the gastrointestinal tract. JAMA 1951; 146:560.
32. McAlpine D, Araki S: Minamata disease. An unusual neurological disorder caused by contaminated fish.
Lancet 1958; 2:629.
34. Neal PA, Flinn RH, Edwards TI, et al: Mercurialism and its control in the felt-hat industry. Public Health
Bulletin 263. Washington, DC, U.S. Government Printing Office, 1941.
35. Nielsen JB, Andersen O: Effect of four thio-containing chelators on disposition of orally administered
mercuric chloride. Hum Exp Toxicol 1991; 10:423.
36. Powell PP: Minamata disease: A story of mercury’s malevolence. S Med J 1991; 84:1352.
37. Ross WD, Gechman AS, Sholiton MC, et al: Need for alertness to neuropsychiatric manifestations of
inorganic mercury poisoning. Comp Psych 1977; 18:595.
38. Sasso FS, Ferraiuolo R, Gursky E, et al: Mercury exposure among residents of a building formerly used
for industrial purposes—New Jersey, 1995. MMWR 1996; 45:422.
39. Singer R, Valciukas JA, Rosenman KD: Peripheral neurotoxicity in workers exposed to inorganic
mercury compounds. Arch Environ Health 1987; 42:181.
40. Troen P, Kaufman SA, Katz KH: Mercuric bichloride poisoning. N Engl J Med 1951; 244:459.
41. Verity MA: Nervous system. In: Goyer RA, Klaassen CD, Waalkes MP, ed. Metal Toxicology, San
Diego: Academic Press; 1995:199-235.
42. Villanacci JF, Beauchamp R, Perrotta DM, et al: Mercury poisoning associated with beauty
cream—Texas, New Mexico, and California, 1995–1996. MMWR 1996; 45:400.
43. Villanacci JF, Beauchamp R, Perrotta DM, et al: Update: Mercury poisoning associated with beauty
cream—Arizona, California, New Mexico, and Texas, 1996. MMWR 1996; 45:633.
44. Warkany J: Acrodynia—Postmortem of a disease. Am J Dis Child 1966; 112:147.
46. Wright W: A clinical study of fur cutters and felt-hat workers. J Ind Hyg 1922; 4:296.
47. Winek CL, Fochtman FW, Bricker JD, et al: Fatal mercuric chloride ingestion. Clin
Toxicol 1981; 18:261.
48. Zillmer EA, Lucci KA, Barth JT, et al: Neurobehavioral sequelae of subcutaneous injection with metallic
mercury. Clin Toxicol 1986; 24:91.


Uncited references
Adams CR, Ziegler DK, Lin JT: Mercury intoxication simulating amyotrophic lateral sclerosis.
JAMA 1983; 250:642.
Albers JW, Kallenbach LR, Fine LJ, et al: Neurological abnormalities associated with remote occupational
elemental mercury exposure. Ann Neurol 1988; 24:651.
Ambre JJ: Intravenous elemental mercury injection: Blood levels and excretion of mercury. Ann Intern
Med 1977; 87:451.
Hallee TJ: Diffuse lung disease caused by inhalation of mercury vapors. Am Rev Resp Dis 1969; 99:430.
Kew J, Morris C, Aihie A, et al: Arsenic and mercury intoxication due to Indian ethnic remedies.
BMJ 1993; 306:506.
Magos L: Effect of 2,3-dimercaptopropanol (BAL) on urinary excretion and brain content of mercury. Br J
Ind Med 1968; 25:152.
McNeil NI, Issler HC, Olver RE, et al: Domestic metallic mercury poisoning. Lancet 1984; 1:269.
Wright N, Yeoman WB, Carter GF: Massive oral ingestion of elemental mercury without poisoning.
Lancet 1980; 1:206.


Chapter 91 – Thallium and Other Metals
THEODORE BANIA
Essentials
• Acute gastrointestinal symptoms after large acute ingestions
• Painful ascending peripheral neuropathy
• Alopecia
INTRODUCTION
Thallium, an elemental metal discovered in 1861, was used in the late 19th century to treat gonorrhea,
syphilis, gout, dysentery, and the night sweats associated with tuberculosis. It was also widely used as a
depilatory agent in the treatment of ringworm. These therapeutic efforts commonly resulted in death due to
the severe toxicity of thallium.
Until 1965 the main commercial use of thallium was as the primary ingredient in various rodenticides and
insecticides. Incorporated into pastes, powders, and pellets, thallium was sold under such names as Zelio
Paste, Virus Rouge, Mission Brand Roach Killer, Apex Ant Killer, and GTA Bait for Rats. The practice of
spreading a thallium preparation on bread left in a corner resulted in many fatal accidental ingestions. Their
severe toxicity combined with the frequency of accidental ingestion of the thallium rodenticides led the
Department of Agriculture to remove them from the general market in 1965.
Thallium still has some industrial applications. It is used in the manufacture of semiconductors, scintillation
counters, low temperature thermometers, and green-colored fireworks. Its high refractive index makes
thallium useful in the manufacture of optical lenses and imitation precious jewelry. It is also employed as a
catalyst in some organic reactions and incorporated into silver alloys. In medical practice, thallium isotopes
are used in cardiac scanning.
Despite the ban on manufacture of thallium rodenticides in the United States, accidental and suicidal
exposures still occur because of their unrestricted availability in other countries. Occasionally, industrial
exposure also results in poisoning.[15]
Because most thallium salts are colorless, odorless, and tasteless they have been historically touted as the
ideal homicidal agent. Readily soluble in water, they are hard to detect when mixed in coffee, soup, or
drinking water or substituted for salt. In addition, given in multiple small doses thallium toxicity is cumulative,
with a latent period for symptoms that allows a murderer time to cover his tracks. The most infamous
thallium killer was Graham Fredrick Young. Dabbling in toxicology since age 11, he first poisoned his pets,
then his parents and family. His activities were finally discovered when the bizarre neurologic illness that
afflicted several of his coworkers was identified as thallium poisoning. A detailed diary revealed that several
earlier murders had gone undetected.[12]


Toxicology
Thallium is chemically most closely related to potassium. The chlorides of both metals form mixed crystals,
and a number of minerals are known in which thallium and potassium are interchangeable. The nitrate,
sulfate, acetate, and carbonate compounds are more water soluble, and therefore more toxic, than the
chloride compounds. The reported lethal dose of thallium ranges from 4 to 40 mg/kg, with most reported
cases between 10 and 25 mg/kg.[29]
Most cases of thallium toxicity occur after an oral ingestion. Thallium can also be absorbed percutaneously
and through inhalation of contaminated dust and fumes. A case of poisoning followed snorting cocaine that
was mixed with thallium.[23a]
After an oral ingestion of thallium, absorption is complete within 1 to 4 hours. The volume of distribution is
very large (11.2–50 L/kg), with tissue distribution usually complete within 48 hours.[12][13] After distribution,
thallium can be found in all organs, bone marrow, and hair.[13][17][39]
The half-life of elimination is about 8 days in the untreated individual. The primary mechanism of elimination
is intestinal secretion, with additional elimination in bile and through the kidneys. Both enteroenteric and
enterohepatic recirculation occur, prolonging the elimination time and potentiating toxicity. Fecal elimination
is usually twice urinary elimination, but it varies depending on the therapeutic interventions used. Renal
elimination of thallium follows potassium-dependent pathways in the kidneys and is affected by the serum
potassium level.[18] Low serum levels of potassium result in resorption of thallium, potentiating toxicity.
Pathophysiology
Thallium has a high affinity for the potassium-binding sites of Na+,K+-ATPase, which actively facilitates its
transport from the extracellular to the intracellular compartments of the kidney, brain, and myocardium.[20] In
the intracellular space, thallium binds with riboflavin and inhibits flavin adenine dinucleotide
(FAD)–dependent reactions. This results in impaired electron transfer and disruption of pyruvate
metabolism. Thallium also combines directly with sulfhydryl groups of the mitochondrial membrane,
inhibiting many other enzymatic reactions.[21]
The sensory and motor neuropathy seen with thallium poisoning has been attributed to this blockade of
cellular energy production. The longer sensory nerve fibers that are most susceptible to energy deprivation
are affected first, followed by motor nerve fibers as intoxication persists. In advanced cases cranial nerves
and brain stem motor nuclei are also affected.[2]
Acute thallium poisoning initially presents as a gastrointestinal illness with nausea, vomiting, and diarrhea (
Table 91–1 ). The symptoms are immediate with large ingestions but may be delayed 24 to 48 hours with
smaller doses. Duodenitis, paralytic ileus, and constipation are all common complications. In addition,
parotid, pancreatic, and hepatic damage can occur, resulting in elevated lipase, amylase, bilirubin, and
transaminase levels.
Table 91-1 -- Clinical Presentation of Thallium Poisoning

Gastrointestinal: Acute nausea, vomiting, diarrhea
Cardiovascular: Acute myocardial depression
Neurologic: Chronic sensory, motor, autonomic neuropathy
Dermatologic: Alopecia, acne, Mees’ lines
Neurologic symptoms begin 2 to 5 days after ingestion. A sensorimotor neuritis with hyperesthesia,
paresthesia, hyperalgesia, and motor weakness that begins in the soles of the feet and great toe and
spreads to the trunk is a classic finding.[31] The hyperalgesia may be so prominent that the slightest
movement of a hospital sheet or air current produced by walking past the patient can result in intense pain.
The motor neuritis may progress to generalized paralysis, with death resulting from respiratory failure. In
addition, headaches, ptosis, strabismus, optic neuropathy, reduced or altered color vision, convulsions,
coma, delirium, dementia, and psychosis have been reported.[15]
Autonomic neuropathy is common and manifests as salivation, fever, hypertension, tachycardia, and cardiac
dysrhythmias. Patients are at risk for sudden cardiac death associated with autonomic disturbances for
many weeks after exposure. Thallium also has a direct toxic effect on the myocardium, resulting in disruption
of pacemaker function and dysrhythmias. In the massive overdose, the rapid onset of myocardial injury may
result in shock and death before the development of peripheral neuropathic findings.[22]
Several dermatologic disturbances result from the general breakdown of energy metabolism. Alopecia is a
well-known sign that starts 2 to 3 weeks after exposure and involves the entire body, sparing only the inner
third of the eyebrow (sign de sourcil). Large clumps of hair may be lost at one time. It results from transient
inhibition of mitosis in hair follicles, and regrowth is expected in 8 to 10 weeks. Examination of the hair root
under low magnification shows the presence of a black fusiform thickening of the hair root, which likely
represents excess melanin laid down during growth arrest of the hair follicle.
Acneiform eruptions and eczematous lesions are associated with follicular plugging by inspissated
keratinous material.[23] A severe stomatitis may also be seen. Mees’ lines (horizontal white bands on
fingernails) occur secondary to growth arrest in the nail germinal matrix.


Although the chronology of its effects (gastroenteritis neuronitis alopecia) is quite specific, observed at a
single point in time thallium poisoning has components that may mimic other illnesses ( Table 91–2 ). The
nontoxic differential diagnosis of thallium poisoning includes gastroenteritis initially. Later, other entities
associated with neuropathy such as tabes dorsalis, alcoholic polyneuritis, diphtheria, botulism, Guillain-Barré
syndrome, and chronic thiamine deficiency must be considered. Central nervous system signs might be
similar to those of cerebral tumor, bulbar palsy, meningitis, or encephalitis. The initial symptoms of acute
thallium ingestion resemble those of many other metals (see Table 91–2 ). Thallium is distinguished by the
intensely painful paresthesias and alopecia with a characteristic dark line at the hair root (see Table 91–1 ).
Table 91-2 -- Differential Diagnosis of Thallium Poisoning

Nontoxicologic
Gastrointestinal Effects
Acute gastroenteritis
Peripheral Neurologic Effects
Alcoholic polyneuritis
Guillain-Barré syndrome
Diphtheria
Chronic thiamine deficiency
Tabes dorsalis
Central Neurologic Effects
Cerebral tumor
Bulbar palsy
Meningitis
Encephalitis
Botulism
Toxicologic
Arsenic
Colchicine
Mercury
Vinca alkaloids
Selenium (alopecia)


LABORATORY STUDIES
Thallium levels can be measured with atomic absorption spectrophotometry, which has replaced other
screening tests. Urine levels greater than 5 µg/L are considered abnormal, and levels greater than 200 µg/L
are associated with poisoning. Normal total blood thallium concentration is under 2 µg/L, and concentrations
greater than 200 µg/L are toxic. Postmortem tissue thallium levels should also be considered abnormal
because thallium is not destroyed or produced by putrefaction. Many cases of thallium poisoning are
confirmed months to years after exposure.
Because thallium is radiopaque, suspected food sources can be examined by radiograph to confirm
contamination. In addition, abdominal radiographs can demonstrate a recent ingestion in the gut lumen or
may also show diffuse deposits in the liver.


Decontamination
Ingested thallium should be removed immediately by gastric lavage. Activated charcoal effectively increases
thallium elimination and should be administered in multiple doses to disrupt enterohepatic and enteroenteric
recirculation.[27]
Table 91-3 -- Treatment of Thallium Poisoning

Decontamination
Orogastric lavage
Activated charcoal, 0.5–1.0 g/kg/dose every 6 hours
Prussian blue, 250 mg/kg/d divided into three to four doses; administer with 50 mL 15% mannitol or 70%
sorbitol
Elimination
Hemodialysis (first 48 hours)
Prussian blue (potassium ferric hexacyanoferrate [II]) is an orally administered insoluble unabsorbable
molecule that exchanges potassium ions for thallium in the gut lumen. Prussian blue blocks the
enterohepatic and enteroenteric recirculation of thallium, increasing fecal elimination. It has been shown to
decrease the elimination half-life of thallium from 8 to 3 days[2][19][25] and to decrease mortality in an animal
model.[30]
Prussian blue is administered orally with 50 mL of 15 per cent mannitol or 70 per cent sorbitol at a dose of
250 mg/kg/day divided into three to four doses. No adverse effects are reported, and the release of cyanide
is negligible. It can be obtained from a German drug company Chroma-Gesellschaft (Schmid GmbH and
Co., Kuferstrasse 2, D-73257 Kongen, Postfach 1110, D-73253 Kongen, Telephone—0 70 24/8 36 46).
Prussian blue is safe and effective during both the predistribution and postdistribution phases.
Sodium iodide has been suggested as a lavage solution in the hope of converting a toxic-soluble thallium to
a nonsoluble state. Although theoretically reasonable, the clinical use of sodium iodide has not been
adequately studied and is not recommended. Most cases are recognized well after exposure and absorption
has occurred.
Predistribution Therapy
Hemodialysis, hemoperfusion, and combinations have all been used in individual cases to increase
elimination. These therapies are recommended and most effective if started within 48 hours, before
distribution into tissue is complete. Thallium is avidly bound to extravascular tissue, and a rebound in blood
levels is seen after termination of hemodialysis or hemoperfusion due to redistribution from these
sites.[2][18][19] Hemodialysis clearances of 96 to 150 mL/min were reported in one case.[28]
Postdistribution Therapy
Hemodialysis and hemoperfusion have been used in the postdistribution phase (greater than 48 hours post
ingestion) but are much less effective and therefore not recommended. Potassium supplementation during
the postdistribution phase appears to release thallium from the extravascular space, increasing the serum
thallium level. The serum thallium concentration is then able to redistribute into neural tissue.[3] A more
recent study showed no survival advantage of adding potassium to Prussian blue therapy in a murine toxicity
model. Also in this study, survival in the potassium-treated group trended down compared with untreated
controls.[32] For this reason, potassium is not recommended.
Investigational Therapies
Riboflavin, which forms an insoluble precipitate with thallium, has theoretical potential to block the
enterohepatic and enteroenteric recirculation of thallium.[12] This has not been studied in any clinical setting.
Dithiocarb (diethyl dithiocarbamate) has been shown to increase the elimination of thallium in the urine.[35]
However, the dithiocarb-thallium chelate is very lipophilic and readily passes into neural tissue, worsening
symptoms.[25]
The cardiac glycosides represent another theoretical but untested treatment for thallium poisoning. Ouabain
has been shown to inhibit the Na+,K+-ATPase pump used to transport thallium in a rat myometrium.
Potentially other cardiac glycosides such as digoxin may block the intracellular transport of thallium.


DISPOSITION
All patients with suspected thallium poisoning require admission to the hospital for treatment and supportive
care.


SEQUELAE
Long-term neurologic complications include painful sensorimotor neuropathy, ataxia, abnormal reflexes,
tremors, psychosis, and dementia.[29][34]


OTHER METALLOIDS
The clinical effects and treatment of toxicity from other metals is presented in Table 91–4 .
Table 91-4 -- Other Metals/Metal Compounds

Metal Clinical Effects of Poisoning Accepted Treatment of Acute Poisoning
Acute Oral magnesium sulfate
Acute renal failure
Cardiac dysrhythmias
Barium salts[33][37] Seizures
Rhabdomyolysis
Hypokalemic paralysis
Hypertension
Paresthesias
Acute Supportive therapy
Renal tubular necrosis
Pneumonitis, pulmonary edema
(inhalation)
Cadmium[16]
Chronic
Emphysema, chronic obstructive
pulmonary disease
Renal tubular disease
Lung cancer
Nasogastric aspiration within 1–2 hours of
Acute
ingestion
Acute tubular necrosis
No proven role for dialysis, ascorbic acid, or
Acute liver failure
Chromium chelation
(hexavalent)[4][10][38]
Methemoglobinemia
Chronic
Irritant dermatitis
Skin ulcerations (chrome holes)
Lung cancer
Supportive therapy (N-acetylcysteine,
CaNa2-EDTA, DMSA used as chelators in
Ingested
animal experiments, no human confirmatory
data)
Cardiomyopathy
Goiter
Cobalt[5]
Other
Occupational asthma
Interstitial pulmonary fibrosis (hard metal
dust exposure [tungsten + cobalt])
Contact dermatitis
CaNa2-EDTA, BAL used as chelators (effect
on outcome uncertain)
Copper Acute renal failure
sulfate[1][6][24][26]
Acute hepatic failure
Hemolysis
Methemoglobinemia
Acute(potassium permanganate) Bradykinetic-hypertonic syndrome
Corrosive gastrointestinal injuries,
CaNa2-EDTA
hemorrhage
Renal tubular necrosis Potassium permanganate
Manganese[9]
Methemoglobinemia Treat like acid ingestion
Chronic Chelators ineffective
Bradykinetic-hypertonic syndrome
(resembles parkinsonism)
Acute(nickel carbonyl) Nickel carbonyl
Early—respiratory tract irritation,
dyspnea, cough, headache, Dermal decontamination
nausea/vomiting
Late (12–120 hours)—pulmonary
edema, pneumonitis, gastroenteritis, Antidote: diethyldithiocarbamate
delirium, seizures, cerebral edema, and (investigational) *
Nickel, nickel hemorrhage
carbonyl[7][11]
Chronic
Occupational asthma
Rhinitis, sinusitis, nasal polyps, nasal
perforation
Dermatitis
Lung and nasal cancer
Acute No proven role for dialysis or chelation
Gastroenteritis
Selenium salts,
Cardiomyopathy
selenic acid[14][36]
Vasodilation
Alopecia, Mees’ lines
Caustic gastrointestinal injury ? CaNa2-EDTA
Renal tubular necrosis, interstitial
Zinc[8] nephritis
Pneumonitis, adult respiratory distress
syndrome (inhalation)
Metal fume fever (zinc oxide)
* Dr. F. William Sunderman, Sr., Institute for Clinical Science, Pennsylvania Hospital, Philadelphia, PA (215/829–7068).


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2. Backer W, Zachee P, Verpooten GA, Majelyne W: Thallium intoxication treated with combined
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3. Bank WJ, Pleasure DE, Suzuki K, et al: Thallium poisoning. Arch Neurol 1972; 26:456-464.
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6. Barceloux DG: Copper. J Toxicol Clin Toxicol 1999; 37:217-230.
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8. Barceloux DG: Zinc. J Toxicol Clin Toxicol 1999; 37:279-292.
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10. Bradberry SM, Vale JA: Therapeutic review: Is ascorbic acid of value in chromium poisoning and
chromium dermatitis?. J Toxicol Clin Toxicol 1999; 37:195-200.
11. Bradberry SM, Vale JA: Therapeutic review: Do diethyldithiocarbamate and disulfiram have a role in
acute nickel carbonyl poisoning?. J Toxicol Clin Toxicol 1999; 37:259-264.
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thallium neurotoxicity. Neuropathol Appl Neurobiol 1991; 17:3-9.
13. Cavanagh JB, Fuller NH, Johnson HRM, Rudge P: The effects of thallium salts, with particular reference
to the nervous system changes: A report of three cases. Q J Med 1974; 170:293-319.
14. Civil ID, McDonald MJ: Acute selenium poisoning: Case report. NZ Med J 1978; 87:354-356.
15. Desenclos JC, Wilder MH, Coppenger GW, et al: Thallium poisoning: An outbreak in Florida, 1988.
South Med J 1992; 85:1203-1206.
16. Goyer RA: Toxic effects of metals. In: Klaasen CD, ed. Casarett & Doull’s Toxicology: The Basic
Science of Poisons, 5th ed. New York: McGraw-Hill; 1996:699-702.
17. Groot GD, Heijst ANP: Thallium concentration in body fluids and tissue in a fatal case of thallium
poisoning. Vet Hum Toxicol 1985; 27:115-119.
18. Groot GD, Heijst ANP, Kersteren RG, Maes RAA: An evaluation of the efficacy of charcoal
haemoperfusion and the treatment of three cases of acute thallium poisoning. Arch Toxicol 1985; 57:61-
66.
19. Groot GD, Van Heijst ANP: Toxicokinetic aspects of thallium poisoning: Methods of treatment by toxin
elimination. Sci Total Environment 1988; 71:411-418.
20. Grover AK, Frederickson M, Daniel EE: Thallous ion activation of p-nitrophenylphosphatase of rat
myometrium plasma membrane. Can J Physiol Pharmacol 1981; 59:1180-1183.
21. Hasan M, Chandra SV, Dua PR: Biochemical and electrophysiologic effects of thallium poisoning on rat
corpus striatum. Toxicol Appl Pharmacol 1977; 41:353-359.
22. Heath A, Ahlmen J, Branegard B, Lindstedt S: Thallium poisoning-toxin elimination and therapy in three
cases. J Toxicol Clin Toxicol 1983; 20:451-463.
23. Heyl T, Barlow RJ: Thallium poisoning: A dermatological perspective. Br J Dermatol 1989; 121:787-
792.
23a. Insley BM, Grufferman S, Ayliffe HE: Thallium poisoning in cocaine abusers. Am J Emerg
Med 1986; 4:545-548.
24. Jantsch W, Kulig K, Rumack HB: Massive copper sulfate ingestion resulting in hepatotoxicity. Clin
Toxicol 1984; 22:585-588.
25. Kamerbeek HH, Rauws AG, Ham M, Heijst A: Dangerous redistribution of thallium by treatment with
sodium diethyldithiocarbamate. Acta Med Scand 1971; 189:149-154.
26. Lamont DL, Duflou JA: Copper sulfate: Not a harmless chemical. Am J Forensic Med
Pathol 1988; 9:226-227.
27. Lund A: The effect of various substances on the excretion and toxicity of thallium in the rat. Acta
28. Malbrain ML, Lambrecht GL, Zandijk E, et al: Treatment of severe thallium intoxication. J Toxicol Clin
Toxicol 1997; 35:97-100.
29. Mayfield SR, Morgan DP, Roberts RJ: Acute thallium poisoning in a 3-year-old child. Clin
Pediatr 1983; 23:461-462.
30. Meggs WJ, Cahill-Morasco R, Shih RD, et al: Effects of Prussian blue and N-acetylcysteine on thallium
toxicity in mice. J Toxicol Clin Toxicol 1997; 35:163-166.
31. Meggs WJ, Hoffman RS, Shih RD, et al: Thallium poisoning from maliciously contaminated food. J
32. Meggs WJ, Goldfrank LR, Hoffman RS: Effects of potassium in a murine model of thallium poisoning
[abstract]. J Toxicol Clin Toxicol 1995; 33:558-559.
33. Mills K, Kunkel D: Prevention of severe barium carbonate toxicity with oral magnesium sulfate. Vet
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35. Nogue S, Mas A, Prese A, Nadal P: Acute thallium poisoning: An evaluation of different forms of
treatment. J Toxicol Clin Toxicol 1982–1983; 19:1015-1021.
36. Pentel P, Fletcher D, Jentzen J: Fatal acute selenium toxicity. J Forensic Sci 1985; 30:556-562.
37. Sharn ThF, Olbricht CH, Schuler A, et al: Barium carbonate intoxication. Intensive Care
Med 1991; 17:60-62.
38. Stift A, Friedl J, Laengle F: Liver transplantation for potassium dichromate poisoning. N Engl J
Med 1998; 338:766-767.
39. Talas A, Pretschner DP, Wellhoner HH: Pharmacokinetic parameters for thallium (I)-ions in man. Arch
Toxicol 1983; 53:1-7.


Chapter 92 – Antiseptics, Disinfectants, and Sterilizing Agents
YOUNG-JIN SUE KATHLEEN A. DELANEY
ANTISEPTICS
Essentials
• Antiseptics are chemicals that are applied to living tissues to kill bacteria or inhibit their growth.
• Free iodine (I2) has significant concentration-dependent tissue and systemic toxicity.
• Iodide (I-) causes a negative anion gap and is associated with thyroid disorders, salivary gland
disorders, and dermal reactions.
• Most acute exposures to boric acid are benign. Severe toxicity results from chronic exposure or massive
exposure.
• Characteristic symptoms of boric acid toxicity include green-blue vomit and diarrhea, erythroderma with
desquamation, and central nervous system (CNS), renal, bone marrow, and hepatic injury.
Iodophors, Iodine, and Iodide
Iodophors such as povidone-iodine (Betadine) are complex detergent-based solutions of iodide (I-), free
iodine (I2), and iodine bound to povidone, a carrier molecule that limits the availability of free iodine. Only 1
per cent of all forms of iodine in a 10 per cent solution of povidone-iodine are freely solubilized. The toxicity
of iodine is much greater than that of iodide. Most iodophors contain only 80 to 120 µg/100 mL of free iodine,
making them much less toxic than older iodine preparations such as tincture of iodine, which contains 2 g of
iodine in 100 mL. Nevertheless, severe toxicity after exposures to iodophors have been reported.[10][37][56]
The iodophors are used as antiseptics and irrigants. Iodine-containing solutions are also used as
expectorants, as vaginal irrigants, for contrast studies in radiology, and as therapy for acute
hyperthyroidism.[55] Lugol’s iodine solution, commonly used in the acute treatment of hyperthyroidism,
contains 5 per cent I2 and 10 per cent potassium iodide (I -). [12]
Pathophysiology
The antibacterial property of iodide is facilitated by a covalent linkage to bacterial cell surface glycoproteins,
which enhances the bactericidal properties of polymorphonucleocytes.[12] The mechanism of iodine toxicity
in human poisoning is not well defined. Based on the significant lactic acidosis seen in acute iodine toxicity,
the cellular toxicity has been attributed to interference with cellular oxidative metabolism and adenosine
triphosphate production.[12] Chronic exposure results in disturbances of thyroid structure and function and
may be manifest as hyperthyroidism, hypothyroidism, goiter, or thyroiditis.[55] These seemingly paradoxical
responses are due to the stimulation of increased thyroid hormone production in some individuals
(Jodbasedow reaction) and the blockade of thyroid hormone production in others (Wolff-Chaikoff effect).[55]
The developing fetus is especially susceptible to the thyroid suppressant effects of iodine.[55][74]
Iodine toxicity occurs through ingestion, through absorption during wound irrigation with iodophor-containing
solutions, through mucosal exposure, and during topical application to dermal burns.[10][12][37][55] In one
study, a single vaginal application of undiluted 10 per cent povidone-iodine resulted in a 5- to 14-fold
increase in serum iodine levels.[74]
Acute ingestion of iodine (I2)-containing solutions results in gastrointestinal irritation, gastrointestinal

ulceration, and chemical pneumonitis ( Table 92–1 ). These effects are concentration dependent, so that
ingestion of tincture of iodine or Lugol’s iodine solution results in far more tissue injury than does ingestion of
povidone-iodine. Any acute exposure to significant amounts of iodide may lead to acute tubular necrosis,
hemolytic anemia, and hyperthyroidism. Early toxic symptoms are related to stimulation of increased
secretions, leading to rhinorrhea, conjunctivitis, and cough productive of serous fluid. Acute respiratory
distress, severe lactic acidosis, renal dysfunction, cardiogenic shock, and death occur within hours.[10][12]
Anaphylactic and anaphylactoid reactions also occur.[55]
Table 92-1 -- Clinical Presentation of Exposure to Antiseptics, Disinfectants, and Sterilizing Agents
Respiratory irritation, distress, or failure
Dermal and mucous membrane irritation and burns
Lethargy, coma, seizures
Metabolic acidosis
Embolic phenomena (hydrogen peroxide)
Erythroderma (boric acid), ioderma (iodides)
Hyperchloremia, negative anion gap (iodides)
Chronic ingestion of iodine leads to thyroid disorders in some individuals. Large or chronic exposure to
iodides results in sensitivity reactions manifest as painful salivary gland enlargement and a variety of dermal
eruptions, so-called ioderma.[55]
Measurement of serum electrolytes is indicated in all cases of suspected iodine poisoning. Iodide is
measured as chloride in laboratory autoanalyzers, causing a disproportionate elevation of the serum chloride
on the order of 3 mEq/L in a case of iodine ingestion[12] to 26 mEq/L after iodide ingestion.[16] This may
result in a negative anion gap in some cases.[16] In addition to this apparent hyperchloremia, there may be a
superimposed lactic acidosis in critically ill patients that leads to an anion gap that is lower than would be
expected based on the magnitude of measured lactate.[12]
Total iodine (I2 and I-) levels can be measured and their levels correlated with toxicity, although the minimum
level at which fatalities occur has not been determined. Normal values range from 5 to 8 µg/dL. Reported
levels in severely poisoned patients were 7,000 µg/dL,[12] 10,000 to 40,000 µg/dL,[37] and 60,000 µg/dL.[12]
Peak levels of 2,500 µg/dL are associated with 11 per cent mortality in rabbits.[15]
The differential diagnosis of acute iodine toxicity includes a spectrum of agents that cause gastrointestinal
symptoms, such as heavy metals, caustics, mushrooms, and infectious causes ( Table 92–2 ). Pneumonitis
may follow ingestion of hydrocarbons, paraquat, and opiate and sedative-hypnotic overdoses. The exposure
history is most helpful in confirming the diagnosis. Hyperchloremia is seen as a consequence of bicarbonate
loss in severe diarrhea and renal tubular acidosis. A low anion gap is seen in cases of poisoning with
bromides and in multiple myeloma, owing to a large increase in unmeasured positive charges on the
myeloma proteins.
Table 92-2 -- Differential Diagnosis of Exposure to Antiseptics, Disinfectants, and Sterilizing Agents
Irritant reaction: soaps, antiseptics, solvents
Caustic effect: strong acids and bases, quaternary ammonium compounds, vesicants
Gastrointestinal effects: arsenic, mercuric compounds, chromium
Low anion gap: iodide, bromide, multiple myeloma
Treatment
Good supportive care is critical in the management of all cases and is all that is required in most cases of
povidone-iodine ingestion ( Table 92–3 ). After ingestion of significant amounts, gastric decontamination
may be done by aspiration with a small nasogastric tube. Iodine may be converted to less toxic iodide by the
administration of starch or milk. Sodium thiosulfate will also convert iodine to iodide. Activated charcoal is
indicated unless significant symptoms suggest the need for endoscopic evaluation of caustic injury.[12]
Iodine is removed by hemodialysis. Anecdotal reports of the use of hemodialysis in significantly poisoned
patients indicate an 80 per cent mortality despite hemodialysis.[12]
Table 92-3 -- Treatment of Exposure to Antiseptics, Disinfectants, and Sterilizing Agents

Stabilize patient and provide supportive care
Decontaminate skin and mucous membranes with water (all) or polyethylene glycol—industrial methylated
spirits (phenol)
Treat dermal or mucous membrane burns
Institute fluid management
Perform endoscopy and surgical intervention for gastrointestinal burns
Enhance elimination
Hemodialysis: formaldehyde, boric acid, iodine (severe poisoning)
Hyperbaric oxygen therapy: emboli with hydrogen peroxide
Symptomatic patients with chronic exposure to iodine-containing medications require evaluation of thyroid
function.
Boric Acid
Boric acid had significant medical uses in the past as a topical antiseptic and irrigant. At one time it was
mixed with honey and glycerine and sold to treat topical mucosal sores in children.[20] Historically, significant
toxicity and fatalities occurred after chronic exposure to boric acid preparations. In one series, 11 infants
died when inadvertently fed a 2.5 per cent boric acid solution over several days.[77] Because of its weak
antiseptic properties and significant toxicity it is no longer used in medicinal preparations.[20] A common
cause of exposure today is related to accidental ingestion of powdered boric acid used to kill cockroaches.
Acute accidental ingestions rarely result in significant toxicity. whereas chronic exposure results in more
serious toxicity.[19][20][39][40][61] Suicidal ingestions of large amounts (280 g in one case) may be fatal.[61]
Pathophysiology
Boric acid is easily absorbed across mucosal surfaces, through abraded skin, and in the gastrointestinal
tract. It is eliminated unchanged in the kidneys with a half-life of 21 hours in patients with normal renal
function.[61] Excretion is markedly prolonged in seriously poisoned patients.[61][77] The mechanism of its toxic
effects is not known.
The characteristic presentation of boric acid poisoning is the development of blue-green vomiting and
diarrhea, followed by intense erythroderma that has a boiled lobster appearance. This progresses to
desquamation and erosion of mucosal surfaces.[61][62][77] Renal, bone marrow, and hepatic injuries
occur.[61][65] CNS symptoms include seizures, delirium, and coma.[20][77]
The differential diagnosis of significant acute boric acid poisoning includes toxic shock syndrome, Steven-
Johnson syndrome, and toxic epidermal necrolysis.
Although levels of boric acid do not correlate well with toxicity, levels in seriously poisoned patients with
acute exposure generally fall above 34 mg/dL.[40] Seizures in one child with chronic exposure were
associated with a serum boric acid level of 9.44 mg/dL.[20] A fatal case of acute boric acid poisoning in an
adult had a 52-hour level of 42 mg/dL.[61] Boric acid levels in Wong’s series of 11 fatal pediatric poisonings
ranged from 2 to 160 mg/dL.[77]
Treatment
Treatment in most cases is supportive. Activated charcoal does not absorb boric acid effectively.[11] For
acute ingestions in children weighing less than 30 kg the authors of one large series recommended
observation for ingestions less than 200 mg/kg, ipecac-induced emesis for 200 to 400 mg/kg, and lavage
and emergency department evaluation for more than 400 mg/kg. Lavage was recommended for a 12-g
ingestion in larger patients.[40] Hemodialysis may be indicated for severely poisoned patients.[61] Exchange
transfusions have been used in severely poisoned neonates.[77]
Disposition
Most acute ingestions of boric acid and iodophors are benign. Patients with massive ingestions of boric acid
or an iodophor, or any ingestion of iodine, should be observed for symptoms or laboratory abnormalities.
Patients with symptoms after acute ingestion of any antiseptic agent should be admitted for observation and
further treatment.


DISINFECTANTS AND STERILANTS
Disinfectants are agents that are applied to inanimate objects to inhibit or kill microorganisms. Sterilants kill
all forms of microorganisms, including spores.
Formaldehyde
Essentials
• Upper airway and mucous membrane irritation
• Nausea, vomiting, diarrhea, abdominal pain
• Hemodynamic instability
• Severe systemic acidosis
Introduction
Formaldehyde is a commonly available substance. It is used as a disinfectant in either a 2 or 8 per cent

solution or a 37 per cent solution (formalin USP) formulated in 10 to 15 per cent methanol that is added to
prevent polymerization. It is also used in the manufacture of tissue fixatives, textiles, resin glues, plastics,
and urea-formaldehyde foam insulation. Formaldehyde is released into ambient air from these products
either as excess free formaldehyde or as a result of decomposition. It is also a product of combustion from
appliances and cigarette smoke. Mean conventional home levels were estimated by the Environmental
Protection Agency to be about 0.03 ppm.[31] Because it often coexists with other environmental irritants, the
contribution of formaldehyde exposure to disease is difficult to assess. Although adverse effects have
reportedly occurred throughout a great range of ambient air levels of formaldehyde, mucous membrane
irritation occurs consistently at 1 ppm.[41] The OSHA time-weighted average (TWA) workplace standard for
formaldehyde has been set at this level.[9] Irritation at lower levels may be due to individual hypersensitivity.
Pathophysiology
Formaldehyde is a protoplasmic poison, precipitating proteins and causing coagulation necrosis. It promotes
allergic reactions by binding to and altering tissue proteins. Repeated exposure is believed to result in
allergic contact dermatitis (type IV hypersensitivity reaction). Type I hypersensitivity reactions are thought to
precipitate the bronchospastic disease associated with formaldehyde, but IgE antibodies to formaldehyde
have not been demonstrated.[31] Formaldehyde is readily absorbed from the gut and lungs and rapidly
metabolized through formate to carbon dioxide and water by the liver and erythrocytes. Formaldehyde is a
naturally occurring product of tetrafolate reactions with endogenous tissue levels of 3 to 12 ng/g. [2]
Inhalational Exposure
Formaldehyde has an easily detectable odor at 0.5 ppm and is frankly irritating to upper airways and mucous
membranes at 1 ppm. These unpleasant attributes serve as an early warning and tend to limit inhalational
exposure. Severe respiratory irritation develops at higher concentrations, producing dyspnea at 10 ppm.
Inhalation of 100 ppm may be life threatening.[9]
Formaldehyde is believed to be a potent sensitizer in immune-mediated bronchospasm. However,

differentiation of hypersensitivity from the primary irritant effects of formaldehyde is often difficult. [25] Chronic
low-level exposure to up to 1.6 ppm produced fatigue, headache, and mucous membrane irritation but did
not produce significant changes in pulmonary function tests.[44] The incidence of dermal sensitization may
be as high as 5 per cent in the general population. [9]
Chronic off-gassing of formaldehyde from urea-formaldehyde foam insulation (UFFI) has been suggested as
the cause of a myriad of complaints such as headache, nausea, upper airway irritation, reactive airway
disease, dermatitis, and insomnia. Studies have shown that formaldehyde levels in UFFI homes were similar
to those found in control homes, offering little support for the role of UFFI in health problems.[52]
Oral Exposure
Ingestion of formaldehyde results in gastrointestinal injury with nausea, vomiting, diarrhea, abdominal pain,
and lethargy. Serious ingestions may be complicated by hemorrhage, shock, coagulation necrosis of
stomach and distal esophagus, severe metabolic acidosis, and death.[14][35][63] Multiple factors contribute to
the acidosis, including the metabolism of formaldehyde to formate, increased tissue lactate, and concomitant
methanol poisoning. Methanol levels were elevated for over 13 hours in a 58-year-old man who ingested 4
ounces of formalin. This prolonged course was attributed to delayed absorption due to “fixation” of the
gastric mucosa.[8] Perforation and strictures of the gastrointestinal tract may limit recovery. Inadvertent
parenteral exposure to 2 per cent formalin from incompletely purged hemodialysis machines has resulted in
intravascular hemolysis.[59]
Sequelae
Strictures may follow significant gastrointestinal injury. Dermal sensitization is associated with eczematoid
dermatitis. Nasopharyngeal carcinomas are produced in rats exposed to concentrations of formaldehyde not
tolerated by humans (14–15 ppm).[31][72] However, several human studies have failed to prove a significant
association of formaldehyde with human carcinogenicity or teratogenicity.[27][47][53][54] Studies that have
implicated formaldehyde in various upper airway carcinomas have been confounded by multiple concomitant
occupational exposures, long latencies of the carcinomas, and insufficient power of the studies to detect a
small increase in risk over the low baseline rate of the malignancies.[71] The National Institute for
Occupational Safety and Health–International Agency for Research on Cancer (NIOSH-IARC) has classified
formaldehyde as a potential human carcinogen.[9]
Related Agent: Glutaraldehyde
Glutaraldehyde, a superior sterilant that is chemically similar to formaldehyde, is effective against all
organisms, including viruses and spores. It is produced as a 2 per cent solution in 70 per cent isopropanol
(Cidex). Less volatile than formaldehyde, its fumes are not as irritating but can nonetheless cause contact
nasal irritation, epistaxis, headache, nausea, bronchospasm, and contact dermatitis. [33][51] OSHA
permissible exposure level (PEL) has been set at 0.2 ppm.[9] Gluteraldehyde-associated colitis has been
reported from the use of improperly cleansed sigmoidoscopes.[13][76]
Phenol
Essentials
• Whitish mucous membranes, brownish or whitish discoloration of skin
• Gastrointestinal injury, nausea, vomiting, diarrhea, abdominal pain
• CNS stimulation, depression
• Metabolic acidosis
• Hemodynamic instability, dysrhythmias
Introduction
Phenol (C6H5OH) is also known as carbolic acid. Historically used as an antiseptic, it is currently found in
disinfectants, solvents, toiletries, analgesic preparations, and wood preservatives. It is used in the chemical
industry as an intermediary and in the materials industry as a phenol-formaldehyde resin adhesive for wood
and plastics. Large-scale human exposures have occurred from contamination of drinking water from
industrial plants and freight trains.[1][32] In addition, it is present in cigarette smoke. Phenol is used in many
over-the-counter preparations for its local anesthetic properties. It is present in Chloraseptic oral rinse (1.7
per cent) and Campho-Phenique topical anesthetic (4.7%). The odor threshold of phenol is 7.9 ppm in water
and 0.05 ppm in air. The OSHA PEL is 5 ppm as a TWA.[73]
Pathophysiology
Phenol is a protoplasmic toxin that disrupts cell walls and denatures proteins. These properties promote
rapid pulmonary and gastrointestinal absorption. Dermal absorption is rapid even through intact skin.[4] High
concentrations of phenol disrupt the dermal barrier and penetrate skin effectively.[4] Its local anesthetic
action produces a relatively painless coagulum. Although a small amount of phenol undergoes conjugation
with glucuronic and sulfuric acids within 1 to 2 days of exposure, most is excreted unchanged in the urine.[73]
The half-life of phenol is estimated at 3.5 hours.[7]
Topical exposure to phenol results in brown, relatively painless patches on the skin and whitish patches on
the mucous membranes. Ingestion results in gastrointestinal symptoms that range in severity from nausea,
vomiting, diarrhea, and abdominal pain to hematemesis and hematochezia. Inhalation or aspiration
produces coughing, stridor, and an aromatic odor of the breath. Systemic complaints from acute exposure
include CNS stimulation and depression, seizures, coma, tachycardia, ventricular dysrhythmias,
hypotension, hypothermia, metabolic acidosis, and acute tubular necrosis.[5][22][42] Significant
gastrointestinal burns are uncommon and depend on phenol concentration and duration of exposure. Spiller
and associates analyzed 72 cases of Creolin (26 per cent phenol) ingestion reported to poison control
centers.[70] The analysis revealed a rapid onset of CNS depression from 15 minutes to 1 hour. Of 17 patients
who underwent endoscopy, 16 had first-degree gastrointestinal burns. The exception was a 3-year old who
had “minor tissue sloughing.” Although the lethal oral dose has been estimated at about 3 g, survival has
been reported after ingestion of 26.7 g.[22] Lewin and Cleary reported a fatality from the topicalapplication of
a scabicide with a brush that had been steeped in 80 per cent phenol.[38] The 24-year-old patient
complained of a stinging sensation on application and developed an unsteady gait within 10 minutes. This
was followed by seizures and cardiorespiratory arrest.
Chronic exposure has been associated with sore throat, diarrhea, oropharyngeal sores, and dark bilirubin-
free urine. The substance responsible for darkening the urine has not been identified but is probably an
oxidative product of phenol metabolism. “Phenol marasmus” is a syndrome that was described in health
care workers chronically exposed to nebulized phenol (5–10 per cent) applied as a disinfectant in the 1800s.
They developed anorexia, weight loss, headache, vertigo, salivation, muscle aches and weakness, dark
urine, and hepatitis.[48]
Related Agents: Substituted Phenols
Cresols, a mixture of methylated phenols with more potent germicidal action but less toxicity than phenol,
have the advantage of a greater therapeutic index.[23] Creosote is a mixture of aromatics and phenol.
Hexachlorophene, a trichlorinated bis-phenol, was associated with vacuolar encephalopathy and cerebral
edema in premature infants washed with a 3 per cent solution.[68] Herskowitz and Rosman reported an 8-
day-old infant who developed vomiting, diarrhea, twitching, and hypertonicity after ingestion of 10 to 15 mL
of a 3 per cent solution. [26] The infant recovered fully. Martinez and associates reported a 7-year-old boy
given 45 mL of pHisoHex (hexachlorophene) over 3 days who presented with lethargy and blindness.[45] His
condition deteriorated, and he died within 3 days. Pathologic findings included diffuse vacuolization of white
matter and optic neuronal necrosis.
Dinitrophenol and pentachlorophenol are substituted phenols that are used as preservatives and herbicides.
These agents disrupt cellular respiration by uncoupling oxidative phosphorylation, leading to metabolic
acidosis, hyperpyrexia, and dehydration.
Hypochlorite
Essentials
• Dermal irritation or burns
• Respiratory irritation or distress
Introduction
The disinfectant properties of sodium hypochlorite arise from its slow release of hypochlorous acid. It is
found in bleaches, deodorizers, and water purifiers. Most solutions intended for household use are 5 per
cent in concentration or less. Granular bleaches have more caustic potential owing to greater local
concentration of hypochlorite and longer duration of adherence by the particles.
Pathophysiology
The toxicity of hypochlorite arises from its oxidizing activity. Toxicity, which is expressed as available
chlorine, ranges from irritant effects of dilute solutions (available chlorine less than 6 per cent) to caustic
injury (available chlorine greater than 15 per cent). Large volumes and longer duration of contact may
exacerbate caustic injury.
The inhalational toxicity of hypochlorite is concentration dependent, ranging from mucous membrane
irritation and cough to dyspnea and bronchospasm. Mixing bleach with ammonia is a common household
error, resulting in the release of chloramine gas (NH2Cl and NHCl2), which produces nausea, vomiting,
dyspnea, and pulmonary edema. Likewise, mixing bleach with acid-containing cleaners may release the
highly irritating chlorine gas that may also produce dyspnea and pulmonary edema. Dermal exposure to
dilute solutions of bleach usually results in irritation and erythema. Intense pain and vesication follow dermal
and mucous membrane exposure to concentrated bleach.
The ingestion of dilute bleach produces mild gastrointestinal irritation. No significant gastrointestinal burns
were found in a review of 129 ingestions of Clorox (5 per cent hypochlorite).[57] However, even for dilute
hypochlorite solutions, ingestion of large quantities or prolonged exposure may lead to more consequential
symptoms. French and colleagues reported two cases of stricture formation after the ingestion of several
ounces of household bleach.[17] The ingestion of highly concentrated solutions may result in metabolic
disturbances. Hypernatremia and hyperchloremic metabolic acidosis developed in a 66-year-old woman
after the ingestion of 500 mL of a 10 per cent sodium hypochlorite solution.[75] The serum sodium value was
169 mmol/L, and that of chloride was 130 mmol/L. She suffered superficial burns of the mouth but recovered
fully. The inadvertent intravenous injection of about 1 mL of 5 per cent hypochlorite caused chest pain and
vomiting in a 31-year-old man.[49] Massive hemolysis, hyperkalemia, and cardiac arrest resulted from the
inadvertent parenteral exposure to a 3 per cent bleach disinfecting solution during dialysis.[28]
Hydrogen Peroxide
Essentials
• Local irritation or burns
• Gastrointestinal upset
• Subcutaneous emphysema
• Embolic phenomena
Introduction
Hydrogen peroxide is used in disinfectants, in bleaching textiles and paper, in the manufacture of other
chemicals, and in rocket fuel production. It is produced as a 3 per cent solution in water for household use.
Concentrations of industrial solutions range from greater than 10 per cent to 70 per cent. Recently, the
ingestion of a 35 per cent solution of hydrogen peroxide has been advocated for “hyperoxygenation
therapy.”[29]
Pathophysiology
Local toxicity from hydrogen peroxide results from direct oxidation by peroxide and by hydroxyl radicals
produced from peroxide. The extent of injury is dependent on the concentration of hydrogen peroxide and
the duration of exposure. Local tissue injury ranges from mere irritant effects by dilute solutions to caustic
injury from more concentrated preparations. In addition to local tissue oxidation, the catalase-mediated
breakdown of hydrogen peroxide to oxygen and water produces large volumes of gas. One milliliter of 3 per
cent hydrogen peroxide liberates 10 mL of oxygen under standard conditions of temperature and pressure.
Massive distention may occur, exacerbating local injury or leading to life-threatening gas embolization.
Toxic injuries occur after inhalation, dermal and mucous membrane exposure, wound irrigation, or ingestion.
Intense respiratory exposures may lead to pulmonary edema, coma, and seizures. High concentrations (>30
per cent) pose an explosion hazard. Dermal application produces symptoms ranging from irritation and
erythema with dilute solutions to blistering and necrosis from concentrations greater than 30 per cent.
Ingestion of hydrogen peroxide produces a whitish discoloration or erythema of mucous membranes,
vomiting, abdominal pain, and bloating. Ingestion of more concentrated solutions may produce seizures and
gastric mucosal hemorrhage and edema.[18] A 33-year-old woman who ingested an unknown quantity of 35
per cent hydrogen peroxide suffered persistent neurologic deficits after recurrent seizures. Endoscopy
revealed transmucosal emphysema. A 40-year-old woman developed portal venous gas after ingesting a 35
per cent solution of hydrogen peroxide. She recovered without sequelae.[43] Portal gas has also been
reported after the ingestion of dilute hydrogen peroxide. A 2-year-old boy developed hematemesis and
hepatic air after ingesting an unknown quantity of 3 per cent hydrogen peroxide.[60] He recovered fully.
Bowel irrigation with 1 per cent hydrogen peroxide led to mesenteric embolization and gut necrosis in a
neonate.[66] Subcutaneous emphysema and embolic complications have resulted from forceful wound
irrigation with 3 per cent hydrogen peroxide.[3][69]
Ethylene Oxide
Essentials
• Nausea, lightheadedness
• Anaphylactoid reactions
• Motor and sensory neuropathies
Pathophysiology
Ethylene oxide is used in the cold sterilization of heat-sensitive medical instruments, as an intermediate in
the synthesis of other chemicals, and in the manufacture of rocket propellants. It is an alkylating agent that
binds covalently to DNA and RNA, leading to the formation of point mutations. Ethylene oxide is both a
carcinogen and reproductive toxin in animals. On the basis of this limited evidence, the NIOSH regards
ethylene oxide as a potential human carcinogen and recommends that the 8-hour TWA not exceed 0.1
ppm.[36][67] The limit of detection for odor is high at 700 ppm, at which point the odor is similar to that of
ether. The mechanism by which ethylene oxide causes its neurotoxic effects is unclear. Animals have
developed weakness and seizures after exposure to ethylene oxide concentrations as low as 200 ppm. [21]
Type I hypersensitivity reactions have been reported after chronic exposure.[36]
Acute exposure causes irritation to the skin, mucous membranes, conjunctivae, upper airway, and
gastrointestinal tract. Significant dermal exposures may result in burns, vesication, and frostbite. Nausea,
lightheadedness, headache, malaise, ataxia, syncope, and seizures also occur after acute exposure. [64]
Anaphylactoid reactions have occurred when ethylene oxide was used to disinfect hemodialysis machines,
leading to symptoms such as dyspnea, chest pain, urticaria, sweating, flushing, itching, bronchospasm,
tachycardia, and hypotension.[46] Chronic exposures have been associated with motor and sensory
neuropathies and muscular atrophy in both animals and humans. There is some evidence that the rate of
spontaneous abortion is increased in workers occupationally exposed to ethylene oxide.[24]
The differential diagnosis includes exposure to any agent that causes respiratory, dermal, or gastrointestinal
irritation. The most useful tool in the differential diagnosis is the exposure history.
Laboratory Studies
Arterial blood gas and serum electrolyte measurements aid in the diagnosis and management of acid-base
and electrolyte disturbances. Chest and abdominal radiographs are indicated if pulmonary edema or
gastrointestinal perforation due to caustic injury is suspected. They may also demonstrate abnormal areas of
gas development after hydrogen peroxide ingestions. Routine toxicologic analysis is not useful.
Formaldehyde
The utility of blood and urine formaldehyde levels is limited because formaldehyde is a naturally occurring
tissue metabolite and is difficult to assay after acute exposure. Blood formate levels in normal persons are
not well established and vary widely. However, urine formate levels may be useful for documenting acute
high-level exposure. The patient with formalin ingestion should be assessed for methanol toxicity and
treated appropriately. Patch testing using nonirritating concentrations of formaldehyde according to
standardized techniques may demonstrate type IV dermal hypersensitivity. Studies of reactive airway
disease due to type I hypersensitivity to formaldehyde are not well standardized and are inconclusive.[31]
Phenol
Qualitative phenol assays of blood and urine may serve as markers of recent exposure. Methemoglobin
levels should be determined by co-oximetry in patients who are cyanotic or dyspneic after the ingestion of
some phenols such as nitrophenol and dinitrophenol.
Hydrogen Peroxide
After ingestion or use of hydrogen peroxide in wound irrigation, radiographs may reveal ectopic gas.
Treatment
Resuscitation, including airway management, seizure control, and volume replacement should proceed
simultaneously with decontamination. Topical exposures require thorough irrigation of the skin and eyes.
Gastric emptying after ingestion of potentially caustic materials remains a controversial and potentially
hazardous undertaking. Gentle aspiration of material through a small-bore flexible nasogastric tube may limit
absorption and is a reasonable treatment. Emesis is contraindicated. Activated charcoal may adsorb
selected chemicals but may also hinder endoscopic visualization of gastrointestinal mucosa. Therefore, if
significant gastrointestinal burns are suspected, immediate endoscopic and surgical consultation should be
sought. Volume losses and metabolic acidosis should be treated with appropriate intravenous fluids and
sodium bicarbonate for severe metabolic acidosis.
Formaldehyde
The capacity of activated charcoal to adsorb formaldehyde is unknown. Intravenous ethanol or fomepizole,
as well as hemodialysis, may be indicated in the treatment of methanol toxicity that follows a significant
ingestion of formalin. Hemodialysis effectively clears formaldehyde as well as methanol and formate.[14]
Phenol
Water, low molecular weight polyethylene glycol, and isopropyl alcohol have been used for dermal
decontamination of phenols.[6][30][58] One swine study comparing the efficacy of a mixture of polyethylene
glycol and industrial methylated spirit with water showed that water was equally efficacious.[58] Given these
results, water, which is readily available, is the initial choice for dermal decontamination. Based on in vitro
experiments, activated charcoal may effectively adsorb ingested phenol.[50] In vitro charcoal hemoperfusion
removed free phenol from an aqueous solution.[34] It has not been determined if this finding is applicable to
the clinical setting.
Hypochlorite
Inhalational exposure to chlorine and chloramine gas inhalation should be treated with humidified oxygen
and nebulized bronchodilators if necessary.
Hydrogen Peroxide
In the event of radiographic evidence of air in the heart after hydrogen peroxide exposure, immediate
Trendelenburg positioning should be maintained to free the right ventricular outflow tract and prevent
embolization to the CNS. Hyperbaric oxygen therapy may be useful in the treatment of peroxide-associated
embolic events.
Disposition
Patients who present after topical or inhalational exposures with self-limited symptoms may be discharged
after a few hours of observation for resolution or diminution of complaints. Those with signs of systemic
toxicity must be admitted for further evaluation and treatment. Individuals who have ingested formaldehyde
or phenol should be hospitalized for observation, supportive care, and surgical intervention, if required. The
disposition of patients who have ingested dilute solutions of bleach or hydrogen peroxide depends on the
patient’s symptoms. Patients who have mild mucous membrane irritation or abdominal discomfort that
resolves rapidly may be discharged after evaluation if they are able to drink without difficulty and have no
respiratory symptoms. The presence of oropharyngeal or dermal burns or persistent discomfort or distress
should raise suspicion for the ingestion of more caustic solutions or significant quantities. Any patient who
recovers from a gastrointestinal burn should receive long-term follow-up for the development of strictures. In
the event of a hydrogen peroxide–associated embolus, the patient should be referred immediately for
hyperbaric oxygen therapy. Intensive care monitoring and supportive care are required for patients with
significant symptoms of toxicity.


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32. Jarvis SN, Straube RC, Williams ALJ: Illness associated with contamination of drinking water supplies
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45. Martinez AJ, Boehm R, Hadfield MG: Acute hexachlorophene encephalopathy: Clinico-
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51. Norback D: Skin and respiratory symptoms from exposure to alkaline glutaraldehyde in medical
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52. Norman GR, Newhouse MT: Health effects of urea formaldehyde foam insulation: Evidence of
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Chapter 93 – Ethylene Glycol and Methanol
MARSHA D. FORD KEN McMARTIN
Essentials
• Suspect toxicity in patients who ingest ethanol substitutes or have anion gap metabolic acidosis of
unknown origin.
• Toxic manifestations are delayed until significant metabolism of parent alcohol has occurred.
• Clues to the diagnosis include anion gap metabolic acidosis and (preterminal) hemodynamic stability.
• Toxic clinical manifestations:
° Ethylene glycol: Central nervous system (CNS)— intoxication, stupor, coma, seizures, cerebral
edema with herniation, cranial nerve palsies (late); Cardiopulmonary—cardiogenic and noncardiogenic
pulmonary edema; Renal—acute renal failure, calcium oxaluria; Other—nausea and/or vomiting,
hypocalcemia
° Methanol: CNS—may be alert or have decreased level of consciousness, including coma, seizures,
cerebral edema with herniation, basal ganglia hemorrhage and/or necrosis; Gastrointestinal
(GI)—nausea, vomiting, abdominal pain, pancreatitis; Ophthalmologic—visual disturbances, including
hallucinations, partial to total blindness, papilledema, hyperemic optic discs, retinal edema
• Diagnosis is based on the clinical history; laboratory findings, which may include elevated levels of
ethylene glycol or methanol, and an anion gap metabolic acidosis; and elimination of other differential
diagnoses.
INTRODUCTION
Ethylene glycol and methanol are widely avalaible alcohols with multiple uses ( Table 93–1 ). Humans and
animals exposed to these alcohols can experience severe toxicity, morbidity, and death. The 1997 and 1998
data from the American Association of Poison Control Centers Toxic Exposure Surveillance System show
that 12,185 cases of ethylene glycol exposure and 4917 cases of methanol exposure were reported to
United States poison centers. Moderate to major outcomes occurred in 1008 (8.3%) ethylene glycol cases
and 330 (6.7%) methanol cases, with 49 and 30 deaths, respectively.[63][64] Early diagnosis and rapid
institution of appropriate treatment decreases morbidity and mortality. These toxic alcohols are considered
together because their treatments are similar.
Table 93-1 -- Sources of Ethylene Glycol and Methanol *

Alcohol Sources and Uses
Antifreeze
Alcohol Sources and Uses
De-icing solutions
Humectant (stabilizer of moisture content in tobacco, baked products, dentifrices)
Brake fluid (hydraulic)
Cellophane softening agent
Ethylene Glycol
Foam stabilizer
Solvent
Chemical intermediate (polyester fibers, films, resins)
Condensers and heat exchangers
Glycerin substitute (paints, lacquers, detergents, cosmetics)
Paints and varnishes
Industrial solvent
Manufacture of formaldehyde, acetic acid, methyl derivatives, inorganic acids
Antifreeze
Methanol
Fuel octane booster
Solvent for extraction and pharmaceutical use
Fuel (picnic stoves, torches)
Copier fluids
* See references 5 and 48 .


Ethylene Glycol
Toxicology.
Ethylene glycol is absorbed rapidly from the GI tract. Absorption through intact skin is negligible. Owing to
ethylene glycol’s high boiling point, 197.6°C, vapor inhalation does not occur. Poisoning via inhalation of an
ethylene glycol aerosol is unlikely.[44a ] [107 ] Ethylene glycol rapidly distributes into total body water with a
volume of distribution (Vd ) that ranges from 0.54 to 0.8 L/kg.[8 ] [35 ] [46 ] There is no serum protein binding.
Hepatic alcohol dehydrogenase mediates the initial enzymatic conversion of ethylene glycol into a number of
toxic metabolites ( Fig. 93–1 ). The two rate-limiting steps in the metabolism are conversion of ethylene
glycol to glycolaldehyde and metabolism of glycolic acid (glycolate) to glyoxalate. The latter results in the
accumulation of glycolate, the metabolite responsible for the anion gap metabolic acidosis.[51 ] Elevated
levels of glycolate correlate with an elevated anion gap or decreased levels of serum bicarbonate.[51 ] [78 ]
These metabolites undergo renal excretion. Fomepizole, ethanol, and hemodialysis therapies, as well as
diminished renal function, affect the rate of elimination ( Table 93–2 ).
Figure 93-1 Metabolism of ethylene glycol, showing major important metabolites. *Inhibited by fomepizole (4-methylpyrazole) and ethanol.
Table 93-2 -- Toxicologic and Kinetic Data for Methanol and Ethylene Glycol
Methanol (CH3 OH)
0.7
32
64.7
0.5–1.0
8.5 mg/dL/hr
54.4±4.8 hr
2.8±0.4 hr
30.3–52 hr
2.5–3.5 hr
Formic acid (CH2 O2 )
0.5
46
100.5
NA
—
205±25 min †
185±62.7 min
—
2.51 hr
Ethylene glycol (CH3 CH2 OH)
0.7
62
197.6
0.5
2.5–4.5 hr ‡
19.7±0.33 hr
3.5±0.4 hr
17 hr
2.5–3 hr
Glycolic acid (C2 H4 O3 )
0.55
76
Decomposition
NA
—
626±474 min †
155±42 min †
—
2.4 hr
NA, not applicable; Vd , volume of distribution.
Elimination
Half-Life
(T½e ) *
Effect of
Molecular Boiling Absorption Therapies
Vd Weight Point Peak GI Fomepizole + Ethanol +
(L/kg) (g/mol) (°C) (hr) None Fomepizole Hemodialysis Ethanol Hemodialysis
*
See references 10 , 19 , 20 , 46 , 47 , 52 , 54 , 58 , 71 , 74 , 78 , 86 , 93 , 96 .
†
Fomepizole not expected to affect glycolate or formate clearance, but measurements were performed in patients receiving fomepizole.
‡
Assumes normal renal function.
Pathophysiology.
Target organs include the CNS, kidneys, lungs, heart, liver, muscles, and retina.[17 ] [35 ] [90 ] [91 ] [98 ] Multiple
metabolites contribute to the toxic effects. Glycolaldehyde and glyoxylate are more toxic than glycolate,
although the latter is the only metabolite that accumulates in appreciable amounts, owing to the rate-limiting
effect of lactate dehydrogenase or glycolate oxidase.[4 ] [17 ] [51 ] Glyoxylate can be converted to numerous
metabolites, the most toxic of which is oxalic acid (oxalate) (see Fig. 93–1 ). Oxalate complexes with calcium
to form calcium oxalate crystals, which are deposited in various tissues. The contribution of this crystal
deposition to toxicity is uncertain.[48 ]
Reported tissue effects include the following:
Central nervous system : cerebral edema, meningoencephalitis, loss of cerebellar Purkinje cells
Kidney : proximal and distal tubular dilation, interstitial edema, intratubular deposition of calcium oxalate crystals
Lung : edema, interstitial pneumonitis, hemorrhagic bronchopneumonia
Other : interstitial myocarditis, hepatic centrilobular fatty infiltration, myositis; retinal deposition of calcium oxalate
with histopathologic and electrophysiologic changes[35 ]
Methanol
Toxicology.
Absorption occurs via the GI, dermal, and respiratory routes,[11 ] [36 ] [55 ] with peak GI absorption occurring
30 to 60 minutes post ingestion.[10 ] Hepatic conversion to formaldehyde via alcohol dehydrogenase (ADH)
and then metabolism to formic acid (formate) ( Fig. 93–2 ) represents the major metabolic pathway.
Saturation of the alcohol dehydrogenase enzyme leads to zero-order elimination at a rate of 8.5 mg/dL/hr.[54
] Small amounts of methanol are eliminated unchanged via the respiratory and renal routes by first-order
processes.[57 ]
Figure 93-2 Metabolism of methanol and fate of formic acid. Formic acid is released into the circulation, where it combines with
tetrahydrofolate (THF) to form 10-formyl-THF, which then undergoes several metabolic fates. ADH, alcohol dehydrogenase. (Source:
Liesivuori J, Savolainen H: Methanol and formic acid toxicity: Biochemical mechanisms. Pharmacol Toxicol 1991; 69:157–163.)
Fomepizole, ethanol, and hemodialysis therapies alter methanol elimination (see Table 93–2 ). Fomepizole
and ethanol competitively inhibit the conversion of methanol by ADH.[6 ] [13 ] The consequent impairment of
hepatic metabolism leaves the pulmonary and renal first-order processes as the dominant elimination
routes, resulting in prolonged methanol elimination. In three cases, the elimination half-lives (T½ e ) ranged
from 30.3 to 52.0 hours.[86 ] Both methanol and its significant metabolite, formate, have volumes of
distribution (Vd ) and molecular weights that make them removable by hemodialysis (see Table 93–2 ).[52 ]
[93 ] Hemodialysis markedly decreases the elimination time, with T ½ e reported at 2.5 to 3.5 hours. [47 ] [71 ] [74
]
Several mechanisms eliminate formate (see Fig. 93–2 ): (1) it may combine with tetrahydrofolate (THF), in a
saturable process, to form 10-formyl-THF, which is ultimately converted to carbon dioxide; or (2) it may be
excreted renally, with some proximal tubular reabsorption occurring via the chloride-formate exchanger. [62 ]
The T ½ e is approximately 3.5 hours,[58 ] [96 ] but hemodialysis diminishes this to a T ½ e of 2.51 hours. [52 ]
Pathophysiology.
Formate causes most of the toxic effects associated with methanol poisoning and is responsible for the
metabolic acidosis, although elevated lactate can sometimes be a contributing factor.[25 ] [62 ] [69 ] [73 ] [74 ] [95 ]
Formaldehyde is rapidly metabolized and does not accumulate.[75 ] Its contribution to toxicity remains
unknown but is considered less than that of formate. The parent alcohol, methanol, can cause CNS
depression and, in a canine study of hemodynamic effects, produced decreased cardiac output, stroke
volume, and systemic blood pressure.[27 ]
Formate inhibits the cytochrome oxidase complex at cytochrome aa3 , a site also affected by cyanide,
carbon monoxide, hydrogen sulfide, and azide.[59 ] [62 ] [83 ] This inhibition decreases ATP production,
disrupting cellular homeostasis and increasing anaerobic glycolysis and lactate production.[62 ] The ensuing
systemic acidosis, attributable to both formate and lactate accumulation,[74 ] [95 ] causes several deleterious
effects: (1) increased levels of nondissociated or un-ionized formate, which crosses cellular membranes to
produce further toxicity; (2) increased intracellular calcium; and (3) increased release of calcium by the
sarcoplasmic reticulum.[62 ] Concomitant hydroxyl radical production induces lipid peroxidation, causing
injury to cellular membranes and mitochondria.[18 ] The results of these pathophysiologic effects are cellular
damage and, potentially, cellular death.
Histologically, histotoxic hypoxic changes occur in circulatory watershed areas of both the cerebral and the
distal optic nerve vasculature,[62 ] with the central portion of the optic nerve being more vulnerable than the
periphery.[81 ] In primate experiments, the ophthalmologic changes observed included optic disc hyperemia
and edema, both attributed to stasis of optic nerve axoplasmic flow.[9 ] [44 ] [70 ] In rodents, the retinal and
optic nerve toxicities are directly linked to formate concentration and duration of exposure.[94 ]


Ethylene Glycol
The onset of toxicity usually develops within 4 to 12 hours post exposure; the precise range is unknown.[35]
Concomitant ingestion of ethanol can delay the development of toxicity. Depending on the amount ingested
and the degree of toxic metabolite production, presentations range from alert and asymptomatic, to coma
with severe anion gap metabolic acidosis and incipient renal failure.[7][34][37][48][50] Vital signs are usually
normal or demonstrate mild sympathomimetic effects, with tachycardia and mild elevations in temperature
and blood pressure.[35] Hemodynamic stability until the preterminal stage is typical, and clinically significant
dysrhythmias are rare. Kussmaul respirations are seen in patients with metabolic acidosis.
Table 93-3 -- Clinical Manifestations

Ethylene Glycol Methanol
Onset of toxicity * 4–12 hr =30 hr
Intoxication Alert or inebriated
Stupor Headache
Coma Dizziness
Seizures Agitation
Generalized tonic clonic Stupor
CNS Jacksonian Coma
Cerebral edema Seizures
Herniation syndromes Cerebral edema
Cranial nerve palsies (late) Herniation syndromes
Basal ganglia, infarcts or
hemorrhages
Hypertension Hypertension
Tachycardia or
Tachycardia
bradycardia
Cardiopulmonary (hemodynamic stability
usually preserved until preterminal stage for Hyperpnea, Kussmaul Hyperpnea, Kussmaul
both) respirations respirations
Pulmonary edema,
cardiogenic and
noncardiogenic
Ethylene Glycol Methanol
Acute renal failure
Renal
Calcium oxalate crystalluria
Normal vision (early)
Blurred vision
Photophobia
Visual hallucinations
Partial to total blindness
Ophthalmologic
Pupils sluggish or
nonreactive
Papilledema
Hyperemic optic discs
Retinal edema or
hemorrhages
Anion gap metabolic
Acid-base Anion gap metabolic acidosis
acidosis
Nausea Nausea
Vomiting Vomiting
Abdominal pain
GI
Pancreatitis
Levels of hepatic
transaminases increase
Hypocalcemia
Myoclonic jerks
Other Tetanic contractions
secondary to hypocalcemia
Myositis
* Concomitant use of ethanol may delay onset of toxicity.
Ethylene glycol poisoning initially produces CNS effects similar to those of ethanol, such as intoxication,
stupor, coma, nausea, and vomiting.[35] As the toxicity progresses in untreated patients, cardiovascular and
pulmonary signs and symptoms, such as tachypnea, cyanosis, and cardiogenic or noncardiogenic
pulmonary edema, occur. Metabolic acidosis and elevated levels of serum creatinine and blood urea
nitrogen (BUN) have been reported within 16 hours of ingestion.[34] The metabolic acidosis is relatively
refractory to sodium bicarbonate therapy. Frank renal failure is usually present within 48 to 72 hours post
exposure.[15] During this time, cerebral edema may manifest as progressive CNS depression, prolonged
seizures, or a herniation syndrome.[79] Generalized seizures are typical, but focal seizures, myoclonic jerks,
and tetanic contractions secondary to hypocalcemia have also occurred.[37][87][92] Pulmonary edema can be
both cardiogenic and noncardiogenic in origin, and bronchopneumonia may develop.[22][87] Myositis
manifests as muscle tenderness and elevated levels of creatine kinase. Transient palsies of cranial nerves
II, V, VI, VII, VIII, IX, and X have been reported 4 to 18 days post exposure in patients with delayed or
inadequate treatment or no treatment.[1][14][31][32][68][79][101]
Methanol
The time to onset of toxicity varies and can be delayed for 30 hours or more following exposure. Factors that
influence the rate of development of signs and symptoms include time lapsed since ingestion; the co-
ingestion of ethanol, which retards methanol metabolism; the patient’s underlying folic acid stores; and
individual variations in response.[10][11][25][56] In one study of 46 cases, one-third developed signs and
symptoms more than 30 hours post ingestion.[104] Methanol poisoning affects predominantly the neurologic,
GI, and ophthalmologic systems. Depending on the amount of accumulated formate, the clinical
presentation can range from a few symptoms or none at all to the full spectrum of toxicity. A relative initial
lack of signs and symptoms should not lull the physician into assuming that the patient’s exposure to
methanol is insignificant.
Manifestations
Neurologic.
Patients are often alert on presentation, the period of inebriation having passed. They frequently complain of
headache and dizziness. However, agitation, acute mania, amnesia, a decreased level of consciousness
including coma, and seizures may occur.[11][40][60][82][95][104] In a large series, several patients developed a
clinical picture resembling subarachnoid hemorrhage, with headache, vomiting, nuchal rigidity, hypertension,
and bradycardia.[11] Putamenal necrosis, cerebral herniation, and cerebellar necrosis have been
reported.[3][30][61][81][89]
Gastrointestinal.
Nausea and vomiting are frequently encountered. Other manifestations include flank pain, abdominal pain
that is often severe, GI hemorrhage, diarrhea, liver function abnormalities, and
pancreatitis.[11][54][82][85][95][104]
Ophthalmologic.
Signs and symptoms may develop 6 hours or more post ingestion but can be delayed 24 hours or more.[33]
Their development depends on the duration of elevation of formate concentration.[39][45] In two large series,
all patients presenting with acidemia also had complaints of visual disturbance.[11][28] Patients who present
early, prior to significant metabolism of methanol, may have no ophthalmologic findings. Symptoms, when
present, can include blurred vision; photophobia; visual hallucinations, such as misty vision, “skin over the
eyes,” “snowstorm,” “dancing spots,” or “flashes”; partial to total visual loss; and, rarely, eye
pain.[11][45][47][82][104] The findings on examination range from normal, despite visual complaints, to
conjunctival injection, visual field constriction, sluggish nonreactive pupils, hyperemic optic discs,
papilledema, retinal edema and hemorrhages, and decreased to absent vision.[11][41][45][54][104] Impairment
of the pupillary light reflex implies severe poisoning and a worse prognosis. In Benton’s analysis[12] of the
Atlanta outbreak, patients with fixed and dilated pupils were more likely to die or to have permanent visual
sequelae.
Other.
Sinus tachycardia and increased respiratory rate may be present. The patient may complain of
breathlessness, and Kussmaul respirations occur as a consequence of acidosis.[11][82] The blood pressure is
usually maintained until the preterminal stage.[11][30] Indeed, the presence of a severe metabolic acidosis in
the absence of shock or hypoxia should increase the physician’s suspicion that a toxin, such as methanol or
ethylene glycol is involved. When hypotension develops, left ventricular dilation and dysfunction may be
present and may persist despite correction of serum pH.[23] Sudden respiratory arrest can occur.[11]


Poisoning by ethylene glycol or methanol should be considered in all patients who present with an anion gap
metabolic acidosis ( Table 93–4 ), especially in the absence of shock.[76] In patients with a history of ethanol
abuse, the diagnosis of alcoholic ketoacidosis is frequently considered initially. The demonstration of
ketonuria, with improvement of the acidosis in response to intravenous crystalloid, dextrose, and thiamine
therapies, supports this diagnosis, while worsening acidosis should prompt the continued search for other
etiologies.
Table 93-4 -- Differential Diagnosis of Anion Gap Metabolic Acidosis

Organic Acids Inorganic Acids
Lactic Acidosis Ethylene glycol
Hypoxia Ibuprofen (propionic acids)
Shock Methanol
Spontaneous Salicylates
Methanol Toluene (benzoic acid metabolite)
Metformin Uremia
Phenformin
Carbon monoxide
Cyanide
Hydrogen sulfide
Isoniazid
Iron
Ketoacidosis
Alcoholic
Diabetic
Starvation
Measurement of serum electrolytes and glucose, and renal function tests, can quickly eliminate uremia and
diabetic ketoacidosis as etiologies of the acidosis. Salicylates are detected by adding 2–3 drops of 10 per
cent ferric chloride to 1 mL of urine and observing for a purple or brown discoloration, or by measuring a
serum level. A serum level and an abdominal radiograph taken for the purpose of detecting radiopaque pills
can evaluate iron toxicity. A history of how the patient was found may eliminate the possibility of carbon
monoxide or hydrogen sulfide poisoning. Hypotension and coma develop rapidly with significant cyanide
toxicity. Significant lactic acidosis occurs following seizures in isoniazid toxicity, whereas metabolic acidosis
precedes seizures in ethylene glycol and methanol toxicity.
The finding of an elevated level of lactate does not rule out ethylene glycol or methanol toxicity. [38][51] Rarely
in methanol toxicity, the elevated level of lactate may appear to account totally for the decrease in serum
bicarbonate and the elevation in the anion gap.[95][99] In ethylene glycol poisoning, lactate levels ranging
from 1.4 to 7.1 mmol/L have been reported.[38][51][92] These lactate levels may be artifactually high. Glycolate
can falsely elevate levels of plasma lactate measured by L-lactate oxidase–type analyzers.[80]
In young children, disorders of amino acid and organic acid metabolism should be considered, as well as
child abuse.[35][97][109]


LABORATORY STUDIES
General.
Initial studies should include measurement of arterial blood gases and levels of electrolytes, BUN,
creatinine, glucose, and lactate and an electrocardiogram (EKG), as well as specific methanol and ethylene
glycol levels. A chest radiograph is recommended in patients with suspected aspiration or pulmonary
edema. In methanol poisoning, the base deficit (directly), total serum bicarbonate (indirectly), pH (indirectly),
and anion gap (directly) correlate with blood formate concentrations.[58][66] In ethylene glycol poisoning, an
increased anion gap correlates directly with glycolate levels.[78] An ionized calcium level and a urinalysis for
monohydrate calcium oxalate crystals should be checked in ethylene glycol cases.
Prior to metabolism of ethylene glycol and methanol, arterial blood gases and serum electrolytes show
minimum to no abnormality. Metabolic acidosis develops as metabolism progresses. Reported arterial pH
measurements in poisoned patients range from 6.72 to 7.37.[35][51][105] The anion gap can be high. Anion
gaps ranged from 34 to 46 in a series of six patients with ethylene glycol toxicity[51]; a gap of 58 has been
recorded.[35][92] Early in ethylene glycol cases, BUN and serum creatinine and ionized calcium levels may be
normal. As the toxic metabolites accumulate, the results of renal function tests start to rise, and ionized
calcium levels begin to decrease owing to calcium complexation with oxalic acid. Nonspecific ST-T wave
changes and QT C prolongation on the EKG may reflect hypocalcemia or hyperkalemia, the latter secondary
to renal failure.[37][87]
Urinalysis.
Calcium oxalate crystals occur in two forms, monohydrate (needle-shaped) and dihydrate (envelope-
shaped) ( Fig. 93–3 ). The monohydrate form predominates and is more specific for ethylene glycol, but
these needle-shaped crystals resemble hippuric acid crystals and may be misreported by the
laboratory.[21][46] The absence of calcium oxalate crystalluria does not rule out ethylene glycol toxicity;
repetitive urine specimens should be examined microscopically.[86] Wood’s lamp examination may detect
fluorescence in the urine of a patient who recently ingested an antifreeze that contains fluorescein. [108]
Figure 93-3 Monohydrate (needle-shaped) and dihydrate (envelope-shaped) calcium oxalate crystals from a patient poisoned with
ethylene glycol. The monohydrate form is more specific for ethylene glycol toxicity.
Osmol Gap.
Both ethylene glycol and methanol are low-molecular-weight substances that increase serum osmolality. An
elevated osmol gap, the difference between the measured serum and the calculated serum osmolalities,
may be indirect evidence of a toxic alcohol ingestion. However, a “normal” osmol gap, arbitrarily defined as
10 mOsm/kg or less,[100] does not eliminate ethylene glycol or methanol as intoxicants [38][102] (see Chapter
11 ). The significance of a given osmol gap depends on the patient’s baseline osmol gap, unlikely to be
known, as well as on the degree of metabolism of the parent compound. An osmol gap of 10 in a patient
whose underlying gap is 0 could represent an ethylene glycol level of 62 mg/dL or a methanol level of 32
mg/dL. As the osmotically active parent compound (ethylene glycol or methanol) is metabolized, the
measured osmolality and, hence, osmol gap decrease.
Specific Levels.
Ethylene glycol and methanol levels should be measured by gas chromatography whenever toxic alcohol
ingestion is suspected. A level of 20 mg/dL or more for either substance is considered toxic, even in the
absence of acidosis. Several problems and pitfalls are encountered: (1) few hospital laboratories run these
tests in “real time”; too often the specimens are sent to a reference laboratory, with results not available in
time to affect clinical management (this problem can be alleviated by contractual arrangement with a full-
service laboratory for rapid 24-hour–7-day testing, with immediate delivery of specimens via courier); (2) a
toxic alcohol screen typically measures only ethanol, isopropanol, and methanol; an ethylene glycol level
must be specifically requested or it will not be measured; and (3) the tests measure only the parent
substances, not their toxic metabolites. If metabolism of ethylene glycol or methanol is substantial or
complete, the levels will be reported as low to nondetectable and thus mislead the physician. A level less
than 20 mg/dL accompanied by anion gap metabolic acidosis indicates toxicity. Formate can be assayed in
research laboratories, and glycolate can be measured by a specific gas chromatographic procedure,[110]
although few hospital laboratories have this capability.
False-positive ethylene glycol measurements can occur, depending on the laboratory method
used.[16][67][110] Interference due to propionic acid, propylene glycol, glycerol, 2,3-butanediol, and beta-
hydroxybutyrate have been reported with enzymatic and gas chromatographic assays.[16][54a][67][97]
Computed Tomography and Magnetic Resonance Imaging.
Cerebral edema may be seen in severely ill patients. Frontal lobe and basal ganglia hemorrhages and
infarcts, especially of the putamen, have been reported in patients with methanol poisoning. [3][24][35][43][77][89]
Ethylene glycol toxicity can produce lesions in the basal ganglia, pons, temporal lobe, and cerebellum.[79]


TREATMENT
The therapies for ethylene glycol and methanol toxicity are similar. Thus, in this section, statements apply to
the management of toxicity due to either substance unless otherwise indicated.
Treatment consists of supportive care and three specific therapies: (1) antidotal therapy with an inhibitor of
alcohol dehydrogenase; (2) cofactor therapy; and (3) extracorporeal removal when indicated.
Supportive Care.
Appropriate airway management, intravenous access, cardiac monitoring, and necessary laboratory studies
make up the initial supportive therapies. Ethylene glycol and methanol exist in liquid forms, and gastric
decontamination via nasogastric suction may be effective in patients who have deliberately ingested large
volumes, even when it is performed several hours post ingestion.[103] Gastric decontamination is unlikely to
be helpful in patients who have accidentally ingested small amounts, given the rapid GI absorption. Oral
activated charcoal should be administered for co-ingestants but is relatively ineffective in adsorbing
alcohols.[35]
Intravenous sodium bicarbonate may be necessary for life-threatening acidemia. However, the
administration of this substance so as to produce serum and urine alkalinization for the purpose of ion
trapping of acid metabolites is unlikely to alter the clinical course and is not recommended.[69] Furthermore,
serum alkalinization may worsen the hypocalcemia associated with ethylene glycol toxicity.
Seizures can be managed with standard therapies, such as benzodiazepines and phenobarbital. The
occurrence of seizures or coma should prompt an evaluation for cerebral edema. Depending on the severity
of the cerebral edema, therapies such as intraventricular pressure monitoring, mannitol, and arterial
vasopressors may be needed; the patient should be observed for early signs of cerebral herniation.
Calcium should be administered intravenously for symptomatic hypocalcemia. It should not be administered
to normalize the serum calcium level, since this may increase production of calcium oxalate crystals.[35][49]
Antidotal Therapy.
An inhibitor of alcohol dehydrogenase (ADH) should be administered immediately to all patients with known
or suspected exposure to toxic alcohols. Some patients present early following exposure; this offers an ideal
opportunity to block the metabolism of the toxic alcohol, and the physician should not withhold therapy until
acidosis develops. Fomepizole (4-methylpyrazole) and ethanol are the two inhibitors available. Both are
administered intravenously. Ethanol can also be administered orally when an intravenous preparation is not
available. However, compared to intravenous administration, a larger oral dose may be required to achieve a
therapeutic serum concentration, and peak serum concentration will be delayed.[26]
Fomepizole offers many advantages over ethanol and is the preferred antidote. Its efficacy and safety have
been demonstrated in prospective human studies of ethylene glycol and methanol poisoning, while ethanol
has not been studied in a similar fashion.[19][20] In a study of 19 patients with ethylene glycol ingestion, no
discernible production of glycolate occurred after fomepizole was administered.[20] No adverse effects were
reported, although rash, eosinophilia, and minimal elevations in hepatic transaminases have been reported
in other cases.[7][53] The advantages of fomepizole, compared to ethanol, include ease of dosing and
administration; no CNS depression; no associated hypoglycemia, dilutional hyponatremia, or
hyperosmolality; no need for frequent monitoring of drug levels; reduced nursing and pharmacy work; and no
risk of subtherapeutic antidotal serum levels.[35] Maintaining an adequate ethanol level can be very difficult,
owing to variations in individual kinetics [85]; frequent dose adjustments are usually required. In contrast, the
minimum plasma therapeutic level of fomepizole, 10 µmol/L, is consistently maintained with the
recommended dosing schedule.[20] Dosing schedules for both drugs are detailed in Table 93–5 .

General
I. Supportive care, including appropriate airway management
II. GI decontamination via nasogastric suction for large oral ingestions
III. Sodium bicarbonate IV for life-threatening metabolic acidosis
IV. Calcium IV for symptomatic hypocalcemia
V. CNS toxicity
A. Seizures: treat with benzodiazepines, phenobarbital
B. Monitor for increased cerebral pressure
Alcohol Dehydrogenase Inhibitor
Administer either fomepizole or ethanol as soon as toxic alcohol exposure is known or suspected.
Administer until ethylene glycol or methanol levels are measured below 20 mg/dL and metabolic acidosis has
resolved.
I. Fomepizole (preferred). All doses should be diluted in 250 milliliters of 0.9% NaCl or D5W and administered
as a slow intravenous infusion over 30 min.
A. Loading dose: 15 mg/kg
B. Maintenance doses: 10 mg/kg every 12 hr for 4 doses, then 15 mg/kg every 12 hr for all subsequent doses.
*
C. Dosing in patients requiring hemodialysis
1. Dose at the beginning of hemodialysis
a. Less than 6 hr since last fomepizole dose, no dose required.
b. More than 6 hr since last fomepizole dose, administer next scheduled dose.
2. Dosing during hemodialysis
a. Administer fomepizole at required dose every 4 hr.
3. Dosing at the end of hemodialysis
a. If less than 1 hr since last dose, no dose required.
b. If between 1 and 3 hr since last dose, administer ½ of next scheduled dose.
c. If more than 3 hr since last dose, administer next scheduled dose.
D. Maintenance dosing off hemodialysis
1. Give next scheduled dose 12 hr from last dose administered.
II. Ethanol
A. Loading dose: 0.8 g/kg (approximately 1 mL/kg) of 100% ethanol
1. Intravenous administration: dilute to 5–10% concentration in D 5W.
2. Oral administration: dilute to 20–30% concentration.
B. Maintenance doses
1. Start simultaneously with loading dose.
2. Initial dose: 130 mg (0.16 mL)/kg/hr of 100% ethanol, dilute as above.
3. Monitor ethanol levels hourly until steady state is achieved.
a. Goal is serum ethanol level of 100–150 mg/dL. Increase or decrease infusion rate as necessary.
b. If ethanol level falls below 100 mg/dL, a partial loading dose must be administered. Calculate the partial
loading dose required as follows:
Ethanol (milligrams) = [desired concentration (mg/dL) - known concentration (mg/dL)] × Vd (0.6 L/kg) × body
weight (kg)
c. Increase maintenance infusion two to three times normal dose during hemodialysis.
C. Monitor patient for CNS depression, hypoglycemia, hyponatremia.
D. Check serum ethanol level every 1–2 hr until steady state level of 100–150 mg/dL is achieved.
Cofactors
Administer cofactors until serum levels of toxic alcohol are undetectable and metabolic acidosis has cleared.
I. Ethylene glycol
A. Thiamine, 100 mg/day IV
B. Magnesium supplementation as needed
C. Pyridoxine, 100 mg/day IV
II. Methanol
A. Folinic acid (leucovorin), 1 mg/kg per dose (maximum 50 mg per dose) IV every 4 hr
Institute hemodialysis for one or more of the following conditions:
I. A serum ethylene glycol or methanol level of 50 mg/dL or greater, regardless of symptoms or acid-base
status; or
II. Ongoing metabolic acidosis or evidence of end-organ damage, regardless of the serum level; or
III. Unexplained metabolic acidosis with an anion or osmol gap when serum ethylene glycol or methanol levels
are not readily obtainable and the suspicion of exposure is high[35]
* The maintenance doses follow this schedule, regardless of whether or not the timing of the doses is altered by hemodialysis therapy.
Cofactor Therapy.
Folinic acid (leucovorin) should be given intravenously, 1 mg/kg per dose (maximum dose 50 mg), to all
patients with known or suspected methanol poisoning. Leucovorin should be administered every 4 hours
until the methanol is undetectable and metabolic acidosis has cleared. Exogenous folinic acid presumably
augments the folate-dependent mechanism by which formate is cleared (see Fig. 93–2 ). In primate
experiments, the levels of formate and the degrees of metabolic acidosis were diminished by pretreatment
with either folate or 5-formyl-THA. Post-treatment with 5-formyl-THA decreased methanol toxicity.[84] In
ethylene glycol poisoning, administration of thiamine (100 mg/day), pyridoxine (100 mg/day), and
magnesium theoretically may augment the conversion of toxic to nontoxic metabolites (see Fig. 93–1 ). No
data in human ethylene glycol poisoning exist to support this assumption. However, supplementation of
thiamine and magnesium may be otherwise indicated in patients with a history of ethanol abuse or
inadequate nutrition, and should be given.
Enhanced Elimination.
Hemodialysis enhances the elimination rate of the toxic alcohols as well as the toxic metabolites of ethylene
glycol and is a necessary adjunctive therapy in most cases of toxic alcohol poisoning[35]( Table 93–6 ). It
should be instituted as soon as possible in all patients with metabolic acidosis, a sign of appreciable
accumulation of toxic metabolites. Indications for hemodialysis are listed in Table 93–5 .
Table 93-6 -- Clearance Rates of Toxic Alcohols and Metabolites *

Clearance †
Substance Normal Renal Function ‡ Impaired Renal Function ‡ Hemodialysis §
Ethylene glycol 27.5 ± 4.1 mL/min 1–6 mL/min 156, 198 and 210 mL/min
70 mL/min #
Glycolate 1.08 ± 0.67 mmol/L/hr 170 ± 23 mL/min
Methanol 44mL/min 142–286 mL/min
Formate 223 ± 24.5 mL/min
* See references 24a , 40 , 47 , 54 , 58 , 71 , 78 , 88 , 104 .
† All values represent clearance in the presence of ADH inhibitor therapy, except as noted.
‡ Represents renal clearance only.
§ Represents hemodialysis clearance only.
# No ADH inhibitor present; clearance predominantly due to metabolism.

Hemodialysis may not enhance the elimination of formate. Analysis of formate elimination T½ and clearance
in 11 patients studied in a prospective clinical trial found the nonhemodialysis elimination T½ to be 205 ± 25
minutes, while the hemodialysis elimination T½ was 185 ± 62.7 minutes. [58] All patients in this study also
received leucovorin; whether hemodialysis would enhance formate elimination in patients not receiving
leucovorin is unknown. Some cases of ethylene glycol poisoning with levels greater than 50 mg/dL may be
managed with fomepizole therapy alone, provided that metabolic acidosis has not developed and the patient
is stable. A preliminary report of four patients treated with (two patients) or without (two patients)
hemodialysis did not find significant differences in length of hospitalization or hospitalization charges.[29]
Further study of a larger cohort is required before this management strategy can be routinely recommended.
Hemodialysis offers other benefits, including control of acid-base and fluid status. Hemodialysis should be
continued until the toxic alcohol is eliminated and the metabolic acidosis has resolved. If toxic alcohol levels
cannot be obtained, a minimum of one 8-hour or two 4-hour dialyses are recommended.[35][48][49] Dosing of
the alcohol dehydrogenase inhibitor, fomepizole or ethanol, must be adjusted during hemodialysis (see
Table 93–5 ), and the inhibitor should be continued until the toxic alcohol level is less than 20 mg/dL and the
metabolic acidosis has resolved. If toxic alcohol levels cannot be readily obtained, the inhibitor should be
continued until hemodialysis is complete, then stopped. The patient’s acid-base status should be closely
monitored for evidence of renewed metabolism of any residual toxic alcohol. If the acidosis recurs, the
inhibitor should be restarted and hemodialysis reinstituted. Peritoneal dialysis, hemoperfusion, and
continuous hemodiafiltration are not recommended.
Disposition
Patients should be admitted for treatment for any of the following: (1) suspected intentional ingestion, (2)
serum ethylene glycol or methanol level of 20 mg/dL or greater, (3) metabolic acidosis, or (4) clinical
manifestations of end-organ damage. Most of these patients will require intensive care monitoring; an
exception may be patients who present early with an elevated serum level but without metabolic acidosis:
these patients can be treated in a less intensive setting. Patients with accidental ingestions of small amounts
of ethylene glycol or methanol potentially can be evaluated and managed in the outpatient setting. Ideally,
fomepizole or ethanol therapy is started and serum toxic alcohol levels obtained to definitively rule out
poisoning. In cases of accidental exposure to small amounts of ethylene glycol when immediate laboratory
testing is unavailable, some practitioners observe the patient for 6 to 8 hours, repetitively checking serum
electrolytes to evaluate for metabolic acidosis. This strategy has not been evaluated, and the optimal
duration of observation is unknown. This strategy should never be used when ethanol has been co-ingested,
since co-ingestion will prolong the onset of toxicity. This strategy should also never be used in cases of
suspected methanol exposure, in which the time required for manifestation of toxicity may exceed 30 hours.
All patients with intentional ingestions should undergo psychiatric evaluation at an appropriate time.
Sequelae
Ethylene Glycol.
Patients who develop renal failure may require regular hemodialysis for weeks to months. Recovery of renal
function is expected,[49][51] although persistent renal failure has been reported.[87][103] Patients who develop
severe CNS manifestations, including seizures and coma, can recover full neurologic function.[34][79][87]
Cranial nerve palsies typically resolve over weeks to months.[14][31][79]
Methanol.
In contrast to ethylene glycol toxicity, methanol poisoning can result in permanent ophthalmologic and
neurologic sequelae. In a retrospective review of 50 patients with methanol poisoning, 18 (36%) died and 32
(64%) survived. An increased risk of death was associated with initial seizures, coma, or arterial pH less
than 7. A total of 22 per cent of the survivors had some visual sequelae, including diminished vision, visual
field defects, and blindness. The sequelae were associated with metabolic acidosis that was more prolonged
than that experienced by survivors with no visual sequelae.[65] In a case series of 10 adult patients, a
treatment delay of 10 hours or more or a base deficit greater than 12 mmol/L predicted severe toxicity with
possible permanent sequelae.[66] Parkinsonian-like syndrome, spasticity, resting tremor, cognitive deficits,
and paraplegia have been reported.[2][3][42][72][106]


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Chapter 94 – Isopropanol
MARSHA D. FORD
Essentials
• Fruity breath odor
• Ketosis without metabolic acidosis
• Gastrointestinal and mucosal irritation
INTRODUCTION
Isopropanol is a clear, colorless, volatile alcohol with a characteristic odor. Sold as a 70 per cent (rarely, 91
per cent) disinfectant solution in rubbing alcohol, it also is found in industrial solvents, paints, inks, thinners,
hair tonics, and drugs.[7][22][38] Toxicity occurs primarily in chronic ethanol abusers who find it an
inexpensive, albeit bitter-tasting substitute for ethanol. Indeed, ingestions have occurred in hospitalized
alcoholic patients searching for a drink.[2] Toxicity has also been reported in children sponge-bathed with
isopropanol for temperature reduction, with accidental oral ingestion or inhalational exposure, from chronic
application to an umbilical stump, and after rectal administration in an adult.[5][28][31][41][47][48] Exposures
occur frequently, but deaths are rare. The 1998 Toxic Exposure Surveillance System data reported total
isopropanol exposures of 9474 but only three deaths. Only 21 per cent of exposures were treated in a health
care facility.[29]


Toxicokinetics
Absorption occurs through the gastrointestinal, respiratory, and dermal routes. Two cases of toxicity after
rectal administration have been reported, with one death occurring.[5][17a] Gastrointestinal absorption occurs
within 30 minutes of ingestion, although it may be prolonged in large ingestions or by ingestion with
food.[20][25][40][41] Oral ingestion remains the primary route for absorption. Respiratory, dermal, and mucosal
absorption resulting in toxicity have also been reported, primarily in children.[5][26][28][31][47][48] For years,
toxicity resulting from isopropanol sponge bathing of children for temperature reduction was attributed to
inhalational absorption. However, an animal study demonstrated significant dermal absorption of
isopropanol[31] and prolonged skin application of isopropanol can produce significant toxicity.[33]
Serum levels peak 30 minutes after ingestion,[25][40][41] corresponding to the rapid gastrointestinal
absorption. Metabolism results predominantly from hepatic alcohol dehydrogenase conversion to acetone.
The stability of the carbon-carbon bonds in acetone prevents its conversion to an acid, and thus primary
metabolic acidosis is not a feature of isopropanol toxicity ( Fig. 94–1 ). Acetone levels rise as metabolism
occurs, peaking at greater than 4 hours after ingestion.[10][25][31][37] The acetone metabolite as well as small
amounts of unchanged alcohol are excreted primarily through the renal route, with some pulmonary and
salivary excretion.[3][10][16][34] Elimination follows first-order kinetics for isopropanol with elimination half-life
varying from 2.5 to 6.6 hours.[10][34][41] Acetone is more slowly metabolized. Elimination half-lives ranging
from 10.8 to 31 hours have been reported,[10][37][41] with the longer values found in neonates and patients
with hepatic disease.[41][47] Thus, acetone levels may still be measurable when isopropanol levels are not.
Figure 94-1 Isopropranol is metabolized by alcohol dehydrogenase to acetone. Owing to the stability of the carbon-carbon bonds, a
hydroxyl group (OH) cannot be added to acetone to make an acid (-COOH).
The contribution of acetone to CNS depression is controversial. Because CNS depression in cases of
isopropanol toxicity is often prolonged and because acetone levels continue to rise after isopropanol levels
are declining, acetone previously was considered significantly responsible for the CNS depression.
However, recent case reports documenting clinical improvement in the face of rising acetone levels dispute
this idea.[13][36]
The low molecular weight of 60 g/mol, minimal serum protein binding, and low volume of distribution of
0.7L/kg make isopropanol a candidate for removal by hemodialysis.
Pathophysiology
Depression of the CNS is the predominant toxic effect, with isopropanol exhibiting a 2.7 times greater
intoxicating effect than ethanol.[49] This increased CNS depression has been attributed to its higher
molecular weight.[26] In cases of severe intoxication brain stem depression may result in decreased
respiratory drive and hypotension.[12][13][24][26][43] Depressed cardiac inotropy or peripheral vasodilation may
also contribute to the hypotension.[15] Noncardiogenic pulmonary edema may occur.[1][2] Isopropanol also
irritates mucosal surfaces, resulting in gastritis, gastrointestinal hemorrhage, and, in cases of aspiration,
hemorrhagic tracheobronchitis.[1][3][9][11][39]


Clinical Triad
The combination of CNS depression, fruity breath odor, and ketosis without metabolic acidosis should alert
the clinician to possible isopropanol toxicity ( Table 94–1 ).
Table 94-1 -- Clinical Presentation of Isopropanol Toxicity

Clinical Triad
Central nervous system depression
Fruity breath odor
Ketosis without metabolic acidosis
Lethargy
Somnolence
Nystagmus
Dysarthria
Ataxia
Confusion
Stupor
Coma
Gastrointestinal
Vomiting
Abdominal pain
Hemorrhagic gastritis
Cardiopulmonary
Hypotension
Pulmonary edema
Hemorrhagic tracheobronchitis
Pediatric
Irritability
Hypotonia
Weak cry, poor suck
Absent Moro reflex
Seizures
CNS/Cardiovascular
Depression of the CNS is the most consistent finding in isopropanol intoxication.[5][13][26][28][31][32][43] This
depression typically takes the form of mild to moderate inebriation that resolves with time.[23] The time
course for resolution varies depending on the amount of isopropanol ingested, the alcohol tolerant state of
the individual, and the development of acute isopropanol tolerance. [10] With more severe toxicity, dysarthria,
ataxia, stupor, coma, and brain stem dysfunction with respiratory depression and hypotension can
develop.[1][12][13][24][26][28][31][33][40][43] Clinical deterioration can occur rapidly and unexpectedly with large
ingestions.[40] Coma, respiratory depression, and hypotension have been reported 30 to 45 minutes after
ingestion in both adult and pediatric cases[24][31] or as long as 12.5 hours after inhalational exposure in a
newborn.[47]
Although coma and hypotension have developed in all reported fatal cases,[26][47] their occurrence does not
guarantee death. In one series, 55 per cent of patients with both coma and hypotension survived with
aggressive therapy.[26] Those with fatal outcomes presented either dead on arrival, with shock of unknown
duration, or with complications found on autopsy, such as pulmonary edema, necrotizing bronchitis,
ulcerative tracheitis, hemorrhagic necrotizing gastritis, and crush syndrome.[1]
Other Features
Diminished deep tendon reflexes, muscle weakness, and mild hypothermia may also be present. [23][26][40]
Pupillary findings range from miosis to mydriasis, with nystagmus reported.[1][12][23][26][33][36][43] The sweet
breath odor of acetone may be present if sufficient metabolism of isopropanol to acetone has
occurred.[3][12][13][43][46] Hypoglycemia is not a typical complication[2][45] but should always be sought.
Complications of mucosal irritation include vomiting, abdominal cramping, gastrointestinal hemorrhage, and
hemorrhagic tracheobronchitis.[1][3][11] Acute renal failure may develop secondary to hypotension or
rhabdomyolysis.[21] Trauma due to falls and axillary vein thrombosis with secondary rhabdomyolysis and
acute renal failure can occur.[1][11][21]
Pediatric Manifestations
Irritability, seizures, hypotonia, grunting respirations, weak cry, poor suck, and absent Moro reflex have also
been reported in pediatric cases.[28][33][36][48] Prolonged dermal application of isopropanol pledgets in
neonates resulted in second- and third-degree dermal burns.[44]


The differential diagnosis for CNS depression is broad, and a detailed discussion of the various causes is
found in Chapter 16 . More helpful to the clinician are the smaller number of diagnoses to consider in
patients with ketonemia or ketonuria ( Table 94–2 ). Ketosis without acidosis can be found with ingestions of
isopropanol or acetone, the latter typically found in nail polish remover. In chronic ethanol abusers with
ketosis, the major differential diagnostic consideration is alcoholic ketoacidosis.[5][45] Patients with the latter
typically present with a history of binge drinking, poor oral intake, and a metabolic acidosis that may be
mild. [17]
Table 94-2 -- Differential Diagnosis of Ketosis

Type Acidosis
Ketoacidosis
Diabetic +
Alcoholic +
Starvation +
Toxins/Drugs
Salicylates +
Cyanide +
Isopropanol -
Acetone -
Other
Ketotic hypoglycemia (pediatric) +
Branched-chain ketonuria (Maple syrup urine disease) +
Glucose-6-phosphatase deficiency +
Glycogen synthetase deficiency +
ß-Ketothiolase deficiency +
Propionic acidemia +


LABORATORY STUDIES
Isopropanol levels are not readily available to most practitioners. Therefore, initial laboratory testing should
focus on measuring acetone as an indirect marker for isopropanol ingestion and on looking for underlying
conditions that could explain or complicate the patient’s condition.
Acetone
Acetone, the metabolite of isopropanol, will usually result in a positive ketone assay in serum or urine.
Acetone typically is not detected in the serum until 3 to 4 hours after ingestion of isopropanol,[13] and many
cases without ketonuria have been reported.[4][13][36][42][46] Thus, a single negative serum or urine test for
acetone does not eliminate the possibility of isopropanol ingestion. Acetone levels continue to rise during the
initial metabolism of isopropanol and remain positive longer than isopropanol levels. Thus, finding acetone in
the face of a negative isopropanol assay could still indicate isopropanol ingestion.
Other Tests
Other laboratory tests should include electrolytes, glucose, blood urea nitrogen, and creatinine to look for
electrolyte abnormalities, hypoglycemia, and renal dysfunction. A low serum bicarbonate with or without an
anion gap should suggest another diagnosis, unless the patient is hypoxic or hypotensive from isopropanol
toxicity. In that case lactic acidosis will produce an anion gap metabolic acidosis.[13][26] Serum creatinine
may be falsely elevated due to assay interference by acetone.[18] Further testing will be dictated by the
clinical picture and differential diagnosis and could potentially include arterial blood gas analysis, chest
radiography, computed tomography of the head, lumbar puncture, determination of serum creatine
phosphokinase and urine myoglobin, microbiologic cultures, and measurement of salicylate level. Both
isopropanol and acetone are osmotically active, and measuring serum osmolality might detect an osmol
gap.[8][34] However, the presence of an “elevated” osmol gap is not specific for isopropanol, and its absence
does not eliminate isopropanol ingestion.[14][19] Thus, the usefulness of this measurement is minimal (see
Chapter 11 ).
Isopropanol Measurement
Isopropanol levels should be obtained only if the diagnosis is in doubt, the levels are readily available, and a
positive finding would avoid further unnecessary, costly testing. Isopropanol levels do not necessarily
correlate with the patient’s clinical status and should not be used to determine treatment.[23] In 31 fatalities,
isopropanol levels ranged from 10 to 250 mg/dL,[2] and two patients with coma had levels of 20 and 30
mg/dL, respectively.[23] Conversely, an adult with a level of 432 mg/dL was awake and oriented to time and
place.[8] Interestingly, isopropanol has been detected in the serum of patients with acetonemia due to
diabetic ketoacidosis and no history of isopropanol ingestion. The increased NADH:NAD+ ratio in these
patients is postulated to drive the conversion of acetone to isopropanol.[4]
Measurement Errors
Use of the alcohol dehydrogenase enzymatic assay can result in isopropanol being reported as ethanol, with
an underestimation of isopropanol levels.[46] Gas chromatography and proton nuclear magnetic resonance
imaging are reliable laboratory methods for measurement.[35] Infrared breathalyzer measurements can
detect isopropanol as ethanol, resulting in falsely elevated ethanol levels.[30]


TREATMENT
Airway evaluation and management are the cornerstones of therapy ( Table 94–3 ). Significant respiratory
depression will require endotracheal intubation and ventilatory support; less severely intoxicated patients
can be treated with oxygen. This management should be followed quickly by bedside glucose determination
with administration of dextrose as needed. Cardiac and pulse oximetry monitoring should be instituted in the
moderately to severely intoxicated patient. Precipitous development of respiratory depression and
hypotension[40] mandates continued monitoring until the clinical status of the severely intoxicated patient is
clearly improving. Crystalloid fluids containing dextrose and thiamine, 100 mg, should be administered, and
the patient warmed if hypothermic. It should be stressed that the majority of intoxicated patients will require
minimal supportive care until sufficient isopropanol metabolism occurs.
Table 94-3 -- Treatment of Isopropanol Toxicity

General
Mild toxicity—observe until ambulatory, not suicidal
Moderate/severe toxicity—cardiac and pulse oximetry monitoring; intravenous access
Airway
Oxygen
Endotracheal intubation/ventilation for respiratory depression
BiPAP/CPAP for pulmonary edema
Hypotension
Crystalloids
Vasopressors—dopamine, neosynephrine, norepinephrine
Hypoglycemia (Unlikely)
Dextrose
Hemodialysis
Rarely indicated
Consider for patients with coma and hypotension
Other
Hypothermia—warming
Seizures—benzodiazepines
Standard therapies for complications (e.g., gastrointestinal hemorrhage, crush injury)
BiPAP, bi-level positive airway pressure; CPAP, continuous positive airway pressure.
Because of the rapid absorption of isopropanol,[31] gastric lavage, nasogastric suction, or activated charcoal
is unlikely to be efficacious. An exception would be the patient who drinks isopropanol while in the hospital,
in whom nasogastric suction could be rapidly instituted. Because isopropanol is secreted into saliva and
gastric secretions, continuous nasogastric suction has been recommended for the severely intoxicated
patient.[10][27] The clinical efficacy of this therapy remains unproven; if used, careful monitoring of fluid and
electrolyte status should occur. Oral activated charcoal in the typical dose of 1 g/kg body weight will have
little effect on isopropanol absorption. An in vitro study demonstrated activated charcoal adsorbed 87 to 92
per cent isopropanol when given in a 20:1 ratio.[6] To adsorb approximately 1 ounce of 70 per cent
isopropanol would require 358 g of activated charcoal. Thus, even if rapid gastrointestinal absorption of
isopropanol was not a consideration, sufficient amounts of activated charcoal could not be rapidly
administered to achieve a 20:1 ratio. However, activated charcoal should be given if co-ingestants are
suspected.
Other Measures
Hypotension can be managed with initial crystalloid boluses followed by vasopressors to maintain adequate
tissue perfusion and urinary output of 1 to 2 mL/kg/hr. The remainder of therapy is supportive with further
specific treatments dictated by complicating or coexisting medical conditions, such as gastrointestinal
hemorrhage, noncardiogenic pulmonary edema, traumatic injuries, crush syndrome, or other problems.
Hemodialysis
Hemodialysis is rarely indicated but should be considered for patients with hypotension who do not respond
to initial treatment or whose clinical status continues to deteriorate. In one series of patients reported in the
literature, 5 had hemodialysis and none died whereas 16 received supportive care and 4 died. [26] Patients
with coma but without hypotension are unlikely to require hemodialysis. In the same series, no patient with
coma but without hypotension died.[26] Clinical recovery, rather than a specific isopropanol level, determines
the duration of hemodialysis. For cases reported in the literature, clinical improvement was noted with 1 to 3
hours of hemodialysis.[12][24][43]


DISPOSITION
Disposition depends on the depth of CNS depression and the presence of coexisting or complicating
medical conditions. Mildly intoxicated patients can be observed for 3 to 4 hours, watching for progression of
CNS depression. All patients with active suicidal intent should undergo psychiatric evaluation. If there are no
complicating conditions and if the patient becomes ambulatory, he or she can be discharged to a
detoxification unit, supervised shelter, or home with a responsible adult. The problem of ethanol abuse
should be addressed with referral of the patient to an appropriate treatment program.
All other patients should be hospitalized for a minimum of 12 to 24 hours, with patients requiring
cardiorespiratory support admitted to an intensive care unit. Complicating conditions such as compartment
syndrome or gastrointestinal hemorrhage may require consultants and specific therapies dictated by the
condition. Recovery from isopropanol toxicity is based on clinical improvement, not on a specific isopropanol
serum level.


SEQUELAE
The majority of patients recover completely from isopropanol toxicity with no permanent sequelae directly
attributable to isopropanol. Patients sustaining secondary injuries from a fall, crush syndrome, or other
complication may develop permanent impairments. Deaths can occur.[26][47] However, with vigorous therapy
these are unlikely to result from pure isopropanol toxicity.[2]


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intoxication. South Med J 1971; 64:1409-1411.
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18. Hawley PC, Falko JM: “Pseudo” renal failure after isopropyl alcohol intoxication. South Med
J 1982; 75:630-631.
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20. Jerrard E, Verdile V, Yealy D, et al: Serum determinations in toxic isopropanol ingestion. Am J Emerg
Med 1992; 10:200-202.
21. Juncos L, Taguchi JT: Isopropyl alcohol intoxication: Report of a case associated with myopathy, renal
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22. Kawai T, Yasugi T, Horiguchi S, et al: Biological monitoring of occupational exposure to isopropyl
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J Toxicol Clin Toxicol 1983; 20:497-507.
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and acetone concentrations. Pharmacotherapy 1993; 13:60-63.
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metabolite by proton nuclear magnetic resonance: Application to pharmacokinetic evaluation in a simulated
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36. Mydler TT, Wasserman GS, Watson WA, et al: Two-week-old infant with isopropanol intoxication.
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J Appl Toxicol 1987; 8:67-71.
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Toxicol 1960; 16:217-222.


Chapter 95 – Glycol Ethers and Diethylene Glycol
LAWRENCE W. RAYMOND
Essentials
• Ingestion
° Central nervous system depression
° Acute renal failure
° Nausea, vomiting
° Hemolytic anemia (large or intentional
overdoses)
• Inhalation or other vapor contact

° Irritation: eyes, respiratory
tract
INTRODUCTION
Glycol is the generic name for organic dihydroxy compounds, or diols, such as ethylene glycol and
diethylene glycol.
Ethylene glycol is produced by hydration of ethylene oxide or by treating ethylene with dilute potassium
permanganate. A glycol ether is a member of the class of diols that has undergone etherization of one or
both of its hydroxyl groups, either by reaction of the glycol with the appropriate dialkyl sulfate or by reacting
the respective alcohol with ethylene oxide. Glycol ethers are valuable as solvents, being both hydro- and
lipophilic. Most widely used are the ethers of ethylene glycol, an organic dihydroxy compound or diol. Its
ethers have the following generic formula:
in which R A represents the alkyl part of the molecule, and RB is usually a hydrogen atom, but may be a
second alkyl group, as in diethers. In the widely used solvent 2-butoxyethanol (2-BE, also called butyl
cellosolve or ethylene glycol monobutyl ether), for example, RA = C4H9 and RB = hydrogen. Two other glycol
ethers commonly used are 2-methoxyethanol (2-ME) and 2-ethoxyethanol (2-EE). Their chemical structures,
important physical properties, synonyms, and toxicity are shown in Table 95–1 .
Table 95-1 -- Nomenclature of Common Glycol Ethers [Adapted from Browning and Curry[6] and
Johanson and Boman[29] ]
A wide variety of these compounds is commercially available. The applications of glycol ethers are equally
diverse and include industrial and home cleansers, chemical intermediates, and surface coatings such as
lacquers, paint and lacquer thinners, and some latex paints. In the automotive industry, they are used in
antifreeze and brake fluids. Glycol ethers are also used extensively in semiconductor manufacture. The total
U.S. production of 2-butoxyethanol in 1995 was 285 million pounds, for example, with a projected rise to 310
million pounds in 2000. Of 742 products containing it, 51 per cent were designed for household use.[35] This
may present a special risk of poisoning in children (see later discussion) because these agents are colorless
and have a mild, sweet fragrance or none at all.
One odorless, sweet-tasting glycol ether, diethylene glycol (DEG, 2,2'-dihydroxydiethyl ether) achieved
notoriety via its pharmaceutical misuse six times in this century. The first instance involved DEG’s use as a
diluent for the original sulfa drug, sulfanilamide. This misuse led to the first amendment to the 1906 Federal
Food and Drug Act, to improve safety and require truth in labeling. Of 353 patients for whom the DEG elixir
was prescribed, generally for mild infections, 105 died of renal failure. [46] As recently as mid-1996, liquid
acetaminophen manufactured in Haiti was found to be contaminated with DEG when 30 of 68 children died
of renal failure after ingesting Afebril and Valadon formulations.[38] Similar epidemics occurred in Cape
Town,[3] Bangladesh,[23] Nigeria,[37] and India,[39] apparently due to accidental substitution of DEG for
propylene glycol or medicinal glycerin. With regard to the glycol ethers commonly used as cleansers or
solvents, the toxicity of 2-ME, 2-EE, and 2-BE (see Table 95–1 ) has caused them to be replaced in some
applications by less toxic glycol ethers or other solvents.


TOXICOKINETICS
Glycol Ethers
When ingested, accidentally or in suicide attempts, glycol ethers including DEG are rapidly absorbed.[5] In
rats and mice, the oral LD50 values of many glycol ethers are substantially greater in the fed (versus fasted)
state.[32] Vapors of glycol ethers are readily absorbed through both the human respiratory tract and
unprotected intact skin, especially the latter. Dermal absorption is enhanced by high ambient temperature
and humidity.[21][29] A high temperature-humidity index also favors increased respiratory uptake by
increasing minute ventilation, as would also occur with exertion. The dermal contribution to the overall
uptake of vapor (71–79 per cent), however, appears to be two to three times as high for glycol ethers, as
compared with other solvent vapors. Relative skin absorption of the liquid form of glycol ethers is inversely
related to molecular weight, i.e., 0.62, 0.15, and 0.02 µmol/min/cm2 for 2-ME, 2-EE, and 2-BE,
respectively.[30]
In one study of exposure to 50 ppm of 2-BE vapor, the apparent clearance rate was 3.9 L/min, much greater
than the normal hepatic blood flow in humans, suggesting extra hepatic metabolism.[29] The half-life in blood
was 32 to 36 minutes, similar to the value of 40 minutes found in an earlier study from the same
laboratory,[27] in humans who inhaled 20 ppm of this vapor.
Most glycol ethers are thought to be oxidized to their respective acetic acids via alcohol and acetaldehyde
dehydrogenases, with only very limited pulmonary or renal excretion of the parent ethers. This conversion
does not occur in vitro in whole blood and does follow Michaelis-Menten kinetics, suggesting that this
metabolic pathway is saturable. Other pathways (e.g., glycine conjugation) also appear to be used, because
the recovery of the respective alkoxyacetic acids in urine is low (e.g., 23 per cent for 2-EE, and 17–55 per
cent for 2-BE).[22][26] Nevertheless, the urinary excretion of these acids appears to correlate closely with the
degree of occupational exposure, making them useful markers for medical surveillance.[44] This usage is
appropriate because there is evidence that the alkoxyacetic acids are responsible for the toxic
manifestations of glycol ether exposures.
One case report[40] of massive ingestion of 2-BE provides additional insight into the relative importance of an
alternate metabolic pathway; that is, hydrolysis of the ether linkage of 2-BE, yielding ethylene glycol, which is
converted to oxalic acid. In this patient, who survived after 5 days of ventilatory support, the butoxyacetic
acid and ethylene glycol pathways were of roughly equal importance. The parent compound was not
detectable in urine beyond day 1 postingestion. In another case of massive ingestion of 2-BE, however, no
excess oxalate excretion was found, perhaps because forced diuresis and early hemodialysis prevented
saturation of the butoxyacetic acid pathway.[19]
Diethylene Glycol
As mentioned earlier, DEG is well absorbed by the oral route, but reports of its accidental ingestion have not
included measurements in body fluids. The only reported blood concentrations (1–11 nmol/mL), were in
asymptomatic Egyptian children. [5] Some of them had been treated for schistosomiasis, but no specific
environmental factor, drug, or food was identified as being responsible. Information on the metabolic
handling of DEG is thus limited to that based on small mammals, in which the acute oral LD50 ranges from 4
mL/kg in rabbits to 24 mL/kg in mice.[51] Recent studies in the rat and dog describe rapid distribution in
accordance with organ perfusion rates. Doses of 1–10 mL/kg of 14C-labeled DEG had a blood half-life of 3.4
hours for 64–91 per cent of the administered activity, 73–96 per cent of which appeared in the urine partly
due to osmotic diuresis.[25] Most of the DEG was excreted in unchanged form, with about 30 per cent
excreted as 2-hydroxyethoxyacetic acid (HEAA) in both rat and dog.[34] Employing the same dose range in
rats, Lenk[33] found similar results for urinary DEG (61–68 per cent) and HEAA (16–31 per cent), with
estimated DEG half-lives of 6–10 hours. This initial elimination followed zero-order kinetics, changing to first-
order kinetics with a half-life of 3 hours, at 6, 9, and 18 hours after oral doses of 1, 5, and 10 mL/kg,
respectively.


PATHOPHYSIOLOGY
Glycol Ethers
When ingested acutely in sufficient amounts, most glycol ethers including DEG produce profound metabolic
acidosis, renal failure, and central nervous system depression including coma. Little is known about the
mechanisms that underlie these effects, which appear to be mediated by alkoxyacid metabolites. In the case
of 2-BE/ethanol ingestion mentioned earlier,[19] the patient was comatose when seen 1 hour postingestion,
at which time she had blood levels of 2-BE and ethanol of 432 and 36 mg/L, respectively. Three hours
postingestion, these blood levels were 304 and 1 mg/L, respectively, and she was awake 1 hour later.
Vapors of the volatile glycol ethers produce irritant effects almost immediately, most having a high enough
vapor pressure to produce toxicity by both inhalation and skin absorption, even without liquid contact. Eye
and upper respiratory symptoms predominate, reflecting the water solubility of these compounds.
Diethylene Glycol
DEG’s low volatility and limited skin absorption confine its toxicity to the oral route. The acute oral lethal
dose has been estimated as 1–2 g/kg in humans, 1 mL/kg, 15–100 g, and 40–50 mg/kg, the smallest fatal
dose being 5 mL (3.6 g) in a 7-month infant.[51] In cases of DEG-contaminated sulfanilamide ingestion, a
fatal cumulative dose was estimated as 10 teaspoons (50 mL) in children, and 20 teaspoons in adults.[47]
The pharmacology of DEG in human patients is not fully understood, despite the many accidental
poisonings in which renal, hepatic, neurologic, and gastrointestinal injuries have dominated the clinical
picture, usually with a fatal outcome.
Animal studies have yielded conflicting results regarding the toxic mechanism of DEG, as also noted in the
few case reports of human ingestion poisonings.[6][19][40] Initially, it was thought that DEG is hydrolyzed to
ethylene glycol, which has similar oral toxicity and is known to be metabolized to oxalic acid. [15][24] More
recent studies in the rat found no ethylene glycol or glycolic or oxalic acid. Unlike most glycol ethers, DEG
was mainly (61–85 per cent) excreted in the urine unchanged, while the presence of 2-hydroxyethoxyacetic
acid (2-HEAA) indicated that some DEG had been metabolized by alcohol and aldehyde dehydrogenases,
respectively.[50][51] The weight of evidence in regard to acute human poisoning with DEG seems to favor the
HEAA pathway rather than metabolism via ethylene glycol.[46]
With either of these pathways, ethanol has theoretical usefulness as therapy to interfere with the conversion
of DEG, but direct evidence on the efficacy of such treatment is limited.[4] Wax goes further in his concern
over direct nephrotoxicity of DEG, which might be enhanced by steps such as the use of ethanol or 4-
methylpyrazole to inhibit its metabolism.[46] Other authors imply that ethanol administration should not be
considered routine for serious poisonings with other glycol ethers either; i.e., it elevated blood and urine
levels of 2-BE in one study.[13][30] Pending additional data, it may be most prudent to combine ethanol or
methylpyrazole treatment with hemodialysis in serious cases of poisoning with DEG or other glycol ethers
(see discussion under Treatment).


CLINICAL MANIFESTATIONS ( Table 95–2 )
Although DEG is more notorious for its acute and rapidly fatal toxicity, other glycol ethers have also been
used in suicide attempts, and can have acute inhalation toxicity as well.
Table 95-2 -- Clinical Presentation of Glycol Toxicity

Glycol ethers:
Irritation of eyes, upper respiratory tract
Neurotoxicity: confusion, lethargy, weakness, tremor
Nausea, vomiting, abdominal pain, diarrhea
Metabolic acidosis and nephropathy
Hemolytic anemia (severe overdoses, e.g., suicidal)
Diethylene glycol:
Nausea, vomiting, pain, pancreatitis, liver dysfunction
Neurotoxicity: headache, lethargy, coma
Flank pain, oliguria
Acute Poisoning
Ingested DEG (and glycol ethers in general) can cause central nervous system depression including coma,
in addition to severe injury to the renal and hepatic systems. Although only six cases of acute intoxication by
the other glycol ethers have been reported in the English literature,[6] about 835 cases of DEG poisoning
have occurred.[3][7][23][24][38][39][46] Most DEG-related illnesses begin with severe gastrointestinal symptoms:
nausea, vomiting, abdominal pain and diarrhea, followed in 1–3 days by flank pain, oliguria, acidosis, and
central nervous system depression, sometimes in association with seizure activity. Anuria was often the
presenting complaint in one report of 47 Nigerian children, all of whom died.[37] Physical findings included
hepatomegaly, Kussmaul respirations, fever, tachycardia, and pallor. Seizures, lung crackles, and cough
were present in 10–15 per cent. Hypertension and edema were prominent in the largest series, from
Bangladesh.[23]
The overall mortality rate from DEG is 41 per cent but has reached 100 per cent in some series. Postmortem
findings are remarkable for large, swollen liver and kidneys. Microscopically, the liver shows centrilobular
hydropic degeneration in humans, but not in dogs or rats. Marked tubular necrosis has been reported,[3][7]
but nephrons of surviving patients have shown considerable tubular regeneration.[3] Glomeruli are largely
spared, although a recent report from Buenos Aires described PAS-positive arteriolar hyalinosis in 6 of 7
patients dying of DEG poisoning.[14] These patients also had acute pancreatitis with fat necrosis, and
demyelination in both the central and peripheral nervous systems. Others have described hemorrhagic
changes which were sometimes extensive in the adrenal cortices, and less so in the gastrointestinal
mucosa.[37] Cerebral and pulmonary edema have also been observed.
The initial presentation of the few reported cases of acute ingestion poisoning with other glycol ethers
ranged from transient agitation and confusion to seizures and coma, requiring ventilatory support. Acidosis
and renal insufficiency were present in these severe cases of suicidal ingestion. [6][35]
Inhalation
Irritation of the eyes and upper respiratory tract follows exposure to vapor or liquid phases, reflecting the
high water solubility of these agents. For example, humans exposed to 100–200 ppm of 2-BE for 4–8 hours
immediately developed the preceding symptoms,[8] as well as metallic and other taste sensations.
Headache, belching, and vomiting occurred in some subjects. In one household instance of acute inhalation
exposure, a 32-year-old man used a 5–10 per cent solution of 2-BE to clean the inside of his van for 4–6
hours, and presented to the clinic the next day with marked lethargy and weakness. His proteinuria, red
blood cell casts, and anemia had not been present 3 years earlier, and thus may have been due to the 2-BE
exposure. Contacted twice by telephone, he felt fully recovered and chose not to return for follow-up.[41]
Although animals acutely exposed to glycol ethers other than DEG (e.g., 2-BE) have shown marked
hematologic effects—leukopenia, myelosuppression, and hemolytic anemia—hemolysis was not seen in
three humans who breathed 200 ppm of 2-BE for 8 hours.[8] Hemolytic anemia was evident in a woman who
ingested cleaning fluid containing 12.7 per cent 2-BE and 3.2 per cent ethanol (200–250 mL), but not in
other ingestions of 2-ME, 2-EE, or 2-BE.[6][19][40] In vitro exposure of human red blood cells to 2-BE has
been shown to produce hemolysis, but requires higher concentrations and longer contact times, in
comparison to rat erythrocytes.[2]
Chronic Exposures
A number of adverse effects of chronic exposure to glycol ethers have been documented, including changes
in hematopoiesis, cognitive abnormalities and central nervous system depression, and reproductive effects.
Renal and hepatic toxicities have been shown in animals.[16][51]
Hematologic Effects
Anemia was found in 10 per cent and granulocytopenia in 3 per cent of shipyard painters exposed to 2-EE
and 2-ME (1.2 and 0.5 ppm, medians), but not in a group of unexposed control workers.[49] Previous
exposure to other toxic agents might have contributed to the observed abnormalities. Myelotoxicity was
found by the same laboratory among lithographers exposed to glycol ethers and other solvents, not
including benzene.[11] The latter report suggested that monitoring peripheral blood is not sensitive enough to
identify hematopoietic toxicity of these exposures. However, their actual assessment of such exposures was
limited to concurrent levels of a single workplace solvent (1–6 ppm of dipropylene glycol monomethyl ether),
whereas other unmeasured solvents including 2-EE had also been in use for the previous 7 years.
Two earlier studies focused on workers exposed to higher air concentrations of glycol ethers. In one,[20] 19
workers exposed to 25–76 ppm of 2-ME plus ethanol, methanol, and other solvents demonstrated mild
anemia and abnormal granulocytic immaturity, but normal total white blood cell counts. No bone marrow
examinations were done. In none of these studies was biological monitoring of urinary metabolites reported,
which might have identified skin absorption as an additional route of glycol ether or other solvent intake.
Only 2-BE has been reported as a cause of hemolytic anemia in humans, in the single case report cited
earlier.[40] In general, human erythrocytes resist hemolysis from glycol ethers more so than do those of the
dog, monkey, rabbit, and rodent. [2][8][18]
Reproductive Effects
A large body of experimental information indicates that many glycol ethers can adversely affect reproduction
via several mechanisms in a variety of animal species (see reviews[6][31]). Animal studies with 2-ME or 2-EE
(but not 2-BE) have demonstrated disrupted spermatogenesis, atrophy, and other evidence of testicular
toxicity, as well as teratogenic effects, which were not seen with other glycol ethers.[31][43]
Reproductive effects in humans exposed to glycol ethers have received less investigation, sometimes with
negative results, but several studies found significant abnormalities. In one negative study, men exposed to
2-ME at 5–8 ppm and 4–20 ppm showed no differences in testicular size, sperm count, or sperm
morphology in comparison with unexposed men.[9] Two later reports described semen characteristics of men
exposed to 2-EE in the range of 0–24 ppm.[42][48] Both of these 2-EE–exposed groups had lower sperm
counts than unexposed control subjects, but sperm morphology and motility were unaffected. These results
were confirmed by Veulemans et al.,[45] who found the metabolite of 2-EE (but not 2-ME) significantly more
common (p < 0.004) in cases of subfertility or infertility, than in control subjects. More recently, a large
epidemiologic investigation of female workers and spouses of male workers in the semiconductor
industry[10] documented excess risk of spontaneous abortions, most likely due to skin absorption of 2-EE
acetate and DEG dimethylether. Less familiar studies identified substantial reproductive risks of other glycol
ethers.[17]
Burn Patients
Although not greatly absorbed by intact skin, DEG was implicated as the cause of fatal acute renal failure
and anion-gap acidosis in five burn patients treated with silver sulfadiazine, which contained 6–7 g/kg of
DEG and DEG-stearate.[7] Autopsy in one patient showed tubular dilation with epithelial damage, and
interstitial edema. No calcium oxalate crystals were observed, implying the DEG had been metabolized by
alcohol dehydrogenase through the alkoxyacetic acid pathway.
Pediatric Patients
In theory, glycol ethers pose a pediatric risk since they are so widely used to clean window glass and other
surfaces in the home. Fortunately, the dilution factor is usually greater in most products sold for household
or classroom applications. Thus, only mild symptoms were noted in a total of 24 pediatric poisonings with 2-
butoxyethanol identified in a 5-month retrospective study at Children’s Hospital of Pittsburgh.[13] Only two
children were hospitalized briefly, undergoing gastric emptying, because they had ingested over 15 mL. The
lack of serious systemic effects in these children reflects the dilute concentrations of 2-BE, which ranged
from 0.5–9.9 per cent. Dean and Krenzelok[13] state that gastric emptying and other aggressive therapy are
not needed for ingestions of less than 10 mL of less than 10 per cent 2-BE. Sometimes such household
products contain 15–30 per cent 2-BE,[19][40] ingestion of which might pose more serious risks and hence
warrant hospital observation.
The glycol ether DEG is a notorious exception to the lack of toxicity in the cases described here. When
ingested in concentrated form as a pharmaceutical elixir, even small volumes often caused fatal
toxicity.[3][23][37][38][39][46][51] Such DEG intake may create a medical emergency, as in the recent case in
which suicidal ingestion of brake fluid was followed by severe metabolic acidosis and coma.[4] Fortunately
most brake fluid incidents involve so little actual absorption of DEG that no systemic effects are observed
and serum electrolytes are normal. Thus, unless the amount of DEG ingested exceeds 10 mg in children or
30 mg in adults, or mental status changes occur, the patient is probably best managed by gastric emptying,
oral or intravenous hydration, with monitoring of electrolytes and urine output. Metabolic acidosis, an
osmolar gap (between measured and calculated osmolarity), and oxaluric crystals are reliable as indices of
severe DEG poisoning only when they are present[4] because DEG’s ether linkage can resist hydrolysis and
hence will not be metabolized to oxalic acid (as is seen in ethylene glycol poisoning).
In the absence of an accurate history of ingestion or blood levels of DEG—and lacking the above mentioned
“ethylene glycol triad”—the clinician must rely on nonspecific indicators to gauge the severity of poisoning in
a given case. For example, nausea, vomiting, and inebriated appearance in a child who has ingested an
unknown amount of brake fluid (DEG) or “Magic Marker” eraser fluid (2-BE) may herald the development of
the full-blown DEG syndrome with flank pain, anuria, CNS depression, and seizures. By then, the use of
ethanol (or 4-methylpyrazole, 4-MP) to inhibit formation of DEG’s toxic metabolites, and hemodialysis to
remove the parent compound, may be too late to be effective, as in the 12 patients who died despite the
latter in the Bombay cases.[39] Thus, 4-MP or ethanol and hemodialysis[4] should be used for inhibition of
alcohol dehydrogenase activity early in those cases suspected of being more serious, in terms of the
foregoing early symptoms, or in known DEG ingestion over 10 mL in a child (see Treatment).


As with many toxic agents, glycol ethers including DEG ( Table 95–3 ) often give the clinician no specific
clues to their identity as the cause of a patient’s illness. Even if a reliable history of ingestion, inhalation, or
prolonged skin contact is given, the patient or other informant may not know how much of which glycol ether
was involved, and whether other toxic agents may be implicated. Although other alcohols and hydrocarbons
can cause some degree of CNS depression, only methanol and ethylene glycol commonly cause metabolic
acidosis and, with ethylene glycol, renal injury, which may guide the clinician to consider the diagnosis of
glycol ether intoxication. This picture can also be caused by non toxic renal failure, diabetic ketoacidosis,
lactic acidosis, or poisoning by carbon monoxide, paraldehyde, phenformin, metformin, iron, isoniazid,
salicylates, cyanide, hydrogen sulfide, and solvents such as toluene, among other toxins.[6]
Table 95-3 -- Differential Diagnosis of Glycol Toxicity

Diethylene Glycol Ingestion
Early DEG intoxication producing severe gastrointestinal symptoms may mimic an acute abdomen, with its
broad differential diagnosis, absent the history of a toxic ingestion.
Acidosis Inebriation CNS Depression * Renal Toxicity
Diethylene glycol +++ o +++ ++++
Ethylene glycol +++ o +++ ++++
Ethanol o ++++ ++ o
Isopropanol o ++ +++ o
Methanol ++++ +/- + o
Glycol Ethers in General (Ingestion or Acute Inhalation)
1. Except as above, other alcohols or hydrocarbons do not usually cause acidosis, hematuria, or other renal
effects.
2. Drugs: Salicylates and INH can also cause CNS depression and acidosis, as can others (see text).
3. Other toxins: Carbon monoxide or cyanide can present with acidosis and CNS depression, e.g., after smoke
inhalation.
4. Diabetic ketoacidosis, prolonged hypoxia/hypercapnia may be seen.
* Methanol and ethylene glycol can both cause CNS depression late, via cerebral edema.
Ingestion of DEG, more than the other glycol ethers, may initially present with the clinical picture of an acute
abdominal process, including early biliary tract obstruction or hepatitis. However, the degree of acidosis and
oliguria would likely be out of proportion to the abdominal findings, as would the altered mental status. All
three features—acidosis, oliguria, and changes in mentation—are more severe than those which occur in
intoxications with other alcohols, except as noted here.


LABORATORY STUDIES
Serum electrolytes, blood urea nitrogen (BUN), creatinine, glucose, urinalysis, and a complete blood count
(CBC) should be checked initially, with liver function tests, amylase, and lipase indicated in severe poisoning
cases. No specific DEG or glycol ether levels are readily available in most hospital laboratories. Other
laboratory tests to be obtained depend upon the differential diagnoses, but an ethylene glycol level will
usually be indicated. Determination of serum osmolality by freezing point determination is necessary to
calculate the osmolar gap; the presence of a gap may assist in the diagnosis, whereas the absence of an
osmolar gap does not eliminate DEG ingestion (see Chapter 11 ).
Abnormalities in acute DEG poisoning may be dominated by the acute renal failure, with azotemia and
hyperkalemia, with or without acidosis. When urine is available, urinalysis often shows white blood cells, red
blood cells, and granular casts. Serum alanine amino transaminase levels are usually increased, but
bilirubin is normal. Peripheral blood shows a polymorphonuclear leukocytosis with normal platelets.[3]
Anemia in DEG poisoning is difficult to interpret to determine whether erythrocyte production or survival is
affected. Such patients are often described as dehydrated and azotemic, and some have had Klebsiella
bacteremia. The severity of the acidosis and nephropathy may be related to the amount of glycol ether
absorbed, though in reported series,[23][37] the acidosis was often inferred from a low serum bicarbonate or
breathing pattern, with no direct measurements of pH. Azotemia, on the other hand, has been documented
with creatinine values ranging from 1.6 mg/dL in one study[23] to 5.9 mg/dL in another.[37] Except for the low
bicarbonate, serum electrolytes can remain normal, sometimes even late in the course. However, in one
series hyperkalemia was present in 29 of 45 cases, while hypoglycemia was found in nearly half, [37] but was
not described in another report. [3]
As mentioned earlier, most cases of DEG poisoning involved children, whose urinary sediment contained
numerous red and white blood cells and granular casts,[3] reflecting tubular rather than glomerular injury as
the major DEG lesion. Hemoglobinuria has also been reported, presumably due to intravascular hemolysis.
The frequency of hemolytic anemia in glycol ether poisoning is difficult to judge, due to the absence of
appropriate laboratory observations, and because many such patients are dehydrated and azotemic when
first seen. Elevations in amylase and lipase will reflect pancreatic injury, while transaminase elevations are
often mild.[3] Vitamin K–dependent coagulation tests were normal in one severe case of DEG poisoning
(Scalzo AJ, unpublished).


The initial management should include appropriate airway management, careful evaluation for other toxins,
and laboratory studies as noted. If alertness permits, gastric decontamination with nasogastric tube
evacuation can be performed within the first 1–2 hours after ingestion. The efficacy of activated charcoal is
unknown, but its low binding affinity for other alcohols and glycols[6][51] casts doubt on its value.
Table 95-4 -- Treatment of Glycol Ether Poisoning

Mild exposure (adults: < 30 mg DEG, children < 10 mg):
Gastric decontamination (may not be needed for ingestion of < 10 mL of <10% glycol ethers other than
diethylene glycol)
Hydration
Observed for 4 hours
Consider Social Services consultation to prevent further exposures
Moderate/severe exposure:
Airway support, if needed
Intravenous fluids, maintain urinary flow
Add bicarbonate if pH < 7.20
Correct other electrolyte disturbances
Alcohol dehydrogenase inhibitor
I. Fomepizole. All doses should be administered as a slow intravenous infusion over 30 min.
A. Loading Dose: 15 mg/kg
B. Maintenance Dose: 10 mg/kg every 12 hr for 4 doses, then 15 mg/kg every 12 hr for all subsequent doses.
C. Dosing in Patients Requiring Hemodialysis:
1. Dose at the beginning of hemodialysis:
a. Less than 6 hr since last fomepizole dose, no dose required.
b. More than 6 hr since last fomepizole dose, administer next scheduled dose.
2. Dosing during hemodialysis:
a. Administer fomepizole at required dose every 4 hr.
3. Dosing at the end of hemodialysis:
a. If less than 1 hr since last dose, no dose required.
b. If between 1 and 3 hr since last dose, administer ½ of next scheduled dose.
c. If more than 3 hr since last dose, administer next scheduled dose.
D. Maintenance Dosing Off Hemodialysis:
1. Give next scheduled dose 12 hr from last dose administered.
II. Ethanol
A. Loading Dose: 0.8 g/kg ( mL/kg) of 100% ethanol.
1. Intravenous administration: dilute to 5–10% concentration.
2. Oral administration: dilute to 20–30% concentration.
B. Maintenance Doses
1. Start simultaneously with loading dose.
2. Initial dose: 130 mg (0.16 mL)/kg per hour of 100% ethanol, dilute per above instructions.
3. Monitor ethanol levels hourly until steady state achieved.
a. Goal is serum ethanol level of 100–150 mg/dL. Increase or decrease infusion rate as necessary.
b. If ethanol level falls below 100 mg/dL, a partial loading dose may also need to be administered. Calculate
the ethanol dose required as follows:
Ethanol (mg) = [desired concentration (mg/dL) - known concentration (mg/dL)] × Vd (0.6 L/kg) × body weight
(kg)
c. Increase maintenance infusion to two to three times normal dose during hemodialysis.
C. Monitor patient for CNS depression, hypoglycemia, hyponatremia.
D. Check serum ethanol level every 1–2 hr until steady state level of 100–150 mg/dL achieved.
Hemodialysis should be considered early in severe cases
4-Methylpyrazole or Ethanol
In all DEG poisonings presenting with acidosis, an osmolar gap or oxaluric crystals—or a history of ingestion
suggesting an intake of more than 30 mg (10 mg in children)—4-MP or ethanol should be given to inhibit
alcohol dehydrogenase activity. This treatment should also be considered in cases suspected as being
serious (see discussion under Pediatric Patients). A loading dose of ethanol (800 mg/kg) followed by
80–150 mg/kg/hour should be instituted to produce a serum ethanol level of 100–150 mg/dL.[6] This rate
should be doubled or tripled during hemodialysis therapy. Inhibition of alcohol dehydrogenase with ethanol
was used successfully in a case of DEG poisoning. Blocking the oxidation of DEG by alternate means, i.e.,
4-MP or diethyldithiocarbamate, has also been demonstrated in the rat.[50] 4-Methylpyrazole is approved in
the United States for treatment of ethylene glycol poisoning. Its use in one case of severe poisoning by DEG
and triethylene glycol from brake fluid ingestion yielded a dramatic response.[4] An initial intravenous dose of
10 mg/kg in 250 mL of normal saline was given 3 hours after the ingestion and repeated 2 hours later.
Although Johanson[30] has pointed out that the use of ethanol can result in increases in blood and urine
levels of 2-BE, it is not clear that such increases would have adverse effects. The alkoxyacetic acid
metabolites are probably responsible for the toxicity of many glycol ethers, although this remains unproved.
Hemodialysis
Whether ethanol or 4-MP therapy must be accompanied by hemodialysis in serious cases has not been
studied, but its use seems logical in order to eliminate the parent toxin and its toxic metabolites. Case
reports [19][51] described successful hemodialysis in the treatment of acute renal failure from DEG-
contaminated wine, and after ingestion of 2-BE and ethanol. In other reports[3][39] dialysis was often able to
correct azotemia and electrolyte abnormalities but did not improve survival. Clearly, additional data are
needed to help choose among the therapeutic options. Despite their limitations, human case reports may be
most useful, especially if they include information on timed blood and urine concentrations of DEG and its
metabolites, before, during, and after the use of 4-MP, ethanol, or hemodialysis.
Comments on the therapy of DEG poisoning must be viewed in the context of the very high mortality rate
observed in reported series. However, the diagnosis was not made in these series until suggested by
autopsy, epidemiology, or other investigations.[3][7][39] This suggests the possibility that hemodialysis or other
measures might have reduced the mortality rate if started immediately, rather than a week or more after the
poisoning.[19]
Other Measures
General intensive care measures will be needed, such as the control of seizures, ventilatory support for
comatose patients, meticulous management of fluid and electrolyte balance, and cardiovascular
stabilization.


DISPOSITION
Little follow-up of the few survivors of DEG and other glycol ether poisoning has been published. In general,
patients who should be admitted to hospital include adults who ingest over 30 mg (children, 10 mg) and
those who present with inebriation, metabolic acidosis, an osmolar gap, or oxalic acid crystalluria.
Appropriate plans for psychiatric and other care should be made. In pediatric or geriatric cases, a Social
Services consult may also be needed.


SEQUELAE
Patients with more severe poisoning with DEG or other glycol ethers may have significant renal, neurologic,
hepatic, and/or hematologic dysfunction, and deaths have occurred. Some reported cases appear to have
made complete recovery, although specific data are lacking.[4][19][40]


SPECIAL SITUATIONS
Occupational Exposures
Given the relatively low volatility of some glycol ethers, such agents usually do not pose a risk of inhalation
toxicity unless misused. For example, the use of these solvents in poorly ventilated spaces over prolonged
periods without effective skin and respiratory protection can cause acute toxicity. One such patient, whom
we have evaluated, applied a cleanser containing 5–10 per cent 2-BE for about 4 hours in the back of a
sports vehicle whose tail gate and rear window were jammed. He displayed somnolence, anemia, and
hematuria when seen over 24 hours postexposure.[41]
In less confined situations, skin absorption is likely to be the main route of exposure[29] unless care is taken
to limit cutaneous uptake by gloves and other barriers.[1] However, when used undiluted and without
ventilation, 2-butoxyethanol caused severe irritation to a group of office workers who were briefly exposed to
the concentrated vapor. They later developed benign but worrisome skin angiomas, and several had
persistent hypertension.[41] Chronic skin exposure to 2-propoxyethanol can cause a contact dermatitis, and
in one African-American man resulted in permanent patchy depigmentation.
Methods for monitoring ambient air concentrations of glycol ethers are available,[35][36] but the results may
be misleading as indices of the overall workplace exposures in which skin contact with liquid ethers
predominates. Surveillance of urinary glycol ether metabolites may be more relevant, but less
convenient.[1][28][30]
Encephalopathy and other neuropsychiatric abnormalities were attributed to 2-ME in several small groups of
chronically exposed workers, some of whom were also exposed to methanol, ethanol, and other
hydrocarbons.[6] Drowsiness and headache developed acutely over 4 hours in a 20-year-old man who
applied 2-BE in a 20 per cent dilution as a floor cleaner in unventilated spaces.
Occupational Monitoring
For U. S. industries, the National Institute of Occupational Safety and Health (NIOSH)[35] recommends that
baseline laboratory data be obtained before workers are assigned to duties involving 2-BE, and rechecked at
least annually for workers who are regularly exposed to 2-BE concentrations above 2.5 ppm. This
recommendation includes tests of liver and kidney function in addition to peripheral blood counts, history,
and physical examination.


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2. Bartnik FG, Reddt AK, Klecak G, et al: Percutaneous absorption, metabolism, and hemolytic activity of n-
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4. Borron SW, Baud FJ, Garnier R: Intravenous 4-methylpyrazole as an antidote for diethylene glycol and
triethylene glycol poisoning: A case report. Vet Hum Toxicol 1997; 39:26.
5. Brooks JB, Basta M, Alley CC, et al: Identification of diethylene glycol in sera from Egyptian children by
frequency-pulsed electron-capture gas-liquid chromatography. J Chromatogr 1984; 309:269.
6. Browning RG, Curry SC: Clinical toxicology of ethylene glycol monoalkyl ethers. Hum Exp
Toxicol 1994; 13:325.
7. Cantarell MC, Fort J, Camps J, et al: Acute intoxication due to topical application of diethylene glycol.
Ann Intern Med 1987; 106:478.
8. Carpenter CP, Pozzani UC, Weil CS, et al: The toxicity of butyl cellosolve solvent. AMA Arch Indus
Health 1956; 14:114.
9. Cook RR, Bodner KM, Kolesar RC, et al: A cross-sectional study of ethylene glycol monomethyl ether
process employees. Arch Environ Health 1983; 37:346.
10. Correa A, Gray RH, Cohen R, et al: Ethylene glycol ethers and risks of spontaneous abortion and
subfertility. Am J Epidemiol 1996; 143:707.
11. Cullen MR, Rado T, Waldron JA, et al: Bone marrow injury in lithographers exposed to glycol ethers and
organic solvents used in multicolor offset and ultraviolet during printing processes. Arch Environ
Health 1983; 38:347.
13. Dean BS, Krenzelok EP: Clinical evaluation of pediatric ethylene glycol monobutyl ether poisonings.
14. Drut R, Quijano G, Jones MC, et al: Hallazgos patologicos en la intoxicacion por dietilenglicol.
Medicina (B Aires) 1994; 54:1.
15. Durand A, Auzepy P, Hebert JL, et al: A study of mortality and urinary excretion of oxalate in male rats
following acute experimental intoxication with diethylene-glycol. Preliminary report. Eur J Intens Care
Med 1976; 2:143.
16. Fitzhugh OG, Nelson AA: Comparison of the chronic toxicity of triethylene glycol with that of diethylene
glycol. J Indus Hyg Toxicol 1946; 28:40.
17. Forest W: Teratology [letter] 1995; 52:1.
18. Ghanayem BI, Blair PC, Thompson MB, et al: Effect of age on the toxicity and metabolism of ethylene
glycol monobutylether (2-butoxyethanol) in rats. Toxicol Appl Pharmacol 1987; 91:222.
19. Gijsenbergh FP, Jenco M, Veulemans H, et al: Acute butylglycol intoxication: A case report. Hum
Toxicol 1989; 8:243.
20. Greenburg L, Mayers MR, Goldwater LJ, et al: Health hazards in the manufacture of “fused collars.” I.
Exposure to ethyleneglycol monomethyl ether. J Indus Hyg Toxicol 1938; 20:134.
21. Groeseneken D, Veulemans H, Masschelein R: Respiratory uptake and elimination of ethylene glycol
monomethyl ether after experimental human exposure. Br J Indus Med 1986; 43:544.
22. Groeseneken D, Veulemans H, Masschelein R: Urinary excretion of ethoxyacetic acid after

experimental human exposure to ethylene glycol monoethyl ether. Br J Indus Med 1986; 43:615.
23. Hanif M, Mobarek MR, Ronan A, et al: Fatal renal failure caused by diethylene glycol in paracetamol
elixir: The Bangladesh epidemic. Br Med J 1995; 355:88.
24. Hebert JL, Auzepy P, Durand A: Intoxication aigue humaine et experimentale par le diethylene-glycol.
Semin Hop 1983; 59:344.
25. Heilmar R, Lenk W, Lohr D: Toxicokinetics of diethylene glycol in the rat. Arch Toxicol 1993; 67:655.
26. Johanson G, Kronborg H, Naslund PH, et al: Toxicokinetics of inhaled 2-butoxyethanol (ethylene glycol
monobutyl ether) in man. Scand J Work Environ Health 1986; 12:594.
27. Johanson G, Boman A, Dynesius B: Percutaneous absorption of 2-butoxyethanol in man. Scand J

Work Environ Health 1988; 14:101.
28. Johanson G, Michel I, Norback D, et al: Biological monitoring of exposure to ethylene glycol ethers.
Arch Toxicol 1989; 13(Suppl):108.
29. Johanson G, Boman A: Percutaneous absorption of 2-butoxyethanol vapour in human subjects. Br J

Indus Med 1991; 48:788.
30. Johanson G: Urine butoxyacid acid as a therapeutic guide. Clin Toxicol 1993; 31:501.
31. Kalf GF, Post GB, Snyder R: Solvent toxicology: Recent advances in the toxicology of benzene, the
glycol ethers, and carbon tetrachloride. Ann Rev Pharmacol Toxicol 1987; 27:399.
32. Krasavage WJ, Tehaar CJ: Comparative toxicity of nine glycol ethers: I. Acute oral LD50.
In: Ballantyne B, Marrs T, Turner P, ed. General & Applied Toxicology, Vol I. New York: Stockton
Press; 1993:425. Table 2
33. Lenk W: Pharmacokinetics and biotransformation of diethylene glycol and ethylene glycol in the rat.
Xenobiotica 1989; 19:961.
34. Mathews JM, Parker MK, Matthews HB: Metabolism and disposition of diethylene glycol in rat and dog.
Drug Metab Dispos 1991; 19:1066.
35. NIOSH. Criteria for a recommended standard: Occupational exposure to ethylene glycol monobutyl
ether and ethylene glycol monobutyl ether acetate. Cincinnati: US Department of Health and Human
Services, Public Health Service, CDC, 1990.
36. NIOSH. Criteria for a recommended standard: Occupational exposure to ethylene glycol monomethyl
ether, ethylene glycol monoethyl ether, and their acetates. Cincinnati: US Department of Health and Human
Services, Public Health Service, CDC, 1991.
37. Okuonghae HO, Ighogboja IS, Lawson JO, et al: Diethylene glycol poisoning in Nigerian children. Ann
Trop Paediatr 1992; 12:235.
38. Pan American Health Organization. Epidemic of acute renal failure reported in Haiti. News release,
6/25/96. World Health Organization, Washington, DC.
39. Pandya SK: An unmitigated tragedy. Br Med J 1988; 297:117.
40. Rambourg-Schepens MO, Buffet M, Bertault R, et al: Severe ethylene glycol monobutyl ether poisoning.
Kinetic and metabolic pattern. Hum Toxicol 1988; 7:187.
41. Raymond LW, Williford LS, Burke WA: Eruptive cherry angiomas and irritant symptoms after one acute
exposure to the glycol ether solvent 2-butoxyethanol. J Occup Environ Med 1998; 40:1059.
42. Ratcliffe JM, Schrader SM, Clapp DE, et al: Semen quality in workers exposed to 2-ethoxyethanol. Br J
Indus Med 1989; 46:399.
43. Samuels DM, Doe JE, Tinston D: The effects of single inhalation exposures to ethylene glycol
monoalkyl ethers, in particular ethylene glycol monomethyl ether. Arch Toxicol Suppl 1984; 7:167.
44. Veulemans H, Groeseneken D, Masschelein R, et al: Field study of the urinary excretion of ethoxyacetic
acid during repeated daily exposure to the ethyl ether of ethylene glycol and the ethyl ether of ethylene
glycol acetate. Scand J Work Environ Health 1987; 13:239.
45. Veulemans H, Steeno O, Masschelein R, et al: Exposure to ethylene glycol ethers and spermatic
disorders in man: A case-control study. Br J Indus Med 1993; 50:71.
46. Wax PM: Diethylene glycol toxicity revisited: The 1996 Haitian epidemic. Clin Toxicol 1996; 34:513.
47. Wax PM: It’s happening again—Another diethylene glycol mass poisoning. Clin Toxicol 1996; 34:517.
48. Welch LS, Schrader SM, Turner TW, et al: Effects of exposure to ethylene glycol ethers on shipyard
painters: II. Male reproduction. Am J Indus Med 1988; 14:509.
49. Welch LS, Cullen MR: Effect of exposure to ethylene glycol ethers on shipyard painters: III. Hematologic
effects. Am J Indus Med 1988; 14:527.
50. Wiener HL, Richardson KE: Metabolism of diethylene glycol in male rats. Biochem
Pharmacol 1989; 38:539.
51. Woolf AD: Diethylene glycol. Clin Toxicol Rev 1994; 17:1.


Uncited reference
Cullen MR, Solomon LR, Pace PE, et al: Morphologic, biochemical, and cytogenetic studies of bone marrow
and circulating blood cells in painters exposed to ethylene glycol ethers. Environ Res 1992; 59:250.


Chapter 96 – Radiation
FUN FONG JR. DIRK C. SCHRADER SHOW H. FONG
Essentials
• Details of alleged radiation exposure are critical to understanding the potential for radiation exposure
and should be independently confirmed by history, measurements, or tests.
• Systemic exposure is diagnosed by time to onset of prodromal symptoms and by fall in absolute
lymphocyte count over 48–72 hours.
• Data gathering about the radionuclides involved is more important than efforts to derive dose estimates
on individuals.
• Be suspicious of any skin lesion that does not have a temporal relationship to injury or that fails to heal.
• An occupational history may be important in suspecting radiation etiology.
• A health physicist can confirm the presence of specific radionuclides and can identify radiation response
resources.
INTRODUCTION
Basic Radiation Physics
Ionizing radiation may take the form of an energetic subatomic particle (e.g., alpha or beta particle, neutron)
or electromagnetic radiation (e.g., x-ray, gamma ray). Transfer of energy from these radiations to living
tissue may result in biologic alterations or cellular damage. Alpha particles are helium nuclei stripped of their
electrons. Because they are charged particles and heavy in mass, their range is limited to a few centimeters
in air and less than 100 µm in tissue. Because alpha particles cannot penetrate the keratinized layer of skin,
they are of medical significance only if internalized. Beta particles are high-energy electrons that have a
penetrating power of a few millimeters of tissue. They are hazardous only if internally deposited. However,
“beta burns” can be life-threatening if large areas of skin are contaminated with significant amounts of
radionuclide emitting high-energy beta particles. X-rays and gamma rays are high-energy photons that have
a range up to several centimeters in tissue. However, they can be greatly attenuated by dense metals, such
as iron and lead. Beta, gamma, and x-rays are considered to be radiations with low linear-energy transfer
(LET). The LET of ionizing radiation is defined as energy lost in a medium per unit length traversed. The
biologic damaging effect of a particular radiation usually increases with increasing LET. Neutron emission is
also regarded as potent ionizing radiation, capable of penetrating deeply and creating dense ionization trails.
The major neutron sources are reactors and accelerators. Moisture density gauges represent an example of
other neutron sources used in industry. Alpha and neutron particles are considered to be high-LET radiation.
Injury Settings
Radiation accidents can occur within the following settings: (1) radiography (commonly used to examine
dense metal welding joints), (2) radionuclide production, manufacturing facilities (occupational settings), (3)
reactors, (4) research, (5) military, (6) public domain, and (7) transportation.
Modes of Injury
Organisms are subject to four main types of radiation exposure scenarios: (1) irradiation, (2) external
contamination, (3) internal contamination ( Table 96–1 ), and combined injury. [1]
1. Irradiation—radiation exposure without contamination. The patient is not a health hazard for providers,
and there is no need for patient decontamination.
Table 96-1 -- Internal Contamination: Action Levels for Treatment

Annual Limit of Intake (ALI) Treatment
<1 ALI No treatment necessary
Consider internal decontamination
2–10 ALIs
treatment
>10 ALIs Treatment recommended *
or
Consider internal decontamination
>1 maximum permissible body burden (MPBB)
treatment †
or
>5 rem committed dose whole body, gonads, or marrow or 50 Consider internal decontamination
rem committed to skin, bone, or other organs treatment ‡
Note: for internal contamination, acute dose estimations should be based from maximum credible
incident. Actual calculated data from samples cannot be done in acute clinical time frame.
* Radiation Protection Dosimetry, Vol. 41, No, 1, 1992, p. 25. ALIs may be found in International Commission on Radiological
Protection, Vol 21, No 4 (Publication 61).
† MPBBs are obsolete for regulatory purposes but still used by clinicians. (See National Council on Radiation Protection and
Measurements Report #65.)[10]
‡ Voelz GL: Evaluation and treatment of persons exposed to internally deposited radionuclides. In Mettler FA, Kelsey CA, Ricks
RC: Medical Management of Radiation Accidents. Boca Raton, FL, CRC Press, 1990, p 167.
2. External contamination—radionuclides present on external body surfaces. Radionuclides may be

transferrable, and patients should be treated as such in order to avoid health care worker
contamination.
3. Internal contamination—radionuclides that are deposited internally by inhalation, ingestion, injection,
or wounds. Radionuclides are incorporated into the body in four steps: The radionuclide undergoes
deposition in the body along some route of entry. Radionuclides undergo translocation by solubilization
into the bloodstream, where they become bioavailable and reach target organs. Incorporation keeps
radionuclides within these target organs. Radionuclides may undergo clearance from the target organ,
as an equilibrium of radionuclide deposition and release from the target organ is established.
4. Combined injury—the medical sequelae of nuclear explosions consisting of two or three of the
components of radiation injury, burns, or mechanical injury.[11] Patients with combined injury have
higher rates of morbidity and mortality. Combined injury should be noted during patient triage.


PATHOPHYSIOLOGY
Biologic Effects
The biologic effect of radiation depends on the following two parameters: (1) dose is the amount of energy
absorbed per unit tissue mass. Dose is measured in rads, with 1 rad as 0.01 watt-second energy absorbed
per kilogram of tissue weight. (2) Radiation quality refers to different biologic effects that different types of
radiation have on tissue, depending on their LETs. For the same amount of energy absorbed, alpha particles
are considered to be 20 times more damaging than x-rays, gamma rays, or beta particles. Neutrons are
roughly 10 times more harmful. These factors represent biologic effectiveness for different types of radiation
(e.g., 20 for alpha particles, 10 for neutrons, 1 for x-rays, gamma rays, and beta particles) when the dosage
is estimated for living tissues. When a dose is weighted based on these factors, it is called the dose
equivalent. To evaluate radiation quality, the dose is expressed in rems (roentgen equivalents in man), and
these factors are applied to convert the number of rads into the number of rems. Therefore, the dose
equivalent that corresponds to 1 rad of dose induced by alpha particles is 20 rem, by neutrons it is 10 rem,
and by beta particles it is 1 rem. Rads and rems are traditional units. Modern scientific units in the SI system
are the gray (Gy), which is 100 rads, and the sievert (Sv), which is 100 rem.
According to the law of Bergonié and Tribondeau, less differentiated and actively proliferating cells are more
radiosensitive. Below this radiation threshold, cellular DNA may be permanently affected by radiation and
acquire DNA mutations. These changes could lead to an increased risk of developing cancer later in life.
Above a radiation exposure threshold, some radiosensitive cells are affected by an inhibition of mitosis, and
other cells die while attempting division.
Ionizing radiation may cause two discrete effects: (1) Stochastic effects are health effects that occur
randomly and for which the probability of occurrence, rather than its severity, is assumed to be a linear
function of dose without a threshold. Stochastic effects usually refer to the increased risk of developing
cancer and genetic sequelae. (2) Deterministic effects are health effects that vary with the dose and for
which a threshold exists. Examples of deterministic effects are erythema, hematopoietic depression, organ
or tissue fibrosis, cataract induction, and impairment of fertility.
Tissue Effects
Radiation exposure above specific tissue threshold levels causes a specific inflammatory cascade that has
as its endpoint fibrosis and vascular insufficiency, particularly at the microvascular level.
Organ Effects
Examples of deterministic effects would include organ insufficiency or failure, such as hematopoietic
depression, hepatic veno-occlusive disease, pneumonitis, enteritis, and epithelial skin injury.


CLINICAL PRESENTATION ( Fig.96–1 )
Acute Exposure
Systemic doses of 1–50 rads are usually asymptomatic. Doses above 50 rads are more likely to produce
within 3 hours prodromal symptoms of nausea, vomiting, diarrhea, and malaise. Higher dose exposures are
associated with fever, severe abdominal pain, and an eye-burning sensation. Supralethal exposures of
thousands of rads are thought to be associated with confusion known as early transient incapacitation (ETI).
Figure 96-1 Clinical presentation—signs and symptoms.[8]

Internally contaminated patients may react with anxiety, somatization, and vegetative symptoms of
depression. Only in the most unusual of circumstances will these individuals actually be internally exposed
to systemic threshold doses. The diagnosis is validated on the basis of positive bioassay, chest counts, or
whole-body counts ( Table 96–2 ).
Table 96-2 -- Comparison of Exposure Guidelines, Typical Medical Exposures, and Symptom Threshold
Doses
Exposure Traditional Units SI Units
Radiation protection guidelines
Visitors and public (1 year) 0.1 rem 0.001 Sv
Minors and students (1 year) 0.1 rem 0.001 Sv
Declared pregnant worker (9 months) 0.5 rem 0.005 Sv
Radiologic worker—whole body allowed (1 year) 5 rem 0.05 Sv
Radiologic worker—lens of eye 15 rem 0.15 Sv
Radiologic worker—extremity 50 rem 0.5 Sv
Radiologic worker—target organ 50 rem 0.5 Sv
Typical medical exposures
Chest x-ray (1 view) .015 rem 0.00015 Sv
CT head (dose to head) 1 rem 0.01 Gy
CT abdomen (dose to abdomen) 2–5 rem 0.02–0.05 Gy
Overexposure (subthreshold exposure, stochastic effects)
0.2 × 10-4/rem * 0.2 × 10-2/Sv *
Leukemia
0.9 × 10-4/rem † 0.9 × 10-2/Sv †
4 × 10-4/rem * 4 × 10-2/Sv *
Increased risk of developing solid neoplasms later in life
8 × 10-4/rem † 8 × 10-2/Sv †
Threshold exposure (deterministic effects) ‡ Threshold/D50 dose Threshold/D50 dose
Oligospermia (2 yrs) 30 rads/70 rads 0.3 Gy/0.7 Gy
Ovulation suppression (permanent) 60 rads/350 rads 0.6 Gy/3.5 Gy
Vomiting 50 rads/200 rads 0.5 Gy/2 Gy
Diarrhea 100 rads/300 rads 1 Gy/3 Gy
Death from marrow syndrome (minimal care) 150 rads/300 rads 1.5 Gy/3 Gy
Death from marrow syndrome (supportive care) 230 rads/450 rads 2.3 Gy/4.5 Gy
Thyroiditis 200 rads/1200 rads 2 Gy/12 Gy
Skin—erythema 300 rads/600 rads 3 Gy/6 Gy
Exposure Traditional Units SI Units
Skin—dry desquamation 500–2000 rads/2000 rads 5–20 Gy/20 Gy
Skin—wet desquamation 1200–2000 rads 12–20 Gy
Skin—necrosis 2000–3000 rads 20–30 Gy
Death from pulmonary syndrome lethality 500 rads/1000 rads 5 Gy/10 Gy
Death from gastrointestinal injury 800 rads/1500 rads 8 Gy/15 Gy
CNS incapacitation 600 rads/1700 rads 6.5 Gy/17 Gy
Acute encephalopathy 5000–8000 rads 5–8 Gy
* Biological effects of ionizing radiation (BEIR) III estimated prompt dose risk.
† BEIR V estimated prompt dose risk (for fractionated and protracted doses, the risk may be reduced by a factor of 2–10).
‡ Models from NUREG CR-4214 estimating threshold and estimated D50 prompt doses.
Externally contaminated patients should be evaluated for local radiation injury. They should be
decontaminated after life- and limb-threatening conditions have been medically stabilized.
Chronic Exposure
Chronic radiation syndrome (CRS) has been best described in the Chinese and Russian literature. Because
of vague symptomatology, CRS has been difficult to quantitate and classify. The contamination of the Techa
River and Chelyabinsk areas have led to diagnosis of approximately 90 individuals with CRS. CRS should
be suspected when there is a history of chronic radiation exposure, combined with sequential and
progressive multiorgan system dysfunction that is manifest in the absence of other more common
etiologies.[3]
Pediatric Issues
Because of higher metabolism and mitotic rates, children are generally more susceptible to radiation
exposure than adults for corresponding doses.


Systemic Illness
Gastroenteritis may be confused either with the prodrome of nausea, vomiting, and diarrhea or late
gastrointestinal effects related to mucosal desquamation. Aplastic anemia could also cause a pancytopenia.
A lymphocyte cytogenetics evaluation, a specialized blood test, will demonstrate whole body radiation
effects with exposure greater than 10 rads.
Local Involvement
Pemphigoid lesions are large blisters that may appear identical to those caused by radiation exposure.
Necrotic spider bites usually have a necrotic center; similar radiation lesions may be associated with more
blistering. Very high-dose radiation exposure is associated with large skin lesions and deep eschars. Stasis
and radiation ulcers are both associated with microvascular ischemia. Radiation ulcers may be also
associated with subacute epilation and hyperpigmentation. Dry radiation epidermitis may be confused with
skin neoplasms, especially keratinizing skin lesions. Radiation blistering can also resemble a local herpetic
eruption. A herpetic eruption will resolve cyclically with therapy and time, while a radiation blister may
continue to evolve and exhibit further erosion.
Frequently, the history of radiation exposure is not clear. Local injury may appear as a sore that does not
heal over a period of weeks or months. An occupational radiation history can raise the index of suspicion for
radiation exposure. Local radiation injury spans a wide range of symptoms and therapies.


LABORATORY STUDIES
Irradiation
In cases of suspected irradiation a complete blood count (CBC) with differential blood count should be done,
along with a urinalysis, to establish baseline values. For suspected overexposure of 10–25 rads, the
following assessments are needed:
• Baseline and 6-week postexposure sperm counts
• Blood samples for any of the following tests used for delayed dose estimation: lymphocyte cytogenetics,
lymphocyte micronuclei analysis, and fluorescent in situ hybridization (FISH).
For doses at higher exposure (suspected to be above 25 rads), further studies should include the following:
• Slit-lamp examination (to document cataract formation)
• Liver function tests and blood coagulation studies
• Personal articles, teeth, or tissue samples for electron spin resonance (ESR) test for delayed dose
estimation
• Systemic effects of radiation may be assessed by either (1) the Modified USSR Classification, which
relies on history, physical examination, and laboratory parameters, or (2) the Andrews Lymphocyte
Nomogram, which follows absolute lymphocyte counts periodically over 48 hours ( Fig. 96–2 ).
Figure 96-2 Triage Criteria. A, Andrews Lymphocyte Nomogram.[2] B, Modified USSR Triage Classification (1986).[4][9]
Contamination
For evaluation of external contamination, the following samples are taken:

• Swabs from body orifices
• Swabs from wounds
• Skin wipes
Internal contamination is assessed using the following specimens. All specimens should be collected and
sent to a health physics laboratory.
• Urine: 24-hour specimens taken for 4 days
• Feces: 24-hour specimens taken for 4 days
• Vomitus and sputum analysis
• Serum creatinine assessment
• Irrigating fluids
Other studies that may help evaluate internal contamination include nuclear medicine gamma camera
survey (may be used to screen for contamination for some radionuclides), chest counts (if inhalation of long-
lived radionuclides is suspected), and whole body counts.


TREATMENT
General Care
Critical accident details must be obtained and verified by history from independent “reliable sources” or by
actual on-site measurements by a health physicist. In designing a treatment plan, the emergency physician
must assess the maximum credible exposure to derive worst-case dose estimates (see Tables 96–1 and
96–2 ). A calculated dose estimate derived from bioassay cannot be obtained within an acute time frame,
and initial dose estimates may differ from final estimates by as much as a factor of 100. External beam dose
estimates may be useful in ruling out significant radiation exposure within an acute time frame. The
treatment of internally ingested radionuclides should follow the five golden rules of toxicology:
1. Treat the patient before the poison
2. Prevent or reduce exposure
3. Enhance elimination of the toxin
4. Consider specific antidotes and adjuncts
5. The dose makes the poison
Accident detail data gathering remains the cornerstone of any Haz-Mat accident treatment protocol ( Table
96–3 ).
Table 96-3 -- Treatment Essentials for Radiation Exposure[5]

Irradiation * Internal Contamination External Contamination
Antiemetics/antimotility
General Initial
agents
Consider indoor or outdoor decontamination,
Promethazine Gastric decontamination
depending on circumstances
Lung lavage (as for
Ondansetron Remove clothing
bronchoalveolar proteinosis)
Decontaminate wounds first, followed by skin
Diphenoxylate HCl Specific treatments
decontamination
Antiviral prophylaxis Water dilution (tritium) Cleansers
Acyclovir Potassium iodide (radionuclide) Isolation procedures
Plastic bags, Chux incontinent dressing, or
Ganciclovir DTPA (plutonium/transuranics)
sheeting
Hematopoietic agents Urinary alkalinization (uranium) Gloves
G-CSF or GM-CSF Prussian blue (cesium) 2–3 bedsheet layers
Irradiation * Internal Contamination External Contamination
Warm soap and water; if contamination persists,
can try household bleach, diluting range 1:4 to
1:10
Cornmeal/detergent paste (may require separate
attempts over several days)
G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.
* Life-saving surgical intervention should be performed within 48 hours of exposure in cases of systemic exposure (before
immunocompromised period). Elective surgical intervention should occur once hematopoietic recovery is complete (usually about 60 days
after exposure).[5]
Radiation accidents may be classified according to the following exposure types:

1. Irradiation. Supportive care is the mainstay of treatment. Dose estimates and lymphocyte cytogenetics
will help determine prognosis. Bone marrow depression can be treated with cytokines. Antiviral drug
prophylaxis should be given for patients at risk for herpes simplex, varicella, or cytomegalovirus
reactivation.
2. External contamination. Exposure is reduced dramatically by clothing removal, and cleansing with
soap and warm water. Personnel should avoid self-contamination by strict barrier protection, including
universal precautions and basic Haz-Mat contamination control techniques. Wounds should be
decontaminated first to minimize the potential for internal contamination. Intact skin may be
decontaminated with dilute sodium hypochlorite (household bleach) 1:2–1:10 or with waterless (grease)
cleansers.
3. Internal contamination. Ingestion may be treated with standard gastric decontamination techniques of
lavage (preferred over emesis), activated charcoal, and catharsis as indicated. There is a window of
enhanced therapeutic effectiveness if decontamination is begun early. Inhalation of large amounts of
insoluble radionuclides, in the range of 50–100 units of annual limit of intake (ALIs), may be treated by
nonemergent bronchoscopic lavage 3–5 days later, similar to lavage for bronchogenic alveolar
proteinosis.
4. Combined injury. Lifesaving surgical intervention should be performed within 48 hours of exposure in
cases of systemic exposure (before immunocompromised period). Elective surgical intervention should
occur once hematopoietic recovery is complete (usually about 60 days after exposure).[5]
Toxin-Specific Measures
Plutonium and Transuranics.
Target organs are bone and lung. The chelating agent diethylenetriaminepentaacetic acid (DTPA) has great
efficacy for soluble forms of transuranic (heavier than uranium) compounds with the exception of neptunium.
Ca-DTPA should be used in the initial 24 hours after exposure, followed by Zn-DTPA. DTPA is available
from the Radiation Emergency Assistance Center/Training Site (REAC/TS) by calling Methodist Medical
Center at (865) 481–1000. The dose is 1 g Ca-DTPA given within 4–6 hours either via intravenous route or
nebulization as an unfractionated daily dose. Then 1 g Zn-DTPA should be given over the next 24 hours and
daily after that by similar routes. The drug is usually well tolerated. Stop or slow dosage schedule for
diarrhea, active urine sediment, or hypotension. DTPA from nuclear medicine departments is not suitable for
use.
Uranium.
Target organ for unenriched uranium is the kidney, and nephrotoxicity can occur. Uranium hexafluoride can
cause exothermic generation of hydrofluoric acid (HF), and thus can cause HF thermal, chemical, and
inhalational injury. Urine should be alkalinized to maintain a steady pH of 7.5–8 by means of oral
bicarbonate and potassium chloride tablets for approximately 3 days. Patients should have bioassay results
analyzed at that point to determine the duration of urinary alkalinization required.
Tritium.
Turnover should be facilitated by additional oral tritiated water, approximately 3–4 L/day, to increase
excretion of tritium. Electrolytes should be monitored periodically to prevent electrolyte imbalances. [10]
Iodine and Technetium.
Target organ is the thyroid. Radioiodine is a radionuclide commonly used in reactors and also used
medically. Radiostable iodine is best given 1 hour before potential exposure, but it may also have some
benefit up to 4 hours after exposure. Iodine may be administered orally by mixing supersaturated potassium
iodide (SSKI) in water. A dose of 390 mg (5–6 drops) of SSKI, which delivers 300 mg of iodide, should be
given as soon as possible after the exposure. Duration of therapy is 7–14 days, due to potential recycling of
radioiodine into the thyroid. Adverse effects include angioedema due to sensitivity and iodism (rhinitis,
conjunctivitis, sialoadenitis, headache, fever, rash) with prolonged use.
Cesium.
Target organ is the intracellular compartment. Insoluble Prussian blue (ferric ferrocyanide) is used as a
nonsystemic ion-exchanger to remove this potassium analog from the body. Doses are typically 10 g/day
given orally in three divided doses.[8a] Prussian blue may be available from Radiation Management
Corporation or REAC/TS.


DISPOSITION
Internal contamination and external contamination events usually occur below systemic threshold levels. In
these cases, patients may be followed as outpatients. Overexposures that have potential for rapid threshold
effects will probably have soft tissue symptoms (swelling, erythema, or pain) within 24 hours of exposure.
Local injury may manifest as early as 6 days after injury in extreme cases, but more commonly 14 days after
exposure. Systemic effects are determined by onset of nausea, vomiting, or diarrhea (prodromal symptoms)
within 3 hours of exposure. Such patients may be candidates for admission. Patients with suspected
prodromal symptoms that occur after 3 hours of potential exposure may be followed closely as outpatients. A
dose estimate (which is usually derived in a delayed fashion) may be used to counsel patients on the
implications of an overexposure. NRC publication CR-4214 can be used to correlate deterministic effects,[6]
and BEIR V[7] may be used to estimate long-term effects conservatively. A physician familiar in radiation use
(occupational physician, radiation oncologist, hematologist, or nuclear medicine physician) may be the best
person to counsel the patient. A given patient may have unanswered questions or sequelae about an
overexposure, and referral for close follow-up will facilitate treatment of both the physical and psychological
effects of radiation.


SEQUELAE
After acute exposure, hematopoietic effects may include lymphopenia, neutropenia, and thrombocytopenia.
Pulmonary effects may include pneumonitis and respiratory failure. Gastrointestinal effects may include
mucosal desquamation, electrolyte imbalances, and severe diarrhea. Veno-occlusive liver disease may
occur in high-dose exposures. Neurovascular effects may include early transient incapacitation and altered
mental status in lethal exposures.
Long-term effects include increased risk for developing cancer later in life. BEIR V calculates a general
estimate of increased risk to be exposure to 8 × 10-4 rem. At low-dose rates, this risk may be reduced by a
factor of two to ten.[7] To date, genetic mutations have not been successfully quantitated with human data
despite studies of atomic bomb survivors. Tissue and organ effects may include fibrosis, vascular
compromise, and organ insufficiency or failure.


SPECIFIC SITUATIONS
Radionuclide sources are commonly used in evaluating pipe welds and can cause either local radiation
injury with casual exposure or systemic effects with prolonged exposure. In diagnostic nuclear medicine,
applications contain low-activity sources that can penetrate tissue but are unlikely to cause local or systemic
effects. In therapeutic uses, higher activity sources are designed to cause local effects, such as 131I used to
medically ablate thyroid glands. Research irradiation devices may easily cause local or systemic effects if
improperly used. Research radionuclides are frequently used for tracing purposes and are unlikely to cause
local or systemic effects. Very high activity sources used for bacterial sterilization in irradiation facilities can
cause local or systemic effects in seconds to minutes. Most transported radiographic materials are used for
medical diagnostic purposes. Prehospital personnel are at risk for overexposures. High-activity sources are
transported in type B casks and have had a 100 per cent nonbreach record to date. On rare occasions, high-
activity sources may be improperly discarded within the public domain. In settings where radioactive sources
are misplaced in the public domain, there is more potential for delayed recognition of such a hazard and
therefore increased potential for multiple exposures, resulting in a multiple casualty incident.


REFERENCES
1. A Guide to the Hospital Management of Injuries Arising from Exposure to or Involving Ionizing Radiation.
Chicago, American Medical Association, 1984.
2. Andrews GA, Auxier JA, Lushbaugh CC: The importance of dosimetry to the medical management of
persons accidentally exposed to high levels of radiation (nomogram). Personnel Dosimetry for Radiation
Accidents, Vienna: International Atomic Energy Agency; 1965:3-16.
3. Armed Forces Radiobiology Research Institute. Analysis of Chronic Radiation Sickness Cases in the
Population of the Southern Urals, CR 94-1. Alexandria, VA, Defense Technical Information Center: 1994.
4. BarabanovaA. REAC/TS Newsletter. Winter 1992: pp 1–2 (Oak Ridge, TN).
5. In: Brown D, Weiss JF, MacVittie TJ, Pillai MV, ed. Treatment of Radiation Injuries, New York: Plenum
Press; 1990:219-229.
6. Health Effects Models for Nuclear Power Plant Accident Consequence Analysis. Part II: Scientific Bases
for Health Effects Models, NUREG/CR-4214. Washington, D.C., National Research Council, 1989.
7. National Research Council : Health Effects of Exposure to Low Levels of Ionizing Radiation.
In: BEIR V, ed. Washington, D. C.: National Academy Press; 1989.
8. Hospital Management of Radiation Accidents : REAC/TS Videotape, Oak Ridge, TN, Oak Ridge
Associated Universities, 1980.
8a. Melo DR, Lipzstein JL, de Oliveira CA, Bertelli L: 137Cs internal contamination involving a Brazilian
accident, and the efficacy of Prussian Blue treatment. Health Phys 1994; 66:245.
9. In: Mettler FA, Kelsey CA, Ricks RC, ed. Medical Management of Radiation Accidents, Boca Raton,
FL: CRC Press; 1990:72.
10. National Council for Radiation Protection and Measurements. Management of Persons Accidentally
Contaminated with Radionuclides, NCRP Report No. 65, Bethesda, NCRP, 1980.
11. Schildt B, Thoren L (eds): Proceedings of the Symposium on Combined Injuries and Shock, Uppsala.
June 3–6, 1967.


Chapter 97 – Aliphatic Hydrocarbons
JOHN F. TUCKER
Essentials
• History of exposure
• Distinctive odor on the breath, clothing, or emesis
• Aspiration and chemical pneumonitis
° Respiratory symptoms within 2 to 6
hours
° Radiograph abnormalities within 12
hours
• Precise identification of the product ingested essential (the hydrocarbon may be a vehicle for a more
toxic ingredient)
INTRODUCTION
Ingestion of hydrocarbon solutions ranks among the most common of all toxic exposures.[3][12][24][33] Most
ingestions occur in children younger than 5 years of age.[24][28] These children may be attracted to colorful
packaging or pleasant scents that are often added to these products, or they may mistakenly consume
substances stored in nonproduct containers (e.g., in a soda bottle).[1][12][20] The potential for significant
morbidity and mortality warrants careful management.
Hydrocarbons are organic compounds consisting only of hydrogen and carbon. The aliphatic hydrocarbons
are straight-chained carbon molecules saturated with hydrogen atoms. The aliphatics are used primarily as
fuels, polishes, thinners, or solvents. The terms hydrocarbon and petroleum distillate are often used
interchangeably but are not completely synonymous. Petroleum distillates are the breakdown products
remaining after the processing of crude oil and consist almost exclusively of aliphatic hydrocarbons. The
viscosity of an aliphatic hydrocarbon increases with increasing chain length. At room temperature, methane
(CH4) through butane (CH 3[CH2]2CH3) are gases; pentane (C5H12) through N-hexadecane (C16H34) are
liquids; and longer chains are solids.
Terpenes are hydrocarbons distilled from pinewood, not from petroleum. Examples of terpenes include
turpentine oil and pine oil. Kerosene (coal oil) and automotive gasoline consist of a variable composition of
aliphatics and small amounts of aromatics.
Ingested aliphatic hydrocarbons generally produce little systemic toxicity, but during ingestion they pose a
serious potential risk of pulmonary aspiration. The morbidity and mortality associated with aliphatic
hydrocarbons are related primarily to this aspiration and subsequent pulmonary complications.
Insecticides, metals, and other toxic chemicals with a petroleum base may be contained in a petroleum
distillate vehicle. These substances may markedly change the potential toxicity and necessary treatment
after an aliphatic hydrocarbon ingestion, making it very important to identify every ingredient and additive
within a commercial product. In the absence of these “additives,” patient presentation and management is
similar for various petroleum distillate and terpene exposures.


PATHOPHYSIOLOGY
The gaseous short-chained aliphatic hydrocarbons (i.e., methane, ethane, propane, and butane) act as
simple asphyxiants when inhaled. Their presence displaces air, which lowers the partial pressure of oxygen
and causes hypoxia.
The lung is the primary target organ affected by a liquid aliphatic hydrocarbon ingestion. Several studies
have shown that pulmonary injury results from aspiration of the hydrocarbon and not from gastrointestinal
absorption.[5][8][34][36] Aspiration occurs during either initial ingestion or subsequent emesis. Aliphatic
hydrocarbons within the intestinal tract are poorly absorbed and exert minimal toxicity.
The aspiration potential of a given hydrocarbon depends on its physical and chemical properties,
specifically, viscosity, volatility, and surface tension. Aspiration potential increases with low viscosity, low
surface tension, and high volatility.[20] Viscosity is the most important factor in determining risk of pulmonary
aspiration. Viscosity measures the resistance of a substance to flow. A lower viscosity increases both the
likelihood of entry through the glottic opening and the rate and extent of penetration into the deeper
structures of the tracheobronchial tree.[13] Volatility describes the ability of a substance to vaporize, whereas
surface tension measurements describe the ability of the substance to spread over a contacted surface.
Viscosity is expressed in Saybolt Seconds Universal (SSU) units, a measure of the time required for a
substance to pass through a calibrated orifice at a given temperature. With SSU levels less than 45 at 100°F
(60 at 77°F), there is a very high risk of aspiration. Conversely, when a hydrocarbon’s SSU exceeds 100, the
risk of aspiration is minimal ( Table 97–1 ).[13]
Table 97-1 -- Viscosities of Sample Products

Less Than 60 SSU
Petroleum ether (benzine) Kerosene
Aromatics (benzene, xylene, etc.) Mineral seal oil
Naphtha products (lighter fluid) N-Hexane
Turpentine Stoddard solvent
Gasoline Halogenated hydrocarbons (e.g., carbon tetrachloride, tetrachloroethane)
Mineral spirits
Greater Than 100 SSU
Tar and asphalt Grease
Paraffin wax Diesel oil and fuel
Lubricating oil Rubber cement
Modified from Tinker TD: Hydrocarbon ingestion in children: Its sequelae and management. J Okla State Med
Assoc 1986; 79:96.
Petroleum jelly Moth balls
SSU, Saybolt Seconds Universal.
Modified from Tinker TD: Hydrocarbon ingestion in children: Its sequelae and management. J Okla State Med
Assoc 1986; 79:96.
The volume of hydrocarbon ingested does not correlate well with the incidence of aspiration. In fact, severe
cases of aspiration may involve ingestion of only a small amount of material. [3]
Similar pathologic changes in the lung and mortality rates occur regardless of the particular aliphatic
hydrocarbon aspirated.[9] Initial pulmonary damage is probably due to the chemical destruction of surfactant
in the alveoli and distal airways.[14] This renders the alveoli more unstable, leading to early airway closure,
atelectasis, and pulmonary edema with subsequent ventilation-perfusion mismatching and hypoxia. The
hydrocarbon also increases permeability of the vascular endothelium with subsequent leakage of plasma
and blood into the alveoli. A diffuse hemorrhagic alveolitis with granulocytic infiltrates occurs soon after
aspiration, culminating in a chemical pneumonitis with frank necrosis of bronchial, bronchiolar, and alveolar
tissues. Vascular thrombosis and microabscess formation can occur.[2][13][20] If death does not ensue, these
lesions usually heal over 3 to 8 days.
Observed central nervous system (CNS) effects are not due to direct CNS toxicity of the hydrocarbon but
rather to the hypoxia caused by pulmonary injury. Supporting evidence includes the fact that the primate
brain is resistant to the direct toxic effects of kerosene and that major CNS effects do not occur in the
absence of aspiration.[37]
The gastrointestinal pathology of hydrocarbons is generally mild and self-limited. The pharynx may become
hyperemic with mucosal irritation and inflammation,[2][33] and within the intestinal tract inflammation and
superficial ulceration are common.[20] Although petroleum distillates are poorly absorbed from the
gastrointestinal tract, some systemic absorption does occur. Once absorbed, hydrocarbons exert their
toxicity at the first capillary bed they encounter.[37] Naphtha injected into the portal vein of anesthetized rats
resulted in no pulmonary pathology but in massively enlarged and pale livers with disruption of normal
microscopic architecture and polymorphonuclear infiltration, necrosis, and focal hemorrhage.[5] Fatty
infiltration of the liver may develop after ingestion of an aliphatic hydrocarbon, but frank necrosis is
uncommon, owing to poor gastrointestinal absorption. Renal toxicity is also uncommon in aliphatic
hydrocarbon exposures.


After ingestion, an initial transient gasping or cyanosis may occur even in the absence of aspiration, owing to
volatilized vapors displacing oxygen within the alveoli. Initially, cough is due to local irritation and is very
common but soon subsides. However, prolonged cough, gasping, or choking usually indicates aspiration.
Although the aspiration potential may be high for a given substance, most patients are asymptomatic at the
time of presentation and do not develop toxicity.[1]
When aspiration occurs, symptoms of respiratory distress usually, although not always, appear within 30
minutes of exposure and almost always within 2 to 6 hours.[20] In symptomatic individuals, signs and
symptoms progress over 24 hours, reach a plateau, and subside over 2 to 8 days. [9] Mild physical
examination abnormalities consist of coughing, choking, tachypnea, irritability, and drowsiness. Moderate
signs consist of grunting respirations, lethargy, or flaccidity. Signs of severe toxicity are increased respiratory
effort with grunting respirations and retractions associated with cyanosis, coma, or seizures ( Table 97–2 ).[1]
Table 97-2 -- Frequency of Clinical Signs and Symptoms at Time of Emergency Department Presentation
Frequent Intermediate Uncommon Rare
Asymptomatic XX
Respiratory Symptoms
Initial gasping or cyanosis X
Mild respiratory symptoms (prolonged cough, tachypnea,
X
dyspnea)
Moderate respiratory symptoms (grunting respirations) X
Severe respiratory symptoms (grunting respirations with
X
retractions and cyanosis)
Central Nervous System Symptoms (occur only in presence of
aspiration for aliphatic hydrocarbons)
Mild (irritability or drowsiness) X
Moderate (lethargy, flaccidity) X
Severe (stupor, coma, seizures) X
Gastrointestinal Symptoms
Initial pharyngeal irritation and hyperemia X
Vomiting, abdominal pain, diarrhea X
Hematemesis/hematochezia X
Liver, renal, myocardial involvement X
Fever is often present early, even by the time of emergency department presentation, but the degree of fever
does not correlate with clinical symptoms.[1] Early fever may be at least partially due to direct tissue
toxicity.[15] Most patients defervesce by 24 hours after exposure.[1] Persistence of fever beyond 2 days
should suggest a bacterial superinfection.
Intestinal tract symptoms are common but usually minor. Initial mouth and pharyngeal irritation and burning
are usual after ingestion. Vomiting, abdominal pain, and diarrhea may develop due to mucosal irritation.
Hematemesis or hematochezia occur only rarely. Emesis is a significant risk factor for aspiration,[20][28]
presumably by allowing the glottic opening another exposure to the potential aspirant. Predictably, therefore,
vomiting, spontaneous or iatrogenic, is a common characteristic in patients needing hospitalization.[1]
The presence of CNS symptoms usually indicates aspiration-induced hypoxia but may be due to toxicity of
additives or, possibly, to large (intentional) ingestions. CNS symptoms include lethargy, irritability, dizziness,
or, rarely, stupor, coma, or seizures.[28]
Liver, kidney, or myocardial damage is infrequent after acute ingestions. Sudden death, presumably
secondary to dysrhythmias, may occur. This is theorized to be due to sensitization of the myocardium to
endogenous or administered catecholamines.[23]


Medical conditions with symptoms that may be confused with aliphatic hydrocarbon ingestion include acute
respiratory distress secondary to acute asthma, foreign body aspiration, pulmonary infections, allergic
reactions, pulmonary embolism, pneumothorax, or inhalation of irritant gases ( Table 97–3 ). A thorough
history and physical examination with a chest radiograph should disclose the correct etiology for the
symptoms.
Table 97-3 -- Differential Diagnosis: Disorders Simulating Acute Respiratory Distress Associated With
Aliphatic Hydrocarbon Aspiration (Pneumonitis)
Acute asthma
Pulmonary infections
Pneumothorax
Allergic reactions
Pulmonary embolism
Inhalation of irritant gases
Clinicians should remember that hydrocarbon solutions are rarely pure. Aliphatic hydrocarbon solutions may
also contain varying amounts of aromatic or halogenated hydrocarbons that may affect the solution’s
inherent toxicity. Similarly, the solution may be a vehicle for other toxins, such as metals or metalloids,
camphor, aniline, or insecticides ( Table 97–4 ). The presence and quantity of these “co-ingestants,” which
may have serious systemic toxicity if absorbed, may alter the clinical presentation. Consequently, exact
identification of the ingested material and all its ingredients is essential.
Table 97-4 -- Differential Diagnosis: Co-ingestants Within Aliphatic Hydrocarbon “Vehicle” That Can
Produce Systemic Toxicity
Aromatic hydrocarbons
Metals
Camphor
Insecticides
Aniline
Nitrobenzene
Others (knowing the exact makeup or ingredients of the ingested material is critical)


LABORATORY STUDIES
Chest Radiograph
All symptomatic patients with suspicion of hydrocarbon aspiration should have a chest radiograph. Whereas
radiographic abnormalities may appear as early as 30 minutes after the exposure, they may be delayed for 6
to 12 hours and the initial radiograph may be deceptively clear. Consequently, in patients who are less
seriously ill, waiting 4 to 6 hours before performing the radiograph may yield more information. Maximal
radiographic changes occur from 2 to 72 hours after an exposure.[3][8][9] Whereas up to 75 per cent of
patients admitted for suspected hydrocarbon aspiration have chest radiographic abnormalities, chest film
abnormalities actually correlate poorly with clinical symptoms. The radiographic pneumonitis is typically
bilateral and involves multiple lobes, with the lower lobes affected most severely. Initially, abnormalities
appear as fine, punctate, mottled perihilar densities. Patchy ill-defined densities subsequently develop that
may coalesce to form larger areas of consolidation. Atelectasis, air trapping, and pleural effusions are seen
occasionally; pneumothorax and pneumomediastinum occur uncommonly.[9][11][29]
Asymptomatic patients may have abnormal chest films that clear without the patient ever developing
symptoms. Hence, a chest radiograph is not necessary on admission in the initially asymptomatic patient
with a history of a pure aliphatic hydrocarbon ingestion.
Other Tests
Patients with more than mild clinical symptoms require pulse oximetry and cardiac monitoring. Arterial blood
gas assessment is indicated in patients with low pulse oxygenation measurements or with moderate to
severe respiratory distress. A complete blood cell count, serum electrolyte determination, urinalysis, and
renal and liver function studies are rarely abnormal acutely but may need to be evaluated over 48 to 72
hours in toxic patients. (A rise in the white blood cell count—with or without fever—can occur in the absence
of infection.) Hypoglycemia would not be expected from the hydrocarbon exposure but should be sought in
any patient with an altered mental status.
A toxicologic analysis for hydrocarbons is usually not readily available and has no value in clinical
management. The toxicology laboratory may be used to determine the presence or effect of concomitant
ingestants or toxic additives (e.g., methemoglobin levels in cases of hydrocarbons containing nitrobenzene
or aniline, red blood cell, and plasma cholinesterase levels for solutions containing organophosphate
insecticides).[10]


TREATMENT
Inhalation
Patients exposed to gaseous aliphatic hydrocarbons should be removed from the contaminated
environment, have supplemental oxygen applied, and, if needed, intubated and provided with assisted
ventilation.
Ingestions
Pulmonary Aspiration
For ingestion of pure aliphatic hydrocarbon solutions the primary life threat is respiratory failure due to
aspiration, and treatment is primarily supportive ( Table 97–5 ). Supplemental oxygen is administered if
there is any evidence of respiratory distress. Intubation and ventilatory assistance are indicated for clinical or
arterial blood gas evidence of respiratory failure (PO 2 less than 50 mmHg or rising PCO2 levels). A chest
radiograph should be rapidly obtained after stabilization of the airway, breathing, and circulation to ascertain
the presence of aspiration or pneumothorax and, if indicated, to document correct endotracheal tube
placement.
Table 97-5 -- Treatment of Pure Aliphatic Hydrocarbon Ingestion

Respiratory Support *
Supplemental oxygen
Ventilatory support (assisted ventilation with endotracheal intubation, if needed)
Aerosolized selective ß2-adrenergic bronchodilators for bronchospasm (e.g., albuterol, metaproterenol)
CPAP/BiPAP/PEEP to maintain oxygenation
Extracorporeal membrane oxygenation if conventional measures are not successful
Contraindicated Therapies
Emesis/lavage
Activated charcoal
Prophylactic corticosteroids or antibiotics
Epinephrine
CPAP, continuous positive airway pressure; BiPAP, bi-level positive airway pressure; PEEP, positive end-
expiratory pressure.
* Mortality should be minimized with supportive care.
Altered surface tension due to the destruction of surfactant may lead to the collapse of alveoli and distal
airways.[14] Positive end-expiratory pressure (PEEP) (in the patient who is intubated) or continuous positive
airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) in those not intubated, may be
necessary to maintain adequate oxygenation.[38] When these modalities are instituted, the patient is
observed for pneumothorax, because patients with hydrocarbon pneumonitis are prone to develop
pneumatoceles and pneumothorax.
Extracorporeal membrane oxygenation has been used successfully in patients with ventilatory failure
unresponsive to aggressive airway management.[19]
Bronchospasm may be treated with aerosolized selective ß2-adrenergic agonist bronchodilators (e.g.,
albuterol, terbutaline, metaproterenol). Epinephrine or other nonselective agents with both a- and ß-
adrenergic activity are not recommended because of possible myocardial sensitization to catecholamines
and potential induction of ventricular dysrhythmias.
Corticosteroids or prophylactic antibiotics to prevent or ameliorate hydrocarbon pneumonitis have not been
proven to be efficacious and are not recommended.[6][31] Antibiotics may be indicated if fever persists for
more than 2 days or if there are signs of bacterial pneumonia.
Considerable controversy exists about the risks and benefits of gastric evacuation and the best method, if
any, of accomplishing this. One study[27] suggested that patients treated with syrup of ipecac had a lower
incidence and severity of pneumonia than patients treated with gastric lavage. However, this study was
criticized for using only the chest radiograph, and not clinical monitoring, to diagnose pneumonia and
changes in the patients’ status. Furthermore, there was no control group to assess whether no
decontamination was as good as or better than gastric emptying.[15]
Given that most serious toxicity occurs from aspiration,[8][36] there is little absorption from the gastrointestinal
tract,[26] and that even massive doses of petroleum distillates placed into the gastrointestinal tract of
laboratory animals do not result in pulmonary pathology,[5] there is a strong case against gastric evacuation
by any route that may potentially re-expose the patient’s glottic opening to aspiration.
However, if the hydrocarbon solution contains another toxin with potential systemic toxicity (e.g., pesticides,
aniline, metals, camphor, halogenated or aromatic hydrocarbons), gastric evacuation should be undertaken
if the potential amount of the additive would produce serious toxicity. If the potential toxicity warrants and the
patient’s mental status and airway are normal, emesis with syrup of ipecac may be used. Emesis is
contraindicated if the patient has had previous significant vomiting.
When gastrointestinal decontamination is indicated, gastric lavage should be undertaken with the use of
proper technique after endotracheal intubation with a cuffed endotracheal tube in (1) patients with an altered
mental status or who are at risk for a rapid alteration in mental status or seizure (e.g., ingestion of camphor);
(2) patients who have lost their gag reflex; or (3) patients who have significant toxicity (dysrhythmias,
respiratory signs) and in whom rapid removal of the toxin is indicated. The cuff should be inflated only during
the lavage for children aged 7 years or younger.
Activated charcoal is not recommended for a pure aliphatic hydrocarbon ingestion. Although activated
charcoal may decrease hydrocarbon absorption, [7] its efficacy is limited[21] and its administration may induce
emesis with further risk for aspiration.
Dermal Decontamination
Skin contamination should be treated by removal of hydrocarbon-contaminated clothing, with care to protect
hospital personnel from secondary exposure, followed by cleansing with soap or shampoo and copious
irrigation or soaking. The involved areas should then be given wound care appropriate to treatment of the
expected partial thickness burns.[18]
Other Measures
There are currently no toxin-specific antidotes. An initial trial of surfactant administration for hydrocarbon
pneumonitis in rabbits was found to be detrimental.[30]


DISPOSITION
Outpatient
Patients accidentally ingesting small quantities of aliphatic hydrocarbons can be safely observed at home
(with regional poison control center or health care provider monitoring) provided that the patient is
asymptomatic, has access to a follow-up mechanism, and there is no evidence of abuse or attempted
suicide.[2][25] Any patient who is dyspneic, coughing, or otherwise symptomatic should be immediately
referred to a physician in a health care facility for evaluation.
In the emergency department, patients should be observed at least 4 to 6 hours, although most patients with
aspiration will develop symptoms within 2 hours.[1][2] Initially, asymptomatic or mildly symptomatic patients
who may be discharged after this observation period include (1) initially asymptomatic patients who remain
so or (2) initially mildly symptomatic (or asymptomatic) patients with a mildly abnormal chest radiograph who
become asymptomatic over the time of observation. [1][25] Any discharged patient should be carefully
instructed to return immediately if any respiratory difficulties develop.
Inpatient
Admission is indicated for (1) development, continuation, or worsening of symptoms during emergency
department observation; (2) signs of toxicity such as hypoxia, dysrhythmia, fever, or dyspnea; (3) suicidal
intent (usually with large ingestion); (4) altered mental status; (5) a markedly abnormal chest radiograph; (6)
the presence of significant quantities of toxic additives; or (7) any patient in whom reliable home follow-up
cannot be ensured.[1]


SEQUELAE
Clinical pulmonary involvement reaches its maximum at approximately 24 hours and usually improves with
apparent complete resolution over 3 to 7 days. Case management should depend on the patient’s clinical
status because abnormalities on the chest radiograph may persist for several weeks to months. Mortality is
less than 1 per cent in most series.[33] Potential complications include pneumothorax, pneumomediastinum,
empyema, bacterial pneumonia, sepsis, and respiratory distress syndrome.
In addition to the acute exudative inflammation, a chronic proliferative process with alveolar thickening has
also been identified. [16] This process, initially asymptomatic, may result in pulmonary function abnormalities
years later.[17] Thus, these patients may be at increased risk for development of chronic lung disease.
A small percentage of patients develop pneumatoceles, sometimes with air-fluid levels, days to weeks after
aspiration. The pneumatoceles reportedly resolve without incident.[4]


SPECIAL SITUATIONS
Intramuscular injection or extravasation of an attempted intravenous injection of hydrocarbons can produce

sterile abscesses and an intense inflammatory response, resulting in a compartment syndrome, cellulitis,
sterile abscesses, or fasciitis.[35] High-pressure injection injuries (e.g., from a grease gun or spray painter)
are especially dangerous. Whereas entry sites appear negligible or benign, the hydrocarbon inoculum may
be widely disseminated along fascial planes. Intense tissue inflammation may occur owing to the fat
dissolving or necrotizing properties of the solvent or to coagulation of proteins, leading to severe tissue
necrosis, major infections, and potential loss of limbs. Immediate surgical consultation and operative
decompression with evacuation of the substance and cleansing of the tissues is essential because delay will
compromise outcome.[22]
Hot tar and asphalt burns present a serious problem. The solid tar or asphalt is difficult to remove but, if left
in place, will increase the risk of infection. Treatment includes rapid cooling of the tar or asphalt to solidify
the agent and dissipate the heat. Removal can then be accomplished by using a petroleum-based surface-
active solvent such as Neosporin ointment or cream or Tween 80. De-Solv-It (Orange-Sol, Inc., Chandler,
AZ) is a citrus and petroleum distillate with a hydrocarbon structure able to dissolve the tar or asphalt without
eye or mucous membrane irritation.[32] Once the offending substance is removed, the burn should be treated
according to standard burn management.


REFERENCES
1. Anas N, Namasonthi V, Ginsburg CM: Criteria for hospitalizing children who have ingested products
containing hydrocarbons. JAMA 1981; 246:840-843.
2. Arena JM: Hydrocarbon poisoning—Current management. Pediatr Ann 1987; 16:879-883.
3. Beamon RF, Siegel CJ, Landers G, et al: Hydrocarbon ingestion in children: A six-year retrospective
study. JACEP 1976; 5:771-775.
4. Bergeson PS, Hales SW, Lustgarten MD, et al: Pneumatoceles following hydrocarbon ingestion. Am J
Dis Child 1975; 129:49-54.
5. Bratton L, Haddow JE: Ingestion of charcoal lighter fluid. J Pediatr 1975; 87:633-637.
6. Brown J, Burke B, Dajani AS: Experimental kerosene pneumonia: Evaluation of some therapeutic
regimens. J Pediatr 1974; 84:396-401.
7. Decker WJ, Corby DG, Hilburn RE, et al: Adsorption of solvents by activated charcoal, polymers, and
mineral sorbents. Vet Hum Toxicol 1981; 23(suppl 1):44-46.
8. Dice WH, Ward G, Kelley J, et al: Pulmonary toxicity following gastrointestinal ingestion of kerosene.
Ann Emerg Med 1982; 11:138-142.
9. Eade NR, Taussig LM, Marks MI: Hydrocarbon pneumonitis. Pediatrics 1974; 54:351-357.
10. Edminister SC, Bayer MJ: Recreational gasoline sniffing: Acute gasoline intoxication and latent
organolead poisoning: Case reports and literature review. J Emerg Med 1985; 3:365-370.
11. Foley JC, Dreyer NB, Soule Jr AB, et al: Kerosene poisoning in young children.
Radiology 1954; 62:817-829.
12. Gehlbach SH, Wall JB: Childhood poisoning: A community hospital experience. South Med
J 1977; 70:674-676.
13. Gerarde HW: Toxicological studies on hydrocarbons: The aspiration hazard of hydrocarbons and
hydrocarbon mixtures. Arch Environ Health 1963; 6:329-341.
14. Giammona ST: Effects of furniture polish on pulmonary surfactant. Am J Dis Child 1967; 113:658-663.
15. Goldfrank LR: Hydrocarbons. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al ed. Goldfrank’s
Toxicologic Emergencies, 5th ed. Norwalk, CT: Appleton & Lange; 1994:1231-1244.
16. Gross P, McNerney JM, Babyak MA: Kerosene pneumonitis: An experimental study with small doses.
Am Rev Respir Dis 1963; 88:656-663.
17. Gurwitz D, Kattan M, Levison H, et al: Pulmonary function abnormalities in asymptomatic children after
hydrocarbon pneumonitis. Pediatrics 1978; 62:789-794.
18. Hansbrough JF, Zapata-Sirvent R, Dominic W, et al: Hydrocarbon contact injuries. J
Trauma 1985; 25:250-252.
19. Jaeger RW, Scalzo AS, Thompson MW, et al: ECMO in hydrocarbon aspiration [abstract]. Vet Hum
Toxicol 1987; 29:485.
20. Klein BL, Simon JE: Hydrocarbon poisonings. Pediatr Clin North Am 1986; 33:411-419.
21. Laass W: Therapy of acute oral poisonings by organic solvents: Treatment by activated charcoal in
combination with laxatives. Arch Toxicol 1980; 4(suppl):406-409.
22. Lewis RC: High-compression injection injuries to the hand. Emerg Med Clin North Am 1985; 3:373-
381.
23. Linden CH: Volatile substances of abuse. Emerg Med Clin North Am 1990; 8(3):559-578.
24. Litovitz TL, Klein-Schwartz W, Dyerks KS, et al: 1997 annual report of the American Association of
25. Machado B, Cross K, Snodgrass WR: Accidental hydrocarbon ingestion cases telephoned to a regional
poison center. Ann Emerg Med 1988; 17:804-807.
26. Mann MD, Pirie DJ, Wolfsdorf J: Kerosene absorption in primates. J Pediatr 1977; 91:495-498.
27. Ng RC, Darwish H, Stewart DA: Emergency treatment of petroleum distillate and turpentine ingestion.
Can Med Assoc J 1974; 111:537-538.
28. Press E, Adams WC, Chittenden RF, et al: Report on the subcommittee on accidental poisoning: Co-
operative kerosene poisoning study. Pediatrics 1962; 29:648-674.
29. Reed ES, Leiken S, Kerman HD: Kerosene intoxication. Am J Dis Child 1950; 79:623-632.
30. Shih RD, Mercurio M, Morasco R, et al: Artificial surfactant administration in an animal model of
hydrocarbon induced pulmonary toxicity [abstract]. Clin Toxicol 1996; 34:139.
31. Steele RW, Conklin RH, Mark HM: Corticosteroids and antibiotics for the treatment of fulminant
hydrocarbon aspiration. JAMA 1972; 219:1434-1437.
32. Stratta RJ, Saffle JR, Kravitz M, et al: Management of tar and asphalt injuries. Am J
Surg 1983; 146:766-769.
33. Tinker TD: Hydrocarbon ingestion in children: Its sequelae and management. J Okla State Med
Assoc 1986; 79:95-101.
34. Truemper E, Reyes De La Rocha S, Atkinson SD: Pediatr Emerg Care 1987; 3:187-193.
35. Wason S, Greiner PT: Intravenous hydrocarbon abuse. Am J Emerg Med 1986; 4:543-544.
36. Wolfe BM, Brodeur AE, Shields JB: The role of gastrointestinal absorption in producing pneumonitis in
dogs. J Pediatr 1970; 76:867-873.
37. Wolfsdorf J: Kerosene intoxication: An experimental approach to the etiology of the CNS manifestations
in primates. J Pediatr 1976; 88:1037-1040.
38. Zucker AR, Berger S, Wood LDH: Management of kerosene-induced pulmonary injury. Crit Care
Med 1986; 14:303-304.


Chapter 98 – Halogenated Hydrocarbons
JOHN F. TUCKER RICHARD T. TOVAR
Essentials
• Acute toxicity
° Central nervous system intoxication or
depression
° Cardiac dysrhythmias or sudden death
° Hepatic or renal damage
° Aspiration with chemical pneumonitis
• Smell of solvent present on breath, clothing, or hair
INTRODUCTION
Hydrocarbons are substances made exclusively from carbon and hydrogen atoms. Halogenated aliphatic
hydrocarbons, also known as alkyl halides, are nonaromatic hydrocarbons that have at least one hydrogen
atom replaced by a halogen atom (bromine, chlorine, fluorine, or iodine). These substances are commonly
encountered as solvents, degreasing agents, dry cleaning compounds, paint removers, and vehicles for
paints and varnishes. Commercial products containing halogenated hydrocarbons include typewriter
correction fluid, waterproofing aerosols, and adhesive removers. Most are liquids at room temperature, but
they are extremely volatile. The typical initial symptoms experienced with exposure are those of central
nervous system (CNS) depression. The CNS effects progress through levels of general anesthesia as the
level of exposure increases. [22] In fact, one commonly used anesthetic gas, halothane, is an alkyl
halide.[24][34]
Due to their high volatility, exposures are usually by inhalation. Toxic exposures to these agents generally
occur from industrial exposures or exposure resulting from substance abuse.[2][3][15] Cutaneous and
gastrointestinal exposures are much less common. Development of defined industrial-exposure limits with
close monitoring has made acute industrial exposures uncommon except when workers unknowingly enter
tanks containing these substances or with spills or misuse of these materials.
These compounds may be intentionally inhaled to produce a “high,” or euphoria. They are especially popular
with adolescent males, who use them as inexpensive and legal substitutes for other intoxicants.[19][24][46]


Toxicokinetics
Halogenated hydrocarbon vapors are well absorbed through the lungs and rapidly distributed to the brain
and other organs of high fat content.[19] The amount of halogenated hydrocarbon absorbed is proportional to
its blood:gas partition coefficient. This coefficient actually measures the speed at which the toxin enters the
bloodstream via inspired air. The higher this ratio, the faster the onset of clinical effect.[33] As a result, a high
concentration in the air produces a more rapid clinical neurologic effect. Halothane has a measured
blood:gas coefficient of 2.57 at 37°C and produces clinical effects in minutes.[33][34] Halogenated solvents
such as trichloroethylene exhibit similar properties. Trichloroethylene at high ambient air concentrations can
exhibit a blood:gas coefficient up to 15, producing neurologic symptoms within seconds.[7]
The onset of effects with inhalation of these volatile substances can be as rapid as if they were injected
intravenously.[46] However, peak effects may not occur for more than 30 minutes because of relatively
slower diffusion into tissues.[24] The dose necessary for producing toxic effects by inhalation is typically
small, as pulmonary absorption circumvents the first-pass hepatic extraction and metabolism that occur
following ingestion.
Most of these agents cause dose-related CNS depression. Because the inhibition of cortical function
generally precedes the inhibition of brainstem activity, initial or low-dose effects may include disinhibition
with euphoria or hyperactivity. The effects are generally similar to, but more pronounced than, those
occurring with ethanol. As the dose increases, a state of narcosis resembling general anesthesia ensues,
which may result in coma, seizures, or respiratory arrest, with subsequent death due to asphyxia.
The proposed mechanism for halogenated hydrocarbon–induced CNS toxicity is by direct damage to nerve
cell membranes, thereby altering neurotransmission.[8][13] This alteration may be brief or permanent,
depending on duration of toxin concentration and duration of exposure.[31] Animal studies demonstrate
minimal histologic damage to nerve cells with short-term exposure, whereas studies with long-term
exposures to halogenated hydrocarbons demonstrated inconclusive results with respect to histologic
damage.[21]
Cardiac
Halogenated hydrocarbons “sensitize” the myocardium to the effects of catecholamines,[8][36][38] which may
lead to life-threatening dysrhythmias. Exposure actually stabilizes the myocardial cell membrane to
depolarization.[18] Because of the variability of response of individual cells and the complex way in which
myocardial electrical impulses are propagated, this “stability” blocks impulse transmission and leads to an
increased risk of dysrhythmia. In an animal model, after solvents are inhaled, the dose of epinephrine
required to produce ventricular tachycardia or fibrillation is reduced. In fact, life-threatening dysrhythmias
may be induced with normal physiologic levels of catecholamines in the “sensitized” heart.[38]
Catecholamine release may be augmented by the euphoria or excitement associated with the early CNS
effects of the solvents or by physical activity, further increasing the risk of dysrhythmia and sudden death.[39]
Evidence also indicates that “sensitization” and risk of dysrhythmia is greater in the presence of hypoxia and
hypercarbia (as experienced with breathing a nonoxygenated gaseous product or rebreathing from a
bag).[35][36] Previous use of a product does not appear to protect the individual from dysrhythmias.
Other proposed mechanisms of sudden death after exposure to these agents include anoxia (suffocation) or
depression of cardiac sinus node activity leading to bradycardia with escape ventricular dysrhythmias or
cardiac arrest.[38]
Pulmonary
The most common pulmonary effect is that of simple asphyxia, owing to the fact that these highly volatile
substances decrease the partial pressure of oxygen in inhaled air. Symptoms of hypoxia may develop when
the FIO2 of inspired air falls below 17 per cent and loss of consciousness is associated with inspired levels of
oxygen less than 10 per cent. Furthermore, at high concentrations, hydrocarbon vapors may cause direct
pulmonary injury (chemical pneumonitis), further increasing hypoxemia.[15]
Following ingestion, the risk of aspiration and subsequent aspiration pneumonitis is less than that associated
with many aliphatic hydrocarbons, owing to the higher viscosity of halogenated hydrocarbons, but it can still
occur.
Hepatic
Halogenated hydrocarbons can produce significant hepatic damage, including fatty infiltration, centrilobular
necrosis, and cirrhosis.[1] The mechanisms of toxicity are not well delineated. [1][5][10][11][21][26][44] There is
significant variation in the propensity of various halogenated hydrocarbons to cause liver damage; however,
some substances exhibit more reliable hepatotoxicity than others ( Table 98–1 ). There is also significant
variation between individuals in the propensity of a given substance to cause hepatic
dysfunction.[1][5][9][10][18][21][33]
Table 98-1 -- Relative Hepatotoxicity of Halogenated Hydrocarbons *

Chemical Name Common Name
1,1,2,2-Tetrachloroethane Tetrachloroethane
Tetrachloromethane Carbon tetrachloride
1,1,2-Trichloroethane Tetrachloroethane
Trichloromethane Chloroform
Tetrachloroethylene Perchloroethylene
Trichloroethylene TCE
Dichloromethane Methylene chloride
1,1,1-Trichloroethane Methyl chloroform
* From most to least hepatotoxic.
Carbon tetrachloride (CCl4) produces toxicity by production of reactive free radicals. At concentrations
present in the blood of severely exposed animals, there is no demonstrable direct effect of carbon
tetrachloride itself on the cell membrane. Carbon tetrachloride is microsomally reduced by mixed function
oxidases (MFO) to the reactive trichloromethyl radical (•CCl3). At low oxygen tensions, the •CCl3 forms
•CCl3O2. •CCl3O2 causes lipid peroxidation that initially affects the cellular endoplasmic reticulum, followed
by mitochondrial and diffuse cellular damage. This results in cellular swelling and loss of membrane
integrity. High oxygen tension decreases the amount of •CCl3 formed, owing to inhibition of the MFO by
oxygen, and is protective.
Other small aliphatic halogenated hydrocarbons are also reduced by MFO to CCl4. The toxicity of these
molecules depends on their ability to form free radicals, since the hepatotoxic effect is inversely related to
the ease of dissociation of the carbon-halogen bond.[10]
Halothane has a unique mechanism of hepatotoxicity. The hepatic cytochrome P450 system biotransforms
the halothane into free radicals known as trifluoroacetyl halide. These free radicals bind covalently to liver
proteins and initiate an immune complex–mediated hepatitis.[29][33] Histologically, this form of hepatitis
presents as a centrilobular necrosis.[34] The likelihood of hepatitis increases with repeated use of this
anesthetic. Researchers have postulated that the etiology of halothane-induced hepatitis is multifactorial and
involves immune complex formation, vasoconstriction, and direct chemical toxic mechanisms.[13][34]
Renal
Renal toxicity due to halogenated hydrocarbons is less dramatic than hepatotoxicity. Animal studies report
histologic changes ranging from mild edema (most common) to complete necrosis of the tubular epithelium.
The exact mechanism of toxicity is undetermined. [21]
Dermal
Skin toxicity is primarily that of extreme drying and cracking of the skin after repeated exposures to those
substances with “degreasing” qualities. However, significant burns have been reported from an acute
exposure.[6] Systemic toxicity does not typically result from dermal exposure, with the exception of carbon
tetrachloride, which can be transdermally absorbed in quantities sufficient to cause systemic toxicity.[27]


Toxicity usually occurs in one of three clinical settings: (1) acute massive inhalation (industrial accidents,
anesthesia, or recreational abuse), (2) acute ingestions (accidentally from substances being stored in
mislabeled containers or intentionally from suicide attempts), or (3) chronic low-level exposures (industrial
use).
Acute Toxicity
Intentional inhalation of vapors to produce euphoria or a “high” is performed in several ways. “Sniffing”
involves breathing fumes from an open container. “Huffing” involves pouring the hydrocarbon onto a cloth
and placing it over the face to inhale the volatilized agent. “Bagging” involves pouring the material into a bag,
shaking the bag to volatilize the agent, and then placing the bag over the mouth and nose and inhaling
deeply. “Bagging” produces the highest concentration of inhaled fumes. Reportedly, these activities are
becoming increasingly common, especially among adolescent males who use these substances as readily
available, inexpensive, and legal substitutes for other intoxicants.[19][25] Accordingly, the death rate from the
use of these agents has steadily risen.[2][3][25] Halogenated hydrocarbon inhalation is a common cause of
toxicologic death in adolescents. [25]
Following acute inhalation, CNS disturbances occur that are characterized by rapid onset of intoxication,
followed by rapid recovery. [28] The initial stages of intoxication are similar to those of acute alcohol
intoxication, with an early excitatory phase during which individuals may experience euphoria, disinhibition, a
feeling of invulnerability, and incoordination and may have a staggering gait. The excitatory phase is
followed by CNS depression, resulting in stupor, coma (possibly associated with seizures), respiratory
depression, and death as the exposure increases ( Table 98–2 ). Other characteristic features include
dizziness, flushing, coughing, sneezing, and increased salivation. Differences from typical ethanol
intoxication include a rapid rate of intoxication and recovery, an early disorientation to space and time, and
development of visual and auditory hallucinations that are often pleasant but have also been described as
“frightening.”[46] Increased salivation may signify oropharyngeal burns and edema, which can lead to airway
compromise[2] (see Fig. 2–1 in Chapter 2 ).

Acute Inhalation
Rapid state of intoxication (with rapid recovery)
Early excitatory phase
Disinhibition
Euphoria
Disorientation
Possible hallucinations
Progressive CNS depression
Stupor
Coma
Seizures
Palpitation
Syncope
Sudden death
Ingestion
Abdominal cramping with nausea, vomiting, or diarrhea
Drowsiness
Hepatic or renal toxicity (hours to days)
Dermal Exposure
Skin drying or cracking
Redness around the mouth or on the hands (“Huffer’s rash”)
Cutaneous flush after trichloroethylene exposure and consumption of ethanol (“degreaser’s flush”)
Chronic Toxicity
CNS dysfunction
Hepatic or renal dysfunction (usually mild and reversible)
While the initial presenting symptoms usually relate to altered CNS function, the greatest immediate life-
threatening effect following exposure to halogenated hydrocarbons is cardiac dysrhythmia. Sudden death
typically occurs when an intoxicated patient increases endogenous catecholamines through physical
exertion, thus provoking a dysrhythmia in the myocardium “sensitized” by the halogenated hydrocarbon. A
common scenario is that of the person who, shortly after inhalation, becomes excited, runs about aimlessly,
and suddenly collapses with cardiopulmonary arrest due to ventricular dysrhythmia.[3] Furthermore,
intoxication associated with these substances may lead to impaired judgment, disorientation, and irrational
behavior culminating in traumatic injury. If a history of preceding exposure to these agents is not sought, the
underlying cause of the traumatic event may go undetermined. [3][38]
Cyanosis may also be present owing to asphyxia, CNS depression leading to respiratory depression, or
pneumonitis. Syncope may result from cardiac dysrhythmias, hypoxemia, carbon monoxide poisoning
secondary to methylene chloride (dichloromethane) metabolism, or hypotension. Palpitations with or without
tachycardia, bradycardia, or other cardiac dysrhythmias may also occur.[45] An odor characteristic of
hydrocarbons (sweet, chloroform-like, or pungent) may be noted on the patient’s breath, hair, or clothing.
Following oral ingestion, serious toxicity and death can occur, although death occurs less commonly than it
does with inhalation exposures. The initial signs and symptoms are gastrointestinal, with nausea, vomiting,
abdominal pain, and diarrhea. Central nervous system sedation may follow. A secondary phase of hepatic
damage can occur after 2 to 4 days, with liver tenderness, hepatomegaly, jaundice, and variable elevation of
liver function tests.[1]
Renal damage usually develops concurrently and is characterized by oliguria, proteinuria, and azotemia.
With carbon tetrachloride toxicity, the oliguric phase lasts approximately 1 week and is followed by a diuretic
phase lasting approximately 8 days. [27][30]
A “huffer’s rash”—an area of erythema where the bag has been placed on the mouth or held by the
hands—can be seen in the patient who has been intentionally abusing substances.[38] Otherwise, dermal
toxicity following an acute exposure is unusual, but an acute severe burn has been reported following an
exposure to trichloroethylene or its degradation products.[6] The lipid solubility of halogenated hydrocarbons
permits them to penetrate intact skin, but not usually in quantities sufficient to cause systemic toxicity. An
exception is carbon tetrachloride, topical exposure of which may result in hepatic or, more commonly, renal
toxicity.[32]
Chronic Toxicity
Chronic abusers can develop a neuropsychiatric symptom complex with tremors, giddiness, ethanol
intolerance, and a neurasthenic syndrome with anxiety. Bradycardia, increased lacrimation, reddening of the
skin, decreased sensitivity of the hands, and insomnia may also be seen.[5] Other symptoms occurring with
chronic intentional abuse include cognitive impairment, dementia, and cerebellar ataxia.[17][19]
Hepatic or renal changes are usually mild and reversible with removal of the offending agent. The possibility
of carcinogenesis varies between substances and species, but should be considered.[4][11]
Following repeated exposures, the skin may develop a generalized dermatitis due to the degreasing nature
of these substances.
In young children, especially toddlers, exposure usually occurs by accidental halogenated hydrocarbon
ingestion. However, in older children, especially teenagers, exposure is usually due to recreational abuse.
The clinical presentation for children is not expected to be significantly different from that of the adult patient.


Halogenated hydrocarbons produce clinical effects similar to those of ethanol. The differential includes
substances that can produce acute intoxication, with altered mental status, agitation, incoordination,
disorientation, or hallucinations progressing to CNS depression and coma ( Table 98–3 ). Other common
intoxicants that may cause a similar presentation include isopropyl alcohol, carbon monoxide, ethylene and
diethylene glycol, opioids, cyclic antidepressants, cocaine, amphetamines, phencyclidine, anticholinergic
agents, and hallucinogens. Halogenated hydrocarbons are not detected by routinely available technology.
However, rapid recovery from the intoxicated state is unusual with the other intoxicants. Additionally, the
patient often emits the smell of hydrocarbon on his or her breath, hair, clothing, or hands.
Table 98-3 -- Differential Diagnosis of Intoxication for Halogenated Hydrocarbons *

Toxicologic
Alcohols (ethanol, ethylene and diethylene glycol, isopropanol)
Amphetamines
Anticholinergics
Carbon monoxide
Cocaine
Hallucinogens
Marijuana (THC)
Opioids
Phencyclidine
Sedative-hypnotics
Withdrawal—alcohols, sedative-hypnotics, barbiturates
Nontoxocologic
CNS infection
CNS trauma or hemorrhage
Delirium tremens
Hypercalcemia
Hypoglycemia
Wernicke’s encephalopathy
* Exposures to other families of hydrocarbons (aliphatic and aromatic) or other toxins in solution with the halogenated hydrocarbon must also
be considered.
Nontoxicologic disorders to be considered include hypoglycemia, hypercalcemia, CNS infections, CNS

trauma or hemorrhage, and psychiatric disorders.
Hydrocarbon solutions are rarely pure and usually contain a mixture of various hydrocarbons. Varying
amounts of aromatic or aliphatic hydrocarbons can affect the solution’s inherent toxicity. Consequently,
identification of the various hydrocarbons in the material ingested or inhaled may assist in determining the
management course.


LABORATORY STUDIES
Diagnosis of halogenated hydrocarbon toxicity is usually not made by laboratory studies, but rather the
history and clinical presentation. Many of the common toxicologic and nontoxicologic etiologies in the list of
possibilities in the differential diagnosis can be screened by a rapidly available emergency department
testing, including common drugs of abuse, serum ethanol, electrolytes, serum glucose, and
carboxyhemoglobin. Other laboratory studies are dictated by the clinical scenario and can include
electrolytes, electrocardiography (ECG), arterial blood gas, and computed tomography (CT) scan of the
head and lumbar puncture in patients with altered mental status that does not rapidly improve.
Creatinine, blood urea nitrogen (BUN), urinalysis, and liver function testing should be obtained at admission
and monitored over the ensuing 2 to 7 days for the development of hepatic and renal failure.[5][27]
Additionally, monitoring for subacute (e.g., industrial exposures) development of hepatic and renal toxicity
largely depends on laboratory studies.
If pulmonary symptoms are present at the time of presentation, a chest radiograph should be obtained
initially and 4 to 6 hours after an acute exposure.[2][3][37][46] The risk of aspiration is less than that with
aliphatic hydrocarbons but is still a significant danger following ingestion. Pulmonary edema may develop
after massive inhalation exposure.
Abdominal radiographs may demonstrate radiopaque material in the intestinal tract, indicating the ingestion
of carbon tetrachloride or other chlorinated hydrocarbons.[12][27] The radiopacity correlates with the ratio of
the number of chlorine atoms to molecular weight.[12] This finding may be useful in assessing the
effectiveness of gastric aspiration or lavage.
Reference laboratories can identify many of the specific substances with the use of various gas
chromatographic techniques, such as flame ionization or mass spectrophotometry and solvent extraction,
absorption sampling, electron-capture detection, or headspace sampling.[15][16][24][28][35] Qualitative serum
analysis can confirm an acute exposure.[24][28][35] Quantitative analysis is unnecessary, since there is no
correlation between blood concentrations and clinical toxicity owing to the rapid initial tissue distribution and
elimination. Breath samples can also be analyzed with the use of infrared spectrography or gas
chromatography.[20][41] Detection of volatile substances is influenced by dose, time of sampling since
exposure, and precautions taken in the collection and storage of the specimen.[16][35] Samples for toxicologic
examination should be obtained, properly stored, and analyzed in all cases of sudden unexpected or
traumatic death in teenagers, as postmortem features in deaths due to inhalant abuse are usually minimal or
absent.[16][38]


TREATMENT
Treatment consists primarily of supportive care and symptomatic management ( Table 98–4 ). There is no
specific antidote for the halogenated hydrocarbons. The most immediate concern is airway management.
The patient presenting with respiratory arrest, respiratory depression, or oropharyngeal burns with edema
may necessitate emergent aggressive airway management with endotracheal intubation.

Move to fresh air and apply supplemental oxygen following inhalation exposures
Aggressive airway management, if indicated
Gastric decontamination with nasogastric-tube aspiration if ingestion is recent
Treat ventricular dysrhythmias with lidocaine, magnesium, ss-adrenergic receptor antagonists or amiodarone;
avoid catecholamines and bretylium
Remove contaminated clothing and decontaminate skin with copious water irrigation
Hemodialysis for renal failure
N-Acetylcysteine to prevent hepatic damage should be considered following carbon tetrachloride exposures
Inhalation Exposure
Following inhalation exposure, the victim should be moved to fresh air and given assisted ventilation with
supplemental oxygen as needed. The patient should be monitored for potential cardiac dysrhythmias.
Hypoxia and electrolyte disturbances (e.g., hypokalemia) should be corrected. Catecholamines should be
avoided, as their use may promote life-threatening ventricular dysrhythmias in the “sensitized” myocardium.
Lidocaine and the other class 1-B antidysrhythmic agents have been recommended for the treatment of
halogenated hydrocarbon dysrhythmias. Other recommended treatments for ventricular dysrhythmias
include magnesium, ß-adrenergic receptor antagonists, and amiodarone.[18][36][38][39][45] Theoretically,
bretyllium would be contraindicated in the pharmacologic treatment of ventricular dysrhythmias because it
promotes the release of endogenous catecholamines.[38] In animals experimentally exposed to a volatile
substance and epinephrine, resuscitation was unsuccessful once dysrhythmias developed, even with the
immediate cessation of inhalation of the volatile substance together with adequate oxygenation and full
resuscitative efforts to restore cardiac function.[38]
Supportive care is indicated for renal or hepatic toxicity. Hemodialysis is indicated for renal failure; it is
ineffective in removing these fat-soluble substances from the blood.
Prevention of further episodes of abuse, emphasizing education and counseling, with regulatory and
voluntary restraints on the availability of products, is of paramount importance.
Ingestion
Following an ingestion, decontamination may be advisable owing to significant toxicity of many of these
substances. The amount of ingested material, the time since ingestion, and the specific halogenated
hydrocarbon involved must be considered. Prior to decontamination, the patient should have a protected
airway if necessary, be well oxygenated, and have intravenous access established. Evacuation of retrievable
material via nasogastric tube aspiration is safe. Because of the rapid absorption of these materials,
gastrointestinal decontamination has the greatest chance of retrieving ingested material if it is performed as
soon as possible after ingestion. However, with massive quantities or highly toxic materials, nasogastric
aspiration may be worthwhile even several hours after the ingestion.
Ipecac is contraindicated, because of possible rapid changes in mental status and the risk of aspiration.
Halogenated hydrocarbons are not water-soluble, and therefore a low yield of toxin removal is expected with
lavage. Activated charcoal is not indicated for halogenated hydrocarbon ingestion[23] but may be considered
in the presence of a toxic coingestant that would be adsorbed by the charcoal.
Dermal Exposure
Contaminated clothing should be removed, and exposed skin areas washed with copious soap and water.


DISPOSITION
Individuals with an acute toxic inhalation of a halogenated hydrocarbon (whether accidentally or following an
episode of intentional abuse) can be medically discharged following a return to normal mental status. This
assumes adequate follow-up for counseling regarding the dangers of such exposures and provisions for
necessary protection (voluntary or imposed) against future exposures. Follow-up studies for delayed hepatic
and/or renal toxicity may be indicated.
Patients who demonstrate prolonged mental status changes, ingest halogenated hydrocarbons, or have
evidence of pulmonary toxicity should be admitted. Any exposure to carbon tetrachloride (inhalation,
ingestion, or dermal) warrants admission, with expectant management for hepatic and renal compromise.


SEQUELAE
Following an acute single inhalation exposure, patients usually recover rapidly, without sequelae, unless
they sustain hypoxic damage to the CNS. In surviving patients who develop hepatic or renal toxicity, function
generally returns to normal with appropriate supportive care within days to weeks.[3][5] In severe cases,
dialysis may be necessary until renal function returns.[14]
Despite the well-known acute toxicity and widespread use of many of these substances, epidemiologic
evidence is limited concerning carcinogenicity, teratogenicity, and long-term target organ toxicity, especially
with chronic exposures.[4][11] Current evidence suggests that many halogenated hydrocarbons possess
mutagenic and carcinogenic properties. However, studies with sufficiently large patient populations with well-
defined exposures to specific agents are not currently available to demonstrate increased cancer risk. The
exception is lung cancers among workers exposed to chloromethyl ethers.[4] The low power of currently
available studies does not permit investigators to accurately predict risk.


SPECIAL SITUATIONS
Methylene Chloride (Dichloromethane)
Carbon monoxide is produced by the metabolism of methylene chloride, resulting in elevated

carboxyhemoglobin (COHb) levels following methylene chloride exposures.[40] The elimination half-life of
this carboxyhemoglobin has been shown to be more prolonged than that of carboxyhemoglobin generated
from CO inhalation.[43] The maximum COHb level reached in patients with a methylene chloride exposure
has been reported up to 50 per cent.[40][43] Individuals with underlying respiratory or advanced
cardiovascular disease can be adversely affected. Following a methylene chloride exposure, a COHb level
and ECG should be obtained with administration of high-flow supplemental oxygen to help promote
elimination of the CO and to treat the associated tissue hypoxia. Because the metabolic conversion of
methylene chloride to CO is considerably slower than if exposure occurred by direct inhalation of CO, serial
CO levels should be obtained until a downward trend is seen, along with no evidence of cardiac or CNS
dysfunction. Methylene chloride also produces the CNS and cardiovascular toxicities typical of halogenated
hydrocarbons, which is usually of more clinical significance than the metabolic conversion to CO.
Trichloroethylene (TCE)
Chronic exposure to trichloroethylene in metal degreasers has resulted in a neuropsychiatric symptom

complex consisting of tremors, giddiness, anxiety states, decreased sensitivity of the hands, and insomnia.
An associated ethanol intolerance also causes reddening of the skin, termed “degreaser’s flush.”[7] This
flushing lasts minutes to hours. The precise pathophysiology of the vasodilation is postulated to be
secondary to a direct effect of the cytochrome P450 trichloromethylene metabolite chloral hydrate, which is
further metabolized to trichloroacetic acid.[42]
Carbon Tetrachloride (Tetrachloromethane)
While exposures to CCl4 are decreasing in frequency, [25][27] the mechanism of its toxicity is the most
thoroughly studied of the halogenated hydrocarbons.[27][32][37] The toxicity appears to be secondary to free
radical production during metabolism (see Pathophysiology section). N-acetylcysteine (NAC) has been used,
and is postulated to prevent development of hepatic damage in patients with CCl4 poisoning. While not of
proven benefit in rigorous clinical trials, NAC should be considered early in acute CCl4 poisonings.[28][37]
Intravenous dosing has been used,[30][37] but is not approved in the United States. Consult a regional poison
center for recommendations. Because CCl4 has a longer terminal half-life than that of acetaminophen, the
duration of treatment may need to be extended, ideally guided by CCl4 levels, if available.[28] The use of
vitamin E (with or without selenium), early administration of hyperbaric oxygen,[10] or use of prostaglandins is
without current scientific proof of benefit. [27]
Anesthetic Gases
The risk of spontaneous abortion may be increased in patients exposed to halogenated hydrocarbon
anesthetic gases. A meta-analysis supported the contention that, prior to the introduction of in-line gas-
scavenging machines in the operating room, there was a statistically significant increase in the rate of
spontaneous abortions among operating room personnel.[9]


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8. Bass M: Sudden sniffing death. JAMA 1970; 212:2075.
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11. Condie LW: Target organ toxicology of halocarbons commonly found contaminating drinking water. Sci
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13. England A, Jones RM: Inhaled anesthetic agents from ether to halothane. Br J Hosp
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14. Fogel RD, Davidman M, Polesak MH: Carbon tetrachloride poisoning treated with hemodialysis and
total parenteral nutrition. Can Med Assoc J 1984; 128:560.
15. Garriott J, Petty CS: Death from inhalant abuse: Toxicological and pathological evaluation of 34 cases.
16. Gill R, Hatchett SE, Ossleton MD, et al: Sample handling and storage for the quantitative analysis of
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17. Goodheart RS, Dunne JW: Petrol sniffer’s encephalopathy: A study of 25 patients. Med J
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Chapter 99 – Aromatic Hydrocarbons
RIVKA HOROWITZ
Aromatic hydrocarbons (compounds containing one or more benzene ring structures) are constituents of
many common household and industrial products. Although occupational exposure occurs, toxicity from
aromatic hydrocarbons typically results from intentional inhalation abuse and usually involves toluene
(methylbenzene) and xylene (dimethylbenzene) ( Fig. 99–1 ). The prompt euphoria that results from
inhalation of these readily available solvents has made the abuse of aromatic hydrocarbons, especially by
children and adolescents, a significant worldwide problem. The clinical manifestations of acute and habitual
toluene abuse may include serious, and at times, life-threatening metabolic, central nervous system, renal,
and cardiovascular effects. It is often difficult to isolate the unique effects of a single aromatic hydrocarbon
because mixtures of these substances (and their aliphatic counterparts) are typically present in abused
products such as paint thinners, spray paints, and glues. Furthermore, interpretation of case reports are
confounded by the lack of information on the precise composition of the inhalants used. Nevertheless, most
of the literature describing aromatic hydrocarbon toxicity pertains to toluene, the major constituent in many of
the commonly abused substances. Acute xylene exposure results in respiratory tract irritation and dyspnea
at relatively low concentrations, but other systemic effects are less well defined, since isolated xylene
exposures are uncommon. The third clinically important aromatic hydrocarbon is benzene. Chronic benzene
exposure, seen primarily in the occupational setting, may produce hematologic disorders such as
pancytopenia, aplastic anemia, acute myelogenous leukemia, and lymphoproliferative disorders.[34][62]
Figure 99-1 Metabolism of toluene and xylene.
BENZENE
Essentials
• Altered mental status ranging from euphoria and confusion to central nervous system
depression
• Bone marrow toxicity
• Aplastic anemia, leukemia (AML)
• Cardiac dysrhythmias
• Respiratory complications: hemorrhagic pneumonitis, pulmonary edema
Introduction
Benzene has been historically encountered in the shoe making, glue manufacture, and petroleum industries.
Epidemiologic studies from industries that use or make benzene have confirmed the leukemogenic nature of
benzene[52] and have provided the basis for its classification as a human carcinogen.[18][32] Stringent federal
government regulations have greatly reduced permissible exposure levels and have resulted in reduction of
excess risk of benzene-induced myelotoxicity in the workplace.[80] Acute benzene exposure results in central
nervous system toxicity including euphoria, dizziness, confusion, headache, delirium, and lethargy. Death
has been reported following massive industrial exposure and may have been the result of asphyxiation,
cardiovascular collapse, fatal dysrhythmia.[27]
Nonoccupational exposure to benzene occurs principally from automobile emissions and cigarette
smoke.[2][73] The current benzene content in gasoline ranges between 1.5 and 6 per cent.[43] Its use as a
solvent in household and automotive products has markedly decreased since the carcinogenicity of benzene
was recognized, although trace amounts can still be found in solvents and wax products.[72] Approximately
50 µg of benzene is reported to be contained in the typical cigarette. The clinical significance of low-level
environmental exposure to benzene remains to be studied.
Toxicokinetics
Absorption of benzene occurs rapidly by ingestion, inhalation, and dermal routes. In animal studies, nearly
100 per cent of benzene is absorbed orally[5] but 20–40 per cent is absorbed dermally. [9][65] Nearly 50 per
cent of inhaled benzene is absorbed through the lung.[5] Lipophilic properties permit passage through
alveolar membranes and accumulation in the brain,[10][36] resulting in rapid and potent euphoria. Benzene is
converted by the liver into water-soluble metabolites that are conjugated and excreted through the kidney in
the urine. Up to 80 per cent of metabolites are phenol, with the remaining being either catecol,
hydroquinone, or p-benzoquinone. [7]
Pathophysiology
Exposure to benzene stimulates the cytochrome P-450, which is responsible for oxygenation of benzene,
which generates oxygen-free radicals. These radicals are a major cause of benzene toxicity.[79] The
myelotoxic effects of chronic benzene exposure have been recognized for nearly a century.[58][60] Fatal
aplastic anemia, acute myelogenous leukemia, bone marrow depression, and lymphoproliferative disorders
are now well-recognized sequelae of long-term benzene exposure.[4] Absorbed benzene accumulates in the
fat of the bone marrow,[33] resulting in a reservoir from which in situ bioactivation occurs. The principal
benzene metabolites formed in the marrow are responsible for a variety of myelotoxic effects observed after
chronic exposure to benzene.[17][63]
Insight into the pathogenesis and benzene-induced leukemia has come from analysis of chromosomal
abnormalities found in workers and animals with long-term benzene exposure.[53][68] Although the precise
mechanism of leukemogenesis remains unknown, it may be analogous to the delayed induction of therapy-
related acute myelogenous leukemia which occurs in patients previously treated with chemotherapeutic
agents or radiation for a primary malignancy. Specific clonal chromosomal anomalies such as translocations
or deletions, which involve chromosomes 5 and 7, are present in 90 per cent of patients with therapy-related
acute myelogenous leukemia.[41][56] Like many chemotherapeutic agents, benzene metabolites are known
alkylating agents which interfere with spindle formation and interrupt normal cell cycling. Cytogenetic studies
or workers with chronic benzene exposure who develop acute myelogenous leukemia have demonstrated
similar clonal abnormalities of chromosomes 5 and 7.[4] It is particularly intriguing that the genes for many
hematopoietic growth factors are present on the long arm of chromosome 5. Deletion of these genes would
be expected to have profound effects on normal hematopoietic function.
Clinical Presentation ( Table 99–1 )
Acute Toxicity
Inhalation exposure results in euphoria, lightheadedness, ataxia, headache, and respiratory depression.
After massive exposure to high concentrations, pulmonary edema, hemorrhagic pneumonitis, cardiac
dysrhythmias, seizures, coma, and death have been reported. Following acute ingestion, burning of the oral
pharynx, esophagus, and gastric mucosa results, with nausea, vomiting and abdominal pain. Cutaneous
burns, erythema, and blistering may occur after dermal exposure.
Table 99-1 -- Clinical Manifestations of Aromatic Hydrocarbon Use

System Toluene (Xylene) Benzene
Acute intoxication: euphoria,
Acute intoxication: euphoria, giddiness,
lightheadedness, ataxia, headache,
lightheadedness, ataxia, slurred speech,
respiratory depression, death (after
hallucinations, lethargy, obtundation
massive exposure)
Central nervous
system and Repeated or chronic use: dementia, cerebellar
neuropsychiatric * signs (e.g., ataxia), tremor, movement disorders,
seizures, oculomotor and visual dysfunction,
sensorineural hearing defect, psychiatric
syndromes, pyramidal tract signs (e.g.,
hyperreflexia, positive Babinski sign)
Repeated or chronic use: distal renal tubular
acidosis commonly seen: hyperchloremic, non-
anion gap metabolic acidosis (urinary pH
Renal inappropriately high: >5.5)
Proximal tubular defects also reported:
aminoaciduria, glycosuria, hypophosphatemia,
hypocalcemia, hypouricemia
System Toluene (Xylene) Benzene
Acute intoxication: mucosal
Gastrointestinal Nausea, vomiting, abdominal pain, hematemesis irritation, nausea, vomiting with oral
ingestion
Muscle weakness: mild to profound quadriparesis;
Musculoskeletal
rhabdomyolysis may be present
Hyperchloremic metabolic acidosis, hypokalemia,
Metabolic hypophosphatemia most common; anion gap
metabolic acidosis also reported
Acute intoxication: cutaneous burns
Pain may be present on face and hands
and blisters
Dermatologic “Glue sniffer’s rash” (perioral eczema caused by
repeated exposure of solvent poured into a plastic
bag and inhaled)
Breath Characteristic aromatic solvent odor
Chronic use: aplastic anemia,
myelodysplastic syndromes, acute
Hematologic leukemia (primarily myelogenous
but lymphoproliferative disorders
also reported)
* Acute findings may be superimposed on chronic effect.
Chronic Toxicity
Fatigue, headache, anorexia, and dizziness are common complaints following chronic exposure. Aplastic
anemia, myelodysplastic syndromes, and acute leukemia (primarily myelogenous but lymphoproliferative
disorders) have been reported. Initially after exposure, hypocellularity is noted in the marrow and correlates
clinically with aplastic anemia. Patients may present with pallor, fatigue, petechiae, bruising, bleeding, and
infection.
The differential diagnosis of benzene toxicity includes other aromatic and aliphatic hydrocarbons,
chemotherapeutic and anticancer drugs, nutritional deficiencies, and environmental toxins such as radiation
exposure ( Table 99–2 ).
Table 99-2 -- Aromatic Hydrocarbons: Differential Diagnosis

Condition Alternative Diagnoses
Toluene Toxicity
Uremia
Alcoholic ketoacidosis
Iron poisoning
Methanol, ethylene glycol
Carbon monoxide
Cyanide
Metabolic acidosis Isoniazid
Salicylates
Phenformin, metformin, paraldehyde
Gastrointestinal bicarbonate loss
Acetazolamide
Lactic acidosis—multiple etiologies
Endocrinopathies
Drug-induced myopathies (steroids, ß-adrenergic receptor blockers, etc.)
Muscle weakness
Organophosphates, carbonates
Sepsis
Severe systemic illness
Myasthenia gravis
Drug-induced (cocaine, heroin, amphetamine, etc.)
Rhabdomyolysis
Compression syndromes
Other causes of distal renal tubular acidosis
Chronic pyelonephritis
Hypokalemia associated with
Diarrheal states
nongap metabolic acidosis
Zollinger-Ellison syndrome
Ureterosigmoidostomy
Other renal tubular disorders
Alcoholism
Hypophosphatemia Malnutrition
Hyperparathyroidism
Aromatic hydrocarbons (toluene, xylene ethyl benzene), Aliphatic
Benzene Toxicity
hydrocarbons (methane, butane, propane)
CNS effects Chlorinated hydrocarbons ketones
Chemotherapeutic agents (cisplatin, doxorubicin, methotrexate,
tamoxifen, vinblastine, nitrogen mustards)
Pharmaceutic agents (colchicine, dapsone, podophyllum, NSAIDs,
Hematologic effects phenylbutazone, propylthiouracil, chloramphenicol, nitrous oxide)
Environmental agents (radiation exposure, heavy metals: lead, arsenic)
Nutritional deficiencies (folate, vitamin B12)
Aromatic hydrocarbons (benzene, toluene)
Aliphatic hydrocarbons (methane, butane propane)
Xylene Toxicity
Chlorinated hydrocarbons (TCE, carbon tetrachloride)
Carbon monoxide, hydrogen sulfide, cyanide, methylene chloride
Laboratory Studies
Obtain a baseline complete blood count (CBC) and reticulocyte count, and follow serial levels with significant
exposures for 2–3 months.[69] Monitor for thrombocytopenia anemia, leukopenia, and pancytopenia. Bone
marrow biopsies in benzene-exposed patients may demonstrate a predominance of acute myelogenous
leukemia.[70] Electrolytes and acid-base status should be assessed in patients acutely exposed to benzene.
Additionally, a liver profile, blood urea nitrogen (BUN), and creatinine, urinalysis, and creatine
phosphokinase (CPK) levels should be measured. A chest radiograph and pulse oximetry should be
obtained if inhalation exposure has occurred. Monitor EKG and rhythm strips for evidence of cardiotoxicity.
Patients with any residual neurologic deficits should undergo computed tomography (CT) or magnetic
resonance imaging (MRI) of the brain.
Benzene can be measured in expired air along with urine phenol levels in the occupational setting with
adequate clinical correlation.[31] Expired air analysis can be used for confirmation of exposure in the first 24
hours following exposure. Normal individuals excrete less than 10 mg/L of phenol. Levels above 200 mg/L
are highly suggestive of recent benzene exposure. False positives can be produced by phenol-containing
medicinals such as Chloraseptic and Pepto-Bismol. A superior marker for low-level benzene exposure is
trans,trans-muconic acid, a minor metabolite of benzene that can be measured by using high-performance
liquid chromatography (HPLC) with ultraviolet detection.[48]
Treatment ( Table 99–3 )
Patients with benzene intoxication may be critically ill and require the basic ABCs (airway, breathing,
circulation) of emergency management. Particular attention to the airway is important for two reasons: (1)
patients may have a depressed mental status from the solvent narcosis, and (2) they may have profound
muscle weakness, which may put them at further risk for aspiration or respiratory arrest. With inhalation
exposure, move the patient to fresh air and administer oxygen. With dermal or ocular exposures,
immediately irrigate with tepid water or normal saline solution.
Table 99-3 -- Treatment of Aromatic Hydrocarbon Intoxication
Conditions Requiring
Treatment
Intervention
Respiratory compromise Secure airway with intubation and ventilatory assistance
Hypotension Fluid resuscitation and pressor agents as needed
Follow standard ACLS guidelines, use epinephrine with caution, consider
short-acting ß-adrenergic receptor antagonists
Seizures Benzodiazepines, phenobarbital, general anesthesia for status epilepticus
Avoid emesis with syrup of ipecac, gastric aspiration indicated with recent
Acute ingestion large ingestions of benzene, toluene, and xylene
Airway should be protected
Correction of electrolyte acid- Sodium bicarbonate for severe acidosis

base disturbances Intravenous KCl infusion for severe hypokalemia
Renal complications If renal failure, consider hemodialysis
Urinary alkalinization with sodium bicarbonate, diuresis with IV fluids and
Rhabdomyolysis
mannitol
Neurobehavioral deficits Consult neurology, head CT and MRI imaging
Emesis with syrup of ipecac is not recommended for acute ingestion since benzene may cause respiratory
depression and seizures. Gastric aspiration is indicated with recent ingestions after proper airway protection
is established. Although a hydrocarbon, benzene is considered a dangerous additive, making gastric
aspiration justifiable. Activated charcoal may also be efficacious with recent oral exposures.
Control seizures with benzodiazepines and, if refractory, administer loading doses of phenobarbital. Monitor
the patient for cardiac dysrhythmias. Use epinephrine cautiously, because its administration may exacerbate
the catacholamine sensitization of benzene-exposed myocardial cells resulting in cardiotoxicity.
Disposition
Patients who present with signs and symptoms of mild benzene intoxication may be managed in the
emergency department and discharged if their manifestations of toxicity can be corrected within several
hours. Acute CNS intoxication and delirium usually resolves within a few hours of cessation of the
hydrocarbon exposure, during which time appropriate laboratory tests can be obtained and mildly abnormal
electrolytes corrected. Patients with severe respiratory or CNS depression should be monitored in an ICU
setting. Patients with signs of anemia or pancytopenia or who appear immunocompromised from chronic
exposure should be admitted and evaluated for hematotoxicity.
Sequelae
Leukemia and aplastic anemia may result from chronic exposure. Signs and symptoms may occur rapidly,
but latencies as long as 30 years have been described between last known exposure and clinical toxicity.[27]
Five-year survival rates of approximately 30 per cent have been reported with benzene-induced aplastic
anemia. Thrombocytopenia and lymphoid bone marrow suggest a poorer prognosis.


TOLUENE
Essentials
• Altered mental status ranging from euphoria and confusion to central nervous system depression
• Metabolism disturbances: hyperchloremic metabolic acidosis, hypokalemia, hypophosphatemia with
habitual use
• Characteristics aromatic solvent odor on breath with paint or glue on face or hands
• Muscle weakness and rhabdomyolysis
• Myocardial irritation, cardiac dysrhythmias, cardiac arrest
Introduction
The potential for inhalation abuse of solvents containing toluene is great, especially in children and
adolescents, because these products are readily available in supermarkets and hardware stores. These
products are legal to purchase in most jurisdictions, are inexpensive, and produce the desired euphoria
within minutes. The challenge for physicians lies not only in the recognition and proper management of
patients with aromatic hydrocarbon toxicity, but also in the successful treatment of substance abuse in the
habitual user.
Toxicokinetics
The highly volatile nature of toluene makes inhalation the most efficient route of absorption. These
properties permit passage through alveolar membranes and accumulation in the brain, [10][36] resulting in
rapid and potent euphoria. Up to 50 per cent of an inhaled dose is absorbed, and peak concentrations occur
15 to 30 minutes after inhalation.[23] Approximately 20 per cent of an inhaled toluene dose is exhaled
unchanged.[67] This accounts for the characteristic aromatic, solvent odor on the breaths of patients who
have acutely inhaled toluene. Gastrointestinal absorption is 10 per cent, and peak blood concentrations
occur 1–2 hours after ingestion.[6] Immersion in toluene may also result in significant blood levels following
dermal absorption. The metabolic pathway for toluene is illustrated in Figure 99–1 . Toluene is metabolized
in the liver to benzyl alcohol which is oxidized to benzoic acid. Benzoic acid is then conjugated with glycine
and excreted as hippuric acid.[3]
Pathophysiology
Neurologic Effects of Toluene
Cranial CT scans of patients chronically exposed to toluene reveal cerebral, cerebellar, and brainstem
atrophy.[40][59] Magnetic resonance imaging (MRI) of the brain has provided additional insight into the
pathophysiology of toluene-induced CNS disease. Cerebral, cerebellar, and brainstem atrophy and
subcortical abnormalities have been documented.[30][54][59] In addition, a characteristic pattern of brain
abnormalities, referred to as white matter disease,[30][54][78] has been associated with chronic toluene abuse
and is thought to represent myelin damage.[20] The precise mechanism by which these changes occur is
unknown. However, the lipophilic nature of toluene may result in preferential injury to the lipid-rich
myelinated tissue. Furthermore, because myelin lipids are relatively stable and have a slow rate of
turnover,[16] toluene-induced perturbations in myelin structure may result in prolonged or permanent
neurologic sequelae.[38][54] Comprehensive neuropsychological assessment of habitual toluene “sniffers”
has demonstrated clinical correlation with abnormal MR images and suggests that the degree of dementia is
related to the severity of the white matter disease.[21]
Renal and Metabolic Effects of Toluene
The mechanism of the renal tubular defect is unknown. Speculation exists, however, that toluene[64] or its
metabolite, hippuric acid,[22] may exert direct cytotoxic effects in renal cells. With rare exception, the renal
injury reverses when patients abstain from toluene abuse.
Anion gap metabolic acidosis has also been described in patients abusing toluene,[22][46] although the
unmeasured anion has not been identified. Lactic acid concentration has been normal and only mildly
elevated in this setting and thus does not appear to be responsible for the severe acidosis seen in some
patients.[22] The metabolites of toluene, including benzoic and hippuric acids, may contribute to the
acidosis.[22] Finally, it is unclear what role coingestants such as ethanol may play in the development of
anion gap metabolic acidosis, since some of these patients are known to abuse multiple substances.
Muscle Disorders
Hypokalemia and hypophosphatemia may produce muscle weakness and rhabdomyolysis.[64]

Rhabdomyolysis has been reported in the absence of these metabolic derangements. Thus, toluene may
have a direct toxic effect on the muscle membranes.[64]
Acute Toxicity
The typical manifestations of acute toluene intoxication include euphoria, giddiness, lightheadedness,
ataxia, and decreased inhibitions. Other effects include slurred speech, confusion, disorientation,
hallucinations, tremor, and irritability. Seizures have also been reported.[36] More profound CNS depression
may follow, resulting in lethargy, coma, respiratory arrest, or death.[44] The exact mechanism of death is
unknown in the majority of cases, although cardiovascular collapse, fatal dysrhythmias, and asphyxia have
all been postulated. Finally, some of these patients may have obvious or occult injuries because altered
judgment and delirium predispose them to trauma.[50]
Patients who present with acute intoxication from toluene have an unmistakable aromatic, solvent odor on
their breaths or may have paint on their hands and face that may assist the clinician in identifying the
offending agent. The color of the paint abused is not trivial because the toluene content is generally higher in
metallic based paints, such as gold, copper, and silver. The manifestations of acute aromatic hydrocarbon
intoxication may be seen alone, or may be superimposed on the chronic sequelae of toluene abuse.
Sudden death after acute inhalation is most often due to hypoxia during toluene narcosis, but may be due to
fatal dysrhythmia secondary to sensitization by endogenous catecholamines. Sinus bradycardia, ventricular
fibrillation, and myocardial infarction have been reported.
Chronic Toluene Use
Neurologic Effects
The neurologic findings associated with habitual toluene abuse include transient and persistent cognitive,
cranial nerve, and cerebellar abnormalities. The neurologic and neuropsychiatric sequelae of chronic
toluene abuse include dementia, cerebellar ataxia, tremor, dysarthria, nystagmus, movement disorders,
seizures, and pyramidal tract signs (hyperreflexia with a positive Babinski sign).[25][29] Additional cranial
nerve findings such as oculomotor abnormalities, anosmia, and sensorineural hearing loss have been
reported.[29] Persistent psychiatric disorders such as paranoid psychosis[12] and encephalopathy[38] have
also been associated with chronic toluene abuse.
Renal and Metabolic Effects
Toluene-induced renal injury is complex with broad clinical manifestations. Habitual toluene users may
develop reversible hyperchloremic (non-anion gap) metabolic acidosis with profound hypokalemia and
hypophosphatemia. These abnormalities result from an acquired distal renal tubular defect. (type 1, renal
tubular acidosis)[66] The attendant metabolic and electrolyte derangements may be profound and life-
threatening.[64][66] Fortunately, the renal tubular defect is completely reversible with cessation of toluene
inhalation.[64][66]
Anion gap metabolic acidosis has also been reported in chronic toluene “sniffers”[22][71] and is associated
with mixed distal and proximal renal dysfunction.[46][71] The proximal tubular injury may result in glycosuria,
aminoaciduria, hypouricemia, and hypocalcemia in addition to hypokalemia and hypophosphatemia. Other
documented reversible renal abnormalities include mild renal insufficiency, hematuria, pyuria, and
proteinuria.[64][66] Rhabdomyolysis also occurs in patients with habitual toluene abuse [64] and may contribute
to renal insufficiency. Case reports of recurrent nephrolithiasis associated with chronic toluene sniffing have
also been documented. [39]
Chronic paint or glue sniffers may present with cardiac dysrhythmias, including multifocal premature
ventricular contractions and supraventricular tachycardia. These effects may be due to electrolyte
disturbances or direct cardiac cell membrane toxicity.[44] Dilated cardiomyopathy has also been reported
after chronic inhalation abuse.[76]
Nausea, vomiting, hematemesis, and abdominal pain are common presenting complaints in patients who
inhale aromatic hydrocarbons on a regular basis.[64] Physical examination is typically unremarkable. Liver
function test abnormalities may also be present, although significant liver abnormalities are unusual.
Musculoskeletal Effects
Muscle weakness is a common manifestation of aromatic hydrocarbon abuse and ranges in degree from
mild impairment to quadriparesis.[64][66] Muscle strength usually returns to normal within 3–5 days of
hospitalization and initiation of medical treatment.[64][66] As noted above, mild to moderate rhabdomyolysis
may also be present.[64]
Dermatologic Effects
Evidence of paint on the skin, particularly on the face and hands, may provide a clue to toluene abuse in
patients in whom this is not immediately apparent. A “glue sniffer’s rash” has been described in patients who
inhale volatile solvents from a plastic bag tightened around the mouth. The irritative effects of the
hydrocarbon collecting at the neck of the bag, can cause perioral eczematous dermatitis.[44]
Special Pediatric Considerations
Volatile substances, whether toluene and xylene or aliphatic hydrocarbons (butane, trichloroethylene), are
often the first euphoriants used by children.[15] Unlike ethanol or marijuana, they are legal for minors to
purchase in most jurisdictions, inexpensive, and readily available in supermarkets and hardware stores. In
addition the practice of huffing, the inhalation of vapors through the nose and mouth via a cloth
(handkerchief or shirtsleeve) saturated with solvent, may be easy to conceal in school and at home.
Numerous epidemiologic studies have documented the use of volatile inhalants in the preadolescent,
adolescent, and young adult population. In the United States, Fishburn reported a lifetime prevalence of 9.8
per cent of subjects aged 12–17, and 16.5 per cent for young adults aged 17–25.[23] In the United Kingdom,
a mean prevalence of previous or current volatile substance abuse was 5.9 percent in schoolchildren.[14] In
most instances the practice was sporadic with overall prevalence declining with age. Volatile substance
abuse is more commonly reported in boys than girls and is often a group activity.[15]
Toluene Abuse in Pregnancy
Toluene abuse in pregnancy has significant effects on fetal outcome and development. Its lipophilic nature
permits easy passage through the placenta. Intrauterine growth retardation, premature labor, congenital
anomalies, neonatal acidosis, perinatal death, and developmental delay [26][49][74] have all been associated
with prenatal maternal toluene abuse. Toluene embryopathy, similar to that caused by ethanol, has been
described in the offspring of women who intentionally inhaled toluene during pregnancy. This syndrome
consists of microcephaly, characteristic craniofacial dysmorphic features, and developmental delay.[49]
These profound teratogenic effects mandate that substance abuse counseling or admission to detoxification
programs should be offered to pregnant women abusing toluene.
The differential diagnosis of toluene toxicity is summarized in Table 99–2 and includes those agents which
induce metabolic acidosis, hypokalemia associated with nongap acidosis, rhabdomyolysis, muscle
weakness, and hypophosphatemia.
Laboratory Studies
The metabolic derangements associated with toluene exposure mandate that electrolytes, calcium,
phosphorus, creatinine kinase, and urinalysis tests be performed on these patients. Magnesium levels
should also be obtained because many patients have coexisting malnutrition or alcoholism, which may
predispose them to hypomagnesemia. An ethanol level should be obtained in intoxicated patients to assess
its contribution to the clinical picture. If hypobicarbonatemia is present, coexisting causes of metabolic
acidosis should be ruled out. Other laboratory tests should be obtained as dictated by the clinical setting,
including pregnancy tests in women of childbearing age. An EKG and cardiac enzymes should be obtained if
cardiotoxicity is suspected.
Once the acute toxic metabolic abnormalities are resolved, patients with residual neurologic deficits may
undergo CT or MRI scan of the brain to determine the degree of atrophy or white matter disease present. In
addition, abnormal brainstem auditory evoked responses have recently been described in toluene abusers
with normal MRI and neurologic examinations and may be the most sensitive test for the detection of early
CNS injury.[55]
The diagnosis of aromatic hydrocarbon intoxication is a clinical one. Although serum toluene assays are
available from specialized laboratories, they do not correlate with clinical signs and symptoms[44] and thus
are not useful in the management of intoxicated patients. Similarly, the measurement of urinary metabolites
of toluene (hippuric acid— Fig. 99–1 ) is not a useful adjunct for assessing clinical toxicity. Quantification of
urinary metabolites are routinely done in industry for biomedical surveillance. Even in this setting, however,
levels must be interpreted with caution because hippuric acid may be derived from food or pharmaceutical
sources of benzoic acid and not from toluene.[44] Meredith noted that many patients suspected of abusing
toluene have greater than 1 g hippuric acid per gram of creatinine in their urine,[44] but no confirmation of this
report exists, and thus the test cannot be used to confirm toluene abuse.
Treatment
Patients with toluene intoxication may be critically ill and require the basic ABCs (airway, breathing,
circulation) of emergency management. Particular attention to the airway is important for two reasons. First,
patients may have a depressed mental status from the solvent narcosis, and second, they may have
profound muscle weakness, which may put them at further risk for aspiration or respiratory arrest. Assess
the patient’s cardiac status with continuous monitoring and serial EKGs. Use epinephrine cautiously,
because its administration may exacerbate toluene-induced cardiotoxicity. For tachydysrhythmias, short
acting ß-blockers may be efficacious.
Profound hypokalemia may require prolonged intravenous repletion of potassium. The rate of correction is
governed by the severity of the hypokalemia, and although prompt initiation of potassium infusion is
warranted, complete normalization may not be achieved for 24–72 hours. Care must be taken to resist
overly aggressive potassium replacement, as this may be arrhythmogenic as well. The coexistence of
severe hypokalemia and metabolic acidosis warrants special consideration. Sodium bicarbonate is rarely
indicated to correct the metabolic acidosis associated with toluene toxicity, because it typically resolves with
cessation of toluene exposure and fluid and electrolyte repletion. Should bicarbonate therapy be considered,
however, it should be administered with caution; the alkaline load will drive potassium into the cells,
worsening the hypokalemia. Finally, serum calcium concentrations should be monitored frequently during
fluid and electrolyte replacement, as hypocalcemia associated with tetany and seizures has developed
during this period.[64]
Emesis is not indicated because of aspiration potential and rapid onset of toxicity. Gastric aspiration may be
appropriate with recent ingestions of toluene, particularly if benzene contamination is suspected. The degree
of toluene adsorption to charcoal is unknown but may be efficacious with recent ingestions. Immediately
decontaminate skin exposures with soap and water and irrigate ocular exposures with copious amounts of
tepid water or normal saline.
The delirium of acute toluene intoxication and the neuropsychiatric and cognitive disorders associated with
habitual toluene use may predispose these patients to trauma. As a result, patients with depressed mental
status or neurologic deficits may require emergent CT scan of the brain to rule out traumatic injury.
Disposition
Patients who present with signs and symptoms of toluene intoxication may be managed in the emergency
department and discharged if their manifestations of toxicity are mild and can be corrected within several
hours. Acute CNS intoxication and delirium usually resolve within a few hours of cessation of the
hydrocarbon exposure, during which time appropriate laboratory tests can be obtained and mildly abnormal
electrolytes corrected. Patients may be discharged from the emergency department if the acute change in
mental status and gastrointestinal symptoms have resolved, traumatic injury has been ruled out, fluid and
electrolyte abnormalities have been corrected, and the patient is ambulatory. Patients who fail to meet these
criteria or who have profound muscle weakness and electrolyte abnormalities should be admitted to the ICU
for further management, and monitored for cardiac dysrhythmias.
Sequelae
Progressive, irreversible encephalopathy with cognitive difficulty and cerebellar ataxia and organic affective
disorders have been described in chronic workplace or abuse exposures. Peripheral neuropathy, personality
changes, tremors, recurrent headaches, emotional liability, and memory loss have also been described.[64]
Dilated cardiomyopathy has been reported after chronic inhalation use. Renal tubular defects are usually
reversible with cessation of habitual use.


XYLENE
Essentials
• Altered mental status ranging from euphoria and confusion to central nervous system
depression
• Headache, incoordination, ataxia
• Severe exposure may cause coma, respiratory arrest, and cardiac dysrhythmias
• Skin, mucosal membrane, respiratory tract irritant
Introduction
Xylene is used as a solvent in paints, varnishes, degreasers, paint thinners, and pesticides. It is a high-
octane additive to aviation fuels and used in the synthesis of dyes. The most common exposure in the
occupational and home setting is through spray painting. A common source of laboratory exposure is in the
preparation of tissue specimens for histologic examination.[7] Commercial xylene is a mixture of ortho-,
meta-, and para-xylene isomers, with the m-isomer being the principal component. Xylene is produced by
fractional distillation of petroleum, coal tar, or coal gas, catalytic reforming from petroleum followed by
separation of p-xylene, continuous crystallization, and from toluene by transalkylation.[11] Xylene may be
contaminated with benzene (over 200 ppm may cause benzene toxicity). Other impurities include
ethylbenzene, toluene, and phenol.[19][13] Acute xylene exposure results in respiratory tract irritation and
dyspnea at relatively low concentrations, but other systemic effects are less well defined, because isolated
xylene exposures are uncommon.
Toxicokinetics: Absorption and Distribution
Xylene is rapidly absorbed following inhalation or ingestion. It is less well absorbed through intact skin. The
highly volatile nature of xylene makes inhalation the most efficient route of absorption. Approximately 60 per
cent of inhaled xylene is absorbed, and peak blood concentrations occur 15–30 minutes after inhalation. [47]
Lipophilic properties permit passage through alveolar membranes and accumulation in the brain.[10][36] After
oral exposure, peak blood concentrations occur 1–2 hours after ingestion. Xylene is less well absorbed
through intact skin. Skin breakdown or injury may result in excessive dermal absorption.[19] Immersion of
both hands in m-xylene for 15 minutes equals an estimated pulmonary retention of 100 ppm.[57] The
cytochrome P-450–dependent monooxygenase system is the primary metabolic pathway of xylene. The
metabolic pathways for xylene are illustrated in Figure 99–1 . Up to 95 per cent of absorbed xylene is
biotransformed and excreted in the urine within 18 hours as methylhippuric acid.[8] About 5 per cent is
excreted unchanged in the breath. The elimination half-life is up to 20–30 hours.[8]
Pathophysiology
Xylene is an aromatic hydrocarbon solvent that produces CNS depression, including anesthesia and
narcosis. It is an irritant to the skin and mucous membranes. Xylene is similar to toluene, which accumulates
in the brain and fatty tissue after inhalation. Xylene has lower volatility, lower affinity for the CNS, and less
acute toxicity than toluene or benzene.[77] The metabolites of xylene, methylbenzoic and methylhippuric
acids, may contribute to acidosis.
Acute Intoxication
The typical manifestations of acute xylene intoxication include euphoria, lightheadedness, ataxia, nausea,
vomiting, and headache. [37] Other effects include slurred speech, confusion, short-term memory loss,
disorientation, tremor, and irritability. Seizures have also been reported.[36] More profound CNS depression
may follow resulting in lethargy, coma, respiratory arrest, and rarely, death.[1][45][51] Pulmonary edema
occurred in a patient following intravenous injection of 8 mL of xylene. [61] Only a few case reports of death
associated with xylene exposure are reported in the literature. The exact mechanism of death is unknown,
but respiratory failure and/or fatal arrhythmia have been postulated. Finally, some of these patients may
have obvious or occult injuries because altered judgment and delirium predispose them to trauma.[50] Acute
xylene exposure result in skin, mucosal, and respiratory irritation, and neurologic effects such as headache,
short-term memory loss, ataxia, confusion, and CNS and respiratory depression.
Nausea, vomiting, hematemesis and abdominal pain are common presenting complaints in patients with
inhalational exposure to xylene.[37] Physical examination is typically unremarkable. Transient elevation of
liver function tests were noted following intravenous injection of xylene.[61]
Musculoskeletal Effects
Muscle weakness may be seen following acute xylene exposure.
Chronic Toxicity
Chronic exposure to xylene may cause defatting dermatitis, dyspnea, confusion, dizziness, short-term
memory loss, headache, tremors, irritability, and insomnia.
The differential diagnosis of xylene toxicity includes other aromatic hydrocarbons (benzene, toluene),
aliphatic hydrocarbons (methane, butane, propane), chlorinated hydrocarbons (trichloroethylene, carbon
tetrachloride), carbon monoxide, hydrogen sulfide, cyanide, and methylene chloride.
Laboratory Studies
Symptomatic patients require a complete blood count (CBC), electrolyte evaluation, and urinalysis. Monitor
cardiac, respiratory, renal, hepatic and neurologic function. For patients with inhalation exposure, obtain a
baseline CXR and pulse oximetry or arterial blood gas, as indicated. If cardiotoxicity is suspected, obtain
serial EKGs and cardiac enzymes.
The diagnosis of xylene intoxication is a clinical one. Although serum xylene assays are available in
specialized laboratories via gas chromatography, they do not correlate with clinical signs and symptoms[44]
and thus are not useful in the management of intoxicated patients. Similarly, the measurement of urinary
metabolites of xylene (methylhippuric acid) is not a useful adjunct for assessing clinical symptoms and
treatment.
Neurologic abnormalities resulting from xylene exposure are usually transient. Head CT or MRI should be
obtained if neurologic symptoms do not resolve.
Treatment (see Table 99–3 )
Patients with inhalation exposures should be evacuated from the contaminated area, directed into fresh air,
and administered 100 per cent oxygen. For dermal exposure, the skin should be decontaminated with soap
and water. For ocular exposure, the eyes should be immediately irrigated with copious amounts of tepid
water or normal saline. For patients with oral ingestions, emesis with syrup of ipecac should not be induced,
because of the risk of rapid onset CNS depression, seizures, and pulmonary aspiration. If there has been a
recent ingestion of a large volume of xylene, gastric aspiration may be indicated, particularly if the xylene
has been contaminated with benzene. In this setting, the airway should be protected. Although not well
studied, activated charcoal may be efficacious in recent ingestions. Because pulmonary edema has
occurred with acute xylene exposure, the patient should be monitored for respiratory distress, given
supplemental oxygen and intubated if necessary. If bronchospasm and wheezing occur, inhaled
sympathomimetic agents can be administered. The patient’s fluid and electrolyte status should also be
monitored regularly. Use epinephrine cautiously, since its administration may potentiate the catecholamine
surge on xylene-exposed myocardial cells resulting in cardiotoxicity. For other dysrhythmias, standard
Advanced Cardiac Life Support (ACLS) protocol should be followed. Seizure activity may occur after severe
inhalation exposure, and should be treated with standard doses of benzodiazepines and phenobarbital.
Disposition
Patients who present with signs and symptoms of xylene intoxication may be managed in the emergency
department and discharged if their manifestations of toxicity are mild and can be corrected within several
hours. Acute CNS intoxication and narcosis usually resolve within a few hours of cessation of exposure,
during which time appropriate laboratory tests can be obtained and mildly abnormal electrolytes corrected.
Patients can be discharged from the emergency department if the acute change in mental status and
gastrointestinal symptoms have resolved, traumatic injury has been ruled out, fluid and electrolyte
abnormalities have been corrected, and the patient is ambulatory. Asymptomatic patients may be observed
for 6 hours and discharged if they remain symptom-free. If the patient is symptomatic, admission is
indicated. If the patient has unstable vital signs or respiratory compromise, monitoring in an intensive care
unit is recommended.
Sequelae
Chronic exposure to xylene may cause defatting dermatitis, ocular damage, dyspnea, confusion, memory
loss, headaches, and tremors. Other sequelae include sleep disturbances and emotional lability.


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59. Schikler KN, Seitz K, Rice JF, et al: Solvent abuse associated cortical atrophy. J Adolesc Health
Care 1982; 3:37.
60. Selling L: Benzol a leucotoxine. Studies on the degeneration of the blood and hematopoietic organs.
Johns Hopkins Hosp Rep 1916; 17:83.
61. Sevcik P, Hep A, Peslova M: Intravenous xylene poisoning. Intens Care Med 1992; 18:377.
62. Snyder R, Cocsis JJ: Current concepts of chronic benzene toxicity. CRC Crit Rev Toxicol 1975; 3:265.
63. Snyder R, Lee EW, Cocsis JJ, et al: Bone marrow depressant and leukemogenic actions of benzene.
Life Sci 1977; 21:1709.
Med 1981; 94:758.
65. Susten A, Dames B, Burg J, et al: Percutaneous penetration of benzene in hairless mice: An estimate of
dermal absorption during tire building operations. Am J Ind Med 1985; 7:323.
66. Taher SM, Anderson RJ, McCartney R, et al: Renal tubular acidosis associated with toluene sniffing. N
Engl J Med 1974; 290:765.
67. Toftgard R, Gustafsson J: Biotransformation of organic solvents: A review: Scand J Work Environ.
Health 1980; 6:1.
68. Tough IM, Court Brown WM: Chromosome aberrations and exposure to ambient benzene.
Lancet 1965; 1:684.
69. Travis LB, Li CY, Zhang ZN, et al: Hematopoetic malignancies and related disorders among benzene
workers in China. Leuk Lymphoma 1994; 14:91.
70. Vigiani EC, Saita G: Benzene and leukemia. N Engl J Med 1964; 271:872.
71. Voigts A, Kaufman CE: Acidosis and other metabolic abnormalities associated with paint sniffing.
South Med J 1983; 76:443.
72. Wallace LA, Pellizzari E, Leaderer B, et al: Emissions of volatile organic compounds from building
materials and consumer products. Atmos Environ 1987; 21:385.
73. Wester RC, Maibach HI, Gruenke LD, et al: Benzene levels in ambient air and breath of smokers and
non-smokers in urban and pristine environments. J Toxicol Environ Health 1986; 18:567.
74. Wilkins-Haug L, Gabow PA: Toluene abuse during pregnancy: Obstetric complications and perinatal
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76. Wiseman M, Banim S: Glue-sniffer’s heart?. Br Med J 1987; 294:739.
77. Wolf MA, Rowe VK, McCollister DD, et al: Toxicological studies of certain alkylated benzenes and
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78. Yamanouchi N, Okada S, Kodama K, et al: White matter changes caused by chronic solvent abuse.
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Uncited references
Flannagan RJ, Ruprah M, Merideth TJ, et al: An introduction to the clinical toxicology of volatile substances.
Drug Safety 1990; 5:359.
Hoffman RS: Shoemakers. In: Greenberg MI, Hamilton RJ, Phillips SD, ed. Occupational, Industrial, and
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Machado B, Cross K, Snodgrass WR: Accidental hydrocarbon ingestion cases telephoned to a regional
poison center. Ann Emerg Med 1988; 17:804.
Winek CL, Collom WD, Wecht CH: Fatal benzene exposure by glue-sniffing. Lancet 1967; 1:683.


Chapter 100 – Pine Oil and Turpentine
ANDREW R. TOPLIFF LOUIS J. LING
Essentials
• Distinctive odor of breath, emesis, urine
• Gastrointestinal irritation with nausea and vomiting common
• Mucous membrane and skin irritation possible
• Mild central nervous system (CNS) depression and aspiration pneumonia possible
INTRODUCTION
Terpenes are a class of unsaturated, nonaromatic cyclic hydrocarbons. These volatile substances are found
naturally in oils and oleoresins of plants and flowers. Turpentine is a pine tree distillate consisting of pinene,
diterpenes, and other terpenes. It is commonly used as a thinner for paints and varnishes.[9] Pine oils
contain a variety of terpene alcohols and are found in household cleaners (e.g., Pine Sol, Pine Aroma
Disinfectant, and others) in concentrations up to 35 per cent. Camphor, pine oils, and turpentine are the
most common terpenes involved in poisoning.


PATHOPHYSIOLOGY
The mechanisms of CNS toxicity have not been totally elucidated, but terpenes probably act through
“excitotoxic” type mechanisms seen in other halogenated hydrocarbons. These hydrocarbons are composed
of multiple substances that are metabolized by various hepatic and renal mechanisms and have multiphasic
elimination half-lives.
Turpentine
The acute toxic dose of turpentine is not well defined, and case reports document a wide range of effects
with estimated ingested amounts. In addition, patients frequently vomit, making dose estimates unreliable.
Gastrointestinal symptoms have occurred in children after ingestion of 15 to 60 mL, and 120 to 180 mL is a
potentially lethal dose in untreated adults. Turpentine ingestion of more than 2 mL/kg should be considered
potentially toxic. It is well absorbed from the gastrointestinal tract,[6] but most ingestions are accidental and
involve small amounts. Turpentine is less volatile than other hydrocarbons. However, vapors are easily
inhaled, and aspiration of the liquid may occur during ingestion.
Pine Oils
Pine oils have about one-fifth the toxicity of turpentine in animals.[1] A suggested lethal dose for untreated
adults is 60 to 120 g,[12] although survival after a 400-mL ingestion has been reported. As little as half an
ounce of pure pine oil (14 g) has been reported to be fatal in a child.[8] However, children with small,
accidental ingestions are unlikely to become ill if they ingest a product with less than 20 per cent pine oil
concentration.[3]


Patients frequently have a strong odor of turpentine or pine oil on the breath, in vomitus, or in the urine; and
this may be a valuable diagnostic clue ( Table 100–1 ). As in all toxic exposures, the product name and
contents, the amount ingested, the time since exposure, and symptoms must be sought.
Table 100-1 -- Clinical Presentation of Pine Oil or Turpentine Ingestion

Distinctive odor of breath, emesis, urine
Nausea and vomiting—common
Somnolence, lethargy, and ataxia—common
Possible complications: pulmonary aspiration, mucous membrane and dermal irritation
Unusual complications include seizures, acute renal failure, thrombocytopenic purpura, and bradycardia
Pine Oil
The breath odor of a patient with pine oil ingestion characteristically resembles the smell of violets, owing to
the metabolites that are excreted in exhaled air.[12] Toxicity from gastrointestinal absorption of pine oil rarely
occurs, but pulmonary aspiration is a common problem because of its high vapor pressure. Patients
exposed to pine oil greater than 30 to 40 per cent concentration should be evaluated for corrosive effects.
Patients with significant ingestions usually present with gastrointestinal features (nausea, vomiting, diarrhea,
and abdominal cramping). Respiratory symptoms can include pneumonitis from aspiration, cough, and
respiratory depression after significant ingestions. Signs of CNS toxicity (such as somnolence and ataxia)
are usually mild and develop within 90 minutes. Lethargy and coma may be present in children or adults;
ataxia is more common in children.[2]
Bradycardia with normal blood pressure has occurred with spontaneous resolution within 24 hours.[3]
Irritated oral mucosa[7] and facial erythema have been reported.[12] Renal failure is rare.[7] Hepatotoxicity has
also been reported after massive pine oil ingestions.[11]
Turpentine
Turpentine causes gastrointestinal irritation, with oral burning or lesions and CNS symptoms such as
lethargy, ataxia, and, rarely, seizures. Direct skin contact with turpentine can produce an irritating defatting
dermal injury, and aspiration resulted in multiple pneumatoceles in a 21-month-old child.[1a][14] A single case
of acute renal failure and hemorrhagic cystitis several days after ingestion has been reported.[10] Turpentine
has been implicated in the pathogenesis of thrombocytopenic purpura.[16]


The differential diagnosis includes ingestion of other volatile oils, hydrocarbons, sedative-hypnotic drugs,
and other causes. Lethargy and somnolence, pneumonia, pulmonary aspiration, and oral mucosal irritation
from other causes should be considered ( Table 100–2 ).
Table 100-2 -- Differential Diagnosis of Pine Oil and Turpentine Ingestion

Odor
Naphthalene
Paradichlorobenzene
Other hydrocarbons
Other volatile oils (e.g., camphor)
Lethargy and Somnolence
Head trauma
Infection
Sedative-hypnotic drugs (e.g., chloral hydrate, ethchlorvynol, benzodiazepines)
Ethanol and other alcohols/glycols
Illicit drugs and inhalants (e.g., opioids, propane, butane)
Pneumonia
Aspiration
Other volatile hydrocarbons
Gastric contents
Bacterial and viral etiologies


LABORATORY STUDIES
Specific blood levels are not available. Arterial blood gas analysis or bedside pulse oximetry and chest
radiography should be performed if aspiration is suspected. For symptomatic patients a rapid bedside
glucose should be obtained. Other laboratory tests are performed as indicated by the clinical picture. If
needed, a method has been described to confirm pine oil presence in urine in a suspected abuse situation.[8]


TREATMENT
Supportive care with attention to airway and aspiration risk is the mainstay of therapy ( Table 100–3 ).[14]
Advanced life support measures are instituted as necessary. Any emesis should be tested for blood. The
efficacy of gastric decontamination is unknown. Children with small accidental ingestions are unlikely to
benefit from gastric emptying. Gastric lavage with airway protection should be considered in symptomatic
patients who have ingested more than 2 mL/kg of turpentine. Mineral oil and vegetable oil are no longer
recommended as solvents or cathartics because their use may increase the risk of aspiration and enhance
absorption.[12]
Table 100-3 -- Treatment of Pine Oil and Turpentine Ingestion

Stabilization of airway and breathing, assessment for aspiration risk, assessment of circulatory status
Supportive care
Benzodiazepines (e.g., diazepam, lorazepam for seizures [rare])
Observe:
Patients with gastrointestinal symptoms
Patients with no symptoms for 4 to 6 hours
Discharge if patient remains asymptomatic or if symptoms resolve
Admit:
Patients with altered mental status
Patients with suspected large ingestions or significant symptoms
Renal, hepatic, and bone marrow complications are treated supportively. In the past, lipid hemodialysis
against soybean oil[5] and Amberlite resin hemoperfusion[11] were of no benefit in patients who had ingested
pine oil because of its large volume of distribution.[12]


DISPOSITION
Patients who remain asymptomatic or have only mild gastrointestinal symptoms during the 6 hours after
ingestion are at low risk for serious complications and may be discharged. [5][12] Patients with systemic
symptoms, aspiration, or progressive symptoms need observation in a hospital.[13] Patients with seizures or
CNS depression should be admitted to an intensive care unit. Symptomatic patients should also be
monitored for hematologic, renal, and hepatic complications.


SEQUELAE
Deaths occur very rarely, and patients with pine oil ingestion should be expected to recover readily with
minimal supportive care.[2][4] Patients with pneumonitis secondary to pine oil aspiration typically recover
faster than patients who have aspirated other hydrocarbons.[2]


REFERENCES
1. Beamon RF, Siegel CJ, Landers G, et al: Hydrocarbon ingestion in children: A 6-year retrospective study.
JACEP 1976; 5:771-775.
1a. Bray A, Pirronti T, Marano P: Pneumatoceles following hydrocarbon aspiration. Eur

Radiol 1998; 8:262-263.
2. Brook MP, McCarron MM, Mueller JA: Pine oil cleaner ingestion. Ann Emerg Med 1985; 18:391-395.
3. Conrad F, Wruk KM, Spoerke DG, et al: Pine oil cleaner ingestions: A prospective study [abstract]. Vet
Hum Toxicol 1986 1986; 28:484.
4. Erickson T, Popiel R, Hyrhorczuk DO, Raba JM: Pine oil cleaners in prison [letter]. Ann Emerg
Med 1990; 19:445.
5. Geller RJ, Spyker DA, Garrettson LK, Rogol AD: Camphor toxicity: Development of a triage strategy.
Vet Hum Toxicol 1984; 2(suppl 2):8-10.
JAMA 1968; 203(3):230-231.
7. Gornel D, Goldman R: Acute renal failure following hexol-induced abortion. JAMA 1968; 203(2):146-
149.
8. Hill RM, Barer J, Hill LL, et al: An investigation of recurrent pine oil poisoning in an infant by the use of
gas chromatographic-mass spectrometric methods. Pediatrics 1975; 87(1):115-118.
9. Jacobziner H, et al: Turpentine poisoning. Arch Pediatr 1961; 78:357-364.
10. Klein FA, Hackler RH: Hemorrhagic cystitis associated with turpentine ingestion.
Urology 1980; 16:187.
11. Kopelman R, Miller S, Kelly , et al: Camphor intoxication treated by resin hemoperfusion.
JAMA 1972; 241:727-728.
12. Koppel C, Tenczer J, Tonnesmann U, et al: Acute poisoning with pine oil-metabolism of monoterpenes.
Arch Toxicol 1981; 49:73-78.
13. Machado B, Cross K, Snodgrass WR: Accidental hydrocarbon ingestion cases telephoned to a regional
poison center. Ann Emerg Med 1988; 17:804-807.
14. Ng RC, Darwish H, Stewart DA: Emergency treatment of petroleum distillate and turpentine ingestion.
Can Med Assoc J 1974; 111:537-538.
16. Wahlberg P, Nyman D: Turpentine and thrombocytopenic purpura [letter]. Lancet 1969; 2:215-216.


Uncited reference
Sperling F: In vivo and in vitro toxicology of turpentine. Clin Toxicol 1969; 2:21-35.


Chapter 101 – Polychlorinated Biphenyls and Related Substances
JAMES E. CISEK
Essentials
• Usually asymptomatic with no physical findings in acute setting
• Chloracne (delayed)
• May be carcinogenic
INTRODUCTION
Polychlorinated biphenyls (PCBs) are a group of 209 distinct compounds characterized by a varying number
of chlorine molecules attached to the biphenyl structure. Commercial products are mixtures of PCBs and
were commonly employed in the electrical industry as coolants for transformers and capacitors. Other
industrial applications included use in paints, pesticides, lubricants, heat transfer liquids, and as hydraulic
fluids. These products were colorless to dark brown. They varied from viscous liquids or sticky resins to
crystalline products. The polybrominated biphenyls (PBBs) are a related class of chemicals in which bromine
is substituted for chlorine in the biphenyl molecule. PBBs were used primarily as flame retardants. [20][22][28]
The production and distribution of polyhalogenated aromatic hydrocarbons was discontinued entirely in 1977
because of concern about their prolonged environmental half-lives (many years) and toxicity in animal
studies. Federal mandates require removal of these compounds from most existing applications.
A third group of chemicals, the polychlorinated dibenzofurans (PCDFs) and dibenzodioxins (PCDDs), are
not produced commercially. They occur in trace amounts as intermediates in synthetic chemical reactions,
with wood bleaching in paper production, in fires involving capacitors and transformers, and following the
incineration of halogenated waste materials.[1][20][28] It should be assumed that these compounds are
present in situations involving exposure to heated PCB-containing substances.
Electricians, fire fighters, and individuals involved in the transportation or storage of hazardous materials are
most likely to develop occupational exposures to PCBs. Nonoccupational exposure occurs through the
consumption of contaminated fish.[3][13] In general, PCB levels have been declining in humans, food, and the
environment since the late 1970s.


ABSORPTION, METABOLISM, EXCRETION
PCBs and related chemicals are absorbed through the skin, lung, and gastrointestinal tract. Most workplace
toxicity involves dermal and pulmonary exposure, while contaminated fish represent the main source of
gastrointestinal exposure. PCBs are highly lipid-soluble, having a blood-to-adipose tissue partitioning
coefficient of at least 100:1. They are metabolized in the liver with subsequent elimination via the bile and
urine. Metabolism and excretion have not been adequately defined in humans. The half-life in humans
varies with the degree of chlorination. Less chlorinated biphenyls have an estimated half-life of 6 months,
but more highly chlorinated PCBs can have half-lives over 2 years.[1][16][18][19][20][21][23][28]


PATHOPHYSIOLOGY
With the exception of chloracne, toxic effects in humans are uncommon and not predictable following either
acute or chronic exposures to PCBs. The mechanism by which these chemicals produce human toxicity is
unknown. Animal studies of long-term exposures demonstrate weight loss, chloracne, alopecia, skin edema,
hepatomegaly, bone marrow depression, behavioral changes, and reproductive dysfunction. In Japan (1968)
and Taiwan (1979), oils containing PCBs accidentally contaminated rice oil used for cooking. Patients
developed nausea, vomiting, peripheral neuropathy, and hepatic toxicity.[1][15][20] These symptoms have not
been noted in either acute or chronic exposures in the United States.[1][2][7][8][9][11][17] It is believed that these
two episodes involved distinct PCB isomers not available in the United States as well as high levels of
PCDFs generated during the cooking process.
The Institute of Medicine recently concluded that there is “sufficient evidence of an association” between the
exposure to PCBs (and related compounds) and soft-tissue sarcoma, Hodgkin’s disease, and non-Hodgkin’s
lymphoma.[31] PCBs are not genotoxic but are carcinogens through epigenic mechanisms. Proposed events
include the induction of enzymes, an enhancement of cellular multiplication, and altered intracellular
signaling.


Acute Toxicity
It is rare for PCBs and related compounds to produce any acute symptoms or signs. Ocular, upper
respiratory, and cutaneous irritation occur uncommonly. Oral ingestions are unusual and may induce nausea
and vomiting. There is generally no early toxicity from single acute exposures.[1][10][11][12][16][20][21][28]
Chronic Toxicity
Chloracne is the only consistent manifestation of toxicity and typically requires weeks to develop.
Comedones may be the only lesions following a mild exposure. With increased contact, straw-colored cysts
measuring 1–10 mm intermingle with the comedones. Chloracne occurs in atypical locations such as below
and lateral to the eye, at the angle of the mandible, and behind the ear. More significant exposures are
associated with lesions on the neck, shoulders, abdomen, scrotum, and penis. Asymmetric cutaneous
lesions occur at any site of direct contact. The absence of chloracne does not rule out a significant PCB
exposure, nor is there information available to predict the amount, route, or duration of exposure required to
produce this lesion.[5][7][8][9][11][17][20][24][26]
High-level, chronic exposures to PCBs and related compounds may cause hepatocellular injury in some
patients. This finding is inconclusively described in the literature and of uncertain clinical
significance.[1][2][21][28] In addition, these chemicals stimulate the cytochrome P-450 family of enzymes
involved in the biotransformation of drugs and other chemicals.[27] Accelerated drug metabolism and an
increase in the synthesis of toxic metabolites are possible, although not well documented in the literature.


Chloracne is seen only with PCBs, PBBs, PCDDs, PCDFs, and polychlorinated naphthalenes.


LABORATORY STUDIES
Laboratory studies provide little help to the physician managing an acute exposure to these chemicals. A
baseline complete blood count, aspartate transaminase (AST), alanine transaminase (ALT), and creatinine
may be useful for purposes of follow-up, but initially these studies are usually normal.
No routine laboratory techniques are available to assess PCB levels in human samples. Although serum and
adipose tissue levels indicate chronic exposure, they provide no relevant therapeutic or prognostic
information in the management of exposure to this toxin.


TREATMENT
Decontamination should be initiated at the exposure site prior to hospital transportation. Contaminated
patients must not enter the emergency department because they can significantly contaminate the facility; if
other injuries mandate immediate treatment, the patient should be placed in a decontamination area
equipped with resuscitation equipment. Hospital-based decontamination is best performed in specially
designed facilities or immediately outside the emergency department. The irrigation effluent always must be
collected and disposed of as hazardous waste. Hospital personnel should wear impermeable suits and
gloves. Respiratory protection is not required.
The high viscosity of these chemicals increases the likelihood of secondary contamination of personnel,
vehicles, and hospitals. If secondary contamination of equipment or a facility occurs, then access must be
terminated until an industrial hygienist or the Department of Public Health has determined that cleanup has
been adequate. The financial cost associated with PCB abatement is significant.
It is essential to remove the patient’s clothing as soon as possible, as over 50 per cent of the contaminant
will be eliminated in this fashion. Decontamination must first focus on wounds and ocular exposures.
Copious irrigation under low pressure with warm water is followed by gentle cleansing of the skin with a mild
soap. The use of hot water or brushes may facilitate dermal absorption of the toxin. Repeated applications of
soap followed by irrigation are important because a single decontamination may allow toxin to remain in the
skin.[30] A cotton-tipped applicator should be wiped over the contaminated area after washing and then
analyzed to determine the degree of residual contamination. These post-decontamination residual skin data
will not be available to guide the acute management but will assist in follow-up care.
PCBs and related compounds rarely cause acute neurologic or hemodynamic instability. If the patient
requires intubation or is hemodynamically unstable, then a concomitant intoxication or another medical or
surgical disease must be sought aggressively. There is no specific antidote and no clinical benefit from
extracorporeal elimination techniques such as hemodialysis or hemoperfusion.
In the rare event of a large PCB ingestion, gastric emptying should be accomplished using a small
nasogastric tube. Great care should be given to avoid aspiration and the subsequent risk of hydrocarbon
pneumonitis. The administration of activated charcoal is reasonable, although no data have yet
demonstrated its benefit.
There is no known method to enhance the elimination of PCBs from fat depots. The physician should
discourage the use of special diets, nutritional therapies, or saunas to enhance PCB elimination.
Chloracne usually resolves over months with some lesions requiring many years to heal. Avoidance of
exposure, local cleansing, antibiotics, and topical or systemic retinoic acid are the essentials of treatment (
Table 101–1 ).
Table 101-1 -- Summary of Clinical Presentation, Differential Diagnosis, and Treatment of Exposure to
Polychlorinated Biphenyl Compounds
Acute exposure (symptoms rare)
Irritation:
Ocular
Respiratory
Dermal
Nausea/vomiting—with ingestion
Chronic exposure
Chloracne
Hepatocellular injury (possible association)
Lymphoma, sarcoma (possible association)
Chloracne—exposure to PCBs, PBBs, PCDDs, PCDFs, and polychlorinated naphthalenes
Treatment
Decontamination
Dermal
Copious irrigation with water followed by gentle cleansing with mild soap
Avoid abraiding skin
Ocular
Copious irrigation with normal saline
Oral
Nasogastric suction of stomach contents
Activated charcoal 1 g/kg body weight
Other measures
Airway management
Treatment of underlying injuries
Chloracne—antibiotics, systemic retinoic acid


DISPOSITION
Acute toxicity is rare following PCB exposure, and most patients can be discharged from the emergency
department. A minority of patients may develop delayed symptoms or signs. Medical evaluation several
weeks later should focus on symptoms, abnormal physical findings, and a biochemical assessment of
hepatic function. All patients require referral for counseling concerning carcinogenic risk. The management
of chloracne is very difficult and probably best referred to a dermatologist. The physician should educate
patients on ways to avoid exposures in the future. Unless the exposure has been massive, a mother may
continue to breast feed.[28]


SEQUELAE
PCBs and related compounds are considered to be probable human carcinogens. These agents act as
tumor promoters in animal models. The cancer risk from a single exposure is very low with most data on
chronic exposures in humans being inconsistent and indeterminate.[1][6][20][21][28] The possible association
between PCBs, lymphoma, and soft tissue sarcomas has been described. [31] Although PCBs have a
potential to cause developmental and teratogenic effects, the data in humans are inconclusive.[4]


REFERENCES
1. Andrews J: Polychlorodibenzodioxins and polychlorodibenzofurans.
In: Sullivan Jr JB, Krieger GR, ed. Hazardous Materials Toxicology, Baltimore: Williams & Wilkins; 1992.
2. Acquavella JF, Hanis NM, Nicolich MJ, Phillips SC: Assessment of clinical, metabolic, dietary, and
occupational correlations with serum polychlorinated biphenyl levels among employees at an electrical
capacitor manufacturing plant. J Occup Med 1986; 28:1177.
3. Asplund A, Svensson B, Nilsson A, et al: Polychlorinated biphenyls, 1,1,1-trichloro-2,2-bis(p-

chlorophenyl)-ethylene (p,p’-DDE) in human plasma related to fish consumption. Arch Environ
Health 1994; 49:477.
4. Battershill JM: Review of the safety assessment of polychlorinated biphenyls (PCBs) with particular
reference to reproductive toxicity. Human Exper Toxic 1994; 13:581.
5. Crow KD: Chloracne and its potential clinical implications. Clin Exp Dermatol 1981; 6:243.
6. Fingerhut MA, Halperin WE, Marlow DA, et al: Cancer mortality in workers exposed to 2,3,7,8-
tetrachlorodibenzo-p-dixon. N Engl J Med 1991; 324:212.
7. Fischbein A: Wolff MS, Lilis R, et al: Clinical findings among PCB-exposed capacitor-manufacturing
workers. Ann NY Acad Sci 1979; 320:703.
8. Fischbein A, Wolff MS, Bernstein J, et al: Dermatological findings in capacitor manufacturing workers
exposed to dielectric fluids containing polychlorinated biphenyls (PCBs). Arch Environ Health 1982; 37:69.
9. Fischbein A, Wolff MS, Lilis R, et al: Clinical findings among PCB exposed capacitor manufacturing
workers. NY Acad Sci 1979; 320:
10. Fischbein L: Toxicology of chlorinated biphenyls. Annu Rev Pharmacol 1979; 14:139.
11. Fitzgerald EF, Standfast SJ, Youngblood LG, et al: Assessing the health effects of potential exposure to
PCBs, dioxins, and furans from electrical transformer fires: The Binghamton State office building medical
surveillance program. Arch Environ Health 1986; 41:368.
12. Kimbrough RD: Human health effects of polychlorinated biphenyls (PCBs) and polybrominated
biphenyls (PBBs). Annu Rev Pharmacol Toxicol 1987; 27:87.
13. Kimbrough RD: Consumption of fish: Benefits and perceived risk. J Toxicol Environ
Health 1991; 33:81.
15. Kuratsune M, Shapiro RE: PCB poisoning in Japan and Taiwan. Am J Ind Med 1990; 17:411.
16. Letz G: The toxicology of PCBs—an overview for clinicians. West J Med 1983; 138:534.
17. Maroni M, Colombi A, Arbosti A, et al: Occupational exposure to polychlorinated biphenyls in electrical
workers. II. Health effects. Br J Ind Med 1981; 38:55.
18. McFarland VA, Clarke JU: Environmental occurrence, abundance, and potential toxicity of
polychlorinated biphenyl congeners: Considerations for a congener-specific analysis. Environ Health
Perspect 1989; 81:225.
19. Phillips DL, Smith AB, Burse VW, et al: Half-life of polychlorinated biphenyls in occupationally exposed
workers. Arch Environ Health 1989; 44:351.
20. Rosenman KD: Dioxin, polychlorinated biphenyls, and dibenzofurans. In: Rom WN, ed. Environmental
and Occupational Medicine, 2nd ed. Boston: Little, Brown; 1992:927.
21. Shields PG, Whysner JA, Chase KH. Polychlorinated biphenyls and other polyhalogenated aromatic
hydrocarbons. In Sullivan JB, Jr, Krieger, GR (eds): Hazardous Materials Toxicology. 1992, Chap. 65, p 748.
22. Smith AB, Schloemer J, Lowry LK, et al: Metabolic and health consequences of occupational exposure
to polychlorinated biphenyls. Br J Ind Med 1982; 39:361.
23. Steele G, Stehr-Green Pl, Welty E: Estimates of the biologic half-life of polychlorinated biphenyls in
human serum. N Engl J Med 1986; 314:926.
24. Taylor JR: Chloracne—A continuing problem. Cutis 1974; 13:585.
26. Tindall JP: Chloracne and chloracnegens. J Am Acad Dermatol 1985; 13:539.
27. Ueng T, Alvares AP: Selective induction and inhibition of liver and lung cytochrome P450 dependent
monooxygenases by the PCBs mixture, Aroclor 1016. Toxicology 1985; 35:83.
28. Wabeke R, Weinstein R: Polychlorinated biphenyl toxicity. Clin Toxicol 1990; 23:505.
30. Wester RC, Bucks AW, Marbach HI, et al: Polychlorinated biphenyls: Dermal absorption, systemic
elimination, and dermal wash efficiency. J Toxicol Environ Health 1983; 12:511.
31. Committee to Review the Health Effects in Vietnam Veterans of Exposures to Herbicides. Veterans and
Agent Orange Update 1996. Washington, D.C., Division of Health Promotion and Disease Prevention,
Institute of Medicine, National Academy Press.


Uncited references
Kimbrough RD: Polychlorinated biphenyls and human health: An update. Crit Rev Toxicol 1995; 25:133.
Taylor JS: Environmental chloracne: Update and overview. Ann NY Acad Sci 1979; 320:295.
Weaver G: PCB contamination in and around New Bedford, Mass. Environ Sci Technol 1983; 18:22A.


Chapter 102 – Organophosphates and Carbamates
CYNTHIA K. AARON
Essentials
• High index of suspicion
• Signs and symptoms:
° Central nervous system (CNS): seizures, altered mental status
° Muscarinic: DUMBELS—Diarrhea, Urination, Miosis, Bradycardia, bronchorrhea,
bronchospasm, Emesis, Lacrimation, Salivation
° Nicotinic: adrenergic stimulation, fasciculations, muscular weakness
• Response to atropine and pralidoxime

• Depressed butyrylcholinesterase (BuChE) or erythrocyte acetylcholinesterase (AChE) activity
• Elevation of erythrocyte AChE activity after pralidoxime therapy
INTRODUCTION
Organophosphates and carbamates are cholinesterase-inhibiting chemicals used predominately as

pesticides. They are also used as chemical warfare agents. They are ubiquitous in the environment. Their
toxic effects are similar to those of cholinesterase inhibitors used medically to treat glaucoma
(physostigmine), myasthenia gravis (neostigmine, pyridostigmine), supraventricular tachycardia
(edrophonium), and Alzheimer’s disease (tetrahydroaminoacridine). Exposures to cholinesterase inhibitors
follow both deliberate and inadvertant ingestion or overdose, occupational error and accidents, and
international warfare. Identification of poisoning may be simple when the patient presents with a known
exposure, or it may be exceedingly difficult in a critically ill patient with confusing symptoms and no history of
exposure. Treatment consists of decontamination, blockade of muscarinic hyperactivity with atropine,
reversal of cholinesterase inhibition with oxime nucleophiles (pralidoxime), and correction of metabolic
abnormalities. The majority of patients with significant exposures to organophosphates and carbamates
have a good prognosis. Those who develop organophosphorus-induced delayed polyneuropathy will have
lasting sequelae.


Toxicokinetics
Organophosphorous compounds and carbamates are a family of compounds that share structural
similarities. The kinetics of each group are highly dependent on multiple physical factors. Some of these
include route of administration (ingestion, injection, inhalation, transdermal and transmucosal absorption),
distance from target organs, local versus systemic metabolism and activation, route of elimination,
endogenous hydrolysis, and consumption of the compound by various nonspecific esterases before
reaching target organs. Structural considerations include the groups attached to the sulfur, carbon, or
phosphorus moiety, the tightness of the bond to the central atom, and the affinity of the compound for
cholinesterases.
Onset of symptoms is fastest with inhaled (within seconds for tabun or sarin) or injected compounds and
slowest with transdermal absorption, although VX can cause immediate toxicity after application to the skin.
The majority of agents should show some signs and symptoms of toxicity within 6 to 12 hours after exposure
with the exception of the highly fat-soluble compounds (fenthion, difenthion, chlorfenthion). The fat-soluble
compounds may not manifest toxicity for several days to weeks because the substance must be “leached
out” of the fat until a sufficient amount of cholinesterase is inhibited to cause symptoms. Other agents that
may have delayed onset of symptoms include those compounds that require hepatic activation to convert
the substance to its active toxic state (e.g., parathion to paraoxon).
Patients will remain clinically ill as long as there is active toxin available to bind to any free cholinesterase
and depress the cholinesterase to less than 20 per cent activity. This is affected by the rate of endogenous
hydrolysis (months for organophosphates to hours with carbamates), amount of unbound nonspecific
esterases available to scavenge free toxin, and circulating pralidoxime. With the exception of the fat-soluble
agents, it was initially believed that most organophosphorus residues were eliminated within the first 48
hours after exposure. Newer data suggest these residues may remain for days to weeks,[57] even after
successful treatment of initial symptoms. AChE, if not regenerated by nucleophilic oximes such as the
antidote pralidoxime, must be generated at the nerve terminal, a process that may take several months.
BuChEs are hepatically synthesized acute-phase proteins that can be replaced within several weeks.
Toxicity, however, is dependent on AChE activity.
Pathophysiology
Organophosphorous compounds and carbamates inhibit the function of carboxylic ester hydrolases such as
chymotrypsin, AChE, plasma or BuChE (pseudocholinesterase), plasma and hepatic carboxylesterases
(aliesterases), paraoxonases (asterases), and other nonspecific esterases within the body. The most
prominent clinical effects of poisoning with organophosphorous compounds are related to their inhibition of
AChE.
Acetylcholine (ACh) is a neurotransmitter found at the neuromuscular junction, at preganglionic synapses in

the sympathetic and parasympathetic autonomic nervous system, at postganglionic parasympathetic
(muscarinic) terminals, and within the brain. Action potentials generated by stimulation of the cholinergic
system cause calcium-mediated ACh release at the nerve terminal. The ACh then binds postsynaptic
receptors via G proteins (muscarinic) and ligand-linked ionic channels (nicotinic). Receptor binding alters the
flow of potassium, sodium, and calcium’ ions leading to changes in membrane permeability and altered
membrane potential. This allows for propagation of the action potential.[5] AChE, which hydrolyzes ACh into
acetic acid and choline, is found at each site where ACh is the operative neurotransmitter. It terminates the
effects of ACh binding by rapidly breaking down ACh within the synaptic cleft. When AChE is inactivated,
ACh accumulates and massive membrane depolarization occurs, resulting in tetanic receptor stimulation
and eventual paralysis of function.
AChE is also genetically expressed on the surface of the erythrocyte. The amount of AChE activity in red
blood cells reflects the state of neuronal and muscular AChE activity. BuChE, or pseudocholinesterase, is
manufactured in the liver and is found in plasma, liver, heart, pancreas, and brain. The role of BuChE has
not been established. However, it is easy to assay and its activity mirrors AChE closely enough to provide a
good marker for cholinesterase function.
The mechanism of action of AChE is well defined. ACh binds into an acyl pocket on the AChE molecule.
Near the pocket is an anionic binding site and a serine active site. The shape of the pocket confers
stereospecificity for binding to AChE. ACh enters the pocket and binds at the choline active site, causing an
allosteric change in pocket shape. After the enzymatic hydrolysis of ACh to acetic acid and choline, the
pocket resumes its normal shape. Turnover time for enzyme hydrolysis is approximately 150 µsec.[44][48]
The medically useful anticholinesterase agents bind and inhibit ACh in a reversible manner, preventing it
from hydrolyzing ACh. The rate of recovery of the bound enzyme depends on the structure of the individual
agent.
Both organophosphates and carbamates can bind into the acyl pocket at the active site of AChE. The
binding of a phosphate (organophosphate) or carbamyl (carbamate) group to the serine amino acid at the
active site of ACh changes the configuration of the enzyme molecule, stabilizing it and preventing it from
functioning. The carbamyl group from a carbamate will spontaneously dissociate within 24 hours, leaving a
functional enzyme. However, spontaneous regeneration of phosphorylated AChE requires days to months;
so, from a physiologic perspective, an enzyme phosphorylated by an organophosphate is permanently
inactivated.[47] Function can only be restored if a new enzyme is created or an antidote displaces the
phosphate moiety. Because enzyme regeneration takes weeks, the only real physiologic option is to use an
antidote.
Over time, organophosphorous compounds can permanently alter the shape of the acyl pocket so that
endogenous hydrolysis of the serine-phosphate bond cannot occur and antidote function becomes limited.
This is called “aging.” During the “aging” reaction, the acyl group is lost from the phosphorylated enzyme and
the pocket shape change becomes permanent.[44][48] Carbamates dissociate from the AChE molecule within
24 hours, so they do not cause aging. They also will not pass readily through the blood-brain barrier and
thus have limited CNS toxicity. However, even though their toxicity is time limited, they are powerful
inhibitors of cholinesterase and their peripheral signs and symptoms of toxicity are identical to the
organophosphorous compounds.[47]
Pralidoxime, the antidote that is available in the United States, is one of a class of nucleophilic oximes that
regenerate AChE by removing the phosphate moiety from the acyl pocket. Pralidoxime will also act as a
scavenger for additional nonbound organophosphate. Pralidoxime is less effective in the case of “aged”
AChE.


Cholinesterase inhibitors are a heterogeneous class of agents in which the particular effects of each
individual agent are closely related to its structure. Large hydrophobic side chains confer different degrees of
fat solubility. The most fat-soluble agents are stored in fat tissue and released slowly over time. Other
structural differences affect how tightly the agent will bind to the AChE active site, how long it takes to
hydrolyze, how potent the agent is in blocking the AChE, and latency to onset of signs and symptoms.
Latency is affected by fat solubility, route of exposure, rate of endogenous hydrolysis, how tightly it binds to
the enzyme active site, whether the agent needs to become activated before it is toxic, and whether other
nonspecific esterases can consume it before it reaches the AChE. [19][23][24]
Acute Toxicity
The key component in the diagnosis of cholinesterase inhibition is in suspecting the intoxication. A history of
myasthenia gravis or Alzheimer’s disease is a clue to the possible ingestion of a cholinesterase inhibitor.
Other information such as the patient’s occupation or location where found, specific odors, or activities
preceding the patient’s presentation to the emergency department should provide some clues. Although
classically described as having a garlic-like odor, many organophosphorous compounds are mixed in
hydrocarbon bases and will have a distinctly hydrocarbon or solvent type of odor.
The onset of symptoms of toxicity after the inhalation of cholinesterase inhibitors may occur within seconds,
following their rapid penetration into the pulmonic circulation and dissemination throughout the body. This is
important for the “nerve agents” used in chemical warfare and for pesticides used in crop dusting. Ingested
agents also tend to act rapidly. Transdermal and transconjunctival exposures result in a more delayed onset,
although the chemical warfare agent “VX,” which is absorbed transdermally, has an extremely rapid onset of
action. Unless the agent requires secondary activation by endogenous processes, such as the hepatic
activation of parathion to paraoxon, or is extremely fat soluble (fenthion), the onset of signs and symptoms
will occur within 12 hours after the exposure for most agents. The fat-soluble agents may require several
exposures before the person becomes symptomatic because the agent is stored in the adipose tissue and
slowly leaches out, depressing cholinesterase activity in an additive fashion.
The signs and symptoms of cholinesterase-inhibitor poisoning are related to their effects on three separate
areas of the cholinergic nervous system: (1) postganglionic parasympathetic hollow end-organ (muscarinic)
effects; (2) sympathetic and parasympathetic ganglionic and somatic neuromuscular junction (nicotinic)
effects; and (3) CNS effects. The poisoned patient may present with signs and symptoms related to varying
degrees of cholinergic stimulation in each of these three areas.
Muscarinic stimulation produces what have been commonly called the “wet findings.” These are
characterized by excessive salivation, lacrimation, bronchorrhea, urinary and fecal incontinence, and
vomiting. Bronchoconstriction is a muscarinic finding, as is miosis. Cardiovascular effects are related to
enhanced vagal tone manifest as bradycardia, prolonged sinoatrial and atrioventricular nodal conduction
time, and a decrease in the effective refractory period of the atrium. The mnemonics “SLUDGE” and
“DUMBELS” are useful in remembering these findings ( Table 102–1 ).[19][54]
Table 102-1 -- Mnemonics for Muscarinic Features of Exposure to Cholinesterase Inhibitors

Sludge Dumbels
Salivation Diarrhea
Lacrimation Urinary incontinence
Urinary incontinence Miosis, muscle fasciculations
Diarrhea Bronchorrhea, bronchospasm, bradycardia
Gastrointestinal distress Emesis
Emesis Lacrimation
Salivation
Nicotinic stimulation impairs muscular activity at the level of the neuromuscular junction. In addition,
because ACh is the neurotransmitter in the preganglionic sympathetic nerves, it may also cause stimulation
of the sympathetic nervous system. It is this class of findings that is the most useful in differentiating
cholinesterase inhibitor toxicity from other causes of seizures and pulmonary edema. Sympathetic findings
include mydriasis, tachycardia, hypertension, and pallor. Neuromuscular findings include muscular
fasciculations, muscle cramping, weakness, and paralysis. Diaphragmatic weakness may result in
respiratory difficulty and respiratory failure.[23][39][41][54]
CNS toxicity is reflected in anxiety, restlessness, headache, tremor, confusion, slurred speech, delirium,
psychosis, seizures, and death. Emotional lability and personality changes have also been described ( Table
102–2 ).[23][30][39][41][53][54][55]
Table 102-2 -- Clinical Presentation of Organophosphate and Carbamate Exposure

Consider Diagnosis
Occupation or Hobby
Gardener, homeowner, child (exploring), elderly (loss of visual acuity)
Exterminator, crop duster, trucker, mixer, maintenance person, greenskeeper, farmer, hardware store
employee, pesticide worker
Drug abuser
Access to Cholinesterase Inhibitor
Elderly with Alzheimer’s disease, history of myasthenia gravis, hardware store clerk, pesticide worker, child
Suicidal
Signs/Symptoms
Muscarinic
Tearing, drooling, profuse diaphoresis, emesis, urinary and fecal incontinence, gastrointestinal cramping
Bronchospasm and bronchorrhea (rales and rhonchi)
Miosis, bradycardia, hypotension, conduction blocks
Nicotinic
Respiratory difficulty, respiratory arrest, diaphragmatic weakness
Muscle weakness, fasciculations, clonus, tremor
Mydriasis, hypertension, tachycardia, re-entrant dysrhythmias, cardiorespiratory arrest
Malaise, memory loss, confusion
Disorientation, delirium, seizures, coma
Note: Patients frequently present with a mixture of the above. Do not be confused if patient has mydriasis,
tachycardia, and hypertension associated with drooling and rales.
Chronic Toxicity
Patients with chronic low-level exposure may not show any signs and symptoms until cholinesterase has
been inhibited beyond a critical point. The body can maintain normal physiologic function until
cholinesterase activity is inhibited by 20 to 50 per cent. ACh is constantly being degraded and regenerated
endogenously. Bound enzyme will spontaneously hydrolyze, and nonspecific esterases will combine with
organophosphates and carbamates and prevent them from reacting with the AChE. At some point these
defenses may be overwhelmed, and the patient becomes symptomatic. Chronic low level exposure is
clinically similar to poisoning by fat-soluble organophosphates because both expose the enzyme to continual
low levels of inhibition. These patients may show signs of toxicity at greater than 12 hours from exposure.
Other factors that may alter an individual response to exposure include medications that inhibit
cholinesterases or congenital deficiency in cholinesterase function. These patients may get into trouble
during seemingly innocuous situations. Impairment of pseudocholinesterase function during chronic
exposure to cholinesterase inhibitors also affects levels of medications and toxins that are normally
metabolized by pseudocholinesterase. These include succinylcholine, morphine, codeine, esmolol, and local
ester anesthetics such as cocaine and tetracaine.[43] The development of unexplained toxicity to one of
these agents in a patient with occupational exposure to pesticides should suggest chronic poisoning.
Infants and neonates have lower baseline cholinesterase activity and are at increased risk when exposed to
equivalent amounts of organophosphorous compounds or carbamate.[28] Their underdeveloped, less
myelinated nervous system may show additional long-term toxicity, but this has yet to be documented.
Cholinesterase levels are also depressed during pregnancy, especially during the first two trimesters.


Components of the complex of symptoms associated with cholinesterase inhibitor poisoning may lead to
misdiagnosis based on similarities with more familiar conditions. Patients with severe bronchorrhea and
respiratory distress may be mistakenly diagnosed with cardiogenic pulmonary edema or asthma. A hypoxic
seizing patient may be erroneously assumed to have aspirated. The severe vomiting and diarrhea that may
follow acute ingestion may be mistaken for gastroenteritis. The odor of garlic or hydrocarbon or the presence
of fasciculations, motor weakness, miosis, or significant bradycardia may suggest the correct diagnosis.
Diagnosis is important in that treatment delay may predispose the patient to a prolonged hospital course,
aspiration, and rhabdomyolysis ( Table 102–3 ). Therapies used to treat other conditions that mimic this
intoxication, such as nitrates and diuretics, will worsen the patient’s overall condition. Finally, there is an
exposure risk to health care providers if the poisoning is not identified. Exposure to contaminated clothing,
hair, or secretions can poison unprotected health care providers and contaminate the rest of the emergency
department ( Table 102–4 ).
Table 102-3 -- Diagnostic Criteria for Cholinesterase Inhibitors

Presentation consistent with poisoning and access to chemical
Positive response to atropine and pralidoxime
Requirement for continued therapy with atropine and/or pralidoxime
Electromyographic pattern consistent with decremental conduction with repetitive nerve stimulation and acute
cholinergic illness
Development of ascending sensorimotor polyneuropathy with electromyographic pattern consistent with axonal
degeneration and occurring 1 to 3 weeks after exposure to an organophosphate known to produce neuropathy.
Acute cholinergic illness may or may not have preceded the polyneuropathy.
Depressed cholinesterase activity below 20 to 50% of population normals
Elevation in cholinesterase activity therapy with pralidoxime in treated patient.
Serial elevations in cholinesterase activity after acute illness resolves in an untreated patient
Table 102-4 -- Differential Diagnosis of Cholinesterase Inhibitor Toxicity

Miosis Central a2-agonists (e.g., Should lack muscarinic and nicotinic signs
clonidine) and symptoms
Meprobamate and other
sedative-hypnotics
Opioids
Phencyclidine
Phenothiazines (varies)
Pilocarpine (topical)
Pontine hemorrhage
Should lack nicotinic findings: patient
Bethanecol should have no muscle weakness or
fasciculations
Mushrooms:
Muscarinic signs/symptoms
Inocybe
Clitocybe
Pilocarpine
Nicotine (patches, gum,
May have seizures, fasciculations,
insecticide), smoking while
vomiting, sialorrhea, and bronchorrhea.
using nicotine replacements
Nicotinic signs/symptoms
Should not have miosis. Apnea common
Nicotiana
in severe poisonings.
Lobelia
Should lack sialorrhea, diarrhea,
Asthma
cramping, myoclonus, or fasciculations.
Bronchorrhea/respiratory distress Metabolic acidosis Respiratory activity should be present.

Pulmonary edema/embolism
Salicylism
Should have findings consistent with the
causative agent (fever, focality, abnormal
Idiopathic
metabolic screen). Should lack muscarinic
and nicotinic findings.
New-onset seizure Infection
Metabolic
Toxic
Structural
Should lack majority of “DUMBELS” or
Hypertension, seizures, Cocaine or other
“SLUDGE” muscarinic findings. Muscular
tachycardia, mydriasis, tremor, sympathomimetic intoxication
activity should be coordinated.
clonus, diaphoresis
Sedative-hypnotic withdrawal
Toxins and medications whose effects are similar to the cholinesterase inhibitors include the synthetic
choline ester drugs such as bethanechol, methacholine, and carbachol. These agents have primarily
muscarinic effects, although carbachol also has nicotinic effects at the sympathetic ganglia. Naturally
occurring alkaloids that have cholinergic activity include pilocarpine and muscarine. Muscarine is found in
several species of mushroom, including Amanita muscaria, Inocybe, and Clitocybe species. The
predominant effect of muscarine is stimulation of muscarinic receptors.[5] All of these agents lack effects at
the neuromuscular junction. Many signs and symptoms of nicotine poisoning closely resemble those of
poisoning with cholinesterase inhibitors, especially vomiting, seizures, fasciculations, and motor weakness
(see Chapter 123 ).


LABORATORY STUDIES
The demonstration of depressed cholinesterase activity is the gold standard to identify cholinesterase
inhibitor toxicity. Because cholinesterase levels are rarely available in a timely way, this confirmation is
almost always obtained after diagnosis and successful treatment. Additionally, a single cholinesterase level
may not provide useful information. Cholinesterase activity “normals” are ranges based on population
estimates. The range is such that someone who tests in the “low normal” range could have either normally
functioning enzyme or have significantly depressed activity. Ideally, the patient should have a baseline
cholinesterase activity level determined and then subsequent levels compared with that. Unfortunately,
unless the person is in a job-related surveillance program, this is rarely the case. Diagnosis then hinges on
an increase in erythrocyte AChE activity immediately after treatment or an increase in plasma
pseudocholinesterase with time.
Cholinesterase activity can be assayed either by erythrocyte AChE activity levels or BuChE activity levels.
As previously stated, erythrocyte AChE is the same enzyme that is found in the nervous system. The activity
level of this enzyme is an indicator of what is occurring on the neuronal level. BuChE is more easily
assayed, but its activity does not correlate as well with neuronal effects. Erythrocyte AChE responds to
antidotal therapy in the same way as neuronal AChE, showing increased activity after pralidoxime therapy.
The response of BuChE to antidotal therapy is less predictable and less dramatic. In the absence of
antidotal treatment erythrocyte AChE will regenerate to normal levels in 5 to 7 weeks, the rate it takes to
regenerate new blood cells (1 per cent per day). BuChE activity shows a rapid improvement over 7 to 10
days, then normalizes within 4 to 6 weeks. Because BuChE is an acute-phase protein, it is altered by
anything that affects hepatic function and protein stores, such as malnutrition, chronic illness, cirrhosis,
neoplasia, and infection.[8][9][22][23][41][53] Erythrocyte AChE may be altered by changes in the circulating life
of the red blood cell, such as hemoglobinopathies and thalassemia.[8][28]
Other laboratory testing can assist in managing the complications of the cholinesterase intoxication.
Oxygenation may be monitored with continuous pulse oximetry or by arterial blood gas determinations.
Because bronchospasm may play an important part in muscarinic toxicity, end-tidal carbon dioxide wave
monitoring may be a useful indicator of deterioration. Continuous electrocardiographic monitoring and a 12-
lead EKG are useful to evaluate cardiovascular complications. Otherwise, laboratory testing is adjunctive to
therapy. Patients will show a stress leukocytosis with a relatively normal differential. If there has been
significant diaphoresis, vomiting, and diarrhea, the hematocrit should show hemoconcentration and the
blood urea nitrogen level will be elevated. An anion gap acidosis may occur if perfusion is compromised.
Owing to the stress reaction, there will be evidence of hyperglycemia, hypokalemia, and hypomagnesemia.
Urine toxicologic drug screening will not identify cholinesterase inhibitor poisoning. In the case of a
suspected deliberate exposure, the possible co-ingestion of other agents such as salicylates or
acetaminophen should be considered. In any female of child-bearing age, a urine pregnancy test is
important. This is not only because the pregnancy may be a causative factor in the exposure but also
because the extent of fetal cholinesterase inhibitor toxicity is not fully elucidated and the mother will require
future guidance. In some situations, urinary nitrophenols can help to identify exposure to a particular
cholinesterase inhibitor.


TREATMENT
Treatment of cholinesterase inhibitor poisoning is directed toward supportive care, decontamination,

restoration of oxygenation, treatment of muscarinic signs and symptoms, and antidotal therapy to regenerate
AChE ( Table 102–5 ).
Table 102-5 -- Treatment of Organophosphate and Carbamate Exposure

Decontamination
Gastrointestinal
If ingestion occurred within last 30 to 60 minutes, place nasogastric tube and empty stomach of all contents.
Administer activated charcoal, 1 g/kg orally, unless emesis prevents this.
Do not use cathartic, owing to anticipated diarrhea.
Dermal
Remove patient’s clothing and discard it.
Wash patient’s skin and hair with copious amounts of soap and water.
Health care workers should wear protective barriers.
Masks with eye shield
Water-resistant gowns and shoe covers
Nitrile or neoprene gloves
Tape gloves and shoe covers to gown.
Protect environment from contamination.
Treatment
Establish airway; administer 100% oxygen.
Establish intravenous access; obtain cholinesterase activity level.
Atropine, 1–2 mg intravenously test dose (pediatric: 0.05 mg/kg).
Double the dose every 5–10 minutes until tracheobronchial secretions are dry and patient can be oxygenated.
Disregard pupil size change.
Consider atropine infusion if extremely large doses required (50 mg in 250 mL normal saline, yielding a
concentration of 0.2 mg/mL; titrate to effect). and
Pralidoxime (2-PAM or ProtoPAM) *
Load:
Adult: 1–2 g IV infusion in saline over 15–30 minutes
Pediatric: 20–40 mg/kg to maximum 1 dose)
Further Doses:
The dose can be repeated in 1 hour and then every 4–8 hours for 24–48 hours, assuming symptoms resolve,
or Infuse:
Adult: 500 mg/hr of a 2.5% solution
Pediatric: 9–19 mg/kg/hr of a 2.5% solution for 24–48 hours, assuming symptoms resolve or 3–4.5 mg/kg
infusion over 15–30 minutes followed by 2–3 mg/kg/hr for at least 24–48 hours †
Obtain electromyogram (EMG) after 48 hours if patient remains symptomatic when pralidoxime is weaned or
patient exposed to agents implicated in intermediate syndrome.
If EMG is abnormal, continue pralidoxime until EMG normalizes.
Monitor erythrocyte acetylcholinesterase activity level during pralidoxime therapy if available; otherwise, stop
pralidoxime after 24–48 hours and reassess clinical status.
After discharge:
Monitor enzyme activity level until normal.
Do not allow patient to return to work with occupational exposure to cholinesterase inhibitors until enzyme
levels have normalized.
Ensure that workplace has been inspected and meets standards.
* Total dose may be given over 2 minutes in patients with life-threatening condition.
† Dosing regimen based on protocols in poisoned patients and in adult human volunteers.[37][57]
Decontamination
Organophosphates and carbamates are found in various forms, including liquid, powder, aerosol, and
granule, or in hydrocarbon/solvent bases. All forms may persist on the human body or clothing. The majority
of compounds have at least some nonpolar constituents and will readily penetrate skin and skin products
(leather). Any patient suspected of organophosphate or carbamate toxicity requires decontamination before
definitive therapy. This becomes an issue if the airway is compromised and requires immediate treatment.
The person rendering this aid must be protected from contamination or he or she will become the next
victim. Because organophosphates will penetrate normal latex or polyvinyl gloves, nitrile or neoprene
(chemical resistant) gloves are recommended. Aspiration of gastric contents through a nasogastric tube may
be indicated if ingestion has occurred within the past hour. However, often copious, ongoing vomiting
prevents further gastrointestinal measures, including use of activated charcoal. If the agent is aerosolized or
in a fine powder, respiratory precautions should be taken. Clothing and shoes should be covered with
protective water impermeable materials, and masks with eye shields should be used. All clothing and
protective materials should be discarded before the patient is moved into the clean area. Clothing is toxic
waste and needs to be double bagged. The patient should be washed down with copious amounts of water.
Gentle cleaning with soap and water is effective and will not abrade the skin and enhance absorption. The
rinse water is considered to be contaminated. If the person ingested a large amount of an organophosphate,
then the body fluids may be contaminated. Chlorine bleach (4–5 per cent hypochlorite) will deactivate the
organophosphate or carbamate and can be used to decontaminate instruments and other equipment. It
should never be used in the eyes.[18][51]
Atropine
Pharmacologic therapy begins with establishing a patent airway. The majority of patients with life-threatening
exposures will be at risk for airway compromise, either by seizure, loss of diaphragmatic activity, or
bronchorrhea and bronchospasm. Atropine, a competitive ACh antagonist at the postsynaptic muscarinic
nerve membrane, will dry respiratory secretions and bronchodilate. Atropine is administered with an initial
test dose of 1 to 2 mg intravenously (0.05 mg/kg). If no intravenous access is available, it can be given
intramuscularly. Atropine has onset within 1 to 4 minutes after administration, and peak effect is by 8
minutes; so, if there is no effect from the administered dose, then the dose can be doubled every 5 minutes
until muscarinic findings subside. The endpoint of successful atropinization is drying of the tracheobronchial
tree and the ability to oxygenate the patient. Dilated pupils or tachycardia are not contraindications to the
administration of atropine. The heart rate is expected to increase by 10 to 20 beats per minute.
Glycopyrrolate (0.05 mg/kg IV) may also be used to treat the peripheral muscarinic effects. It does not
penetrate the CNS and will only treat peripheral findings. Once the adequate atropine dose has been
established, this dose should be adjusted to maintain a dry tracheobronchial tree for 24
hours.[17][23][39][41][50][51][54]
The amount of atropine needed may be very large. In some cases, hundreds of milligrams of atropine were
required. An atropine drip can be made by reconstituting the powdered form into an infusion of dextrose 5
per cent in water (D5W) or normal saline. There is no specific concentration for the drip, but it would seem
reasonable to start at the dose of atropine that reduces respiratory secretions and administer this dose over
an hour. The drip can then be adjusted upward or downward depending on signs, symptoms, and side
effects. Once the patient has been atropinized, decontaminated, and antidotal therapy instituted, atropine
can be slowly withdrawn.
Pralidoxime
Any patient presenting with significant organophosphate toxicity should have a trial of antidotal therapy,
which if effective, should be continued.[22][25][38][45][50] Antidotal therapy is provided in the United States with
pralidoxime, one of a class of nucleophilic oximes that regenerate the AChE by removing the phosphate
moiety from the acyl pocket. Pralidoxime will act as a scavenger for additional nonbound organophosphate.
Although pralidoxime is less effective in the case of “aged” AChE, the time to complete inactivation of the
AChE by aging is not fully known and may vary between different agents. Consequently, there is no
restriction to using pralidoxime even if more than 24 to 48 hours have passed.
Pralidoxime may be administered as an intramuscular injection, intravenous bolus, or intravenous infusion.

The usual intravenous bolus is 1 to 2 g (20–40 mg/kg) dissolved into normal saline and infused over 30 to
120 minutes. This may be repeated in 1 hour. Because pralidoxime can potentially cause neuromuscular
blockade if administered too rapidly, it should not be given as a rapid intravenous bolus unless the patient is
in extremis. Other side effects include respiratory arrest, diastolic hypertension, dizziness, nausea and
vomiting, and blurred vision.[38] Dosing is repeated every 4 to 12 hours as needed. The clinical therapeutic
endpoint is resolution of muscle weakness and fasciculations. Pralidoxime is synergistic with atropine, and
muscarinic signs and symptoms will start to resolve within 10 to 40 minutes. Pharmacokinetic evaluation of
the drug has suggested that a serum level greater than 4 mg/L is necessary to be effective in treating
organophosphate toxicity. [37][56][57] A study in volunteers who were not poisoned showed that serum levels
dropped below this level by 2 hours after administration.[37] To prevent this, a continuous infusion of 500
mg/hr has been suggested. Two weight-based models have been published. The weight-based model
designed in poisoned patients used a 4.42-mg/kg load over 30 minutes followed by 2.14 mg/kg/hr.[57] The
alternative model in normal volunteers used 4 mg/kg infused over 15 minutes followed by 3.2 mg/kg/hr.[37]
Both maintained serum levels greater than 4 mg/L. The pharmacokinetics are more complicated in the
poisoned patient, because organophosphate residues present in the serum may consume the pralidoxime
and lower its circulating concentration. Additionally, the same group noted that the organophosphorous
residues remain in the serum for a much greater length of time than originally believed. Some non–fat-
soluble residues have been found in serum for several days to weeks after exposure.[57] Current
suggestions are to continue the infusion based on clinical response, with the endpoint being the absence of
signs and symptoms when the pralidoxime is discontinued.
The CNS effect of organophosphate intoxication may be partially treated by pralidoxime. Although
pralidoxime is a polar compound, there is evidence to suggest that it has a positive effect on the
CNS.[4][32][33] Patients with signs of CNS toxicity should be treated with this agent. In multiple animal studies,
the addition of diazepam to the atropine and pralidoxime has shown to improve survival and may improve
CNS outcome. Animals treated with diazepam had decreased incidence of seizures and neuropathy
associated with less histologic evidence of cardiac and brain cellular damage.[32][35][36][50][51] Certainly, if the
patient develops seizures, then the use of high-dose benzodiazepines is indicated. When a second
anticonvulsant is required, phenobarbital may be preferable to phenytoin. Phenytoin’s autonomic effects and
altering of the sodium channel are undesirable. During nerve activation, the binding of ACh to postsynaptic
receptors is mediated through G proteins (muscarinic receptor). Activation of the G protein alters potassium,
sodium, and calcium ionic currents and membrane potential. Phenytoin inhibits some of the same channels;
and although it may suppress seizure activity, it will also suppress cardiac activity and physiologic autonomic
response. Although barbiturates may worsen hypotension, the effect on -aminobutyric acid and the chloride
channel will be synergistic with benzodiazepines.
Carbamate Treatment
Carbamate exposures are treated in the same way, although they will spontaneously unbind within 24 hours.
The exception to this is poisoning from the carbamate carbaryl (Sevin). There is increasing evidence to
suggest that, in animal models, treatment with pralidoxime or obidoxime may worsen toxicity.[31][42][52]
However, unless the offending agent is known to be carbaryl, the use of pralidoxime is still recommended for
carbamate toxicity.
Patients with isolated ocular toxicity may benefit from local instillation of atropine or scopolamine.[41]
Similarly, if the patient presents with isolated bronchospasm, or has continued bronchorrhea after systemic
treatment, nebulized atropine or ipratropium will help with oxygenation.
Patients requiring rapid sequence intubation for airway control present a unique problem. Succinylcholine,
which is the most frequently used rapid-onset depolarizing agent, is metabolized via plasma BuChE. In
organophosphorus or carbamate poisoning, BuChE is inactivated. Consequently, succinylcholine-induced
paralysis will persist for several hours to possibly days until new BuChE is generated. Alternatively, because
there is an abundance of ACh present at the receptor, patients will show resistance to nondepolarizing
agents such as pancuronium or vecuronium, requiring higher doses to achieve paralysis. Atracurium,
although partially metabolized by plasma BuChE, is predominately eliminated through Hoffman degradation.
Its rapid onset and alternative metabolism may be a useful alternative to succinylcholine. However, if the
patient requires immediate intubation, succinylcholine remains the most rapidly available agent. Once the
patient is on a ventilator and treated, prolonged paralysis is less of a problem.
Patients poisoned with highly fat-soluble agents such as fenthion can have prolonged toxicity. Because the
organophosphorus-containing agent is sequestered in fat tissue, fat biopsy for organophosphate assay may
help in determining length of pralidoxime therapy.


DISPOSITION
All patients exposed to cholinesterase inhibitors should be decontaminated and evaluated. If the patient
remains asymptomatic for 6 to 12 hours, the person may be discharged home with close follow-up. Any
contaminated clothing, including shoes, belts, or other leather items, should be destroyed. During patient
treatment, the exposure site should be decontaminated and any exposed health care workers should start
medical surveillance.
In work-related exposures, the demonstration of increasing levels of serum or erythrocyte cholinesterase

several weeks after treatment can give a retrospective diagnosis. If the initial level is clearly below normal
cutoff, then the patient can be considered exposed and poisoned and should be removed from the work
environment until levels return to approximately 75 per cent of normal. The person should be cautioned to
avoid opioids or ester anesthetics and to inform the anesthesiologist if surgery is required. A “normal”
cholinesterase value should also be rechecked in several weeks to detect any change.
Any symptomatic patient should be admitted to the hospital for at least 24 hours.[17][39][41][54] Although still
controversial, all patients who require atropine treatment should probably also receive pralidoxime. With the
continued knowledge that organophosphate residues are more persistent in the serum than originally
believed, the administration of pralidoxime may help in preventing future toxicity.[57] Patients who show
nicotinic symptomatology or airway compromise belong in an intensive care unit setting until all signs have
resolved.


SEQUELAE
There are three different neurologic sequelae that may result from poisoning with organophosphorous
compounds.
First, prolonged memory impairment, peripheral neuropathy, confusion, personality change, and thought
disorders have all been reported. Cause and effect has not been clearly documented, although one report
demonstrated changes in the basal ganglia on single-photon emission computed tomography. [6][27][30]
The intermediate syndrome (IMS) is characterized by respiratory failure; bulbar, nuchal, and proximal limb
muscle weakness; and depressed reflexes. It has been associated with the organophosphorous compounds
dimethoate, methamidifos, parathion, methylparathion, diazinon, malathion, fenthion, and dicrotophos. First
described in 1987,[49] it occurs 24 to 96 hours after resolution of the acute cholinergic crises.
Electromyographic studies show decremental conduction with repetitive nerve stimuli. Recovery is
associated with incremental conduction improvement and normalization of electromyograms. The recovery
is much longer than the time of onset. Cholinesterase activity appears to be 20 per cent or less during onset
of IMS.[2][49]
The etiology of this syndrome is controversial. Symptoms of IMS occur simultaneously with the depression
of cholinesterase activity levels and detection of organophosphorus residues in the serum, urine, and gastric
fluid. At the nadir of serum levels the electromyographic pattern at the neuromuscular junction is at its worst.
Slow improvement then ensues. Theoretically, this syndrome may represent the final partitioning of
organophosphate from serum to motor endplate.[1][2][3][10] Although still controversial, a consensus supports
inadequate oxime therapy as the causative factor. Although many IMS patients have received oxime
therapy, the association of IMS with persistent organophosphorus residues suggests that treatment may
have been prematurely discontinued. Because IMS occurs at the motor endplate, there may be a differential
need of oxime at the endplate that has yet to be determined. [1][10][11][12][13][14][15][16][21]
Organophosphate-induced delayed neurotoxicity (OPIDN) or polyneuropathy (OPIDP) is a sensorimotor

polyneuropathy that occurs 1 to 3 weeks after exposure to certain organophosphates. The initial toxicity may
be mild without the full-blown cholinergic presentation. The patient initially complains of distal motor
weakness in the lower extremities and sensory paresthesias. Eventually, the patient develops calf cramping
and pain. The motor weakness progresses to muscle atrophy and paralysis with footdrop. Ataxia develops,
and the distal tendon reflexes are lost. The neuropathy continues to spread, involving upper extremities and
may eventually develop into a flaccid symmetric paralysis that mimics Guillain-Barré syndrome. Some
patients may recover over 12 to 15 months, but permanent losses with spasticity and persistent upper motor
neuron findings have been reported.[20][26][40][46] On a pathologic level, the large distal neurons develop
axonal degeneration followed by myelin degeneration. This has been called the “dying back” phenomenon.
Degeneration occurs in association with the onset of paralysis and ataxia.[40]
OPIDN can be reliably reproduced in a hen model and has been studied extensively. It involves an axonal
membrane–bound enzyme named neuropathy target esterase (NTE) and appears unrelated to AChE activity
and more related to the leaving group on the central phosphorous atom. Specific organophosphorous
compounds bind to NTE at its active site. Organophosphates have the general structure of two side groups
containing an O R linkage off the central phosphorus atom. If the compound is a phosphate [P-(O-R)2-],
phosphonate [P-(R)(OR)], or phosphoraminate [P-NH-C-], NTE “ages” by losing one of its carbon groups.
The carbon group then binds to an adjacent undetermined site on the enzyme. Once NTE undergoes this
conformational change, axonal transport is disrupted. If greater than 70 per cent of NTE is inhibited, clinical
signs will develop. If the organophosphorous compound is a phosphonate [P-(R)2-], sulfonate [SO2-R-], or
carbamate [no P but an N C bond instead], then NTE cannot “age” and the enzyme is protected. [26]
Although onset of signs may be delayed for days to weeks, the damage is probably immediate and related to
the differential rate of axonal degeneration.


SPECIFIC SITUATIONS
Since the Persian Gulf War, interest in “nerve agents” and alternative forms of therapy has surged. The
nerve agents were developed before World War II in Germany as insecticides. These agents, designated by
“G” for German, are tabun (GA), sarin (GB), and soman (GD). VX was developed in England at a later time.
Cyclohexylmethylphosphonofluoridate (CMPF) has been designated GF and was recently
declassified.[18][20][50][51] All of these agents are extremely potent, with the G agents having inhaled lethal
doses in the milligram range. VX is an oily liquid that is rapidly absorbed transdermally.[46] The G and V
agents, when bound, “age” the cholinesterase extremely rapidly, with GB and GD causing “aging” in minutes
to hours, GF doing so in 4 to 38 hours, and GA taking greater than 40 hours. This means that the therapeutic
efficacy of available oximes (obidoxime, pralidoxime) is extremely limited. Since the Persian Gulf War,
several new therapeutic nucleophiles have been developed. The largest group, whose activity has been
tailored to the nerve agents is “Hagedorn” group. Two members of this group, HI-6 and HLo-7, have shown
some therapeutic promise.[7][29][34] Because of the unavailability of effective oximes during the Persian Gulf
War, using animal experiments as a basis, the United States Armed Forces took a different approach to
protect soldiers. In animals exposed to soman, pretreatment with a carbamate such as physostigmine or
pyridostigmine improved postexposure results with pralidoxime and atropine. Theoretically, if some of the
cholinesterase of a soldier is already partially bound (“protected”) with a much less toxic carbamate, then the
nerve agent cannot bind to this “protected” cholinesterase. If the soldier were subsequently exposed to
soman, spontaneous carbamate hydrolysis and immediate treatment with atropine and pralidoxime would
free the carbamoylated, or “protected,” cholinesterase and allow the soldier to continue functioning.
Pyridostigmine was chosen for “protective” treatment of troops with potential exposure to nerve agents,
because it does not cross the blood-brain barrier and has a better therapeutic index.[18][20][22][46][50]


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56. Willems JL, DeBisschop HC, Verstraete AG, et al: Cholinesterase reactivation in organophosphorous
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57. Willems JL, Langenberg JP, Verstaete AG, et al: Plasma concentrations of pralidoxime methylsulphate
in organophosphorous poisoned patients. Arch Toxicol 1992; 66:260-266.


Chapter 103 – Insecticides: Pyrethrins, Pyrethroids, Organochlorines
BARBARA INSLEY CROUCH E. MARTIN CARAVATI
PYRETHRINS AND PYRETHROIDS
Essentials
• Contact dermatitis, allergic rhinitis, and asthma in individuals who are sensitive to ragweed pollen or
chrysanthemums may occur in individuals exposed to pyrethrins.
• Paresthesias and other cutaneous sensations are common after topical and vapor exposure to
pyrethroid-containing insecticides.
Introduction
The term pyrethrins refers to six active compounds (pyrethrin I, pyrethrin II, jasmolin I, jasmolin II, cinerin I,
cinerin II) found in pyrethrum, which is an extract of dried chrysanthemums.[7][10] Pyrethroids are synthetic
derivatives of pyrethrins. They are classified in two groups based on whether the chemical structure contains
a cyano group at the a carbon of the phenoxybenzyl moiety.[5] Pyrethrins and pyrethroids are common
ingredients in household insecticides and are usually combined with a synergist such as piperonyl butoxide
to retard degradation. They are also available in several over-the-counter pediculicides and scabicides.[34]
Pyrethroids are more stable than the natural pyrethrins and are widely used as agricultural insecticides.
Human toxicity from these compounds is quite low, and they are considered to be among the safest
insecticides to humans.
Pharmacology
Pyrethrins and pyrethroids are not appreciably absorbed through the skin, and systemic toxicity from these
compounds rarely occurs with dermal application. After ingestion, both pyrethrins and pyrethroids undergo
rapid biotransformation by liver enzymes, which also limits systemic toxicity.
Pathophysiology
Both immediate and delayed hypersensitivity reactions have been reported after exposure to pyrethrum-
containing products. The exact mechanism of action by which pyrethrins produce immediate and delayed
hypersensitivity reactions is not known. It is likely related to increased bronchial reactivity to histamine and
other pharmacologically active mediators released from mast cells.[9] It was originally thought that the
hypersensitivity response was due to impurities in the manufacturing process.[7] However, both immediate
and delayed hypersensitivity reactions have persisted despite improvements in the purification process.
Pyrethroids exert their effects through delaying closure of the inward sodium channel of the nerve
membrane. As a result, neurotransmitter release may be enhanced and hypersensitivity to sensory stimuli
has been reported. [42] In arthropods, pyrethrins produce a hyperexcitable state. Several distinct toxic
syndromes in rats have been noted. [41] Pyrethrins and non-cyano pyrethroids such as permethrin,
resmethrin, and bioresmethrin have been associated with tremors and loss of strength (T-syndrome) in
rodents. Cyano-containing pyrethroids such as fenvalerate, cypermethrin, and deltamethrin are associated
with choreoathetosis and salivation (CS syndrome). Despite these distinctions in the laboratory, clinical
experience in humans has not shown such a fine distinction.[17]
Allergic and Hypersensitivity Manifestations
Allergic and hypersensitivity reactions are the most common manifestations of pyrethrin toxicity but are
uncommon after pyrethroid exposure. Allergic rhinitis, contact dermatitis, asthma, hypersensitivity
pneumonitis, and an anaphylactoid reaction have been reported.[6][9][22][26][43] The more refined pyrethrins
currently available are believed to be less allergenic than crude pyrethrin. Allergic reactions, however, can
still occur, especially in individuals with known sensitivity to ragweed pollen or chrysanthemums. A 37-year-
old woman died of severe bronchospasm after the use of a flea dip containing pyrethrins.[43] Another
individual with a dermal and vapor exposure to a pyrethrin-containing flea dip developed severe
gastrointestinal symptoms, shortness of breath, fatigue, dizziness, and a tingling sensation of the hands.[27]
Dermal and Systemic Manifestations
Pyrethroids commonly cause abnormal cutaneous sensations after dermal, oral, or vapor
exposure.[7][16][17][20][39] These sensations are described as stinging or burning and can progress to
numbness, including temporary numbness of the lips and tongue. In one survey of workers using
fenvalerate, all workers described some degree of cutaneous sensation.[39] The onset of cutaneous
sensations generally occurs within several hours of exposure, and these sensations dissipate within 24
hours.[17][39] After ingestion of pyrethroids, the most common symptoms were abdominal pain, nausea, and
vomiting. These symptoms occurred 10 minutes to 1 hour after exposure.[17] Systemic symptoms reported in
573 cases of acute pyrethroid poisoning included weakness, dizziness, headache, paresthesias, chest
tightness, palpitations, blurred vision, and increased sweating.[17] More serious exposures resulted in muscle
fasciculations, alterations of consciousness, and seizures. Seizures, although uncommon, have been
reported after ingestion of pyrethroids and after occupational exposure.[17] Because pyrethrins and
pyrethroids are rapidly cleared from the body, chronic toxicity is unlikely ( Table 103–1 ).
Table 103-1 -- Clinical Presentation of Exposure to Pyrethrins, Pyrethroids, and Organochlorines

Pyrethrins
Contact dermatitis
Allergic rhinitis
Asthma
Pyrethroids
Paresthesias
Abdominal pain, nausea, vomiting
Organochlorines
Seizures
Tremors
Aplastic anemia (with chronic exposure)
Other Manifestations
Because many pyrethrin- and pyrethroid-containing insecticides are formulated in a hydrocarbon base,
ingestion of these compounds could result in hydrocarbon aspiration. Ocular exposure to several over-the-
counter pediculicides resulted in corneal abrasions and decreased visual acuity.[28][29]
Pyrethrins should be considered in the differential diagnosis of individuals who present with an acute
allergic-type response. Pyrethroid poisoning should be considered in individuals who develop signs of heat
stress, ciguatera or other food poisoning, or a respiratory illness, especially in agricultural workers.
Organophosphate and carbamate poisoning should also be considered ( Table 103–2 ).
Table 103-2 -- Differential Diagnosis of Exposure to Pyrethrins/Pyrethroids and Organochlorines

Pyrethrins/Pyrethroids Organochlorines
Contact with other allergens Epilepsy and other causes of seizures
Other toxins causing seizures (DEET, camphor, water hemlock,
Asthma due to other etiologies
isoniazid)
Food poisoning Organophosphate/carbamate poisoning
Organophosphate/carbamate
Meningitis
poisoning
Respiratory infections Head trauma
Ciguatera poisoning
Laboratory Studies
Tests to confirm pyrethrin exposure are not practical.[23] Biologic monitoring of workers exposed to the
pyrethroids deltamethrin and fenvalerate has been conducted using urinary concentrations. Concentrations
in the urine did not correlate with symptoms.[44]
Treatment
Unintentional small ingestions in children do not require gastrointestinal decontamination, owing to the low
toxicity of these compounds. However, in large intentional or unintentional ingestions (greater than 30 mL),
gastrointestinal decontamination in a health care facility should occur. Aspiration of the stomach contents
with a nasogastric tube is probably sufficient for most ingestions. However, caution should be used to avoid
increasing the risk of pulmonary hydrocarbon aspiration during this process. Activated charcoal may be
given, but whether activated charcoal binds significantly to pyrethrins or pyrethroids is unknown.
Mild to moderate allergic-type reactions are treated with antihistamines. Adults may be given
diphenhydramine, 25–50 mg, orally, intravenously, or intramuscularly. In children, a diphenhydramine dose
of 5 mg/kg/day in divided doses to a maximum of 300 mg/day may be used. In more severe allergic
reactions, aggressive therapy with oxygen, epinephrine, and bronchodilators may be necessary.
Patients with dermal exposure should undergo decontamination by washing the skin with copious amounts
of soap and water. For ocular exposures, the eye should be irrigated for 15 minutes, followed by an
ophthalmologic examination to detect corneal lesions ( Table 103–3 ).
Table 103-3 -- Treatment of Exposure of Pyrethrins, Pyrethroids, and Organochlorines

Topical Exposures
Dermal and ocular decontamination when appropriate
Oral Exposures
Gastrointestinal decontamination: cautious aspiration of liquid preparations via a nasogastric tube. Avoid syrup
of ipecac for organochlorine insecticides.
Activated charcoal: 1 g/kg PO
Allergic reactions: administer diphenhydramine PO, IM, or IV, 25–50 mg q6–8h prn for adults or 5 mg/kg/day
divided q6–8h prn for children.
Anticonvulsant therapy (monitor respiratory status during therapy):
Diazepam, 5–10 mg IV for adults, 0.1–0.2 mg/kg for children. May repeat every 15 minutes as necessary. After
doses of 30 mg in adults, or 5 mg in younger children (<5 years), or 10 mg in older children (= 5 years),
consider switching to phenobarbital.
Lorazepam, 2–4 mg IV for adults, 0.05 mg/kg for children; may repeat.
Phenobarbital, 10–20 mg/kg IV loading dose for adults and children.
Disposition
The majority of exposures to pyrethrins and pyrethroids do not result in any adverse effects. Occupational
exposures to pyrethroids usually produce cutaneous sensations, which occur within several hours after
exposure and resolve within 24 hours. The majority of those exposed through the workplace develop little if
any systemic toxicity. In these cases, observation for 2 hours after exposure is sufficient unless a psychiatric
evaluation is needed following intentional ingestions. Patients with severe allergic reactions such as
anaphylaxis will require admission to a monitored bed until all symptoms have resolved.
Special Situations
No increased incidence of malformations after the therapeutic use of pyrethrin- or pyrethroid-containing

pediculicides in pregnancy has been reported.[4] Because pyrethrins and pyrethroids are poorly absorbed
topically, such agents as A-200 Lice Control, Nix, RID, and other products containing pyrethrins and
pyrethroids are preferred for use in pregnant women.
The combination of pyrethrins, DEET, and pyridostigmine has been evaluated for possible association with
the Gulf War syndrome. However, insufficient evidence prohibits forming any definitive conclusions.[1]


ORGANOCHLORINES
Essentials
• Seizures may be the first sign of toxicity.
• Acute and chronic exposures primarily target
° Central nervous system
(CNS)
° Liver
° Hematopoietic system
Introduction
The organochlorine insecticides may be divided into four distinct groups: DDT
(dichlorodiphenyltrichloroethane) and related analogs (methoxychlor); cyclodienes (aldrin, endrin,
heptachlor, dieldrin, chlordane, endosulfan, chlordecone); hexachlorocyclohexane (lindane); and toxaphene
and related compounds. Organochlorine insecticides were widely used during the mid 1940s to mid 1960s
as insecticides for malaria-carrying mosquito control and termite extermination. Because the
organochlorines were found to persist in the environment and to accumulate in various organisms, including
humans, their use has been dramatically curtailed ( Table 103–4 ). Many organochlorine compounds have
been banned from use in the United States, and the Environmental Protection Agency has markedly
restricted the application of others. One notable exception is lindane (gamma-hexachlorocyclohexane),
which is an insecticide and a pharmaceutical preparation used topically as a scabicide and pediculicide.
Table 103-4 -- Organochlorines: Range of Toxicity and Current Availability

Range of Toxicity Organochlorine Current Availability
Moderately toxic LD50 (0.5–5 g/kg) Methoxychlor No restrictions on use
DDT Canceled
Very toxic LD50 (50–500 mg/kg) Endosulfan No restrictions on use
Lindane Restricted use
DDT Restricted use
Aldrin Canceled
Chlordane Canceled (existing stock may be used)
Chlordecone Canceled
Range of Toxicity Organochlorine Current Availability
Dieldrin Canceled
Heptachlor Canceled
Hexachlorocyclohexane (BHC) Canceled
Extremely toxic LD50 (5–15 mg/kg) Toxaphene Restricted use
Endrin Canceled
Pharmacology
In contrast to the pyrethrins and pyrethroids, the majority of organochlorine insecticides are well absorbed
from the skin as well as the gastrointestinal tract and the lungs.[23] They are distributed into fat, where they
can accumulate and persist for a long period of time. Variability among the organochlorines regarding their
accumulation in fat is largely due to different rates of metabolism and excretion.[15] Compounds such as
DDT and dieldrin are stored to a large degree, whereas methoxychlor and endrin have less accumulation.
High concentrations of some chlorinated hydrocarbons induce hepatic microsomal enzymes, but the clinical
significance of this is unknown.[15] Elimination half-lives for the majority of compounds are quite variable and
prolonged. Dieldrin has a half-life in blood of greater than 250 days, and lindane has a reported elimination
half-life of between 20 hours and 10 to 20 days.[12][38][40] Organochlorines may undergo enterohepatic
recirculation.[23]
Pathophysiology
Although all organochlorine insecticides are CNS stimulants, their exact mechanisms of action may vary.
DDT and related compounds share a mechanism of action similar to the pyrethroids, whereas the
cyclodienes, hexachlorocyclohexanes, and toxaphene and related compounds are thought to exert their
toxic effects through inhibition of -aminobutyric acid.[25]
Acute Toxicity
Acute exposure to organochlorine insecticides may produce CNS stimulation. [23][38] In some cases, seizures
may develop rapidly and be the first sign of exposure. In other cases, patients develop prodromal symptoms
such as headache, dizziness, ataxia, and tremors before the onset of seizures.[23] Seizures have been
reported after ingestion as well as after inappropriate topical use of lindane. The majority occur within 1 to 2
hours and are self-limiting.[31] Children and the elderly are at greatest risk for CNS toxicity, possible even at
therapeutic doses.[37] Death from lindane toxicity has resulted after a 6-mg/kg ingestion in a child and a 48-g
ingestion in an adult.[30] Although not common, prolonged seizures have been reported after both oral and
intravenous exposures to endosulfan.[13][35] Disseminated intravascular coagulation and subsequent
myoglobinuria have developed after intentional ingestions of both lindane and endosulfan.[3][36] Because
many chlorinated insecticides are formulated in a hydrocarbon base, ingestion may result in a hydrocarbon
aspiration pneumonia.
Chronic Toxicity
Chronic exposure to various organochlorines can result in adipose tissue accumulation, with toxicity
manifesting after a critical tissue concentration is reached. A group of workers chronically exposed to
chlordecone developed tremors, rapid and irregular eye movements, hepatomegaly, and hypospermia.[14]
These symptoms dissipated as chlordecone stores in blood and adipose tissue declined. Chronic exposure
to organochlorines has also been associated with chronic motor neuron disease.[11] Repeated inhalation and
dermal exposures to lindane have been associated with various blood dyscrasias, including leukopenia,
leukocytosis, thrombocytopenia, pancytopenia, and aplastic anemia. [2][3][24][32] Workers exposed to
hexachlorocyclohexane for 10 years developed marked elevations in hepatic enzymes.[19] Regarding
carcinogenicity, for the majority of organochlorine insecticides there are limited animal data and insufficient
human data to classify their potential as human carcinogens.[18]
Other CNS stimulants that produce little cardiovascular toxicity, such as camphor or water hemlock, should
be considered, as well as other causes of seizures, including CNS disease, trauma, or drug withdrawal (see
Chapter 70 ). Organophosphate and carbamate poisoning should also be considered (see Table 103–2 ).
Laboratory Studies
Chlorinated insecticide concentrations in the serum are not clinically useful or readily available after an acute
exposure, nor are they necessary for routine surveillance of individuals who are occupationally exposed.[8]
However, if necessary for medicolegal purposes, chlorinated hydrocarbons may be detected in serum using
gas chromatography. [33] Organochlorines may also be quantitatively measured in urine and adipose tissue,
but these levels are also not clinically useful after an acute exposure. Depending on the clinical situation, the
following should be ordered as needed to evaluate other diseases and toxins: complete blood cell count,
electrolyte studies, blood urea nitrogen and creatinine levels, serum calcium and magnesium levels, cranial
computed tomography or magnetic resonance imaging, and cerebrospinal fluid studies.
Treatment
In patients exposed topically, contaminated clothing should be removed and the skin washed copiously with
soap and water. Special care should be taken to decontaminate the patient’s fingernails and skin folds and
to avoid secondary contamination of health care personnel. For ocular exposures, the eye should be
irrigated with a liter of normal saline, followed by an ophthalmologic examination.
Ipecac-induced emesis is contraindicated after ingestion of organochlorine insecticides, owing to the

potential for rapid onset of seizures. If the ingestion is recent, gastric lavage or aspiration of liquid stomach
contents through a nasogastric tube may be considered. Caution should be taken to avoid increasing the
risk of aspiration during this process. Activated charcoal should be administered. Because most seizures are
short lived, benzodiazepines alone should be sufficient treatment. Continuous seizures may require more
aggressive therapy with barbiturates.
Disposition
In the majority of patients acutely exposed to organochlorine insecticides, seizures occur within the first
several hours. Asymptomatic patients may be observed for 4 hours and then discharged, unless a
psychiatric evaluation is needed after intentional ingestions. Patients with neurologic findings after an acute
exposure should be admitted for treatment and further diagnostic workup. Patients with chronic exposures
can be monitored on an outpatient basis.
Special Situations
No increased incidence of malformations after the therapeutic use of lindane-containing pediculicides has
been reported.[4] However, intentional ingestion of a concentrated lindane solution in a 25-year-old patient,
16 weeks pregnant, resulted in death of twin fetuses.[21]


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1. Abou-Donia MB, Wilmarth KR, Jensen KF, et al: Neurotoxicity resulting from coexposure to
pyridostigmine bromide, DEET, and permethrin: Implications of Gulf War chemical exposures. J Toxicol
2. Berry DH, Brewster MA, Watson R, et al: Untoward effects associated with lindane abuse. Am J Dis
Child 1987; 141:125-126.
3. Blanco-Coronado JL, Repetto M, Ginestal RJ, et al: Acute intoxication by endosulfan. Clin
Toxicol 1992; 30:575-583.
4. Bologa M, Koren G, McGuigan M, et al: Drugs and chemicals most commonly used by pregnant women.
In: Koren G, ed. Maternal-Fetal Toxicology, New York: Marcel Dekker; 1990:29-51.
5. Bronstein AC, Sullivan JB: Herbicides, fungicides, biocides, and pyrethrins.

In: Sullivan JB, Kriegger GR, ed. Hazardous Materials Toxicology, Baltimore: Williams &
Wilkins; 1992:1075.
6. Carlson JE, Villaveces JW: Hypersensitivity pneumonitis due to pyrethrum: Report of a case.
JAMA 1977; 237:1718-1719.
7. Casida JE: Pyrethrum flowers and pyrethroid insecticides. Environ Health Perspect 1980; 34:189-202.
8. Coye MS, Lowe JA, Maddy KJ: Biological monitoring of agricultural workers exposed to pesticides: II
Monitoring of intact pesticides and their metabolites. J Occup Med 1986; 28:628-636.
9. Culver CA, Malina JJ, Talbert RL: Probable anaphylactoid reaction to a pyrethrin pediculicide shampoo.
Clin Pharm 1988; 7:846-849.
10. Dorman D, Beasley V: Neurotoxicology of pyrethrin and the pyrethroid insecticides. Vet Hum
Toxicol 1991; 33:238-243.
11. Fonseca RG, Resende LAL, Silva MD, et al: Chronic motor neuron disease possibly related to
intoxication with organochlorine insecticides. Acta Neurol Scand 1993; 88:56-58.
12. Ginsberg CM, Lowry W, Reisch JS: Absorption of lindane (gamma benzene hexachloride) in infants and
children. J Pediatr 1977; 91:998-1000.
13. Grimmett WG, Dzendolet I, Whyte I: Intravenous thiodan (30% endosulfan in xylene). Clin
Toxicol 1996; 34:447-452.
14. Guzelian PS: The clinical toxicology of chlordecone as an example of toxicological risk assessment for
man. Toxicol Lett 1992; 64/65:589-596.
15. Hayes WJ: Pesticides Studied in Man, Baltimore: Williams & Wilkins; 1982:75-81. 161–283
16. He F: Synthetic pyrethroids. Toxicology 1994; 91:43-49.

17. He F, Wang S, Liu L, et al: Clinical manifestations and diagnosis of acute pyrethroid poisoning. Arch
Toxicol 1989; 63:54-58.
18. International Agency for Research on Cancer (IARC) Overall evaluations of carcinogenicity : An
updating of IARC monographs, volume 1–42. Lyon, France: IARC; 1987.
19. Kashyap SK: Health surveillance and biological monitoring of pesticide formulators in India. Toxicol
Lett 1986; 33:107-114.
20. Knox JM, Tucker SB, Flannigan SA: Paresthesia from cutaneous exposure to a synthetic pyrethroid
insecticide. Arch Dermatol 1984; 120:744-746.
21. Konje JC, Otolorin EO, Sotunmbi PT, et al: Insecticide poisoning in pregnancy: A case report. J Reprod
Med 1992; 37:992-994.
22. Mitchell JC, Dupuis G, Towers GHN: Allergic contact dermatitis from pyrethrum (Chrysanthemum spp.).
The roles of pyrethrosin, a sesquiterpene lactone, and of pyrethrin II. Br J Dermatol 1972; 86:568-573.
23. Morgan DP: Recognition and Management of Pesticide Poisonings, 4th ed. Washington, DC, United
States Environmental Protection Agency, 1989.
24. Morgan DP, Stockdale EM, Roberts RJ, et al: Anemia associated with exposure to lindane. Arch
25. Narahashi T, Frey JM, Ginsburg KS, Roy ML: Sodium and GABA-activated channels as the targets of
pyrethroids and cyclodienes. Toxicol Lett 1992; 64/65:429-436.
26. Newton JG, Breslin ABX: Asthmatic reactions to a commonly used aerosol insect killer. Med J
Aust 1983; 1:378-380.
27. Paton DL, Walker JS: Pyrethrin poisoning from commercial-strength flea and tick spray. Am J Emerg
Med 1988; 6:232-235.
28. Pe’er J, BenEzra D: Corneal damage following the use of the pediculicide A-200 pyrinate. Arch
Ophthalmol 1988; 106:16-17.
29. Quan MP, Anderson IB: Ten cases of ocular injury after using OTC pyrethrin-containing pediculicides.
Vet Hum Toxicol 1989; 31:378.
30. Sunder Ram Rao CV, Shreenivas R, Singh V: Disseminated intravascular coagulation in a case of fatal
lindane poisoning. Vet Hum Toxicol 1988; 30:132-134.
31. Rowley DL, Rab MA, Hardjotanojo W, et al: Convulsions caused by endrin poisoning in Pakistan.
Pediatrics 1987; 79:928-934.
32. Rugman FP, Cosstick R: Aplastic anaemia associated with organochlorine pesticide: Case reports and
review of evidence. J Clin Pathol 1990; 43:98-101.
33. Saady JJ, Poklis A: Determination of chlorinated hydrocarbon pesticides by solid-phase extraction and
capillary GC with electron capture detection. J Anal Toxicol 1990; 14:301-304.
34. Sadik F: Insect sting and bite products. In: Covington TR, ed. Non-Prescription Drug Handbook, 10th
ed. Washington, DC: American Pharmaceutical Association; 1993:597-607.
35. Shemesh Y, Bourvine A, Gold D, et al: Survival after acute endosulfan intoxication. Clin
Toxicol 1988; 26:265-268.
36. Sunder Ram Rao CV, Shreenivas R, Singh V: Disseminated intravascular coagulation in a case of fatal
lindane poisoning. Vet Hum Toxicol 1988; 30:132-134.
37. Tenenbein M: Seizures after lindane therapy. J Am Geriatr Soc 1991; 39:394-395.
38. Tordoir WF, van Sittert NJ: Organochlorines. Toxicology 1994; 91:51-57.
39. Tucker SB, Flannigan SA: Cutaneous effects from occupational exposure to fenvalerate. Arch
Toxicol 1983; 54:195-202.
40. United States Public Health Service : Toxicological Profile for Aldrin/Dieldrin. Agency for Toxic
Substances and Disease Registry, US Public Health Service, Washington, DC: Government Printing
Office; February 18, 1992:44-52.
41. Verschoyle RD, Aldridge WN: Structure-activity relationships of some pyrethroids in rats. Arch
Toxicol 1980; 45:325-329.
42. Vijverberg HPM, van der Bercken J: Neurotoxicological effects and the mode of action of pyrethroid
insecticides. Crit Rev Toxicol 1990; 21:105-126.
43. Wax PM, Hoffman RS: Fatality associated with inhalation of a pyrethrin shampoo. Clin
Toxicol 1994; 32:457-460.
44. Zhang Z, Sun J, Chen S, et al: Levels of exposure and biological monitoring of pyrethroids in spraymen.
Br J Ind Med 1991; 48:82-86.


Chapter 104 – Insecticides: N,N-Diethyl-3-methylbenzamide (DEET)
E. MARTIN CARAVATI BARBARA INSLEY CROUCH
Essentials
• Toxicity may occur from acute ingestion and acute or chronic dermal exposure.
• Systemic toxicity results in confusion, ataxia, generalized seizures, and encephalopathy.
• Hypotension and bradycardia may occur in severe systemic poisonings.
• Plasma concentrations of DEET may help confirm the diagnosis but will not affect treatment.
INTRODUCTION
Diethylmethylbenzamide, previously known as diethyltoluamide (DEET) ( Fig. 104–1 ) has been marketed
commercially as a personal insect repellent since 1956. An estimated 30–40 per cent of the U.S. population
uses DEET-containing insect repellents annually. In the late 1980s Lyme disease generated increased
concern about the prevention of tick bites, and public awareness campaigns emphasized the use of insect
repellents to prevent exposure to these and other disease-carrying insects. Product formulations of DEET
include aerosols, pump sprays, lotions, liquids, roll-on sticks, and impregnated towels. The DEET
concentrations in these formulations range from 6–100 per cent ( Table 104–1 ). There are over 56 trade
name products containing DEET and most exposures occur during the summer months. Almost 40 million
packages of DEET products were sold in 1989 and over 2800 exposures were reported to Poison Control
Centers nationwide.[21] DEET-containing insect repellents are intended for human use and have a large
margin of safety. The majority of cases reported to Poison Control Centers are accidental childhood
exposures with good outcomes. Nevertheless, severe toxicity and fatalities have been reported from both
ingestion and copious dermal application of DEET.
Figure 104-1 Chemical structure of N,N-diethyl-3-methylbenzamide (DEET).
Table 104-1 -- Concentrations of Selected DEET-Containing Over-the-Counter Insect Repellents

Selected Products DEET Concentration (%)
OFF! Skintastic 6.65
Deep Woods OFF! 20–30
Cutter Outdoorsman 28.5
3M Ultrathon Insect Repellent 31.6
Muskol lotion or liquid 100
REI Jungle Juice 100


PATHOPHYSIOLOGY
Absorption and Excretion
Approximately 5–17 per cent of topically applied DEET is systemically absorbed at a steady rate.[13][17]
Maximum serum concentration occurs 1–2 hours after topical application.[18] The principal route of excretion
is renal.[17]
Physiologic Effects
Dose-related hypotension and bradycardia have been observed in animal studies. Canine cardiac output
was decreased, but stroke volume and total peripheral resistance remained normal. It appears that the
hypotension resulted primarily from DEET-induced bradycardia.[7] It has been suggested that DEET may be
hazardous to individuals with defects in the urea cycle enzymes. Increased serum ammonia levels two to
three times that of control animals have been observed after toxic exposures.[5]
Range of Toxicity
The acute oral median lethal dose (LD50) in albino rats is about 2 mL/kg of 90 per cent DEET.[1] Human
fatalities have been noted with ingestions of 25–50 mL of 90 per cent DEET.[20] Seizures have been
reported after two total body applications of 95 per cent DEET in 1 day.[8]


Acute Exposure
Acute toxicity may result from either ingestion or topical application of highly concentrated DEET-containing
products ( Table 104–2 ). Most reports of systemic toxicity secondary to dermal exposure have occurred in
children. Generalized seizures may develop without prodrome or warning symptoms in children,[8] and the
interval between last use of DEET and onset of seizures has ranged from 8–48 hours.[2] Restlessness,
altered behavior, lethargy, confusion, slurred speech, ataxia, and encephalopathy have also been reported
after acute dermal exposures to DEET.[4][14][19]
Table 104-2 -- Signs and Symptoms of Systemic DEET Toxicity

Symptoms Signs
Lethargy Incoherent speech
Insomnia Confusion
Muscle cramps CNS depression
Urinary hesitancy Tremors
Coma
Generalized seizures
Hypertonia
Opisthotonos
Tenenbein reported five adult cases with severe DEET toxicity after ingestion. Clinical manifestations
included tremors, slurred speech, hypotension, seizures, and coma. There were two fatalities reported in this
case series resulting from ingestion of approximately 50 mL of 90 per cent DEET.[20]
Chronic Exposure
Chronic dermal exposures have resulted in severe toxicity in both children and adults. A study of 143
workers at Everglades National Park found that highly exposed workers had significantly higher prevalence
of insomnia, muscle cramps, mood disturbances, skin rashes, and urinary hesitancy. These workers applied
DEET daily in concentrations from 15–100 per cent with a median dose of 2.6 g/wk. There appeared to be a
dose-response relationship between the symptoms and the employee use of DEET.[10]
During a 10-day period a 5-year-old girl developed progressively worsening headaches, agitation,
disorientation, disturbed speech, ataxia, and finally seizures after nightly application of 10 per cent DEET
insect repellent for 3 months.[24] An 18-month-old girl developed progressive weakness, ataxia, tremors,
opisthotonic posturing, and myoclonic jerking over a 9-day period. She had a history of daily application of
20 per cent DEET insect repellent for approximately 3 months prior to presentation.[3]
A 30-year-old male developed irritability, grandiose delusions, and aggressive paranoid behavior consistent
with manic psychosis after daily applications of 70 per cent DEET insect repellent to a truncal rash for 2
weeks. The patient was hospitalized and had rapid resolution of symptoms within 72 hours and complete
resolution within 6 days. There was no prior family or personal history of bipolar illness.[19]
One case of acute systemic anaphylaxis has been reported secondary to topical application of DEET.[11]
Dermatologic Effects
Acute dermatologic reactions occur infrequently but have been documented with application of high
concentrations (50 to 75 per cent) of DEET. Skin manifestations have included contact urticaria,[22] contact
dermatitis, bullous eruptions, and skin irritation and desquamation.[13] Erythema, large blisters, skin
necrosis, and residual scarring isolated to the antecubital fossa have been reported in soldiers who applied
50 to 75 per cent DEET to the skin.[6][12]
Ocular Exposure
Experimental rabbits and mice whose eyes were exposed to 20 per cent, 30 per cent, and 100 per cent
DEET solutions developed conjunctival irritation, edema, and purulent drainage. Corneal lesions were also
noted. All effects resolved within 1 week of exposure.[1][9]
Pediatric Concerns
Small children have a larger surface area to mass ratio compared to adults and may be at higher risk for
greater absorption of topically applied insect repellents. However, most exposures reported to Poison
Control Centers involve young children who usually ingest the product, and children less than six years of
age were not more likely to develop adverse effects from DEET than older children or adults.[21] Children
have also been noted to lick their skin after application of the insect repellent which may increase their risk
for systemic toxicity.[3]


The possibility of exposure to DEET should be considered in patients with unexplained seizures. However,
DEET should not be accepted as the cause of the seizure until an appropriate examination has reliably
excluded other possible etiologies ( Table 104–3 ).
Table 104-3 -- Differential Diagnosis for CNS Toxicity Associated with DEET Exposure
Reye syndrome
Viral encephalitis
Metabolic encephalopathies
Intracranial lesions
Other CNS toxins


LABORATORY STUDIES
Although obtaining a plasma concentration of DEET may help to confirm the diagnosis, toxic levels have not
been established and patients usually are managed without laboratory confirmation. DEET can be measured
in the urine and serum by high pressure liquid chromatography. The limit of detection is 0.09 µg/mL in urine
and 0.09 µg/g in serum.[18] Examination of the cerebrospinal fluid (CSF) is typically normal,[14] but
lymphocytic pleocytosis has been reported.[24] Abnormal electroencephalograms have been observed in
patients with symptoms of encephalopathy.[8][14] A complete blood count, serum electrolytes, glucose, blood
urea nitrogen, liver function tests, serum ammonia, head computed tomography or magnetic resonance
imaging scan, and CSF examination should be obtained in cases of neurologic toxicity to eliminate other
diagnostic possibilities.


TREATMENT
Ipecac-induced emesis is contraindicated following ingestion of DEET because coma and seizures have
been reported. If the ingestion is recent (e.g., within 1 hour of presentation), nasogastric suction may be
useful in removing DEET from the stomach. Activated charcoal should be administered. Seizures are treated
with intravenous benzodiazepines, phenytoin, and/or phenobarbital ( Table 104–4 ). For dermal exposures
the skin should be washed with copious amounts of soap and water. Eye exposures should be irrigated for
at least 15–30 minutes. Supportive care is indicated for other toxic manifestations.
Table 104-4 -- Treatment Essentials for DEET Toxicity

Dermal, ocular, and gastric decontamination
Activated charcoal for ingestions
Seizures: IV benzodiazepines, phenytoin, and/or phenobarbital


DISPOSITION
Toxic symptoms after the ingestion of DEET should occur within 2 hours of exposure. Adults who have been
decontaminated and are asymptomatic after this period may be referred for psychiatric evaluation if the
ingestion was intentional. Adults and children with accidental ingestions may be discharged home in the
company of a reliable adult who can monitor the patient for any delayed symptoms. Any patient with
neurologic symptoms following acute ingestion or dermal application of DEET should be admitted to the
hospital for a full diagnostic work-up.
Patients who are discharged home should receive the following precautions in order to minimize the
possibility of toxicity or adverse reactions to DEET.
• Apply sparingly and only to exposed skin or clothing.

• Avoid applying high concentration products to the skin, especially of children.
• Avoid inhalation, ingestion, or eye exposure.
• Wear long sleeves and pants and apply repellent to clothing rather than the skin to reduce exposure.
• Avoid applying to children’s hands because of likely contact with eyes or mouth.
• Do not apply to wounds or irritated skin.
• Use repellent sparingly. Saturation does not increase efficacy.
• Wash repellent-exposed skin after coming indoors. If a suspected reaction occurs, again wash the skin
and call a regional Poison Control Center.[2]


SPECIFIC SITUATIONS: EXPOSURE AND PREGNANCY
There has been no evidence of reproductive or developmental toxicity in rats and rabbits who were
administered DEET during gestation.[16][23] However, a case of mental retardation and craniofacial
dysmorphology has been reported in a 4-year-old boy whose mother applied DEET daily throughout her
entire pregnancy in addition to the prophylactic use of chloroquine.[15]


REFERENCES
1. Ambrose AM: Pharmacologic and toxicologic studies on N,N-Diethyltoluamide. Toxicology 1959; 1:97.
2. Centers for Disease Control : Seizures temporally associated with the use of DEET insect
repellent—New York and Connecticut. MMWR 1989; 38:678.
3. Edwards DL, Johnson CE: Insect repellent induced toxic encephalopathy in a child. Clin
4. Gryboski J, Weinstein D, Ordway NK: Toxic encephalopathy apparently related to the use of an insect
repellent. N Engl J Med 1961; 264:289.
5. Heich HMC, Peterson RG, Dalpey-Scott M, et al: Insect repellent, N,N-diethyl-m-toluamide, effect on
ammonia metabolism. Pediatrics 1988; 82:373.
6. Lamberg SI, Mulrennan JA: Bullous reaction to diethyl-toluamide (DEET). Arch

Dermatol 1969; 100:582.
7. Leach GJ, Russell RD, Houpt JT: Some cardiovascular effects of the insect repellant N,N-diethyl-m-
toluamide (DEET). J Toxicol Environ Health 1988; 25:217.
8. Lipscomb JW, Kramer JE, Leikin JB: Seizure following brief exposure to the insect repellant N,N-diethyl-
m-toluamide. Ann Emerg Med 1992; 21:315.
9. MacRae SM, Brown BA, Ubels JL, et al: Ocular toxicity of diethyl-toluamide (DEET). J Toxicol Cutan
Ocular Toxicol 1984; 3:17.
10. McConnell R, Fidler AT, Chrislip D: Everglades National Park Health Hazard Evaluation Report.
Cincinnati, Ohio, US Dept of Health and Human Services, Public Health Service, NIOSH health hazard
evaluation report no. HETA-83-085-1757, 1986.
11. Miller JD: Anaphylaxis associated with insect repellant. N Engl J Med 1982; 307:1341.
12. Reuveni H, Yagupsky P: Diethyl-toluamide-containing repellant. Arch Dermatol 1982; 118:582.
13. Robbins PJ, Cherniack MG: Review of the biodistribution and toxicity of the insect repellant N,N-diethyl-
m-toluamide (DEET). J Toxicol Environ Health 1986; 18:503.
14. Roland EK, Jan JE, Rigg JM: Toxic encephalopathy in a child after brief exposure to insect repellants.
Can Med Assoc J 1985; 132:155.
15. Schaefer C, Peters PW: Intrauterine diethyl toluamide exposure and fetal outcome. Reprod
Toxicol 1992; 6:175.
16. Schoenig GP, Neeper-Bradley TL, Fisher LC, et al: Teratologic evaluations of N,N-diethyl-toluamide
(DEET) in rats and rabbits. Fundam Appl Toxicol 1994; 23:63.
17. Selim S, Hartnagel RE, Osimitz TG, et al: Absorption, metabolism, and excretion of N,N-diethyl-m-
toluamide following dermal application to human volunteers. Fundam Appl Toxicol 1995; 25:95.
18. Smallwood AW, DeBord KE, Lowry LK: N,N-Diethyl-m-toluamide (M-DET): Analysis of an insect
repellant in human urine and serum by high performance liquid chromatography. J Anal
Toxicol 1992; 16:10.
19. Snyder JW, Poe RO, Stubbins JF, et al: Acute manic psychosis following the dermal application of N,N-
diethyl-toluamide (DEET) in an adult. J Toxicol Clin Toxicol 1986; 24:429.
20. Tenenbein M: Severe toxic reactions and death following the ingestion of diethyl-toluamide-containing
insect repellants. JAMA 1987; 258:1509.
21. Veltri JC, Osimitz TG, Bradford BC, et al: Retrospective analysis of calls to poison control centers
resulting from exposure to the insect repellant in N,N-diethyl-m-toluamide (DEET) from 1985–1989. J
22. Von Mayenburg J, Rakoski J: Contact urticaria to diethyl-toluamide. Contact Dermatitis 1983; 9:171.
23. Wright DM, Hardin BD, Goad PW, et al: Reproductive and developmental toxicity of N,N-diethyl-M-
toluamide in rats. Fundam Appl Toxicol 1992; 19:33.
24. Zadikoff CM: Toxic encephalopathy associated with the use of insect repellant. J
Pediatr 1979; 95:140.


Chapter 105 – Metaldehyde
WESLEY B. PALATNICK
Essentials
• History of ingestion of a molluscicide
• Delay from ingestion to onset of symptoms
• Gastrointestinal symptoms predominant with lower doses
• Neurotoxicity including seizures and coma with higher doses
• Anion gap metabolic acidosis in severe cases
INTRODUCTION
Metaldehyde, an isomer of paraldehyde, is composed of acetaldehyde moieties arranged in an eight-

membered ring. It is used as a molluscicide in North America. In Europe it is also used as a solid fuel.
Formulations in the United States are limited to 4 per cent by weight, whereas fuel tablets in Europe may
contain concentrations as high as 50 per cent.[1] The trade names of formulations available in North America
are listed in Table 105–1 . Poisoning is uncommon in humans but fairly common in animals.[1] Unintentional
exposure of children to small quantities is usually benign.[1][8] The deliberate ingestion of large amounts of
the 4 per cent formulations or of the solid fuel tablets may cause severe toxicity and even death.[7][9]
Table 105-1 -- Trade Names for Metaldehyde

Antimilace
Ariotox
Meta
Slug Death
Antimitace
Cekumeta
Halizan
Metason
Namekil
Slugit Pellets
Cekumeta
The 1995 American Association of Poison Control Centers Annual Report listed 325 exposures to
molluscicide formulations of metaldehyde. Of these, 228 were children younger than the age of 6 years and
44 were adults older than 19 years. Only one of these exposures was intentional. Only 48 patients were
treated at a health care facility. No toxicity occurred in 114 patients, whereas toxicity was classified as minor
in 20, moderate in 6, and major in 1. No life-threatening symptoms were reported.[8]
Mini Slug Pellets
The 1995 American Association of Poison Control Centers Annual Report listed 325 exposures to
molluscicide formulations of metaldehyde. Of these, 228 were children younger than the age of 6 years and
44 were adults older than 19 years. Only one of these exposures was intentional. Only 48 patients were
treated at a health care facility. No toxicity occurred in 114 patients, whereas toxicity was classified as minor
in 20, moderate in 6, and major in 1. No life-threatening symptoms were reported.[8]
The minimum toxic or lethal dose of metaldehyde is unknown. The ingestion of a 2-inch-long tablet resulted
in the death of a child,[7] whereas an adult survived an ingestion of 18.6 g.[9] An association of the dose of
metaldehyde with symptomatology has been demonstrated.[9]


Pharmacology
Metaldehyde is hydrolyzed in the stomach to acetaldehyde.[1] Elimination appears to follow first-order

kinetics with an apparent half-life of 27 hours.[11]
Pathophysiology
The clinical effects of metaldehyde poisoning are similar to those produced by the alcohol-disulfiram
reaction, which results in the accumulation of toxic amounts of acetaldehyde. This observation adds support
to the hypothesis that excess acetaldehyde is the toxic agent. [9]
One study of metaldehyde poisoning in mice demonstrated a significant decrease in brain -aminobutyric
acid (GABA) concentration. This decrease in GABA is a likely cause of the seizures associated with
metaldehyde poisoning. The mechanism for this decrease in GABA is unknown, but it may be due to
acetaldehyde acting as a releasing factor for neuronal GABA.[3] Acetaldehyde also increases monoamine
oxidase activity,[3] which accounts for the observed decreases in brain levels of noradrenaline, 5-
hydroxytryptamine, and its metabolite 5-hydroxyindoleacetic acid.[2]


Although symptoms may occur within 2 hours after a significant ingestion,[9] a longer delay in the onset of
symptoms is characteristic of nonfatal cases.[6][13] This delay is likely related to the time required to
metabolize metaldehyde to acetaldehyde. Gastrointestinal signs and symptoms are common and may be
present in otherwise minor exposures. They include nausea, vomiting, abdominal cramps, excessive
salivation, and diarrhea.[7][9][11][12] Neurologic symptoms such as drowsiness, lethargy, muscle spasms,
tremor, convulsions, and coma occur in more serious exposures.[7][9][11][13] Other reported clinical effects
include hyperpyrexia, rhabdomyolysis, cyanosis, increased tracheobronchial secretions, and hepatic and
renal toxicity ( Table 105–2 ).[9] Inhalation of smoke produced by the burning of a product that contained
metaldehyde and sodium carbonate produced pneumonitis and noncardiogenic pulmonary edema in a 14-
year-old girl.[4]
Table 105-2 -- Clinical Presentation of Metaldehyde Poisoning

Gastrointestinal
Nausea
Vomiting
Abdominal pain
Excessive salivation
Diarrhea
Drowsiness
Lethargy
Muscle spasms
Tremors
Seizures
Coma
Other
Cyanosis
Hyperpyrexia
Rhabdomyolysis
Anion gap metabolic acidosis
A review of 213 cases reported to the Swiss Toxicological Information Center between 1966 and 1969
described a relationship between the dose of metaldehyde and the severity of clinical effects. Small doses of
a few milligrams per kilogram, such as may occur when a child licks the toxin from a container, were
associated with minor effects such as salivation, facial flushing, abdominal pain, nausea, and vomiting.
Ingestion of 50 to 100 mg/kg was associated with ataxia and increased muscle tone, whereas ingestion of
100 to 200 mg/kg produced hyperreflexia, convulsions, and muscle twitching. Doses of 400 mg/kg were
associated with coma and death ( Table 105–3 ).[9]
Table 105-3 -- Metaldehyde Poisoning: Relationship Between Ingested Dose and Clinical Effects
Dose Clinical Effects
Traces (a few Salivation, facial flushing, fever, abdominal cramps, nausea, vomiting
mg/kg)
Drowsiness, tachycardia, spasms, irritability, salivation, abdominal cramps, facial flushing,
<50 mg/kg
nausea
50–100 mg/kg Ataxia, increased muscle tone
100–150 mg/kg Convulsions, tremor, hyperreflexia
150–200 mg/kg Muscle twitching
~400 mg/kg Coma, death
Adapted with permission from Longstreth WT, Pierson DT: Metaldehyde poisoning from snail bait ingestion. West
J Med 1982; 137:134–137.
Symptoms usually resolve within 24 to 48 hours in moderate intoxications.[1] However, weakness and
altered mental status were present for 9 days in a severe self-poisoning.[9]


The differential diagnosis of metaldehyde poisoning is extensive and includes any toxin that causes
gastrointestinal symptoms and neurologic effects such as seizures and coma. Toxins such as lead, iron,
theophylline, and salicylates may produce similar effects. Structural and infectious central nervous system
lesions are also associated with vomiting and seizures ( Table 105–4 ).
Table 105-4 -- Differential Diagnosis of Metaldehyde Poisoning

Toxins That Cause Vomiting and Seizures
Iron
Salicylates
Theophylline
Lead
Arsenic
Thallium
Organophosphates
Organochlorines
Paraquat/diquat
Isoniazid
Monomethylhydrazine-containing mushrooms
Coprinus mushroom-ethanol combination
Infections
Acute meningoencephalitis
Structural Lesions
Brain tumors
Acute cerebrovascular accident
Head injury
Metabolic Disorders
Uremia
Hyponatremia
Hypernatremia
Nonketotic hyperglycemia


LABORATORY STUDIES
Gas chromatographic detection of acetaldehyde in serum and urine from metaldehyde poisoned patients
has been reported. [5][11] However, direct confirmation of poisoning by these methods is not routine.
Most laboratory abnormalities are nonspecific. Routine measurements of serum electrolytes and arterial
blood gases are helpful in the supportive management of a seriously ill patient. An increased anion gap
acidosis is common in severe intoxication and is probably due to lactate accumulation from prolonged
seizure activity. However, the metabolism of acetaldehyde to acetate may contribute to the acidosis in a
manner similar to that of paraldehyde.[5][9]
Other laboratory abnormalities may include mildly elevated creatine kinase and serum aminotransferase
levels.[9]


TREATMENT
The management of metaldehyde poisoning is supportive ( Table 105–5 ). Initial resuscitation should ensure
the adequacy of the airway, breathing, and circulation. Seizures should be managed initially with an
intravenous benzodiazepine, either diazepam[3] or lorazepam. Recurrent seizures require aggressive
anticonvulsant management. The postulated mechanism of GABA depletion makes phenobarbital, rather
than phenytoin, the logical next agent of choice for further seizure control. Neuromuscular paralysis with
continuous electroencephalographic monitoring may be indicated in severe cases. Paraldehyde should not
be used because it is a congener of metaldehyde and may contribute to its toxicity.[9]
Table 105-5 -- Treatment of Metaldehyde Poisoning

Resuscitation
Activated charcoal
Adults: 50–100 g
Children: 25–50 g
Ipecac is contraindicated
Supportive Care (Management of Seizures)
Benzodiazepines
Diazepam
Adults: 5–10 mg
Children: 0.2–0.3 mg/kg
Lorazepam
Adults: 2–8 mg
Children: 0.05–0.10 mg/kg
Phenobarbital
Adults: 10–20 mg/kg initially
Children: 10–20 mg/kg
Elimination Enhancement
Hemodialysis, hemoperfusion, and forced diuresis are not effective.
Activated charcoal, although not specifically studied, may be effective for gastric decontamination and
should be administered as early as possible. Because most ingestions of metaldehyde in North America are
benign, routine gastric lavage is not recommended based on a risk-benefit assessment. Ipecac is
contraindicated owing to the possibility of either decreased level of consciousness or seizures. Methods to
enhance toxin elimination such as forced diuresis, hemodialysis, or hemoperfusion are not effective.


DISPOSITION
Severely poisoned patients require admission to an intensive care unit. Asymptomatic or mildly symptomatic
patients with a history of significant exposure, such as the ingestion of the solid fuel tablets or deliberate
self-poisoning, should be admitted for observation. An asymptomatic patient with a trivial exposure may be
observed at home if there is good supervision and close follow up.[8]


SEQUELAE
Experience with metaldehyde poisoning is limited, and long-term sequelae are not frequently described.
Episodes of memory loss that persisted for weeks to months, and even up to 1 year, have been
reported.[9][10]


REFERENCES
1. Booze TF, Oehme FW: Metaldehyde toxicity: A review. Vet Hum Toxicol 1985; 27:11-19.
2. Homeida AM, Cooke RG: Pharmacological aspects of metaldehyde poisoning in mice. J Vet Pharmacol
Ther 1982; 5:77-81.
3. Homeida AM, Cooke RG: Anticonvulsant activity of diazepam and clonidine on metaldehyde induced
seizures in mice: Effects on brain and aminobutyric acid concentrations and monoamine oxidase activity. J
Vet Pharmacol Ther 1982; 5:187-190.
4. Jay MS, Kearns GL, Stone V, et al: Toxic pneumonitis in an adolescent following exposure to snow storm
tablets. J Adolesc Health Care 1988; 9:431-433.
5. Keller KH, Shimuzu G, Walter FG, et al: Acetaldehyde analysis in severe metaldehyde poisoning. Vet
6. Knowles CO: Miscellaneous pesticides. In: Hayes Jr WJ, Law Jr ER, ed. Handbook of Pesticide
Toxicology, Volume 3, Classes of Pesticides, San Diego: Academic Press; 1991:1493-1496.
7. Lewis DR, Madel GA, Drury J: Fatal poisoning by “meta fuel” tablets. BMJ 1939; 1:1283-1284.
8. Litovitz TL, Felberg L, White S, et al: 1995 Annual Report of the American Association of Poison Control
Centers toxic exposure surveillance system. Am J Emerg Med 1996; 14:487-537.
9. Longstreth WT, Pierson DJ: Metaldehyde poisoning from snail bait ingestion. West Med
J 1982; 137:134-137.
10. Miller R: Poisoning by “meta fuel” tablets (metacetaldehyde). Arch Dis Child 1928; 3:292-295.
11. Moody JP, Inglis FG: Persistence of metaldehyde during acute molluscicide poisoning. Hum Exp
Toxicol 1992; 11:361-362.
12. Spighel A, Alroy-Spighel M: Metaldehyde poisoning. Lancet 1958; 2:1017-1018.
13. Goulding R (ed): Wilkinson RD: Metaldehyde. Toxicological case records. The
Practitioner 1968; 200:319-320.


Chapter 106 – Paraquat and Diquat
BRENT R. EKINS RICHARD J. GELLER
Essentials
• History or suspicion of paraquat or diquat ingestion, or history of unusual skin/mucous membrane
exposure (Paraquat is a blue-green liquid; diquat is brown.)
• Paraquat and diquat: Rapid development of multisystem organ failure in cases of substantial ingestion
(more than 40 mg/kg for paraquat)
• Paraquat: Gastrointestinal symptoms followed by renal failure and pulmonary fibrosis in moderate
poisoning (ingestion of 20–40 mg/kg) [50]
• Laboratory confirmation by urine or blood level (quantitative) or sodium dithionite test (qualitative)
• Paraquat: Unexplained pulmonary fibrosis with or without other skin/mucous membrane effects
INTRODUCTION
Paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) [CAS #1910-42-5] and diquat (1,1'-ethylene-2,2'-

dipyridylium dibromide) [CAS #85-00-7] are the most commonly used herbicides in the bipyridylium
quaternary ammonium compound group. Paraquat was first described in 1882. Subsequent to its
development as an herbicide in the 1950s it was used as an indicator for chemical oxidation-reduction
reactions and was known by the common name methyl viologen ( Fig. 106–1 ).
Figure 106-1 Diquat and paraquat structures. (From Sabapathy NN: Quaternary ammonium compounds. Toxicology 1994; 91:93.)
Bipyridylium herbicides (BHs) are used throughout the world as contact herbicides and as crop desiccants
on products such as cotton. Product formulations differ by country. They are most commonly sold as liquids.
Zeneca is the largest manufacturer/distributor in the United States. It produces paraquat most commonly as
Gramoxone Extra (37.00 per cent w/v aqueous formulations paraquat ion), and diquat as Reward or Diquat
Herbicide, both 36.4 per cent diquat cation. Granular and gel forms are also encountered.
Paraquat and diquat are highly potent systemic poisons. More is known about the human toxicology of
paraquat than diquat, owing to the much higher frequency of reported exposures to paraquat causing
sickness and death. An estimated lethal dose of 20 per cent paraquat is 10 to 20 mL for adults[12] and 4 to 5
mL for children.[18] Diquat is estimated to be slightly less toxic, with a lethal dose for adults of 6 to 12 g
(30–60 mL of 20 per cent diquat).[51]
More than 1000 deaths per year from paraquat ingestion led Japanese authorities in 1986 to ban the use of
20 per cent paraquat. Almost any oral exposure to this concentration should be viewed as potentially fatal
and should be managed accordingly. A mixture of 4.5 per cent w/v paraquat and 4.5 per cent w/v diquat is
now used in Japan.[55]
In the United States, the American Association of Poison Control Centers reported 3 diquat and 29 paraquat
fatalities between 1983 and 1998.[25] Overwhelmingly, American deaths are intentional and by ingestion,
with rare cases of intentional injection. [1]


Toxicology
Absorption
Gastrointestinal absorption rates for paraquat and diquat are similar. [2] Paraquat is known to be very rapidly
but incompletely absorbed from the gastrointestinal tract. Absorption occurs primarily in the small intestine
and is estimated to be 1 to 5 per cent in humans.[7] Extensive caustic injury to the gastrointestinal tract may
increase the amount absorbed. Peak plasma levels occur within 2 hours of ingestion.[44]
Prolonged dermal contact time or contact with damaged skin is generally required for systemic
absorption.[5][8][20][44] Inhalation of paraquat used in an agricultural/occupational setting does not allow
sufficient absorption to cause systemic disease, because droplet size prohibits deep lung exposure and
absorption.[23] Concern regarding the smoking of paraquat-sprayed marijuana in the early 1970s has proved
unfounded, because paraquat is destroyed by pyrolysis.
A fatal case of paraquat absorbed per vagina has been reported.[36] Ocular exposure causes local caustic
injury but is unlikely alone to produce systemic toxicity.
Distribution
Excluding bile, paraquat distributes most avidly to lung, kidney, liver, and muscle.[2] It has an apparent
volume of distribution of 1.2 to 1.6 L/kg.[22] Also excluding bile, diquat distributes primarily to kidney, with
less appreciable concentrations found in spleen, lung, liver, and muscle.[2]
Paraquat, but not diquat, is taken up against a concentration gradient by the type I and type II pneumocytes.
This occurs through an ATP-dependent active transport mechanism.[45] A critical plasma threshold is
needed for active pulmonary uptake to occur.[30] Experimentally, lung fibrosis can be induced by exposure of
rat lung to diquat, but at doses much larger than required for paraquat.[28]
Metabolism
Paraquat elimination is virtually entirely renal and is accomplished by both glomerular filtration and active
tubular secretion. Greater than 90 per cent is excreted unchanged within 12 to 24 hours of ingestion, if renal
function remains normal.[22] Ingested diquat is excreted by the kidneys and gastrointestinal tract.[26]
Pathophysiology
Paraquat and diquat undergo cyclic reduction/oxidation in conjunction with NADPH and oxygen, resulting in
the formation of the superoxide radical (· O2-). Dicationic bipyridyls are reduced by NADPH to monocationic
free radicals and cyclically return to their original forms by giving up an electron to oxygen to form
superoxide radical ( Fig. 106–2 ).
Figure 106-2 Redox cycle of paraquat (PQ). (From Sabapathy NN: Quaternary ammonium compounds. Toxicology 1994; 91:93.)
In the first phase of this cycle, dicationic paraquat (PQ2+ ) plus NADPH undergo a reaction producing the
reduced paraquat ion (PQ1+ ) plus NADP+. PQ1+ reacts almost immediately with O 2, regenerating PQ 2+ plus
the superoxide radical (· O2-). Assuming availability of NADPH and O2, the redox cycle of paraquat
continues on and on, with the continued depletion of NADPH, and generation of (· O2-).The superoxide free
radical subsequently reacts with itself to form hydrogen peroxide (H2O2), and with H2O2 plus iron to form
hydroxyl (· O2-) free radicals.[47]
The redox cycle involving paraquat, oxygen, and NADPH, as well as the subsequent generation of the
hydroxyl free radical, spawns multiple mechanisms of cellular damage. Depletion of NADPH leads to cell
death. Hydroxyl free radicals are highly toxic and react with lipids in cell walls, a destructive process known
as lipid peroxidation.[54] DNA and proteins critical to cell survival are also destroyed by hydroxyl free radicals.
The cellular consequences of free radical formation (superoxide and others) by bipyridyls are the subject of
a large body of medical literature.[10][11][18][22][37][38][47][48] Experimental treatments aimed at modification of
free radical pathophysiology have included deferoxamine, superoxide dismutase, alpha-tocopherol, and
ascorbic acid in conjunction with forced diuresis. Unfortunately, none of these can be recommended at the
present time.
Although the complete detail of paraquat-generated free radical toxicology is unknown, what is known is that
the basis for poisoning is the interaction among paraquat, NADPH and oxygen. Oxygen at the cellular level,
then, is a critical factor in the genesis of disease caused by paraquat. This is the basis for withholding
supplemental oxygen in the early treatment of the paraquat-poisoned patient.
Bipyridyls are caustic and produce an injury similar to alkaline corrosives on contact with skin, eyes, and
mucous membranes. The major target organs for systemic paraquat poisoning are the gastrointestinal tract,
kidneys, and lungs. The gastrointestinal tract is severely injured by a direct corrosive effect when exposed to
significant concentrations in a deliberate ingestion. The kidney is the organ of elimination for paraquat and
diquat and has high concentrations of the bipyridyls compared with other organs.
Paraquat, but not diquat, is actively taken up by the lung through an energy-dependent process.[45] The lung
undergoes a biphasic injury pattern after paraquat exposure. A destructive phase, characterized by
destruction of alveolar epithelium, results from the consequences of the redox cycle. Subsequently, a
proliferative phase, regarded as a consequence of the destructive phase, produces additional destruction. In
this second phase, normal epithelial cells are replaced by fibrous tissue, leading to massive pulmonary
fibrosis, hypoxemia, and death.


A rapid but thorough history is imperative. Note the precise formulation of the substance involved, whether
or not it was diluted or concentrated, the amount ingested, the time since ingestion, the presence or absence
of food in the gut, and whether spontaneous emesis has occurred. A careful physical examination should
include a search for oral, skin, or mucous membrane lesions. Vomitus should be examined for color and
blood and saved for analysis.
Poisoning of children by both paraquat and diquat has been reported.[27][42] The clinical approach for
children who have been poisoned does not differ from that of poisoned adults.
Paraquat
Paraquat poisoning can be divided into three different presentations depending on the amount ingested or
injected.[50]
Severe Toxicity
Ingestion of paraquat ion of greater than 40 mg/kg results in rapidly progressing multisystem organ failure
(40 mg/kg is 14 mL of a 20 per cent solution for a 70-kg patient). Caustic mucous membrane damage, with
vomiting, massive myonecrosis, and renal, hepatic, respiratory, cardiac, neurologic, adrenal, or pancreatic
failure can cause death within hours to a few days, at most.
Moderate Toxicity
Ingestion of paraquat ion of 20 to 40 mg/kg produces a more indolent illness. Early symptoms include local
damage to the gastrointestinal tract, including the oropharynx, severe vomiting, and gastrointestinal
bleeding, as well as constitutional symptoms. Complications of this early phase have included
pneumopericardium, pneumomediastinum, and pneumothorax.[9] Renal failure gradually occurs and may
produce an unusually rapid rise in serum creatinine relative to the rise in blood urea nitrogen (low
BUN/creatinine ratio). In one case seen by the authors, the observation of an unusually high creatinine value
in a case of upper gastrointestinal bleeding (where one might expect to see an unusually large increase in
BUN but not creatinine) led to the diagnosis of paraquat toxicity even though the patient denied ingestion.
Eventually, in cases of moderate ingestions, pulmonary fibrosis intervenes after days or weeks. Death
occurs in the majority of persons with 20- to 40-mg/kg ingestions of paraquat ion.
Mild Toxicity
Ingestion or injection of paraquat ion of less than 20 mg/kg produces no symptoms or only mild
gastrointestinal tract symptoms. Full recovery is expected in all cases.[50] Bismuth[7] regards doses of less
than 30 mg/kg as benign, 30 to 50 mg/kg as moderately severe, and greater than 55 mg/kg as lethal.
Although deliberate ingestion or injection is responsible for most cases of serious bipyridylium herbicide
toxicity, morbidity and mortality can occur from other routes of exposure.
Skin exposure can cause death when prolonged or unusual contact with a concentrated BH occurs. Death
has followed paraquat application to beard and scalp (to treat lice) and whole-body (except face) paraquat
application to treat scabies.[13] Multiple case reports document death from prolonged exposure to clothes
soaked in concentrated paraquat.[53] Cutaneous exposure to paraquat diluted according to directions or brief
dermal exposure to concentrated paraquat is unlikely to cause systemic illness. Direct eye contact with
concentrated solutions will produce caustic ocular injury dependent on contact time and concentration.
Community exposure to a paraquat drift in California caused a variety of local and some systemic
symptoms, including cough, diarrhea, headache, nausea, fatigue, rhinorrhea, and excessive tearing. These
symptoms were significantly increased when compared with a control population.[3] Careless occupational
exposure can produce mucous membrane irritation: corneal and conjunctival inflammation, epistaxis, and
sore throat.
Diquat
Diquat exposures produce signs and symptoms similar to those of paraquat except for one important
system—the pulmonary system. Because diquat is not actively taken up by lung pneumocytes in a manner
similar to paraquat, pulmonary fibrosis is typically missing from the clinical picture of diquat intoxication.
Brainstem hemorrhagic infarction may be more common with diquat,[47] although there are insufficient
numbers of case reports to draw this inference conclusively. The estimated lethal dose of diquat was 10 g in
a 16-year-old and 4 g in a 60-year-old.[26][42][51][52] A 10-year-old boy survived a 6-g ingestion.
Clinical syndromes that should suggest the possibility of BH poisoning are listed in Table 106–1 . Symptoms
associated with BH poisoning are catalogued in Table 106–2 , along with differential diagnostic
considerations.
Table 106-1 -- Clinical Syndromes Suggestive of Bipyridylium Herbicide Poisoning

Unexplained acute renal failure
Idiopathic pulmonary fibrosis or symmetric perihilar infiltrates (paraquat only)
Unexplained multisystem organ failure
Severe gastroenteritis ± upper gastrointestinal bleeding ± oropharyngeal lesions
Brainstem hemorrhagic infarction
Table 106-2 -- Clinical Manifestations Associated with Bipyridylium Herbicide Poisoning and the
Differential Diagnosis of Toxins and Drugs That May Mimic It
Pulmonary Fibrosis Multisystem Organ Severe Vomiting/Diarrhea +
Acute Renal Failure
(Paraquat Only) Failure Upper Gastrointestinal Bleeding
Acetaminophen Aluminum Abrin (rosary pea) Antineoplastic drugs
Acute Renal Failure
Aminoglycosides Amiodarone (chronic use) Colchicine Barium
Amphotericin B Antineoplastic drugs Fluorides Boric acid
Fluoroacetate
Arsine Bleomycin Carbamates
(compound 1080)
Beta-lactam antibiotics Cyclophosphamide Iodide Cardiac glycosides
Boric acid/borates Asbestos Iron Caustics
Cisplatin Beryllium Metals: Colchicine
Cyclosporine Chromium Arsenic Ethanol
Diethylene glycol Gold Barium Fluoride
Chromium
Dinitrophenol Kaolin Iodide
(hexavalent salts)
Nitrofurantoin (chronic
Ethylene glycol Mercury (salts) Iron
use)
Halogenated
Ozone Phosgene Metaldehyde
hydrocarbons
Metals: Phosgene Phosphine Metals:
Arsenic Silica (silicosis) Ricin (castor bean) Arsenic
Cadmium Talc Salicylates Chromium
Chromium Tocainide Zinc phosphide Mercury
Copper Organic tin
Mercury (salts) Thallium
Thallium Mushroom and plant ingestions
Nonsteroidal anti-
Nicotine
inflammatory drugs
Phosphine Opioid withdrawal
Phosphorus Organophosphates
Polymyxin Paraldehyde
Radiographic contrast
Phenol
agents
Sulfonamides Phosphorus
Vancomycin Podophyllin
Salicylates
Theophylline
Acute Renal Failure
Zinc chloride
Zinc phosphide


A patient presenting with a history of BH ingestion and multisystem organ failure presents little diagnostic
challenge. Less obvious are cases in which exposure has been accidental, of smaller magnitude, homicidal,
or deliberately concealed by the patient. Table 106–2 lists some differential diagnostic considerations by
clinical presentation and by specific toxin or disease exposure.


LABORATORY STUDIES
Quantitative BH testing is rarely obtainable in the clinical setting, being available at only a few reference
laboratories. Testing can be used to confirm exposure and, in paraquat cases, to estimate prognosis. If the
time of paraquat ingestion is known, probability of death can be estimated using a blood level and the Hart
nomogram ( Fig. 106–3 ).[19]
Figure 106-3 Contour graph showing relation between plasma paraquat concentration (µg/mL), time after ingestion, and probability of
survival. (From Hart TB: A new statistical approach to the prognostic significance of plasma paraquat concentrations. Lancet 1984;
2:1222.)
The nomogram estimates the likelihood of survival (percentage) based on probability curves determined by
blood paraquat levels drawn at specific times after ingestion.
BH levels do not indicate the need for specific medical interventions, such as is the case with the
acetaminophen nomogram, and thus time is “not of the essence” in obtaining the results. They do assist in
predicting severity of illness and probability of death.
Other indirect laboratory testing may help assess the patient and prevent the institution of invasive or
ineffective measures in patients who cannot be expected to survive. Serial renal function tests, including
serum creatinine and blood urea nitrogen, and blood electrolyte determinations measure the degree and
progress of renal tubular injury. The presence of acute tubular necrosis is an ominous finding in the
presence of BH intoxication. A baseline chest radiograph should be obtained for all paraquat cases.
Paraquat and diquat emergency testing can be arranged 24 hours per day by calling ZENECA Ag Products
Emergency Information Network: 1-800-FASTMED (1-800-327-8633). This contract service by Zeneca will
provide advice and will make arrangements to ship samples from any location worldwide to a laboratory in
California. Samples must be collected in a heparinized plastic syringe, then spun down and shipped in a
plastic container on ice. Once the sample is received in the laboratory, turnaround time is 5 hours. Zeneca
also provides an 800 number for information on specific products: 1-800-759-2500.
The presence of both paraquat and diquat may be determined quickly in qualitative fashion with the
alkali/sodium dithionite urine test. This test is used primarily to exclude the diagnosis of a significant
exposure. It reduces the BH to a free radical, creating a dramatic color change in urine. The test is
performed by adding 10 mL of urine to 2 mL of 1 per cent sodium dithionite in 1 N sodium hydroxide.[4][8][44]
A blue color change indicates paraquat, whereas diquat produces a yellow-green color. Sensitivity is such
that a negative test is good evidence that significant BH ingestion has not occurred in the past 24 hours.
A respiratory index (RI) has been devised to measure pulmonary function trends in paraquat exposures.[49]
This may be of more value in patients who present more than 36 hours after ingestion of BH. In a series of
51 patients, all 43 patients with an RI greater than or equal to 1.5 died; all 8 with an RI less than 1.5 survived
(p<.0001). RI is calculated from arterial blood gas data and equals A - aDO 2/PO 2, where A - aDO2 is
calculated:
The respiratory quotient (R) was assumed to be 0.8.[7]


Many empirical therapies for systemic BH exposures have been based on the postulated pathophysiology of
these agents, but, unfortunately, most have not proven effective. At the time of a patient’s presentation to a
health care provider, the outcome has usually already been determined by the degree of exposure.
However, supportive care may be necessary for patients with a good prognosis and should be provided to
those with a poor prognosis.
Table 106-3 -- Treatment of Bipyridylium Herbicide Poisoning

Airway management and advanced life support, as needed
Decontamination
Gastrointestinal: multidose activated charcoal, 1 gm/kg PO
Dermal and ocular: copious irrigation
Intravenous crystalloids to maintain urine output at
1–2 mL/kg/hr
Oxygen: administer only for hypoxia
Analgesic and anxiolytic drugs, as needed
Extracorporeal removal
Hemoperfusion controversial, probably does not alter outcome
Hemodialysis only for renal failure
No role for forced diuresis or peritoneal dialysis
Decontamination
Although gastrointestinal decontamination has never been shown to change outcome in BH poisoning, early
decontamination is probably the single most valuable therapy available for oral ingestions. Activated
charcoal, 100 g for adults and 1 g/kg body weight for children, should be given unless there is a
contraindication, such as protracted vomiting or severe burns of the oral mucous membranes. Multiple doses
of activated charcoal have not been studied in BH ingestion; however, they should not cause harm provided
emesis has been controlled. A total of three doses of activated charcoal at 2-hour intervals is sensible.
Fuller’s earth and bentonite clay were at one time listed as the decontamination agents of choice, but
activated charcoal is more easily available and probably as effective.[14][30][34]
Rapid absorption of BH and caustic injury to the gastrointestinal tract, as well as lack of proven efficacy,
preclude significant roles for orogastric lavage, syrup of ipecac, or whole-bowel irrigation. Ipecac may be of
value in a home setting if immediately available. The risk of worsening the gastrointestinal caustic injury
must be balanced against the lethality of the amount ingested. Gastric lavage may be of value if performed
within 1 hour of ingestion, but benefit must be balanced against risk of perforation.
The authors have seen deliberate ingestions of paraquat (4 patients) and diquat (1 patient) present to our
community hospital. The sole survivor was a farmer who intended suicide by means of ingesting
concentrated paraquat but who had the good fortune to eat a large “last meal” of pancakes. He then had
spontaneous emesis and presented to the emergency department within 5 minutes of ingestion, where
activated charcoal was immediately given, followed by orogastric lavage, followed by more activated
charcoal.
Dermal and ocular exposures should be managed with copious irrigation. In the case of ocular exposure, pH
should be monitored and irrigation continued until pH is normalized.
Extracorporeal Removal
Charcoal hemoperfusion (CHP) has been a controversial treatment of potentially lethal BH ingestions.
Although Okenek and associates demonstrated increased clearance of paraquat using CHP in rodent
studies[31][32][33][35] and have strongly advocated this therapy in BH ingestions,[31][32][33][35] the current
consensus is that CHP does not change outcome.[5][6][15][16][17][21][29][39][40][43][50] Although charcoal
hemoperfusion can increase elimination of BH, prognosis is not changed. This is because of at least three
factors: (1) the patient has usually ingested many times the lethal dose; (2) there is no reliable way to rapidly
separate lethal from nonlethal ingestions; and (3) the delay before the procedure begins is usually sufficient
to allow absorption and distribution of fatal amounts of BH, even when the decision to hemoperfuse is made
quickly. Furthermore, the renal clearance with normal kidneys is much greater than clearance by means of
hemoperfusion.[41]
Hemodialysis (HD) may have to be performed because of acute renal failure, but neither HD nor peritoneal
dialysis is effective in increasing BH clearance.
Supportive Therapies
Early crystalloid administration is important to correct dehydration, which is often severe, and to maintain a
urine output of 1 to 2 mL/kg/hr. The primary mode of BH elimination is renal. An adequate urine output is
critical to early elimination and may delay the onset of renal failure, which in turn slows elimination. There is
no role for forced diuresis, however.
Supplemental oxygen should not be administered routinely. Oxygen may increase lung injury by providing
additional substrate for superoxide radical formation. However, hypoxic breathing mixtures have not been
shown to prevent this phenomenon,[5] and supplemental oxygen should be given to hypoxemic patients.
Good supportive care, including relief of pain and anxiety, is essential. Because medical therapy is so
abysmally unsuccessful in reversing moderate to severe BH ingestions, the health care providers, their
patients, and the patients’ families are often bewildered. The art of medicine is crucial here, as is a
multidisciplinary approach to assisting with impending death. Honesty about prognosis, without taking away
hope, and emphasizing what can be done (i.e., pain relief and pastoral and social service care) are keystone
approaches to a grim situation.[50]
Lung transplantation has been unsuccessful.[46]


DISPOSITION
All patients suspected of BH ingestion should be admitted to the hospital. Either qualitative or preferably
quantitative testing of BH levels should be performed. Aggressive supportive medical and psychiatric care
should be initiated and continued as the clinical situation or laboratory-driven prognosis dictates.


SEQUELAE
Patients with significant BH exposures usually either die or recover fully. Long-term pulmonary fibrosis has
been reported in survivors, but this is unusual. [24] Case reports documenting survival after diquat ingestion
are rare, and little is known about long-term effects in survivors.


REFERENCES
1. Almog C, Tal E: Death from paraquat after subcutaneous injection. Br Med J 1967; 3:721.
2. Ameno K, Fuke C, Shirakawa Y, et al: Different distribution of paraquat and diquat in human poisoning
cases after ingestion of combined herbicide. Arch Toxicol 1994; 68:4-137.
3. Ames RG, Howd RA, Doherty L: Community exposure to a paraquat drift. Arch Environ
Health 1993; 48:47-52.
4. Berry DJ, Grove J: The determination of paraquat (1,1'-dimethyl-4,4'-bipyridylium cation) in urine. Clin
Chim Acta 1971; 34:5-11.
5. Bismuth C, Garnier R, Baud FJ, et al: Paraquat poisoning: An overview of the current status. Drug
Safety 1990; 5:243-251.
6. Bismuth C, Garnier R, Dally S, et al: Prognosis and treatment of paraquat poisoning: A review of 28
cases. J Toxicol Clin Toxicol 1982; 19:461-474.
7. In: Bismuth C, Hall AH, ed. Paraquat Poisoning: Mechanisms, Prevention, Treatment, New York: Marcel
Dekker; 1995.
8. Braithwaite RA: Emergency analysis of paraquat in biological fluids. Hum Exp Toxicol 1987; 6:83-86.
9. Chen K, Wu M, Huang J, et al: Bilateral spontaneous pneumothoraces, pneumopericardium,

pneumomediastinum, and subcutaneous emphysema: A rare presentation of paraquat intoxication. Ann
Emerg Med 1994; 23:1132-1134.
10. Davies DS: Paraquat poisoning: The rationale for current treatment regimes. Hum Exp
Toxicol 1987; 6:37-40.
11. Farrington JA, Ebert M, Land EJ: Bipyridylium quaternary salts and related compounds: V Pulse
radiolysis studies of the reaction of paraquat radical with oxygen: Implications for the mode of action of
bipyridyl herbicides. Biochem Biophys Acta 1973; 314:372-381.
12. Fisher HK, Humphries M, Bails R: Paraquat poisoning: Recovery from renal and pulmonary damage.
Ann Intern Med 1971; 75:731-736.
13. Garnier R, Chataigner D, Efthymiou ML, et al: Paraquat poisoning by skin absorption: Report of two
cases. Vet Hum Toxicol 1994; 36:313-315.
14. Gaudreault P, Friedman PA, Lovejoy FH: Efficacy of activated-charcoal and magnesium citrate in the
treatment of oral paraquat intoxication. Ann Emerg Med 1985; 14:123-125.
15. Hampson EC: Is repeated hemoperfusion an effective treatment for paraquat poisoning?. Vet Hum
Toxicol 1989; 31:335.
16. Hampson EC, Effeney DJ, Pond SM: Efficacy of single or repeated hemoperfusion in a canine model of
poisoning. J Pharmacol Exp Ther 1990; 254:732-740.
17. Hampson EC, Pond SM: Failure of haemoperfusion and haemodialysis to prevent death in paraquat
poisoning: A retrospective review of 42 patients. Med Toxicol 1988; 3:64-71.
18. Harley JB, Grinspan S, Root RK: Paraquat suicide in a young woman: Results of therapy directed
against the superoxide radical. Yale J Biol Med 1977; 50:481-488.
19. Hart TB, Nevitt A, Whitehead A: A new statistical approach to the prognostic significance of plasma
paraquat concentrations. Lancet 1984; 2:1222-1223.
20. Hoffer E, Taitelman U: Exposure to paraquat through skin absorption: Clinical and laboratory
observations of accidental splashing on healthy skin of agricultural workers. Hum Exp Toxicol 1989; 8:483-
485.
21. Honore P, Hantson PH, Fauville JP, et al: Paraquat poisoning: “State of the art.”. Acta Clin
Belg 1994; 49:220-228.
22. Houze P, Baud FJ, Mouy R, et al: Toxicokinetics of paraquat in humans. Hum Exp Toxicol 1990; 9:5-
12.
23. Howard JK: The myth of paraquat inhalation as a route for human poisoning. J Toxicol Clin
Toxicol 1983; 20:191-193.
24. Hudson M, Patel SB, Ewen SWB, et al: Paraquat induced pulmonary fibrosis in three survivors.
Thorax 1991; 46:201-204.
25. Litovitz T, et al: 1983–1998 Annual reports of the American Association of Poison Control Centers
National Data Collection System. Am J Emerg Med 1983; 2:420.1984; 3:423; 1985; 4:427; 1986; 5:405;
1987; 6:479; 1988; 7:495; 1989; 8:394; 1990; 9:461; 1991; 10:452; 1992; 11:494; 1993; 12:546; 1994;
13:551; 1995; 14:487; 1996; 15:447; 1997; 16:443; 1998; 17:435.
26. McCarthy LG, Speth CP: Diquat intoxication. Ann Emerg Med 1983; 12:394-396.
27. McDonagh BJ, Martin J: Paraquat poisoning in children. Arch Dis Child 1970; 45:425-427.
28. Manabe J, Ogata T: Lung fibrosis induced by diquat after intratracheal administration. Arch
Toxicol 1987; 60:427-431.
29. Mascie-Taylor BH, Thompson J, Davison AM: Haemoperfusion ineffective for paraquat removal in life-
threatening poisoning. Lancet 1983; 1:1376-1377.
30. Meredith TJ, Vale JA: Treatment of paraquat poisoning in man: Methods to prevent absorption. Hum
Exp Toxicol 1987; 6:49-55.
31. Okonek S: Hemoperfusion in toxicology: Basic considerations of its effectiveness. Clin

Toxicol 1981; 18:1185-1198.
32. Okonek S, Baldamus CA, Hofmann A: Survival despite potentially fatal plasma paraquat concentrations.
Lancet 1980; 2:589.
33. Okonek S, Hofmann A, Henningsen B: Efficacy of gut lavage, hemodialysis, and hemoperfusion in the
therapy of paraquat or diquat intoxication. Arch Toxicol 1976; 36:43-51.
34. Okonek S, Setyadharma H, Borchert A, et al: Activated charcoal is as effective as fuller’s earth or
bentonite in paraquat poisoning. Klin Wochenschr 1982; 60:207-210.
35. Okonek S, Weilemann LS, Majdandzic J, et al: Successful treatment of paraquat poisoning: Activated
charcoal per os and “continuous hemoperfusion.”. J Toxicol Clin Toxicol 1982–1983; 19:807-819.
36. Ong ML, Glew S: Paraquat poisoning: Per vagina. Postgrad Med J 1989; 65:835-836.
37. Onyeama HP, Oehme FW: A literature review of paraquat toxicity. Vet Hum Toxicol 1984; 26:494-502.
38. Petry TW, Wolfgang GHI, Jolly RA, et al: Antioxidant-dependent inhibition of diquat-induced toxicity in
vivo. Toxicology 1992; 74:33-43.
39. Pond SM: Manifestations and management of paraquat poisoning. Med J Aust 1990; 152:256-259.
40. Pond SM: Extracorporeal techniques in the treatment of poisoned patients. Med J Aust 1991; 154:617-
622.
41. Pond SM, Rivory LP, Hampson EC, et al: Kinetics of toxic doses of paraquat and the effects of
hemoperfusion in the dog. J Toxicol Clin Toxicol 1993; 31:229-246.
42. Powell D, Pond SM, Allen TB, et al: Hemoperfusion in a child who ingested diquat and died from
pontine infarction and hemorrhage. J Toxicol Clin Toxicol 1983; 20:405-420.
43. Proudfoot AT, Prescott LF, Jarvie DR: Haemodialysis for paraquat poisoning. Hum Toxicol 1987; 6:69-
74.
44. Proudfoot AT, Stewart MS, Levitt T, et al: Paraquat poisoning: Significance of plasma-paraquat
concentration. Lancet 1979; 2:330-332.
45. Rose MS, Smith LL: Tissue uptake of paraquat and diquat. Gen Pharmacol 1977; 8:173-176.
46. Saunders NR, Alpert HM, Cooper JD, et al: Sequential bilateral lung transplantation for paraquat
poisoning. J Thorac Cardiovasc Surg 1985; 89:734-742.
47. Smith LL: Mechanism of paraquat toxicology in lung and its relevance to treatment. Hum Exp
Toxicol 1987; 6:31-36.
48. Smith LL, Rose MS, Wyatt I: The pathology and biochemistry of paraquat. Ciba Found
Symp 1978; 65:321-341.
49. Suzuki K, Takasu N, Arita S, et al: A new method for predicting the outcome and survival period in
paraquat poisoning. Hum Exp Toxicol 1989; 8:33-38.
50. Vale JA, Meredith TJ, Buckley BM: Paraquat poisoning: Clinical features and immediate general
management. Hum Exp Toxicol 1987; 6:41-47.
51. Vanholder R, Colardyn F, De Reuck J, et al: Diquat intoxication: Report of two cases and review of the
literature. Am J Med 1981; 70:1267-1271.
52. Williams PF, Jarvie DR, Whitehead AP: Diquat intoxication: Treatment by charcoal haemoperfusion and
description of a new method of diquat measurement in plasma. Clin Toxicol 1986; 24:11-20.
53. Wohlfahrt DJ: Fatal paraquat poisonings after skin absorption. Med J Aust 1982; 1:512-513.
54. Yasaka T, Okudaira K, Fujito H, et al: Further studies of lipid peroxidation in human paraquat poisoning.
Arch Intern Med 1986; 146:681-685.
55. Yoshioka T, Sugimoto T, Kinoshita N, et al: Effects of concentration reduction and partial replacement of
paraquat by diquat on human toxicity: A clinical study. Hum Exp Toxicol 1992; 11:241-245.


Chapter 107 – Anticoagulant Rodenticides
KEITH K. BURKHART
Essentials
• Identification of ingredients in witnessed unknown acute rodenticide ingestions
• Coagulopathy without liver disease or history of a bleeding diathesis
• Laboratory evidence for vitamin K–dependent coagulation factor deficiencies
• History or physical evidence of anticoagulant exposure
INTRODUCTION
Anticoagulant rodenticide poisonings were considered clinically insignificant prior to 1976. Up to that time,
rodenticides contained small quantities of warfarin. Acute human poisoning, although common, was only
serious following rare chronic ingestions. After long-term exposure to warfarin, rodents acquired a resistance
that is transmitted by a single dominant autosomal gene; in response, potent long-acting anticoagulant
rodenticides were developed.[15] The number of standard warfarin anticoagulant rodenticides reported to the
American Association of Poison Control Centers Toxic Exposure Surveillance System in 1998 was less than
10 per cent of the 17,724 total anticoagulant rodenticide exposures.[24] Anticoagulant rodenticide exposures
were common, totaling 0.8 per cent of all reported human exposures in this system. In the United States
brodifacoum-containing products are the most common. Table 107–1 lists currently available long-acting
rodenticides reported in Poisindex.[34]
Table 107-1 -- Available Forms of Long-Acting Anticoagulant Rodenticides

Rodenticide Concentrations Forms Brand Names
4-Hydroxycoumarins
0.005% Bait D-Con Mouse Prufe II
Brodifacoum
Talon, Talon G, Havoc
0.005% Bait Bromone, Super-Caid
Bromadiolone
Ratimus, Maki
Difenacoum 0.005% Bait Ratak
Endox, Endrocid
Coumatetralyl Endrocide, Racumin
Racumin 57, Rodentin
Rodenticide Concentrations Forms Brand Names
Indanediones
0.005% Bait Caid, Drat, Ramucide
0.25% Solution Liphadione, Ratomet
Chlorphacinone
2.5% Concentrate Microzul, Rozul
Topitox, Raviac
0.005% Cake Diphacin
Diphacinone 0.05, 0.1, 0.2% Bait Promar
2.0% Concentrate Ramik
0.025, 0.1, 0.2, 0.5% Powder Pival, Pivacin
Pindone
0.5, 1.5, 2.0% Concentrate Pivalyn, Tri-Ban


PATHOPHYSIOLOGY
Absorption
These products are well absorbed by the gastrointestinal tract, with ingestion being the predominant mode of
exposure. Percutaneous absorption of the anticoagulants leading to toxicity appears possible. Rabbits and
guinea pigs absorb warfarin through the skin.[13] A farmer using warfarin and two workers involved in the
manufacture of the anticoagulants brodifacoum and difenacoum developed coagulopathy, possibly by
percutaneous absorption.[13][30]
Mechanism of Action
Activation of clotting factors II, VII, IX, and X, along with protein S and protein C, requires vitamin K as a
cofactor ( Fig. 107–1 ). Carboxylation of specific terminal glutamic acid residues activates these coagulation
proteins. During this enzymatic reaction, vitamin K is oxidized to an epoxide. Vitamin K 2,3-epoxide
reductase converts the epoxide into the quinone form. Another sulfhydryl-dependent vitamin K reductase
then catalyzes another reduction to the quinol, active form. Inhibition of these vitamin K reductases is the
mechanism of action for warfarin and warfarin-like long-acting anticoagulants.[6][15][23][40] Elevated ratios of
vitamin K 2,3-epoxide to vitamin K (normal 0.1–0.2) have been documented in human overdose.[31]
Figure 107-1 Role of vitamin K1 in coagulation factor activation. (1) Vitamin K1 is reduced by several quinone reductases to the (2)
active quinol. A carboxylase/epoxidase enzyme complex simultaneously catalyzes the (3) -carboxylation of inactive vitamin
K–dependent coagulation factors, rendering them active, while converting the quinol to the (4) inactive vitamin K1 2,3-epoxide. This
epoxide is recycled by vitamin K1 2,3-epoxide reductase to vitamin K1. The slanted bars indicate sites where the 4-hydroxycoumarin
and indandione rodenticides block this cycle. The most sensitive site for blockade is vitamin K1 2,3-epoxide reductase. (5) An
NAD(P)H-dependent quinone reductase is not affected by these drugs, and thus, vitamin K administered exogenously may still be
reduced to its active form to counteract the anticoagulation effect. The role of protein Z has not been elucidated.
A coagulopathy becomes evident when the anticoagulant critically reduces the active factor levels below 30
per cent of baseline.[17] Of the vitamin K–dependent factors, factor VII has the shortest half-life, 5 hours.
Therefore, a measurable effect will not occur until approximately 15 to 24 hours following an exposure.
Clinical bleeding usually will not develop until 2 to 3 days or longer after ingestion.
Duration and Elimination
The elimination half-life (T½e) of warfarin is 24 to 36 hours, while the T½e for brodifacoum is weeks to
months in human overdoses.[1][6][18][19][43] Elimination half-life determinations for chlorphacinone have been
6 to 23 days.[7] The long-acting anticoagulants, second-generation anticoagulants, or superwarfarins are
more lipophilic and occupy the hepatic warfarin binding sites with greater affinity. Clinical recovery from an
acute ingestion of warfarin occurs within 5 days.[21] The amount of warfarin contained in the standard
commercial preparations is sufficiently low (0.025–0.05 per cent) that chronic ingestion is required to
produce clinical bleeding. The anticoagulant effect of the superwarfarins, however, persists for months to
years, depending upon the dose.[6][20][42][43] It has been hypothesized that de novo synthesis of the
reductases may be required following long-acting rodenticides.[25]


In most cases the emergency physician will manage accidental pediatric ingestions, which usually are small
in quantity and of no clinical significance. On the other hand, most adult presentations or pediatric cases of
Munchausen syndrome by proxy will follow large acute or chronic ingestions. These anticoagulant-poisoned
patients present for medical treatment after a bleeding complication develops. The bleeding may be minor or
in some cases life-threatening. A review of the literature did not uncover any case in which the
anticoagulant-poisoned patient immediately provided the history of ingesting a long-acting anticoagulant
rodenticide. Some patients confessed, when confronted with compelling laboratory information. Many
patients, however, continue to deny a known exposure even when confronted with specific serum
anticoagulant levels.
The bleeding site(s) that lead to the clinical presentation can involve almost any organ system. Epistaxis,
bleeding gums, bruising, hematomas, and petechiae are common
presentations.[1][2][7][8][10][12][16][17][19][20][21][39][43] Flank pain and hematuria are common chief
complaints.[7][15][17][18][21][31][41] Abdominal pain with or without hematemesis and melena may also be
presenting symptoms.[7][8][17][20][21][41] Hemoptysis from alveolar hemorrhage has resulted in the need for
prolonged ventilatory support.[2] Extremity pain eventually diagnosed as compartment syndrome has been
reported in a number of cases.[38][42][43] Vaginal bleeding is another common presentation.[2][7][10][32]
Fatalities have been noted following subarachnoid, subdural and intracerebral hemorrhages and vaginal
bleeding.[3][16][22][32] Most important, the patients in these reports presented with evidence of bleeding from
more than one site or organ system.
Bleeding from multiple sites or markedly prolonged bleeding from one site should prompt a detailed
examination ( Table 107–2 ). The history should identify any previously diagnosed bleeding disorder such as
hemophilia, von Willebrand’s disease, or other coagulation factor deficiency. Malnutrition or vitamin K
deficiency is rare in North America. The most likely diagnosis for an acquired coagulopathy other than
anticoagulant intoxication is liver disease. A previous history of alcohol abuse or jaundice may exist. In many
cases the diagnosis is missed on the first presentation.[27] Factor replacement or vitamin K therapy
temporarily reverses the coagulopathy. These patients will subsequently present again with further abnormal
bleeding.[8][38]
Table 107-2 -- Clinical Presentation of Anticoagulant Rodenticide Poisoning

Acute poisonings
Rare gastrointestinal symptoms; nausea, vomiting, abdominal pain
Most asymptomatic for the first 24 hours or more
Chronic poisonings and late acute poisonings
Bleeding from multiple sites on physical exam
No medical historical explanation
Coagulopathy in absence of liver disease
The physical examination often uncovers multiple sites of bleeding. Bruises in various stages of healing,
petechiae, and possibly oozing from lacerations or venipuncture sites may be found on skin examination.
The nose and gingiva may be oozing blood. On rectal examination melena or occult bleeding may be
discovered. A bedside urinalysis may identify hematuria. Emesis, when present, should also be evaluated
for the presence of blood.
Acute or chronic ingestions of long-acting anticoagulants will usually have similar bleeding presentations. An
adult patient will rarely present with the history of having ingested the product shortly before arrival in the
emergency department.[27] The presentation will usually be delayed until the coagulopathy produces the
bleeding complication. This time period may vary from days to weeks after the exposure. In cases of chronic
exposure, patients present after the critical amount of anticoagulant concentrates in the liver and bleeding
develops.
The vast majority of pediatric patients to be treated for rodenticide poisoning will be brought for medical
attention after being found eating the bait. Most of these children will be asymptomatic, although a few may
complain of nausea, vomiting, or abdominal pain.[36] Unfortunately, there are no reliable historical or physical
signs, such as blue-green discoloration around the mouth, that predict a significant exposure. Although a
few pellets are considered a nontoxic ingestion, it is rare that the amount ingested is clearly known.
Fortunately, the concentration of anticoagulants is sufficiently low that a clinically significant coagulopathy
will rarely develop. In a series of 26 patients (25 pediatric) only one patient with a history of epistaxis
became symptomatic with a nosebleed.[5] In another series of 88 patients (82 pediatric) of which 92 per cent
underwent gastric decontamination, none developed an abnormal prothrombin time (PT).[37]
Rarely, pediatric patients may present in a manner similar to adult patients.[1][14][39][42] Parental poisoning of
children, Munchausen syndrome by proxy, with rodenticides has been reported. [1] The mother sprinkled rat
bait onto the child’s cereal even during the hospitalization. In other cases the children, although not
witnessed, were suspected of eating the bait as candy or possibly consuming rat feces that contained the
anticoagulant.[14][42]


Although other sources of coagulopathy must be considered and ruled out, the list is not extensive and can
be quickly narrowed down. Congenital factor deficiencies are rare. In the adult patient, a pre-existing
diagnosis would be most likely. In cases of a consumptive coagulopathy, another etiology such as sepsis is
often apparent ( Table 107–3 ). Liver dysfunction, however, is common and may present with PT
prolongation and abnormal bleeding. Hepatotoxins such as acetaminophen or amanitin may have this
presentation. Ethanol abuse, viral hepatitis, and other liver diseases may also present with bleeding
diatheses.
Table 107-3 -- Differential Diagnosis of Anticoagulant Poisoning

Decreased coagulation factors
Congenital
Factor VIII (hemophilia)
Factor IX (von Willebrand’s)
Factor XI
Factor XII (Hageman factor)
Acquired
Liver dysfunction
Vitamin K deficiency from malnutrition or malabsorption
Warfarin ingestion
Consumption of coagulation factors
Severe hemorrhage
Disseminated intravascular coagulation following sepsis, snake envenomation, and hyperthermia
Coagulation inhibitors (usually circulating antibodies)
Thrombolytic agents
Thrombocytopenia


LABORATORY STUDIES
Initial Tests
Prolongation of the PT is the first clue to the diagnosis of anticoagulant poisoning. Many laboratories now
report results as the PT ratio or the INR (international normalized ratio). In cases of severe toxicity the partial
thromboplastin time (PTT) will also be prolonged. In the severely bleeding patient fibrinogen and fibrin split
products should be measured to rule out other etiologies such as hypofibrinogenemia from crotalid
envenomation or disseminated intravascular coagulation, either as the primary diagnosis or as a secondary
complication of severe hemorrhage. A hemoglobin and hematocrit rapidly assess the severity of blood loss.
A platelet count will rule out thrombocytopenia as the etiology for the bleeding. Liver function tests may
elucidate hepatotoxicity as the cause.
Advanced Tests
When a history of anticoagulant poisoning is lacking, a number of diagnostic laboratory tests can aid in
confirming the diagnosis. Mixing normal plasma with the patient’s plasma can rule out the possibility of a
coagulation inhibitor.[31] Mixing 10 per cent normal plasma with the patient’s blood will yield a significant
improvement, and mixing 50 per cent should correct to a near-normal INR. The actual measurement of the
vitamin K–dependent factors is now available at a number of facilities, although not usually on a stat basis.
All four vitamin K–dependent factors are reduced with anticoagulant toxicity, while others such as factor V
remain normal. This laboratory information essentially clinches the diagnosis. If a patient still denies self-
ingestion, then actual rodenticide measurements would be warranted. A number of techniques have been
described, including radioimmunoassay, enzyme-linked immunosorbent assay, high-performance liquid
chromatography with fluorescence detection, and gas chromatography/mass spectrometry. [26][32][41][42][43]
Therefore, many reference laboratories can perform these assays.
Asymptomatic Pediatric Patient
A baseline PT is unnecessary in a child who presents immediately after ingesting a small amount of
anticoagulant. A follow-up PT in 48 to 72 hours may or may not be indicated (see Disposition).


TREATMENT
Decontamination
Gastric decontamination of patients has been recommended by most regional poison centers if the patient
presents within 1 hour of an ingestion of a large or unknown amount.[5][21][37] In the home setting, syrup of
ipecac can be used to induce emesis, although ingestions of one or two pellets require no intervention. In
the hospital activated charcoal is advised. A large ingestion appears to be greater than 0.0125 mg/kg of
brodifacoum.[21] The limited reported experience of other long-acting anticoagulants has not yet defined a
large ingestion for these compounds. Multiple doses of activated charcoal did not alter the clinical course of
one patient.[11]
Therapy for Anticoagulant Effects
Symptomatic Anticoagulated Patient
The severity of bleeding dictates what therapeutic interventions are needed ( Table 107–4 ). In life or limb-
threatening situations, such as intracerebral or gastrointestinal hemorrhage, vaginal bleeding, or
compartment syndromes, whole blood and fresh frozen plasma are required. These blood products contain
active coagulation factors that will immediately initiate clotting. Therefore, the initial coagulation studies must
be obtained before blood products are given in order to ascertain accurate diagnostic information.
Table 107-4 -- Treatment Essentials for Anticoagulant Poisoning

1. Severe bleeding requires whole blood or packed cells, as necessary.
a. Fresh frozen plasma or factor concentrates, units as needed to correct PT and halt bleeding
b. Vitamin K1 therapy, 10–25 mg. The subcutaneous route is the safest. Physicians who choose the
intravenous route must be prepared to treat serious anaphylactoid reactions with epinephrine,
diphenhydramine, cimetidine, and glucocorticosteroids. The benefit of therapy begins in approximately 6 hours
c. Oral vitamin K1 = 100 mg. Action delayed additional 2–3 hours for absorption
2. Stable patient, prolonged coagulation studies:
a. Oral vitamin K1, 100 mg, in three to four divided doses daily
b. Consider admission to safe environment—psychiatric ward or hospital
3. Maintenance therapy:
a. Oral vitamin K1, up to several hundred milligrams daily, in three or four divided doses
b. Increase dose as needed to correct PT/INR
c. As vitamin K dose is tapered, recheck PT within 24–48 hours of a dose reduction
4. Decontamination:
a. Syrup of ipecac or activated charcoal, in home setting, for known recent ingestion. Not recommended for
chronic exposure
b. Activated charcoal, 1 g/kg, for acute ingestions. Multiple doses (MDAC) not proved to be efficacious
Vitamin K therapy should also be started. Intravenous administration carries a significant risk for
anaphylactoid reactions. Therefore, the subcutaneous route is the safest and may be as efficacious.
AquaMEPHYTON is the only preparation available for parenteral administration in the United States. The
American College of Chest Physicians Consensus Conference on antithrombotic therapy has made dosage
recommendations for vitamin K based upon the INR from anticoagulation.[4] For patients with serious
bleeding, 10 mg is recommended. In patients without bleeding and INRs of 6.0–10.0, 10.0–20.0, and over
20.0, vitamin K 0.5–1.0 mg, 3–5 mg, and 10 mg, respectively, are recommended. Controversy exists about
the use of intravenous vitamin K, especially when the patient is not bleeding, because of the risk of
anaphylaxis or a severe anaphylactoid reaction associated with the intravenous route.[28] The lipophilic
formulation is based upon solubilization in a polyoxyethylated castor oil substance that may initiate the
anaphylactoid reaction.[33] A slow intravenous push, 1 mg vitamin K per minute, of a dilute solution seems to
minimize this risk, although severe anaphylactoid reactions have been reported following these
recommendations.[33] Table 107–4 summarizes vitamin K treatment doses and administration. Vitamin K 1 is
required, as the other forms of vitamin K are ineffective.[21]
Asymptomatic Anticoagulated Patient
In patients without active bleeding or life-threatening hemorrhage but with prolonged coagulation studies, the
oral administration of vitamin K1 is recommended. Doses greater than 100 mg/day have been administered
to normalize the PT.[35] These supratherapeutic doses have generated active coagulation factors.[29] Vitamin
K has a short therapeutic half-life. Human volunteers with or without anticoagulation, given 10 mg vitamin K1
intravenously, had a half-life of 0.9–2.8 hours.[9][29] The coagulopathy will reappear 24 to 48 hours after
stopping vitamin K, because of the short elimination half-lives of both vitamin K and factor VII (5–6 hours).
The decision to stop vitamin K treatment is empirical. A successful regimen in a number of case reports has
been to continue treatment until the PT becomes normal. [19][20] A repeat PT should be performed 24–48
hours after discontinuation of vitamin K. If the PT is still abnormal, further vitamin K therapy will usually be
required. INRs of 1.2–1.5 are considered therapeutic. Therefore, clinical judgment should determine the
need for further vitamin K administration in cases of minimal INR elevations.
Asymptomatic Nonanticoagulated Patient
Prophylactic vitamin K should not be administered to patients presenting acutely after a known or suspected
ingestion. Such administration may prolong the period for monitoring the PT.
Adjunctive Therapy
The long-acting anticoagulants are metabolized by the hepatic microsomal mixed function oxidase enzyme
system. Phenobarbital induces these enzymes such that anticoagulant metabolism may be increased.
Therefore, phenobarbital administration has been suggested to potentially enhance elimination. A clinical
benefit in humans, however, has not been demonstrated.[17][32][39] Phenobarbital may also enhance the
turnover of vitamin K.[44]


DISPOSITION
Symptomatic Patients
Any patient that presents with severe bleeding will require admission to an intensive care unit until the
coagulopathy is corrected and bleeding is controlled. Nonbleeding patients with prolonged coagulation
studies should also be admitted to a nonintensive care unit to optimize oral vitamin K therapy. Some patients
may have vitamin K adjustments while on the psychiatric ward. Once patients are not bleeding and have
INRs less than 3.0, they may be safe for outpatient therapy. Outpatient management of these patients
clearly has risks. The coagulopathy may make some suicide attempts or gestures more serious than others.
Many of these patients are not compliant with their medications and may reingest the rodenticide during the
recovery period.[2][39][43] There is one report of a patient committing suicide the day after discharge. [41]
All pediatric patients with a significant coagulopathy should be admitted to the hospital while diagnostic
evaluation is performed. A search of the home and evaluation of the social situation appears warranted,
since reports of significant ingestions in this patient population are rare.[21] Munchausen syndrome by proxy
should be a strong consideration.
Asymptomatic Patients
Asymptomatic pediatric patients may be discharged home with instructions to return if signs of bleeding
occur. A follow-up PT at 48–72 hours may or may not be required. Children, unless intentionally poisoned or
in rare cases with a suspicion of eating rat feces, have not developed significant toxicity.[36] Although clearly
a rat bait pack contains enough anticoagulant to poison a child, as a population, small children have not
reportedly ingested sufficient quantities (greater than 0.0125 mg/kg, with brodifacoum) to induce clinically
significant toxicity. Because of this growing experience, some poison information centers are no longer
recommending emergency department visits, nor that a 48–72 hour PT be assessed. A consultation with the
regional Poison Information Center should provide the current standard of care for the community. All adult
patients with intentional ingestions should be hospitalized for sequential coagulation studies and psychiatric
evaluation.


SEQUELAE
A full recovery from long-acting rodenticide ingestions is expected, as long as bleeding complications can be
avoided. The only sequelae noted in a number of case reports was cortical blindness following occipital
hemorrhages.[42]


REFERENCES
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Pediatr Hematol Oncol 1993; 15:126.
2. Barnett VT, Bergmann F, Humphrey H, et al: Diffuse alveolar hemorrhage secondary to superwarfarin
ingestion. Chest 1992; 102:1301.
3. Basehore LM, Mowry JM: Death following ingestion of superwarfarin rodenticide: A case report. Vet
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Med 1995; 155:149.
5. Bennett DL, Caravati EM, Veltri JC: Long-acting anticoagulant ingestion: A prospective study. Vet Hum
Toxicol 1987; 29:472.
6. Breckenridge AM, Cholerton S, Hart JAD, et al: A study of the relationship between the pharmacokinetics
and the pharmacodynamics of the 4-hydroxycoumarin anticoagulants warfarin, difenacoum and brodifacoum
in the rabbit. Br J Pharmacol 1985; 84:81.
7. Burucoa C, Mura P, Robert R, et al: Chlorophacinone intoxication: A biological and toxicological study.
8. Chong L, Chau W, Ho C: A case of superwarfarin poisoning. Scand J Haematol 1986; 36:314.
9. Choonara IA, Scott AK, Haynes BP, et al: Vitamin K1 metabolism in relation to pharmacodynamic
response in anticoagulated patients. Br J Clin Pharmacol 1985; 20:643.
10. Chow EY, Haley LP, Vickars LM, et al: A case of bromadiolone (superwarfarin) ingestion. Can Med
Assoc J 1992; 147:60.
11. Donovan JW, Ballard JO, Murphy MJ: Brodifacoum therapy with activated charcoal: Effect on
elimination kinetics. Vet Hum Toxicol 1990; 32:350.
12. Exner DV, Brien WF, Murphy MJ: Superwarfarin ingestion. Can Med Assoc J 1992; 146:34.
13. Fristedt B, Sterner N: Warfarin intoxication from percutaneous absorption. Arch Environ
Health 1965; 11:205.
14. Greeff MC, Mashile O, MacDougall LG: “Superwarfarin” (bromodialone) poisoning in two children
resulting in prolonged anticoagulation [Letter]. Lancet 1987; 2:1269.
15. Hadler MR, Shadbolt RS: Novel 4-hydroxycoumarin anticoagulants active against resistant rats.
Nature 1975; 253:275.
16. Helmuth RA, McCloskey DW, Doedens DJ, et al: Fatal ingestion of a brodifacoum-containing
rodenticide. Lab Med 1989; 20:25.
17. Hoffman RS, Smilkstein MJ, Goldfrank LR: Evaluation of coagulation factor abnormalities in long-acting
anticoagulant overdose. Clin Toxicol 1988; 26:233.
18. Holford NHG: Clinical pharmacokinetics and pharmacodynamics of warfarin: Understanding the dose-
effect relationship. Clin Pharmacokinet 1986; 11:483.
19. Hollinger BR, Pastoor TP: Case management and plasma half-life in a case of brodifacoum poisoning.
20. Jones EC, Growe GH, Naiman SC: Prolonged anticoagulation in rat poisoning. JAMA 1984; 252:3005.
21. Katona B, Wason S: Superwarfarin poisoning. J Emerg Med 1989; 7:627.
22. Kruse JA, Carlson RW: Fatal rodenticide poisoning with brodifacoum. Ann Emerg Med 1992; 21:331.
23. Leck JB, Park BK: A comparative study of the effects of warfarin and brodifacoum on the relationship
between vitamin K1 metabolism and clotting factor activity in warfarin-susceptible and warfarin-resistant rats.
Biochem Pharmacol 1981; 30:123.
25. Mosterd JJ, Thijssen HHW: The long-term effects of the rodenticide, brodifacoum, on blood coagulation
and vitamin K metabolism in rats. Br J Pharmacol 1991; 104:531.
26. Murphy MJ, Ray AC, Reagor JC, et al: A high performance liquid chromatography method for the
detection of brodifacoum in serum. Vet Hum Toxicol 1989; 31:228.
27. O’Reilly RA, Aggeler PM: Covert anticoagulant ingestion: Study of 25 patients and review of world
literature. Medicine 1976; 55:389.
28. O’Reilly RA, Kearns P: Intravenous vitamin K1 injections: Dangerous prophylaxis. Arch Intern
Med 1995; 155:2127.
29. Park BK, Scott AK, Wilson AC, et al: Plasma disposition of vitamin K1 in relation to anticoagulant
poisoning. Br J Clin Pharmacol 1984; 18:655.
30. Park BK, Choonara IA, Haynes BP, et al: Abnormal vitamin K metabolism in the presence of normal
clotting factor activity in factory workers exposed to 4-hydroxycoumarins. Br J Clin
Pharmacol 1986; 21:289.
31. Ross GS, Zacharski LR, Robert D, et al: An acquired hemorrhagic disorder from long-acting rodenticide
ingestion. Arch Intern Med 1992; 152:410.
32. Routh CR, Triplett DA, Murphy MJ, et al: Superwarfarin ingestion and detection. Am J
Hematol 1991; 36:50.
33. Rubia J, Grau E, Montserrat I, et al: Anaphylactic shock and vitamin K1. Ann Intern
Med 1989; 110:943.
34. In: Rumack BH, Hess AJ, Gelman CR, ed. Poisindex System, Englewood, CO: Micromedex; 1996.
35. Sheen SR, Spiller HA, Grossman D: Symptomatic brodifacoum ingestion requiring high dose
phytonadione therapy. Vet Hum Toxicol 1992; 34:340.
36. Smolinske SC, Scherger DL, Kearns PS, et al: Superwarfarin poisoning in children: A prospective study.
37. Sullivan MP, Dean BS, Krenzelok EP: Long-acting anticoagulant rodenticides: An evaluation of 88
cases. Vet Hum Toxicol 1989; 31:361.
38. Swigar ME, Clemow LP, Saidi P, et al: “Superwarfarin” ingestion: A new program in covert anticoagulant
overdose. Gen Hosp Psychiatry 1990; 12:309.
39. Travis SF, Warfield W, Greenbaum BH: Spontaneous hemorrhage associated with accidental
brodifacoum poisoning in a child. J Pediatr 1993; 122:982.
40. Trivedi LS, Rhee M, Galivan JH, et al: Normal and warfarin-resistant rat hepatocyte metabolism of
vitamin K 2,3-epoxide: Evidence for multiple pathways of hydroxyvitamin K formation. Arch Biochem
Biophys 1988; 264:67.
41. Wallace S, Worsnop C, Paull P, et al: Covert self poisoning with brodifacoum, a “superwarfarin.”. Aust
NZ J Med 1990; 20:713.
42. Watts RG, Castleberry RP, Sadowski JA: Accidental poisoning with a superwarfarin compound
(brodifacoum) in a child. Pediatrics 1990; 86:883.
43. Weitzel JN, Sadowski JA, Furie BC, et al: Surreptitious ingestion of a long-acting vitamin K
antagonist/rodenticide, brodifacoum: Clinical and metabolic studies of three cases. Blood 1990; 76:2555.
44. Wilson AC, Park BK: The effect of phenobarbitone pre-treatment on vitamin K1 disposition in the rat and
rabbit. Biochem Pharmacol 1984; 33:141.


Chapter 108 – Nonanticoagulant Rodenticides
JOHN J. CIENKI
The introduction of the anticoagulant rodenticides in the 1950s caused a dramatic reduction in the use of all
other agents. It is estimated at this time that anticoagulant rodenticides account for 95 per cent of all
rodenticides in use today. However, the appearance of rodent resistance resulted in the use of other
agents.[16] Older agents have been stored in garages, basements, and barns, and are still in use in other
countries and in some regions of the United States ( Table 108–1 ). Newer sources of some agents make
them still available for deliberate poisoning.[33]
Table 108-1 -- Nonanticoagulant Rodenticides

Usual
Rodenticide Commercial Products
Concentration
Celio or Zelio Paste; Celerici; Gizmo Mouse Killer; GTA Rat Bait;
Thallium 3–45%
Martin’s Rat Stop Liquid; Senco’s Corn Mix
0.11–0.55%
Fluoracetamide Ratbane 1080; Compound 1081
mixed
Sodium
90% conc Fluorokil 100
monofluoracetate
El Roy Mouse Bait; Gopher Death; Gopher Getter; Gopher Go; Hot
Spring Buttons; Mole-Nots; Mole Maize; Mologen Mouse Lure; Kilmice;
Strychnine 0.3–0.6% mixed Mice Doom Pellets; Orco Gopher Bait; Pied Piper Kwik-Kill; Pigeon-9;
Mo-Go; Rad-Seed; Senco Poison Oat Kernels; Saraseed Mouse Seed;
Sweeney’s Poison Wheat
0.9–2% mixed Celphos; Quickphos; Synfume; Phosfume; Acme Mole and Gopher
Zinc phosphide
60–80% conc Killer; Kilrat; Mous-Con: Phosvin; Rumetan; Zinc-Tox; Field Rat Powder
J-O Paste; Rough on Rats; Paste Electrica; Stearn’s Electric Brand

Phosphorus 1.38–3.0%
Paste; Blue Death Rat Killer; Common Sense Rat Killer; Rat Nip
Rough on Rats; Red Seal Rodenticide; Paris Green; Poulious Rat
Arsenic Doom; Senco Microfine Powder; Singletary’s Pest Control; Chipman’s
Top Killer
PNU/pyriminil 2–10% Vacor, DLP-787; DLP-787 10% for Mouse Tracking; Compound RH-787
ANTU (a-naphthyl- 20–25% mixed Bontu Prep Rat Biats or Powder; Nott’s Rat-TU; Dr Hess’s Anturat;
thiourea) 92% conc College Brand Rodenticide
Cholecalciferol 0.75% Quintox Rat and Mouse Bait, Quintox Mouse Seed, Rampage
Usual
Rodenticide Commercial Products
Concentration
Bromethalin Assault Mouse and Rat Place Packs
K-R-O Powder and Bix-Kit; Rat-Nets; Rat-Suax: Triple-X Rat Poison;
Red squill 3.5–10% Rodene; Rat-O-Cide Bait; Rat’s End; Topzol Rat Bait and Syrup; Pied
Piper Rodenticide
1% mixed Shoxin; RATicate; Raticide
Norbormide
5% conc
SPECIFIC AGENTS
High Toxicity
Thallium
Thallium sulfate is a white, odorless, tasteless powder easily absorbed by inhalation, dermal contact, and
through the gastrointestinal (GI) tract. Its use as a rodenticide has been prohibited in the United States since
1972, but it is still used in industries to make semiconductors, refractive glass, and thallium for cardiac
imaging.[47] Thallium has been used in homicides and suicides.[33]
The exact method of toxicity remains unknown. One postulate is that the similarity of thallium’s ionic radii to
that of potassium allows it to be substituted for potassium in many reactions. Thallium has a 10 times
greater affinity for K+, Na+-ATPase as well as for binding sites on the ribosomes. In the heart, thallous ion
antagonizes the effect of calcium and reverses the effect of hypokalemia.[21] Another proposed mechanism
of toxicity is the ability of thallium to bind sulfhydryl groups found at the active sites of many enzymes and
inactivate them. This affinity is greatest for enzymes of the mitochondrial respiratory chain.[48] Protein
synthesis is inhibited, particularly the incorporation of cysteine. This inhibition prevents keratinization and
accounts for the alopecia seen in thallium toxicity.
Toxicity can be acute or chronic, and wide variability exists in both symptoms and their onset ( Table 108–2
). In a review of more than 70 cases, Moeschlin found certain symptoms important for the diagnosis. These
include deposits of dark pigment at the roots of the hair; retrosternal chest pain and/or abdominal cramps;
constipation; hysteriform behavior; polyneuritis with a primary peripheral distribution; tachycardia; alopecia;
and nail stripes (Mees lines).[34] Nausea and constipation are the only consistent early findings. The dark
pigmentation at the base of the hair may appear by the third or fourth day. After about 1 week, retrosternal
and diffuse abdominal pain and tenderness and pain in the legs develop. At this time, the central nervous
system symptoms include excessive thirst, insomnia, restlessness, and hysteriform behavior. By the second
week, alopecia, tachycardia, dry skin, destruction of the sweat glands, and a painful sensory neuropathy of
the lower extremities develop. Some cases with massive ingestions have a more rapid clinical course.
Severe GI symptoms, with rapid progression to coma and death within 30 hours, have been reported.[2]
Table 108-2 -- Clinical Presentation and Treatment of Rodenticide Toxicity

Rodenticide Clinical Presentation Treatment Essentials
High Toxicity
GI: nausea, vomiting, watery
diarrhea, abdominal pain
Neuro: headache, stupor, coma,
Arsenic seizures Chelators: dimercaprol, 3–5 mg/kg IM
every 4 hrs; succimer, 10 mg/kg PO t.i.d.
CV: hypotension, ventricular for 5 days, followed by b.i.d. until urine
dysrhythmias, cardiovascular arsenic <50 µg/L/24 hr
collapse
Neuro: paresthesias, muscular
Gastric lavage
weakness, paralysis
Barium
GI: vomiting, diarrhea, abdominal Magnesium sulfate PO (experimental)
pain Potassium IV to correct hypokalemia
GI: oral burns, vomiting, diarrhea, Irrigate with potassium permanganate
abdominal pain solution, 1:5000
Neuro: restlessness, lethargy,
Elemental phosphorus Activated charcoal
stupor, coma, seizures
Other: hypotension, renal and
hepatic toxicity, bleeding diathesis
GI: nausea, vomiting, diarrhea,
Gastric lavage, activated charcoal
abdominal pain
Fluoroacetamide/sodium Neuro: facial paresthesias, auditory
Early ethanol infusion (experimental)
monofluoracetate hallucinations; seizures, coma
CV: tachycardia, cardiac
dysrhythmias
Endocrine: hyperglycemia, diabetic
Gastric lavage
ketoacidosis
PNU (N-3-pyridylmethyl-N'- Activated charcoal
p-nitrophenylurea) Neuro: autonomic dysfunction,
Niacinamide
peripheral neuropathy
Niacin (controversial)
Neuro: agitation, myoclonic jerking, Activated charcoal
hyperreflexia, tonic extensor
contractions (“spinal seizures”),
Benzodiazepines
trismus, opisthotonos
Strychnine
Barbiturates
CV: bradycardia, hypertension Crystalloids to maintain urine output
Avoid noxious stimuli
GI: nausea, vomiting, abdominal
Rodenticide Clinical Presentation Treatment Essentials
GI: nausea, vomiting, abdominal
Activated charcoal
cramps, constipation
Derm: dark pigment at hair roots,
Thallium Potassium ferric hexacyanoferrate
alopecia, dry skin, Mees lines
Neuro: hysteriform behavior, painful
sensory neuropathy
GI: nausea, vomiting, black emesis,
Dilution with milk or sodium bicarbonate
and stools
Pulm: chest tightness, cough,
Activated charcoal
dyspnea, rales
Zinc phosphide
CV: hypotension, shock Calcium for tetany
Neuro: ataxia, seizures, coma
Other: renal failure, tetany
Moderate Toxicity
Pulm: cough, cyanosis, rales,
Gastric lavage
pulmonary edema
ANTU (a-naphthyl-thiourea) Neuro: peripheral neuropathy,
Activated charcoal
atonomic dysfunction
Derm: irritation
GI: anorexia, vomiting Activated charcoal
Monitor serum calcium levels
Cholecalciferol
Neuro: confusion, coma, seizures Treat hypercalcemia: intravenous
crystalloids, diuretics, corticosteroids,
calcitonin
Low Toxicity
Neuro: headache, confusion, Activated charcoal

Bromethalin
tremors, myoclonus, seizures, coma Anticonvulsants
Minimal human toxicity Activated charcoal

Norbormide Neuro: transient hypothermia
CV: hypotension
GI: vomiting, diarrhea Activated charcoal
Neuro: blurred vision, seizures Digoxin Fab fragments
Red squill
CV: dysrhythmias, conduction
delays
GI, gastrointestinal; Neuro, neurologic; CV, cardiovascular; Derm, dermatologic; Pulm, pulmonary.
The treatment of thallium toxicity is controversial, with some modalities actually worsening the course.
General supportive care, along with the following therapies, has been proposed, but further study is
required. Decontamination with activated charcoal, which binds thallium,[25] is recommended. Potassium
ferric hexacyanoferrate (Berlin or Prussian blue) or potassium ferric hexanocyanate may be more effective
than charcoal in binding thallium and preventing its absorption and reabsorption from the GI tract, but neither
is readily available or approved for this use in the United States. The oral dosing for this purpose is 125
mg/kg in 50 mL of diluent given twice a day, or two 500-mg capsules t.i.d. One rodent model suggests the
combination of either Prussian blue or activated charcoal decontamination, coupled with furosemide
diuresis, to be the most effective treatment.[24] Another rodent model demonstrated increased survival with
Prussian blue.[31] Potassium chloride increases the excretion of thallium by its competition for thallium
reabsorption sites in the distal renal tubules. However, intravenous KCl may produce a general mobilization
of thallium from the tissues, possibly increasing plasma levels and worsening symptoms, especially central
nervous system (CNS) symptoms.[32] This same increase of thallium in the blood and CNS is seen with
chelators, most notably diethyldithiocarbamate (dithiocarb).[22] A combination of hemodialysis and
hemoperfusion may reduce the body burden of thallium without increasing distribution to the CNS.[10]
However, the total amount of thallium removed by hemodialysis is small.[36]
Fluoroacetamide and Sodium Fluoroacetate
Sodium fluoroacetate or compound 1080 is a white, odorless, tasteless crystalline powder available only for
commercial use. It is derived from several plants and is found rarely as a naturally occurring organofluoride.
Several plants contain monofluoroacetate, the most common being the South African ôgifblaarö, which is
toxic to livestock. Fluoroacetamide is a less toxic synthetic derivative with a slower onset of symptoms,
owing to the need for conversion of fluoroacetamide to fluoroacetate. Either product can be inhaled as well
as absorbed through broken skin and mucous membranes. Fluoroacetate combines with acetyl coenzyme
A, and this product combines with oxaloacetate to form fluorocitrate. Fluorocitrate cannot be converted to
cis-aconitate by aconitase, and this disrupts the Krebs cycle[37] ( Fig. 108–1 ). The resulting build-up of
citrate also chelates serum calcium, causing hypocalcemia.
Figure 108-1 Sodium monofluoracetate combines with acetyl coenzyme A (CoASH) to form fluoracetyl coenzyme A (fluoracetyl CoA),
which then reacts with oxaloacetate to form fluorocitrate. Fluorocitrate cannot be converted to cis-aconitate by aconitase, thus
disrupting the Krebs cycle. (Adapted with permission from Timbrell JA: Principles of Biochemistry Toxicology. London, Taylor &
Francis, 1987.)
Symptoms typically occur from 30 minutes to 2.5 hours, but up to 20 hours, after ingestion.[6] They include
nausea, vomiting, diarrhea, abdominal pain, apprehension, facial parasthesias, and auditory hallucinations,
potentially followed by cardiac dysrhythmias, seizures, coma, respiratory and cardiac arrest.[6] In the limited
human case reports, the cause of death has been cardiac.[38] The progression of cardiac symptoms includes
tachycardia with increased T-wave amplitude followed by ST elevation, progressing to irregular rhythms and
premature ventricular contractions. [38] This terminates in ventricular tachycardia and fibrillation. Hypokalemia
and hypocalcemia can occur frequently.[6]
Treatment should focus on aggressive gastrointestinal decontamination and supportive care. Gastric lavage
should be followed by activated charcoal, although adsorption has not been examined. In mice only,
simultaneously administering calcium gluconate, 130 mg/kg, with sodium succinate, 240 mg/kg, was shown
to have an antidotal effect.[29] Other studies found an infusion of ethanol, which is metabolized to acetate, to
be helpful in mice and rabbits but ineffective in dogs.[49] Rhesus monkeys responded to 6 mg/kg glycerol
monoacetate but did not benefit from ethanol therapy, possibly because of the monkey’s inability to convert
ethanol to acetic acid at a sufficient rate.[5] The ability of these treatments to increase available acetate in
humans is unknown. Ethanol was administered to five of seven fatalities reported in a large case series
without obvious benefit.[6]
In a retrospective case series of 38 patients with sodium monofluoroacetate poisoning, predictors of

mortality included systolic blood pressure less than 90 mm Hg, elevated serum creatinine, and decreased
pH.[6] All patients should be observed for 48 hours for signs of toxicity.
Strychnine
Strychnine is an odorless, crystalline white powder with a bitter taste. It is an alkaloid obtained from the seed
of the Strychnos nux vomica, a tree native to India. Strychnine has been used as a rodenticide since the
16th century. It is rapidly absorbed from the gastrointestinal tract and mucosal surfaces. Strychnine works by
antagonizing the effect of glycine, the major postsynaptic inhibitory neurotransmitter in the spinal cord.[3]
Glycine is structurally similar to a portion of the strychnine molecule ( Fig. 108–2 ). The binding of strychnine
to a site on the glycine receptor lowers the receptor’s affinity for glycine. [53] By reducing the binding of
glycine to its receptor, strychnine produces excitation of the spinal cord and brainstem ( Fig. 108–3 ).
Figure 108-2 The superposition of glycine with strychnine illustrates the glycine-like fragment contained within strychnine. Glycine
(C 2H5NO2) is depicted in bold lines to the right of the strychnine molecule. (Redrawn from Aprison MH, Lipkowitz KB, Simon JR:
Identification of a glycine-like fragment on the strychnine molecule. J Neurosci Res 1987; 17:209–213.)
Figure 108-3 Strychnine blocks uptake of glycine, the major inhibitory neurotransmitter, by motor neurons in the spinal cord. Similar
effects are produced by tetanus toxin, which blocks glycine release, and picrotoxin, which competes with GABA for presynaptic
inhibitory neurons. (Adapted from Heiser JM, Daya MR, Magnussen AR, et al: Massive strychnine intoxication: Serial blood levels in a
fatal case. J Toxicol Clin Toxicol 1992; 30:269–283.)
A prodrome of nervousness, myalgia, myoclonic jerks, hyperperception, hyperreflexia, hyperpnea,

bradycardia, and hypertension usually precedes the characteristic “spinal seizures” of strychnine. These
“seizures,” during which the patient remains alert, can occur as early as 15 minutes after ingestion, but
delays up to 2 hours have taken place before symptoms occur. The “seizures” are tonic and extensor in
nature, accompanied by opisthotonos. Normally, when an extensor motor neuron is stimulated, glycine acts
to produce hyperpolarization of the corresponding flexor motor neuron. With strychnine blocking this
inhibitory effect of glycine, flexor muscles will contract simultaneously during contraction of extensor
muscles. As the extensor group is usually the most developed at each joint, there is a tonic extensor
movement. This exaggerated reflex arc can be precipitated by even the slightest of stimuli. The tonic
extensor activity of the neck and back causes the opisthotonos, which is frequently accompanied by trismus.
The fixed grin is referred to as risus sardonicus. As the patient is alert, this activity is quite painful and
frightening. There is no postictal period or amnesia of the incident. This activity causes profound muscle
tenderness and can result in rhabdomyolysis, severe lactic acidosis, hyperthermia, and myoglobinuria. [46]
The primary goal of treatment is protection of airway and control of the tonic activity. Benzodiazepines are
the initial treatment for this motor activity. They displace strychnine bound to glycine receptor sites in the
brain and spinal cord.[53] In resistant cases, paralysis with nondepolarizing neuromuscular blocking agents is
recommended. Although rat models have shown some effect from glycine and other inhibitory
neurotransmitters, none are available clinically.[18]
Prevention of further absorption is undertaken next. Syrup of ipecac and lavage are inappropriate, given that
the slightest stimulation can precipitate epileptiform activity. The patient should be placed in the quietest,
most dimly lit location in the emergency department to avoid sensory stimuli. Activated charcoal binds
strychnine and should be given.[1] If a nasogastric tube is needed, pretreatment with benzodiazepines is
recommended.
Further therapy is supportive, including ensuring adequate urine flow to avoid myoglobinuric renal failure.
Forced diuresis, hemodialysis, and hemoperfusion are of no benefit in increasing clearance. Symptoms
usually resolve within 24 hours, and if epileptiform activity is controlled and hypoxemia is prevented, limited
sequelae ensue. Hypertonicity and hyperreflexia have persisted for up to 1 week after ingestion.[12]
Zinc Phosphide
Zinc phosphide is a dark-gray, crystalline powder that has a disagreeable odor of acetylene or rotten fish.
Aluminum phosphide is also used in rodenticides and demonstrates a similar toxicity. Among animals,
rodents alone exhibit a fondness for this agent. The toxicity of zinc phosphide is mediated by reaction with
water and hydrochloric acid in the stomach to generate phosphine gas. The reaction is catalyzed by the
presence of elemental phosphorus, which is often present as a contaminant. The mechanism of toxicity is
not completely known, but lesions suggest some direct damage to blood vessels and erythrocyte
membranes. Zinc phosphide is also a gastric irritant that may cause nausea and vomiting.
The symptoms of toxicity usually develop rapidly, sometimes within 15 minutes, and start with anorexia,
lethargy, and profuse vomiting. These symptoms are followed by rapid deep respirations, with chest
tightness, cough, and dyspnea. A rotten fish odor on the breath may or may not be present. Pulmonary
capillary breakdown, pulmonary edema, pleural effusions, and subpleural hemorrhages may develop.[44]
Inhalation of zinc phosphide dust may induce the pulmonary signs and symptoms. Other symptoms include
severe colicky abdominal pain, black emesis or stools, diaphoresis, weakness, ataxia, coma and seizures,
metabolic acidosis, hypotension, cardiovascular collapse, hypocalcemia, hypomagnesemia, renal failure,
and tetany.[7][44] One study found a positive correlation between mortality and lower serum and red blood cell
magnesium levels.[8]
Treatment is mainly supportive. Because an acidic gastric environment enhances conversion of zinc
phosphide to phosphine, initial dilution with milk or a bicarbonate solution may be helpful. Activated charcoal
should be administered to decrease the absorption of phosphide particles, which are thought responsible for
delayed toxic effects.[39] Intravenous calcium gluconate or chloride is indicated for tetany. If symptoms do
not develop within 6 hours after ingestion, the patient should remain asymptomatic. [23]
Elemental Phosphorus
Yellow or white phosphorus, the type of elemental phosphorus used as a rodenticide, is a yellow or brown
waxy paste often mixed with molasses or peanut butter. Although overdose is very rare in the United States,
large series of overdoses have been reported in Puerto Rico, Colombia, and Venezuela.[11] Yellow
phosphorus is corrosive. It has a direct toxic effect on the myocardium, kidney, and peripheral vessels, and
causes fatty degeneration of the brain.[45][52] Rat models show a depressive effect on myocardial protein
synthesis.[4]
Toxicity may manifest with gastrointestinal symptoms, a central nervous system syndrome, or with signs and
symptoms of both. Gastrointestinal signs and symptoms consist primarily of oral burns, vomiting, abdominal
pain, diarrhea, and bleeding. The supposed smoking luminescent quality of the stool or emesis and garlic
odor to the breath were rarely reported in the only case series in the United States.[30]
Central nervous system toxicity presents with restlessness, irritability, drowsiness, lethargy, stupor, and
coma. There may be a delay of up to 2 weeks before development of central nervous system symptoms, but
often this latent period is absent. Hypotension, shock, bleeding diathesis, liver atrophy, renal toxicity,
seizures, and coma may result. Symptoms may present as rapidly as 15 minutes or may be delayed up to 24
hours. Hepatomegaly, rapid onset of jaundice, azotemia, and hypoglycemia all are poor prognostic factors.
Treatment is directed at decontamination. Copiously irrigating the stomach with a potassium permanganate
solution 1:5000 has been recommended, as this solution supposedly reacts with phosphorus to form
harmless phosphorus oxides. However, no clinical studies examining the efficacy of this have been
performed. Activated charcoal adsorbs phosphorus and its byproducts and should be administered. Milk
increases absorption and should not be given. After decontamination, supportive care is the mainstay of
therapy.
Arsenic
Arsenic toxicity is discussed in Chapter 88 .
Barium
Barium carbonate is a white, flour-like powder no longer commercially available as a rodenticide in the
United States. It produces a depolarizing neuromuscular blockade resulting in weakness of striated, smooth,
and cardiac muscle.[20] Hypokalemia also occurs as a result of intracellular shift of potassium.[40]
The symptoms include profound weakness; paresthesias of the mouth, hands, and feet; vomiting; abdominal
pain; and diarrhea. This can progress to cardiac collapse, generalized paralysis, severe hypokalemia, and
pulmonary toxicity.
Treatment is aimed at decontamination and detoxification. Early gastric lavage is indicated. Magnesium
sulfate, 30 g (250 mg/kg in children) may form insoluble barium sulfate in the gastrointestinal tract, but there
is no proven benefit from this therapy. If it is given, it should be repeated in 1 hour if symptoms develop, and
magnesium levels and renal function should be monitored. Activated charcoal is not indicated. Potassium
levels should be monitored frequently, and intravenous replacement therapy given as indicated.
PNU (Vacor)
N-3-Pyridylmethyl-N'-p-nitrophenylurea, or PNU, was developed in an attempt to find a highly effective

single-dose rodenticide that was nontoxic to humans. The numerous human poisonings that occurred within
5 years after PNU’s release in 1975 led to its being withdrawn from the United States market. PNU is a
yellow-green powder. Toxicity results from inhibition of nicotinamide metabolism, particularly in the beta islet
cells of the pancreas. PNU is substituted for nicotinamide in nicotinamide-adenine dinucleotide (NAD) or
nicotinamide-adenine dinucleotide phosphate (NADP), preventing NAD or NADP from serving as hydrogen
carriers in oxidoreductase reactions.
Four to twenty-four hours after ingestion, the patient may develop insulin-deficient hyperglycemia or even
diabetic ketoacidosis. Autonomic nervous system dysfunction with postural hypotension, bladder atony, and
gastrointestinal hypomotility is a consistent if sometimes late-occurring finding. Peripheral neuropathies may
also develop, with motor and sensory loss as well as absence of deep tendon reflexes occurring within 6
hours. These manifestations are often irreversible.[15] Death may result from ketoacidosis, gastrointestinal
perforation, or cardiac dysrhythmias.
Treatment should begin with aggressive gastric decontamination, either with activated charcoal in the
prehospital setting or with gastric lavage and activated charcoal in hospital. Adults should receive 500 mg
niacinamide (nicotinamide) slow IV push, immediately followed by 100 to 200 mg IV or IM every 4 hours for
48 hours. The dosing frequency should be increased to every 2 hours if toxic manifestations develop. Total
daily adult dose should not exceed 3 g/day. Small children should receive one half the adult dose. Oral
therapy with 100 mg of niacinamide can be given three to five times daily for 2 weeks when the patient can
tolerate oral medication.[42] Although niacinamide is still manufactured, it is not routinely a part of hospital
formularies. Concerns over substituting niacin (nicotinic acid) for niacinamide (nicotinamide) include niacin’s
vasodilatory effect, which may exacerbate the postural hypotension, and aggravation of glucose intolerance.
However, some experts support its use if niacinamide is not readily available.[14]
Management of the end-organ effects includes insulin for the diabetes and fluorocortisone for persistent
postural hypotension resulting from peripheral neuropathy.[26]
Moderate Toxicity
ANTU
a-Naphthylthiourea (ANTU) was developed in the 1940s following the observation that phenylthioureas are
more toxic to rats than humans. ANTU lacks the bitter taste of other phenylthioureas and is an odorless, fine
blue-gray powder.
ANTU produces pulmonary edema and pleural effusion in exposed animals by increased capillary
permeability.[9] ANTU may require a reaction with sulfhydryl groups to release hydrogen sulfide and produce
toxicity. Pulmonary hypertension due to the formation of microemboli has been observed, and increased
permeability of kidney membranes may also occur.[43] A direct toxic effect on pancreatic beta islet cells
results in hyperglycemia.[13] Large overdoses present with lassitude, anorexia, abdominal pain, hypoxia,
cyanosis, dyspnea, and rales. Cases of motor and sensory peripheral neuropathy, autonomic dysfunction,
and CNS disorders have been reported.[43] Acute inhalation of the dust produces coughing, dyspnea,
pulmonary edema, tracheitis, and pneumonitis. Dermal contact can cause skin and mucous membrane
irritation. Occupational exposure has been suspected of causing bladder cancer but the actual carginogen
might be the impurity ß-naphthylamine.[13] Occupational exposure has also been associated with
hypothyroidism.[13]
Treatment includes gastrointestinal decontamination with activated charcoal, supportive care, and
monitoring of electrolytes and glucose. Pulmonary edema may be delayed up to 72 hours. Patients ingesting
more than 5 mg/kg body weight should be admitted for observation.
Cholecalciferol
The fact that rodents and other species are more sensitive to small changes in calcium balance led to the
recent marketing of cholecalciferol (vitamin D3) as a rodenticide. In animals, the hypercalcemia produces
calcification of the coronary vessels with resultant myocardial infarction, osteomalacia, and metastatic
calcification of the kidneys, stomach, and lung.[17] Cholecalciferol is a white, odorless crystal that is mixed
with various baits.
In humans, cholecalciferol can produce elevated plasma calcium. The symptoms to be expected are those
of hypercalcemia: confusion, anorexia, nausea, vomiting, and diarrhea. At higher calcium levels, renal
insufficiency and metastatic calcification in the kidney, heart, lungs, stomach, and blood vessels can
occur.[35]
In humans, small ingestions of a few pellets or seeds should not pose a problem, and no treatment is
necessary. In larger ingestions, gastrointestinal decontamination with activated charcoal, intravenous
hydration, and monitoring of serum calcium levels should be performed. A normal serum calcium level 48
hours after ingestion makes a significant ingestion unlikely.
Low Toxicity
Bromethalin
Bromethalin is a pale-yellow odorless crystalline solid that produces neurotoxicity by uncoupling oxidative
phosphorylation in the mitochondria of the CNS. There is a decrease in ATP production and diminished Na+-
K+ gradient maintained by Na+-K+ ATPase. As the Na+-K+ gradient diminishes, fluid accumulates in the cell.
Most tissues can accommodate this effect, but in a rodent model CNS fluid accumulation leads to fluid-filled
vacuoles developing between myelin sheaths.[51] This results in decreased nerve conduction, increased
intracranial pressure, and eventual paralysis and death. The symptoms include headache, confusion,
personality changes, tremors, seizures, and coma.
Exposure to small amounts, such as a few pellets, should not cause serious effect. Larger ingestions should
be treated with decontamination and 24-hour observation for CNS symptoms. Seizures should be treated
with benzodiazepines and phenobarbital, as needed. In animal models, hyperventilation, dexamethasone,
and mannitol diuresis have been shown effective in treating toxicity and cerebral edema.[51]
Norbormide
Norbormide is an odorless, white powder selectively toxic to rats. It acts directly on the smooth muscle of the
peripheral arterioles, causing intense vasoconstriction and ischemia. It is not toxic to humans, cats, dogs,
fowl, or farm animals. Volunteers given up to 300 mg experienced no effects. With higher doses, slight
transient decreases in temperature and blood pressure occurred.[19] Chronic dermatitis resulting from
occupational handling of norbormide has been reported.[50]
Treatment of human exposure should include gastrointestinal decontamination with activated charcoal and
supportive care if necessary.
Red Squill
Red squill has been used as a rodenticide since medieval times in Europe. It came into widespread use in
the late 19th century with standardization of production. It is extracted from the fleshy inner bulb of the plant
Urginea maritima, or sea onion, and is a bitter powder. The extracted active ingredient, scilliroside, contains
the cardiac glycosides scillaren A and scillaren B.
In humans, red squill is a powerful emetic and much of the agent is expelled before it is absorbed. Rats,
lacking the ability to vomit, succumb to the cardiac glycoside effect. Symptoms of large ingestions are
nausea, vomiting, abdominal pain, blurred vision, dysrhythmias, cardiac conduction delays consistent with
cardiac glycoside effect, and seizures. Treatment includes gastrointestinal decontamination and supportive
therapy. Management of dysrhythmias is similar to that for other cardiac glycoside–induced dysrhythmias.
Digoxin Fab fragments have been successful in treating the cardiac complications of severe overdose.[41]
Other
Several other rodenticides exist that are uncommonly used. There are few or no reports of human ingestion.
Castrix or 2-chloro-4-dimethylamino-6-methylpyramine in animals produces toxicity similar to strychnine,
with agitation and seizures.[27] Alpha-chloralose is an anesthetic that is metabolized to trichloroethanol.
Respiratory depression, hypothermia, and seizures were noted in a case report, with the seizures responsive
to benzodiazepines. [28] Phosphacetim, or o,o-bis-(chlorophenol) acetimidoylphosphamidothioate, is an
organophosphate used to kill gophers. Overdose should produce characteristic organophosphate-induced
symptoms and respond to therapy directed at organophosphates ( Chapter 102 ).


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15. Gallanosa AG, Spyker DA, Curnow RT: Diabetes mellitus associated with autonomic and peripheral
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16. Gratz NG: A critical review of currently used single-dose rodenticides. Bull Bld Health
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17. Gunther R, Felice LJ, Nelson RK, et al: Toxicity of vitamin D3 rodenticide in dogs.
JAVMA 1988; 193:211.
18. Halsey MJ, Little HJ, Wardley Smith: Systemically administered glycine protects against strychnine
convulsions but not behavioural effects of high pressure in mice. J Physiol 1989; 408:431.
19. Hayes WJ: Pesticides Studied in Man, Baltimore, Williams & Wilkins, 1982.
20. Henn FA, Sperlakis N: Stimulative and protective action of Sr++ and Ba++ on Na, K-ATPase from
cultured heart cells. Biochem Biophys Acta 1968; 163:415.
21. Hughes MN, Man WK, Whaler BC: The toxicity of thallium (I) to cardiac and skeletal muscle. Chem
Biol Interact 1978; 23:85.
22. Kamerbeek HH, Rauws AG, Ham ten M, et al: Dangerous redistribution of thallium by treatment with
sodium diethyl dithiocarbamate. Acta Med Scand 1971; 189:149.
23. Khosla SN, Nand N: Cardiovascular complications of aluminum phosphide poisoning.

Angiology 1988; 39:355.
24. Lehmann PA, Favari L: Acute thallium intoxication: Kinetic study of the relative efficacy of several
antidotal treatments in rats. Arch Toxicol 1985; 57:56.
25. Lehmann PA, Favari L: Parameters for the adsorption of thallium ions by activated charcoal and
Prussian blue. J Toxicol Clin Toxicol 1984; 22:331.
26. LeWitt PA: The neurotoxicity of the rat poison Vacor: A clinical study of 12 cases. N Engl J
Med 1980; 302:73.
27. Lumeij JT, Schotman AJ, DeVries HW: Crimidine poisoning in a dog due to ingestion of the rodenticide
Castrix. Vet Q 1983; 5:107.
28. Manzo L, Richelmi P, Crema A: Electrocerebral changes in acute alpha-chloralose poisoning: A case
report. Vet Hum Toxicol 1979; 21:245.
29. Mara F, Sisodia C: Evaluation of potential antidotes for sodium fluoracetate in mice. Vet Hum
Toxicol 1990; 35:427.
30. McCarron MM, Gaddis GP, Trotter AT: Acute yellow phosphorus poisoning from pesticide pastes. Clin
Toxicol 1989; 18:693.
31. Meggs WJ, Cahill-Morasco R, Shih RD, et al: Effects of Prussian blue and N-acetylcysteine on thallium
toxicity in mice. J Toxicol Clin Toxicol 1997; 35:163.
32. Meggs WJ, Goldfrank LR, Hoffman RS: Effects of potassium in a murine model of thallium poisoning
[Abstract.]. J Toxicol Clin Toxicol 1995; 33:559.
33. Meggs WJ, Hoffman RS, Shih RD, et al: Thallium poisoning from maliciously contaminated food. J
34. Moeschlin S: Thallium poisoning. Clin Toxicol 1980; 17:133.

35. Paterson CR: Vitamin D poisoning: Survey of causes of 21 patients with hypercalcemia.
Lancet 1980; 1:1164.
36. Pedersen RS, Olesen AS, Freund LG, et al: Thallium intoxication treated with long-term hemodialysis,
forced diuresis and Prussian blue. Acta Med Scand 1978; 204:429.
37. Peters RA: Biochemical Lesions and Lethal Synthesis, New York, Macmillan, 1963.
38. Reigart JR, Breuggeman JL, Keil JE: Sodium fluoracetate poisoning. Am J Dis Child 1975; 129:1224.
39. Rodenberg HD, Chang CC, Watson WA: Zinc phosphide ingestion: A case report and review. Vet Hum
Toxicol 1989; 31:559.
40. Roza O, Berman L: The pathophysiology of barium: Hypokalemic and cardiovascular effects. J
Pharmacol Exp Ther 1971; 177:433.
41. Sabourand A, Urtizberrea M, Cano N, et al: Specific anti-digoxin fab fragments: An available antidote for
proscillaridin and scilloriside poisoning. Hum Exp Toxicol 1990; 9:191.
42. Schein PS, Rakietin N, Cooney DA: Streptozotocin diabetes in monkeys and dogs and its prevention
with nicotinamide. Proc Soc Exp Biol Med 1973; 143:514.
43. Sobonya RE, Kleinerman J: Recurrent pulmonary edema induced by naphthyl thiourea. Am Rev Respir
Dis 1973; 108:926.
44. Stephenson JBP: Zinc phosphide poisoning. Arch Environ Health 1967; 15:83.
45. Talley RC, Linhart JW, Trevino AJ, et al: Acute elemental phosphorus poisoning in man: Cardiovascular
toxicity. Am Heart J 1972; 84:139.
46. Teitelbaum D, Ott J: Acute strychnine intoxication. Clin Toxicol 1970; 3:267.
47. Thallium : In: Ryan RP, Terry CE, ed. Toxicology Desk Reference, 4th ed. Washington, DC: Taylor &
Francis; 1997:2121-2132.
48. Thyression N: Experimental investigation of thallium poisoning in the rat. Acta Derm
Venereol 1951; 31:3.
49. Tourtellotte WW, Loon JM: Treatment of fluoracetate poisoning in mice and dogs. J. Pharmacol Exp
Ther 1951; 101:82.
50. Tsyrkunov LP: Skin lesions caused by exposure to a pesticide norbromid. Gigiena Truda I
Professionalye Zabolevaniia 1989; 8:46.
51. VanLier RB, Cherry LD: The toxicity and mechanism of bromethalin: A new single-feeding rodenticide.
Fundam Appl Toxicol 1988; 11:664.
52. Wetham F: Nervous system in acute phosphorus poisoning. Arch Neurol Psychol 1932; 28:320.
53. Young AB, Zukin SR, Snyder SH: Interaction of benzodiazepines with central nervous glycine receptors:
Possible mechanisms of action. Proc Natl Acad Sci USA 1974; 71:2246.


Chapter 109 – Rattlesnakes and Other Crotalids
SEAN PATRICK NORDT RICHARD F. CLARK
Essentials
• Bite—immediate pain, one or more puncture wounds, with progressive edema and ecchymosis at or
proximal to the bite
• Coagulopathies, hypotension, and shock characterize moderate to severe envenomations
• Primary neurotoxicity uncommon, typically myokymia and paresthesias, except in some Mojave
rattlesnake envenomations
• Copperhead and water moccasin envenomations less severe than those of rattlesnakes
INTRODUCTION
Over 2000 crotalid envenomations are reported yearly to the American Association of Poison Control
Centers (AAPCC), but many are unreported and the estimated true number of bites in the United States may
exceed 8000 annually.[53] Vast improvements in supportive care measures and the early administration of
antivenin have decreased overall morbidity and mortality from these bites. Since 1983, only seven deaths
have been recorded by the AAPCC. [31][32][33][34][35][36][37][38][39][40][41][60] Snakebites typically occur between
April and July when outdoor activities are increased and are rare during winter when snakes hibernate. The
majority of victims are adult males, aged 20 to 40 years, often with blood ethanol concentrations of 100
mg/dL or greater.[63] Most injuries occur on the arms and hands and are provoked from attempts to handle
the snake.[63]
Snakes are members of the phylum Chordata and the class Reptilia. Venomous snakes in North America
are further separated into two families: Crotalidae and Elapidae. Three genera compromise the Crotalidae
family: Crotalus (rattlesnakes), Sistrurus (massasauguas or pigmy rattlesnakes), and Agkistrodon. Two
species of Agkistrodon native to the United States, the copperhead (Agkistrodon contortrix) and the
cottonmouth (Agkistrodon piscivoris), are found primarily in the southeastern states. Seventeen species of
crotalids, including 15 species of rattlesnakes, have been identified with representation in virtually every
state in the continental United States.
Several characteristics distinguish crotalids: triangular or diamond-shaped heads in contradistinction to the

smooth, tapered heads of most other snakes; elliptical or “catlike” pupils; a single row of subcaudal scales
behind the anal plate; and facial pits located anteriorly below the eyes, utilized as a heat sensing organ to
detect prey ( Fig. 109–1 ). These pits account for crotalids being known as “pit vipers.” Rattlesnakes typically
have a rattle—horny scales of keratin at the end of the tail that when rubbed together produce a sound.
Copperheads are easily identifiable by their triangular orange to rust-colored heads. The triangular head is
not unique to crotalids; the northern water snake, Nerodia sipedon sipedon, has a similar shaped head and
is often mistaken for a copperhead. Cottonmouths, also known as “water moccasins,” are identified by a
distinctive white buccal cavity. A rattle is not a defining characteristic of rattlesnakes, since one species, C.
cataleninensis, found only on Santa Catalina Island, does not have a rattle.[52] True rattlesnakes may also
lack a rattle due to trauma or genetic anomaly.
Figure 109-1 Identifying characteristics of pit vipers and nonpoisonous snakes. The presence or absence of a single row of
subcaudal plates may be the only identifying feature in a decapitated snake.
Crotalids rarely strike unless provoked or frightened. They envenom through uniquely hinged front fangs
rather than the fixed rear fangs of some other venomous snakes. These fangs may grow as long as 2 cm
and are curved and hollowed. Two venom glands located posteriorly to the eyes are connected to the fangs
by venom ducts. The amount of venom delivered after a strike is controlled by the contraction of specific
muscles surrounding the venom glands. More venom may be delivered when a snake is handled or agitated
compared with accidentally startling the snake.[11]


PATHOPHYSIOLOGY
Snakes use venom not only to kill their prey but also to aid digestion. Crotalid venom contains a complex
mixture of enzymes, amino acids, lipids, and metals such as zinc, copper, and magnesium. [21][22] The exact
composition varies depending on several factors, such as species, age of snake, diet, season, and
geographic location.[14][16][21][22][43][55] The enzymes possess mainly cytotoxic, hemorrhagic, and neurotoxic
properties. The proteolytic enzymes collagenase and hyaluronidase produce the marked swelling and local
tissue destruction at the site of envenomation.[22] Lysis of red blood cells, platelets, and mitochondria may
be the direct result of phospholipase activation in the presence of lecithin and divalent metal ions. [22] Several
different types of hemorrhagins have also been identified. Direct lytic factor, phospholipases, and proteases
may act synergistically with the hemorrhagins, resulting in extravasation of blood, ecchymosis at the bite
site, and possibly systemic hemorrhage.[21] Additionally, phospholipase-A may cause neurotoxicity by
blocking the presynaptic release of acetylcholine from nerve terminals.[22]
Crotalid venom exerts “thrombin-like” effects on fibrinogen molecules. Normally, thrombin forms fibrin by
removal of the low molecular weight peptides, fibrinopeptide A and fibrinopeptide B, from each molecule of
fibrinogen. Thrombin then stimulates fibrin stabilizing factor, adding strength to the fibrin meshwork forming
a clot. Crotalid venom catalyzes the hydrolysis of an arginine sequence of the a chain of fibrinogen, thereby
splitting off fibrinopeptide A but not fibrinopeptide B.[47][66] The resulting monomers aggregate normally, but
form unstable, end-to-end linking instead of normal cross-linking fibrin polymers. These fibrin polymers are
susceptible to normal fibrinolysis and phagocytosis by the reticuloendothelial system, and their presence is
represented clinically by falling fibrinogen levels and elevated fibrin-fibrinogen degradation products. It has
been shown that the rapid infusion of crotalid venom, as seen following a direct intravenous envenomation,
mimics true thrombin activity leading to widespread intravascular coagulation.[9][26] However, true
disseminated intravascular coagulation (DIC) is rarely seen after crotalid envenomation, probably owing to
the low incidence of direct intravenous envenomations.[18] Although the incidence of bites from copperheads
is high, their venom has weak effects on the coagulation cascade, resulting in lower morbidity after
envenomation.[64]
Thrombocytopenia commonly follows crotalid envenomation and is usually reversible with prompt antivenin
administration.[48] The time of onset and degree of thrombocytopenia can be used as markers of bite
severity.[27] The precise pathophysiologic mechanism is unknown. Hypotheses include (1) a direct lytic
action on platelet membranes by phospholipases in the venom; (2) toxin-induced damage to bone marrow
precursors; (3) peripheral consumption of platelets through normal hemostatic mechanisms involved in the
formation of microemboli at the site of envenomation; and (4) a combination of some or all of these
components.[54][62] Bone marrow samples evaluated in rats injected with the venom of C. viridis helleri failed
to demonstrate suppression of megakaryocyte production, suggesting a peripheral cause of
thrombocytopenia.[62] This theory is further supported by the identification of a platelet aggregating protein,
crotalocytin, in the venom of C. horridus horridus.[53] Rabbits injected with radiolabeled platelets along with
C. atrox venom had significant sequestration of platelets at the site of injury. Platelet survival time was
decreased by an average of 60 per cent in these rabbits. A corresponding thrombocytosis also occurred,
presumably to compensate for the increased destruction of platelets. The onset and degree of
thrombocytopenia appeared to be dose dependent. Rabbits who received 3 mg/kg of venom had a more
rapid and more profound onset of thrombocytopenia than rabbits that received either placebo or 2 mg/kg of
venom.[57]
Neurotoxic components in rattlesnake venom enable the snake to overpower small animals. All rattlesnake
venoms have some neurotoxic components, and neurotoxicity is common after moderate to severe
envenomations.[6] Crotalid venom neurotoxins block presynaptic nerve transmission.[19] C. scutulatus
scutulatus (Mojave rattlesnake), the most neurotoxic of rattlesnakes, produces venom estimated to be 10
times more potent than any other North American species on a milligram per kilogram basis.[15] The main
venom components of this snake are type A, primarily a neurotoxin, and type B, a less active constituent
possessing hemorrhagic and proteolytic activity. The reduced activity of type B accounts for the decreased
incidence of local edema and necrosis in Mojave rattlesnake bites.[8] Mojave toxin type A acts
presynaptically, inhibiting the frequency of miniature endplate potentials and indirectly evoked muscle
contraction without affecting muscle responses to direct stimulation or to acetylcholine.[59] Mojave neurotoxin
binds selectively and irreversibly in rats to dihydropyridine calcium channel binding sites on presynaptic
membranes involved in neurotransmission.[59] This interaction appears to be noncompetitive, suggesting the
presence of allosteric binding to the dihydropyridine calcium channel. Mojave venom may also possess
cardiac stimulant and myonecrotic properties.[20]


CLINICAL PRESENTATION ( Tables 109–1 and 109–2 )
Pain usually occurs immediately after envenomation at the bite site. Another common initial complaint is a
“metallic” taste in the mouth, probably resulting from metals such as zinc in venom. This “metallic” taste
develops minutes after envenomation, demonstrating the rapid distribution of some of the venom
components.[53] Victims frequently report weakness, lightheadedness, nausea and vomiting, diaphoresis,
and chills.[3] These systemic effects can be seen initially without any local tissue effects, but significant
edema is usually evident by the time the patient arrives at the health care facility.
Table 109-1 -- Clinical Signs and Symptoms Associated with Crotalid Envenomation
Symptoms Signs
Pain at bite site Local edema
“Metallic” taste Progressive extremity swelling
Perioral numbness Bleeding at bite site
Weakness Fasciculations
Lightheadedness Ecchymosis
Nausea and vomiting Hemorrhagic blisters
Diaphoresis Thrombocytopenia
Chills Elevated prothrombin and partial thromboplastin times
Hypofibrinogenemia
Elevated D-dimer
Table 109-2 -- Rattlesnake Envenomation: Incidence of Symptoms and Signs

Symptom/Sign Incidence (%)
Fang marks 100
Swelling and edema 74
Weakness 70
Pain 65
Numbness or tingling of tongue and mouth, scalp or feet 63
Pulse rate alteration 60
Tingling or numbness of affected part 57
Faintness or dizziness 57
Blood pressure changes 54
Symptom/Sign Incidence (%)
Ecchymosis 51
Sweating and/or chills 43
Nausea, vomiting, or both 42
Change in body temperature 42
Thrombocytopenia 42
Swelling regional lymph nodes 41
Fasciculations 40
Vesiculations 40
Respiratory rate changes 40
Increased blood clotting time 37
Decreased hemoglobin 37
Thirst 34
Necrosis 27
Abnormal electrocardiogram 26
Glycosuria 20
Increased salivation 20
Sphering of red blood cells 18
Proteinuria 16
Cyanosis 16
Thrombocytosis 16
Hematemesis, hematuria, or melena 15
Unconsciousness 12
Blurring of vision 12
Swollen eyelids 7
Muscle contractions 6
Retinal hemorrhage 5
Seizures 1
Adapted with permission from Russell FE: Snake venom poisoning in the United States. Annu Rev Med 1980;
31:247–259.
Bite
Puncture wounds are common, although the number may vary depending on the number of penetrating
fangs and the number of strikes. Local edema usually begins 15 to 30 minutes after a bite where venom is
injected, but may be delayed several hours. The progression of swelling is useful in determining the severity
of envenomation, except with Mojave rattlesnake bites. In addition, the site of the envenomation has been
suggested to be useful in predicting toxicity.[45] Conversely, the absence of swelling may indicate a “dry bite”
in which no venom is delivered. The exact incidence of “dry bites” may be as high as 10 to 25 per cent.[25]
Pain alone may be reported at the bite site from a “dry bite” but is usually self-limiting and rarely requires
analgesia. Rarely, bites may penetrate joints, resulting in fang intra-articular venom injection with
subsequent severe articular surface destruction.[65] In addition, direct intravenous envenomations can occur.
Although this is rare it is often associated with severe toxicity and can result in death, usually from true
DIC.[9]
Edema after envenomation may progress rapidly, involving an entire limb within 6 to 8 hours in severe
cases. The progression is distal to proximal, reflecting the lymphatic drainage of the venom. Antivenin
administration often stops the progression of swelling but may not reverse it. Local tissue injury occurs in
mild to severe envenomations.[63] Ecchymosis can develop within several hours to days ( Fig. 109–2 ).
Hemorrhagic blisters or blebs resembling thermal injuries frequently form around the puncture site. These
blisters are filled with serous or serosanguineous fluid, generally develop over several days, and when
unroofed often reveal third-degree tissue destruction. Severe soft tissue destruction can result in decreased
range of joint motion and cosmetic deformities. Local tissue necrosis necessitating débridement is often
necessary, predominantly in rattlesnake bites, but amputation is rarely required unless the administration of
antivenin is delayed or omitted.[56]
Figure 109-2 Local tissue necrosis from a copperhead (Agkistrodon contortrix) envenomation.
Compartment Syndrome
Extremity Doppler studies in rattlesnake bite victims show that circulatory compromise and ischemia rarely
occur despite massive local tissue swelling, although local tissue damage can mimic a compartment
syndrome. Hand compartment syndrome is a rare but potential complication of untreated crotalid
envenomations. A true compartment syndrome (compartment pressures greater than 30 mmHg) is
extremely uncommon after most crotalid strikes but may develop after a direct intramuscular
envenomation.[10]
Neurotoxicity
Local neurotoxicity can follow rattlesnake envenomation and commonly manifests as “fasciculations”
involving the muscle groups of the bitten extremity, face, or scalp.[2] Electromyographic studies after a C.
horridus horridus envenomation identified these fasciculations as myokymic discharges. Clinically,
myokymia presents as continuous, undulating fine contractions of various muscle groups. Myokymia may be
generalized to the entire body or limited to an extremity or the face. The etiology of these myokymic
discharges has been suggested to be the antagonistic action of crotalid venom on ionized calcium at the
axonal membrane.[2] Systemic neurotoxicity may be seen after envenomation from C. scutulatus scutulatus,
and the onset of symptoms can be delayed 12 to 24 hours. Signs and symptoms can include paresthesias,
muscle weakness, cranial nerve paresis, and respiratory failure.[23] Systemic neurotoxicity does not appear
to be a common finding in Agkistrodon envenomations.[3][64]
Coagulopathies
Abnormal coagulation profiles are a common and clinically significant complication of moderate to severe
crotalid envenomations. Coagulopathies are generally only seen after rattlesnake envenomations.
Copperhead and cottonmouth envenomations rarely result in any significant disruption in coagulation
profiles. As noted earlier, crotalid venom disrupts the “coagulation cascade” at several steps, leading to
elevations in prothrombin time and partial thromboplastin time. Laboratory analyses after envenomation
commonly mimic DIC but with no clinically significant bleeding. Thrombocytopenia, accompanied by
hypofibrinogenemia and elevated D-dimer, frequently develops in moderate to severe cases. La Grange and
Russell evaluated the platelet counts of 30 patients after crotalid envenomation. Eleven patients with
minimal envenomations had no significant platelet decrease, 11 patients classified as moderate
envenomations had a median platelet decrease of 25 per cent, whereas the 8 patients with severe
envenomation demonstrated a dramatic median platelet decrease of 60 per cent. They performed a
validating study in rabbits using various doses of C. viridis helleri venom. Platelets were profoundly
decreased at the higher doses.[27] Massive envenomations, particularly those into or in close proximity to
major arteries and veins, may produce laboratory and physical findings consistent with DIC. These patients
are at high risk for spontaneous bleeding, including gastrointestinal and intracerebral hemorrhages, and
have a higher incidence of mortality.[18]
Cardiovascular Complications
Hypotension and shock can follow severe envenomation for several reasons. Cardiac output may decrease
due to a circulating myocardial depressor protein.[3] In addition, the tremendous third spacing of fluids due to
widespread capillary endothelial disruption and peripheral vasodilation can result in significant ascites,
pleural effusions, and peripheral edema.[25] In animal models this hypovolemia has been attributed to an
increase in capillary permeability to protein and red blood cells.[11]
Severe Envenomation
The clinical course most frequently associated with death after crotalid envenomation is progressive shock
leading to multiple organ failure after several hours to several days. Edema of the heart, lungs, and brain
may occur.[11] In addition, adult respiratory distress syndrome may occur from increased pulmonary capillary
membrane permeability.[25] Acute renal failure results from hypovolemic shock or myoglobinuria secondary
to rhabdomyolysis, rather than from a direct pharmacologic effect of the venom.[9][23] An anaphylactic or
anaphylactoid response to crotalid venom has been reported as a cause of sudden, severe cardiovascular
collapse after a bite.[11]
Copperheads and Cottonmouths
In some parts of the United States, particularly the Southeast, almost all crotalid envenomations are
attributed to either copperheads or cottonmouths.[29][61] These envenomations rarely give rise to any clinical
manifestations other than pain at the bite site, edema, and gastrointestinal complaints such as nausea and
vomiting. Unlike rattlesnake envenomations, perioral numbness, tingling, and fasciculations are not noted
after copperhead or cottonmouth envenomations.[29][61][64] In one case series of 55 patients envenomed by
either copperheads or cottonmouths, 95 per cent had swelling and pain whereas only 14 per cent had
systemic signs (nausea, vomiting, tachycardia). None of the patients had any documented abnormalities in
coagulation profiles, complete blood cell counts, serum electrolytes, or urinalysis except one patient already
on warfarin therapy. No patients suffered any loss of function or significant tissue damage.[61] Antivenin
administration is rarely required after these envenomations.


If the snake was not seen, no rattles were heard, or a positive identification cannot be made by physical
description, the differential diagnosis of the lesion or puncture wound should be broadened to include other
possibilities such as insect stings, blunt trauma, or wounds from inanimate objects ( Table 109–3 ).
Table 109-3 -- Differential Diagnosis of Crotalid Envenomation

Bites from noncrotalid snakes
Insect stings
Spider bites
Scorpion stings
Puncture wounds
Disseminated intravascular coagulation of other causes
Sepsis
Shellfish poisoning: paralytic, neurotoxic, ciguatera


LABORATORY STUDIES
Baseline emergency department blood studies should include a complete blood cell count, fibrinogen
level,D-dimer, platelet count, prothrombin time, and partial thromboplastin time. If no coagulation or platelet
abnormalities are found but tissue swelling is present, studies should be repeated in 2 to 4 hours. If
hematologic abnormalities are noted, these studies should be repeated in 1–2 hours. Crotalid
envenomations rarely cause alterations in cardiac, renal, or hepatic function. Therefore, laboratory studies
such as chemistry panels and electrocardiograms are of limited clinical utility except in severe
envenomations. Massive elevations in creatine kinase may result from severe swelling of muscular
compartments or from the direct action of venom components on myocytes. Urinalysis often shows
proteinuria and red blood cells, which also are rarely of any clinical consequence.[44] Routine radiographs
are unlikely to be beneficial unless a retained fang fragment, joint penetration, or bone injury is suspected.


TREATMENT
Contrary to popular belief, crotalid envenomations are usually not life threatening, and permanent morbidity
can often be avoided by prompt administration of supportive care and antivenin if clinically indicated ( Table
109–4 ).
Table 109-4 -- Treatment of Crotalid Envenomation

Initial Measures
1. Evaluate and maintain airway.
2. Establish intravenous access.
3. Perform timed serial measurements of limb circumference of affected limb.
4. Obtain complete blood cell count, prothrombin/partial thromboplastin time, fibrinogen, D-dimer, platelets.
In Moderate or Severe Envenomations
1. Have resuscitation equipment and drugs available.
2. Skin test (only after the decision to treat with antivenin has been made) with 0.02–0.03 mL of diluted 1:10
horse serum subcutaneously.
3. Use horse serum diluted 1:100 if allergic reaction is suspected.
Administer stabilizing dose of 5–10 vials of Polyvalent (Crotalidae) Antivenin reconstituted.
Adult: Dilute in 100 to 500 mL of normal saline and infuse over 30 to 60 minutes.
Child: Can limit to 20 mL/kg normal saline for dilution.
4. Repeat hematologic studies after antivenin infusion.
5. Repeat antivenin administration in 5- to 10-vial increments as needed (rarely more than 50 vials are
required).
6. Fresh frozen plasma or platelets should be reserved for significant bleeding.
Prehospital Management
The primary objective after crotalid envenomation is safe, expeditious transport of the victim to a medical
facility, preferably one with crotalid antivenin and personnel familiar with its administration. Victims, family
members, friends, bystanders, or emergency personnel should be discouraged from capturing the snake in
an effort to obtain a positive identification. In the field, limiting movement of the envenomed extremity with a
sling or splint may provide some symptomatic relief. If possible, measurements of limb circumference at the
leading edge of swelling should be initiated ( Fig. 109–3 ). Intravenous access and administration of an
analgesic such as morphine sulfate can be accomplished during transport.
Figure 109-3 Measurements of an envenomated extremity. The line curving proximal to the wrist defines the leading edge of the
soft tissue swelling. The parallel straight lines on the hand and distal and mid-forearms denote measurement points of extremity
circumference. At each point the two lines denote the distal and proximal edges of the measurement tape; this detail ensures accurate
placement of the tape for each reading.
Controversial techniques and devices have been employed to extract, neutralize, or retard venom spread;
none of these is advocated for prehospital or hospital management. “Cut and suck” to extract venom
involves making an incision over the fang marks, then placing a device such as the Sawyer extractor[25] or a
human mouth over the incision to create a negative pressure gradient. Pitfalls of this therapy include
difficulty in determining the exact site of venom deposition, because fangs are curved and can be several
millimeters in length, and inoculating the wound with bacteria. A loose tourniquet or constricting band,
exerting no more than 20 mm Hg pressure, has been advocated to impede lymphatic spread of venom to the
systemic circulation.[25] The dangers of this treatment include the risk of increasing local tissue injury by
retarding venom spread from the bite site and impeding venous and arterial circulation, which can further
damage distal tissue. Even constrictive bands applied appropriately may be transformed into circulation-
impairing tourniquets as extremity swelling progresses. High voltage, direct current electric shock therapy
was reported to arrest progressive swelling and systemic effects. Both human and animal reports have
shown that electric shock therapy is not beneficial and potentially detrimental, resulting in local burns and
possible myocardial infarction. [12][20] Finally, the local application of ice has been advocated for analgesia
and slowing of venom spread, but overzealous, prolonged use has resulted in frostbite and necrosis.[25] For
these therapies the risks outweigh any benefits, and none of these is recommended.
Hospital Management
Initial Care
At a health care facility the emphasis should be on good supportive care and, when indicated, the early
administration of antivenin. An adequate airway should be ensured, an intravenous line is placed, and
lactated Ringer’s solution or normal saline is infused. Bites to the face, lips, and tongue can occur; and in
these cases local swelling and edema may lead to airway compromise, necessitating early prophylactic
intubation. In severe cases of facial and neck swelling, a tracheostomy or cricothyroidotomy may be
necessary.[30] Patients with moderate or severe envenomation may be hypotensive or dehydrated from
vomiting or third-spacing of fluid into the envenomed extremity. Constrictive bands, tourniquets, restrictive
clothing, or rings should be immediately removed. Analgesics such as morphine are administered and
repeated liberally as needed for pain relief. Use of a benzodiazepine such as lorazepam or diazepam may
alleviate anxiety.
Grading Severity of Envenomation
Clinical gradation scales may be of some use in determining the degree of severity after a bite.[13] Although
there are no strict definitions, a typical “minimal” envenomation results in only local swelling generally
confined to the bite area, with no systemic symptoms or laboratory abnormalities. “Moderate”
envenomations manifest symptoms beyond the site of envenomation, such as fasciculations and perioral
numbness and laboratory changes such as thrombocytopenia and hypofibrinogenemia. “Severe”
envenomations are distinguished by the rapid progression of tissue swelling usually involving the entire limb,
profound systemic signs and symptoms, coagulopathy, and shock ( Table 109–5 ). An appropriate severity
designation can often be made within the first 6 hours; however, mild envenomations have progressed in a
delayed fashion to a moderate or occasionally even severe category.[17]
Table 109-5 -- Severity of Envenomation

Degree of Envenomation Symptoms Signs Laboratory Abnormalities Antivenin
None ± ± - -
Minimal ++ ± - ±
Moderate +++ +++ +++ +++
Severe ++++ ++++ ++++ ++++
Envenomation severity is probably best estimated by observing the three major manifestations of toxicity:
cytotoxicity, hemotoxicity, and systemic effects. Cytotoxicity is monitored by progressively measuring limb
circumference or the leading edge of progressing edema (see Fig. 109–3 ). Severe cytotoxic reactions are
characterized by rapidly progressive swelling of the bitten extremity. Mild or moderate swelling may require
an hour or more of observation to be appreciated. Comparing the bitten extremity to the unaffected limb is
often helpful. Hemotoxicity is best measured by following the victim’s platelet count and fibrinogen. Various
combinations of thrombocytopenia and defibrination may occur, but cases exhibiting laboratory evidence
and bleeding consistent with true DIC syndromes are rare.[9] A platelet count falling below 100,000 mm3 or
fibrinogen less than 100 mg/dL are reasonable indicators to give antivenin. Blood products, such as fresh
frozen plasma, platelets, or cryoprecipitate, are of little value if administered without concomitant antivenin
and should be reserved for the actively bleeding individual or those with other risk factors for hemorrhage.[4]
Antivenin
Antivenin should be administered for a moderate or severe crotalid envenomation, especially those due to
rattlesnakes. It is more efficacious if given soon after the envenomation. Russell reported decreased
effectiveness at 8 hours post-envenomation.[50][51] Because of the decreased incidence of morbidity and
mortality after copperhead and cottonmouth envenomations, antivenin administration is rarely required.[29]
The risk of antivenin administration often outweighs any potential benefit after a copperhead or cottonmouth
envenomation. However, if the envenomation falls into the moderate to severe category antivenin should be
given.
The only antivenin currently approved by the U.S. Food and Drug Administration for the treatment of crotalid
envenomation is Polyvalent (Crotalidae) Antivenin (Wyeth-Ayerst Laboratories). This is an equine-derived
product of purified immunoglobulins from horses immunized with the venom of four different crotalid species:
C. atrox and C. adamanteus, found in North America, and C. durissus terrificus (tropical rattlesnake) and
Bothrops atrox (fer-de-lance) found in Central and South America. Variability in cross-reactivity between
different crotalid species most likely accounts for the differences in responses to antivenin administration
between snakes.[43] For example, the hematologic abnormalities of crotalid envenomation are often
controlled by antivenin, but the neurologic abnormalities in C. scutulatus scutulatus are often refractory.[15]
This may result from a lack of antibodies to C. scutulatus scutulatus venom in the antivenin, specifically
Mojave toxin type A.[23]
The antivenin “kit” includes a 1-mL vial of 1:10 diluted horse serum for skin testing before the infusion of
antivenin. Approximately 0.02 to 0.03 mL of the solution is administered subcutaneously, and the patient is
observed for 10 to 30 minutes for a local reaction such as wheal and flare. A 1:100 dilution should be used if
the likelihood of an allergic reaction is considered high. Some clinicians have advocated skin testing with the
antivenin itself; however, these data are lacking. Any wheal and flare reaction is worrisome and warrants
reviewing whether antivenin is required. Although skin testing may identify the majority of allergic individuals,
the test is not 100 per cent sensitive. A negative test does not rule out the possibility of anaphylactic reaction
during the administration of antivenin. Conversely, a positive reaction may not preclude the safe
administration of antivenin, particularly in a life-threatening envenomation.[63]
A standard stabilization dose is 5–10 vials, reconstituted, diluted in 100 to 500 mL of normal saline (20
mL/kg for children), and administered over 30 to 60 minutes. An initial 5 vials may be administered for those
copperhead bites judged to require antivenin therapy; a dose less than this is rarely effective. During
reconstitution one should avoid violently shaking the vials, which foams the proteins, thus losing antivenin in
the foam. The infusion should begin slowly at 10 mL/hr and increased if no immediate reaction occurs. The
patient should be continuously monitored throughout the infusion for hypersensitivity reactions such as
decreased blood pressure, bronchospasm, or urticaria ( Fig. 109–4 and Table 109–6 ). Adequate
resuscitation equipment should be available during the administration of antivenin. In the event of an allergic
reaction, the infusion should be immediately stopped. Antivenin reactions are treated identically to any other
acute hypersensitivity reactions with epinephrine and histamine receptor blockers such as diphenhydramine
and cimetidine. Epinephrine can be administered subcutaneously or by a continuous infusion. Once the
symptoms have resolved the infusion may be attempted again at a slower rate. The use of corticosteroids for
these allergic reactions is controversial, because their effects are not immediate and will not assist the initial
resuscitation efforts. Antivenin doses are identical for children and adults.
Figure 109-4 Urticaria on the abdomen that developed during antivenin administration.
Table 109-6 -- Hypersensitivity Reactions Associated with Crotalid Antivenin

Immediate Hypersensitivity Reactions (usually seen during antivenin administration)
Symptoms manifest as a decrease in blood pressure, bronchospasm, or urticaria.
Treatment
1. Immediately stop the antivenin infusion.
2. Infuse epinephrine, 1 mg in 250 mL normal saline. Adult: Begin at 30 mL/hr, titrating to effect. Pediatric (< 17
years): 0.02–1.0 µg/kg/min.
3. Administer an H1 antagonist (e.g., diphenhydramine); consider an H2 antagonist (e.g., cimetidine).
4. A ß2 agonist (e.g., albuterol) may be given for respiratory symptoms.
5. After resolution of symptoms, consider restarting antivenin infusion slowly with concomitant epinephrine
infusion.
Delayed Hypersensitivity or “Serum Sickness” (usually seen 5–10 days after antivenin administration)
Symptoms manifest as nausea, abdominal pain, myalgias, arthralgias, cutaneous eruptions, low-grade fever,
lymphadenopathy, and proteinuria.
Treatment (oral)
1. Corticosteroids: methylprednisolone or prednisone.
2. H1 antagonist to provide symptomatic relief of urticaria: diphenhydramine, hydroxyzine.
Endpoint of Therapy
Antivenin should be administered until coagulopathies are resolving, edema progression has stopped, and
systemic toxicity is controlled. Hematology profiles should be repeated 1 hour after the end of antivenin
infusion. Patients exhibiting persistent coagulopathies or continued progressive tissue swelling should be
redosed in 5- to 10-vial increments. The average moderate envenomation will require 20 to 30 vials for the
resolution of signs and symptoms. Antivenin doses in excess of 50 vials may be required in severe cases.
Most patients will show some response to a stabilizing dose of antivenin. Patients with persistent shock after
initial antivenin administration should be fluid resuscitated with crystalloids and readministered antivenin in
10-vial increments until stabilized. Although the progression of tissue swelling is usually controlled with
antivenin, local edema persists for several days or weeks.
Wound Care
The bite site should be cleaned, débrided if necessary, and bandaged according to standard wound care
procedures. Tetanus toxoid and tetanus immunoglobulin are administered when indicated. Prophylactic
antibiotics are unnecessary and should be reserved for treatment of secondary infections after a bite.[5]
Although crotalids are known to harbor potentially infectious microorganisms within their oral cavity
(Pseudomonas aeruginosa, Proteus sp., Staphylococcus sp., Clostridium sp., and Bacteroides fragilis),
crotalid venom, unlike crotalid saliva, is sterile and may have antibacterial properties.[58] One study
demonstrated a low incidence of infection after crotalid envenomation, and the severity of the bite did not
correlate with the incidence of wound infection.[5] Individuals in whom the bite was incised or sucked may be
at greater risk for secondary infections and should be observed closely for infection.
Fasciotomy
Fasciotomy should be limited to true cases of compartment syndrome, diagnosed by measured elevations in
compartment pressures combined with clinical findings of arterial insufficiency.[49] Data suggest that the
aggressive use of antivenin and extremity elevation can prevent compartment syndrome in most extremity
envenomations. In one study, rabbits were injected with 3 mg/kg of C. atrox venom and were assigned to
one of four groups: antivenin alone, antivenin plus surgery, surgery alone, and an untreated group.
Compartment pressures were measured immediately before envenomation and again before treatment.
Although an elevation in compartment pressures was documented, the increase was not consistent with a
true compartment syndrome. All animals survived in the antivenin alone group compared with survival rates
of 80 per cent in the surgery plus antivenin group and 30 per cent each in the surgery alone and control
groups.[56]
A prospective study examined 25 consecutive rattlesnake bites in humans with noninvasive arterial vascular
studies of the envenomed extremity, using the contralateral extremity as a control.[10] All patients received
antivenin. Despite swelling and discoloration in the bitten extremities, the arterial blood flows of the affected
limbs were increased compared with the contralateral control extremities in all but one patient. This patient
had thrombosis of the ipsilateral popliteal and profunda femoral arteries that was attributed to the application
of a tourniquet before arrival at the health care facility. Seven of the 25 patients initially had decreases in
skin temperature and 3 of these 7 subsequently showed signs of serious vascular insufficiency during
hospitalization. These results suggest that decreased skin temperatures, but not swelling and discoloration,
may be a sensitive indicator of inadequate arterial perfusion. These results also support the concept that
increased tissue pressures, either subcutaneous or compartmental, do not result in ischemia in the majority
of patients envenomed by rattlesnakes. [10]
Experimental Therapy
An affinity-purified ovine Fab antibody fragment antivenom is being tested in clinical trials in the United
States.[6][13a] This antivenom may minimize hypersensitivity reactions. In a murine study comparing the
effectiveness of standard equine polyvalent crotalid antivenin and the Fab crotalid antivenom fragments
against nine United States crotalid venoms, the Fab antivenom was more protective against lethality.[7]


DISPOSITION
Patients bitten by crotalids may be initially observed in the emergency department for the development of
any local or systemic symptoms. If no swelling develops at the bite site after 2 to 3 hours, envenomation is
unlikely and the patient may be discharged. All envenomed patients should be observed for a minimum of 8
to 12 hours. If the patient does not have progression of swelling or a documented coagulopathy, he or she
can be discharged with instructions to return to the emergency department if swelling begins to progress or
other symptoms develop. An exception is a patient with known or suspected Mojave rattlesnake
envenomation, who should be monitored in an intensive care unit. Patients requiring antivenin administration
should be admitted to the intensive care unit for continuous monitoring and further therapy.


SEQUELAE
Most victims of crotalid envenomation have an uneventful recovery with little or no permanent sequelae if
there is no delay in antivenin administration, when indicated. [11] Many patients treated with antivenin will
develop a type III delayed hypersensitivity or serum-sickness reaction. Serum sickness is caused by the
deposition of antigen-antibody complexes in areas of the body including the joints, skin, and kidneys. The
incidence of serum sickness after antivenin administration has been reported between 16 and 75 per cent,
although these figures are based on earlier studies when smaller doses of antivenin were administered.[1][42]
Doses in excess of 10 vials of antivenin will cause serum sickness in virtually all patients.[24][63] Symptoms
usually develop between 5 and 10 days after receiving antivenin, with a range of 4 to 20 days. [23] Signs and
symptoms include nausea, abdominal pain, myalgias, arthralgias, cutaneous eruptions, low-grade fever,
lymphadenopathy, and proteinuria without evidence of glomerulonephritis. [24][28][46] The most common skin
eruption is a morbilliform or urticarial rash that begins on the trunk or extremities as patchy erythema. The
multiple symptoms of serum sickness can be relieved by oral administration of antihistamines and
corticosteroids.[28][46]
Severe envenomations, even those treated with antivenin, may result in long-term pain and swelling of a
bitten extremity. Physical therapy in these cases may hasten rehabilitation. Although mild coagulopathies
may persist or return after a patient is initially stabilized, clinically significant late bleeding has not been
reported.


SPECIFIC SITUATIONS
A patient envenomed for the second time can be problematic. Considerations include the potential for
developing anaphylaxis from the bite itself as the result of antibodies previously produced against the actual
venom, in addition to a possible anaphylactic response to the antivenin. The decision to treat these
individuals with antivenin should be based on clinical reasons, with less consideration given to the previous
antivenin treatment. In these individuals prophylactic measures to arrest anaphylaxis include an initial slower
infusion rate of antivenin and prophylactic administration of histamine antagonists. An intravenous infusion
of 1 mg of epinephrine in 250 mL of normal saline should be available at the bedside. In the event
anaphylactic signs or symptoms develop, the antivenin infusion should be immediately stopped and the
epinephrine infusion begun in adults at a rate of 30 mL/hr or more, titrating to effect (infuse at 0.02 to 1.0
µg/kg/min in children younger than 17 years).


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31. Litovitz T, Veltri JC: 1984 Annual report of the American Association of Poison Control Centers national
data collection system. Am J Emerg Med 1985; 3:423-450.
32. Litovitz T, Schmitz BF, Bailey KM: 1989 Annual report of the American Association of Poison Control
33. Litovitz T, Felberg L, Soloway RA, et al: 1994 Annual report of the American Association of Poison
34. Litovitz T, Schmitz BF, Matyunas N, et al: 1987 Annual report of the American Association of Poison
Control Centers national data collection system. Am J Emerg Med 1988; 6:479-515.
35. Litovitz T, Clark LR, Soloway RA: 1993 Annual report of the American Association of Poison Control
36. Litovitz T, Holm KC, Clancy C, et al: 1992 Annual report of the American Association of Poison Control
37. Litovitz T, Holm KC, Bailey KM, et al: 1991 Annual report of the American Association of Poison Control
38. Litovitz T, Bailey KM, Schmitz BF, et al: 1990 Annual report of the American Association of Poison
Control Centers national data collection system. Am J Emerg Med 1991; 9:461-509.
39. Litovitz T, Normann SA, Veltri JC: 1985 Annual report of the American Association of Poison Control
40. Litovitz T, Martin TG, Schmitz B: 1986 Annual report of the American Association of Poison Control
41. Litovitz T, Schmitz BF, Holm KC: 1988 Annual report of the American Association of Poison Control
42. McCullough NC, Gennaro JF: Treatment of venomous snakebite in the United States. J Toxicol Clin
Toxicol 1970; 3:483-500.
43. Minton SA, Weinstein SA: Geographic and ontogenic variation in venom of the western diamondback
rattlesnake (Crotalus atrox). Toxicon 1986; 24:71-80.
44. Moss ST, Bogdan G, Nordt SP, et al: An examination of serial urinalyses in patients with North
American crotalid envenomation. J Toxicol Clin Toxicol 1998; 36:329.
45. Moss ST, Bogdan G, Dart RC, et al: Association of rattlesnake bite location to severity of clinical
manifestations. Ann Emerg Med 1997; 30:58.
46. Otten EJ, McKimm D: Venomous snakebite in a patient allergic to horse serum. Ann Emerg
Med 1983;624-627.
47. Retzios AD, Markalnd FS: A direct-acting fibrinolytic enzyme from the venom of Agkistrodon contortrix
contortrix: Effects on various components of the human blood coagulation and fibrinolysis systems. Thromb
Res 1988; 52:541-552.
48. Riffer E, Curry SC, Gerkin R: Successful treatment with antivenin of marked thrombocytopenia without
significant coagulopathy following rattlesnake bite. Ann Emerg Med 1987; 16:1297-1299.
49. Roberts RS, Csencsitz TA, Heard CW: Upper extremity compartment syndromes following pit viper
envenomation. Clin Orthop Rel Res 1985; 193:184-188.
50. Russell FE: Snake venom poisoning in the United States. Ann Rev Med 1980; 31:247-259.
51. Russell FE, Picchioni AL: Snake venom poisoning. Clin Toxicol Consult 1983; 5:73-87.
52. Russell FE: Snake Venom Poisoning, Garden City, NJ: Scholium International; 1983:17.
53. Schmaier AH, Claypool W, Colman RW: Crotalocytin: Recognition and purification of a timber
rattlesnake platelet aggregating protein. Blood 1980; 56:1013-1019.
54. Simon TL, Grace TG: Envenomation coagulopathy in wounds from pit vipers. N Engl J
Med 1981; 305:443-447.
55. Snyder CC: Antivenin activity of rattlesnake blood plasma. Nature 1976; 261:259-260.
56. Stewart RM, Page CP, Schwesinger WH, et al: Antivenin and fasciotomy/debridement in the treatment
of severe rattlesnake bite. Am J Surg 1989; 158:543-547.
57. Sullivan JB: More on envenomation coagulopathy from snake bites. N Engl J Med 1982; 306:806-807.
58. Talan DA, Citron DM, Overturf GD, et al: Antibacterial activity of crotalid venoms against oral snake
flora. J Infect Dis 1991; 164:195-198.
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by purified Mojave toxin. Neurotoxicol Teratol 1989; 11:129-133.
60. Veltri JC, Litovitz T: 1983 Annual report of the American Association of Poison Control Centers national
data collection system. Am J Emerg Med 1984; 2:420-443.
61. Whitley RE: Conservative treatment of copperhead snakebites without antivenin. J

Trauma 1996; 41:219-221.
62. Wingert WA, Pattabhirmaman TR, Powers D, et al: Effect of a rattlesnake venom (Crotalus viridis
helleri) on bone marrow. Toxicon 1981; 19:181-183.
63. Wingert WA, Chan L: Rattlesnake bites in southern California and rationale for recommended
treatment. West J Med 1988; 148:37-44.
64. Wingert WA, Pattabhirmaman TR, Cleland ZR, et al: Distribution and pathology of copperhead
(Agkistrodon contortrix) venom. Toxicon 1980; 18:591-601.
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66. Zulys VJ, Teasdale SJ, Michel ER, et al: Ancrod (Arvin) as an alternative to heparin anticoagulation for
cardiopulmonary bypass. Anesthesiology 1989; 71:870-877.


Chapter 110 – Coral Snakes
GREGORY G. GAAR SVEN A. NORMANN
Essentials
• History of bite by multicolored, banded snake. History of snake’s “chewing” or having to be forcibly
removed increases the probability of coral snake envenomation.
• Minimal, if any, local pain or redness at the site of the bite.
• Wounds may appear as rows of teeth marks that ooze blood.
• Bulbar palsy, generalized weakness, and respiratory paralysis can occur; and onset may be delayed.
INTRODUCTION
In the United States there are 6000 to 8000 venomous snake bites per year.[1] Although most of the
venomous exposures are due to pit vipers (Crotalidae), members of the coral snake (Elapidae) family are
responsible for an estimated 1 to 2 per cent of these poisonous snake bites.[3] The clinical presentation and
treatment are markedly different for coral snake envenomations as compared with pit viper envenomations.
The Elapidae family includes coral snakes as well as cobras, mambas, and kraits. The Australian and
Pacific water snakes are also in this family. In the United States, the coral snakes are the native species.
The eastern coral snake (Micrurus fulvius fulvius) is found in the southeastern states (Florida, Georgia, North
Carolina, South Carolina, Alabama, and Mississippi). Micruroides euryxanthus (the Sonoran coral snake) is
found in Arizona, and Micrurus fulvius tenere (the Texas coral snake) is found primarily in Texas, Arkansas,
and Louisiana. It is not uncommon for professional and amateur herpetologists, zoo keepers, and laboratory
workers to encounter this family of snakes outside their native habitat.
These snakes have common physical characteristics, which usually make them readily identifiable.
Compared with the pit vipers, coral snakes are small and slender. The head is small and rounded and has a
black snout, but there are no facial pits. The pupils are round rather than slitlike. The fangs of the coral
snake are short (1 to 3 mm in length) and fixed to the maxillae, unlike the long, hinged pairs of fangs of the
Crotalidae. In the United States, coral snakes have bodies with brightly colored, glossy bands of black and
red that are separated by narrow yellow or yellow-white bands. This coloration allows differentiation of the
eastern coral snake from the nonpoisonous scarlet king snake, which has a red snout and red and yellow
rings separated by black bands ( Fig. 110–1 ). The old rhyme, “Red on yellow, kill a fellow/Red on black,
venom lack” or other variations are used to remember the sequence of colors for purposes of
identification.[14]
Figure 110-1 Color pattern differences between the coral snake and the scarlet king snake. The yellow bands are adjacent to the red
bands in the coral snake, giving rise to the “Red on yellow, kill a fellow” admonition, whereas they lie next to the black bands in the
scarlet king snake—“Red on black, venom lack.”
Coral snakes are timid and usually avoid human contact. Bites most often occur when a person is invading
the snake’s environment. The snake’s nocturnal habits may make bites more likely to occur later in the
evening. Because the snakes are more active and many people are outside in warmer weather, bites are
clustered during the months of April to October. Most bites in adults are usually on the upper extremity.
Adolescent males, many of whom admit to purposefully handling the snake, are common victims. The use of
ethanol or other mind-altering substances is commonly associated.
The most effective treatment for coral snake envenomation is prevention. Physicians and other health care
providers can stress prevention issues in public education venues. It is important for persons to know the
indigenous species of wildlife in areas where they engage in outdoor activities. Protective clothing such as
boots, long, thick pants, and gloves may offer some safeguard. People should avoid putting their hands or
feet into any outdoors hole or other space that is not fully visible.


PATHOPHYSIOLOGY
Eastern coral snake (Micrurus fulvius fulvius) venom is composed of peptides and enzymes that have not
been fully identified. They are neurotoxins, exhibiting curarae-like effects on the neuromuscular junction that
are often delayed in onset and prolonged in duration.[10] This curare-like effect is responsible for the
predominance of neurologic symptoms associated with envenomation. There is some evidence that
Elapidae venoms also act centrally on the respiratory center, which also contributes to respiratory
paralysis.[2] Unlike pit viper venom, there are virtually no proteolytic cytotoxins present to produce local
tissue reactions.[11] The venom of the eastern coral snake has been described as among the most potent of
the venoms of native U.S. species, second only to that of Crotalus scutulatus scutulatus.[6][12]
The venom of the Texas coral snake is similar in its effects. It is considered to be less potent than that of the
eastern coral snake. The Sonoran coral snake venom also demonstrates neurotoxicity without significant
central nervous system involvement. It, too, is considered less potent than the venom of the eastern coral
snake.[8]
The venom of the coral snakes is carried hematogenously in humans in the superficial venous system. This
is unlike the lymphatic spread of the Crotalidae venom. This is important in implementing appropriate first
aid measures.


Patients most often present to a health care facility with a chief complaint of snake bite. It is incumbent on
the practitioner to identify the snake and evaluate the patient’s symptoms and clinical signs to make an
appropriate diagnosis ( Table 110–1 ).
Table 110-1 -- Clinical Presentation of Coral Snake Envenomation

History of snake’s chewing or having to be pulled off
Fang marks commonly appear as rows of teeth marks
No local edema or erythema at bite site
Systemic symptoms may be delayed
Nausea/vomiting
Generalized weakness, paresthesias
Bulbar paralysis with cranial nerve dysfunction
Respiratory failure
Patients often give a history of the snake as “hanging on” to a digit or “chewing.” Kitchens and Van Mierop
report that in 85 per cent of cases in their series, the snake had to be actively removed.[4] The nature of the
coral snake fangs leads to clinical characteristics distinct from the pit vipers in two respects. One, the short
fangs require the snake to have prolonged tissue contact (compared with other snakes) to inject venom.
Second, due to this anatomy, the fang marks often appear as rows of tooth marks that ooze blood. Such
marks were present in 85 per cent of the patients who presented with a history of coral snake envenomation
in one series.[4] It is imperative to remember that a lack of dramatic local signs and symptoms does not
preclude serious envenomation when dealing with eastern coral snake bites,[7] and this is also true for bites
of the Sonoran and Texas coral snakes.
There is usually very little edema or redness at the site of the bite (40 per cent of patients), because coral
snake venom contains almost no cytotoxins.[4] Pain might be present immediately at the time and site of the
bite but is usually minimal.[4] Bullae occur in less than 5 per cent of cases.[4]
The serious neurologic symptoms are due to the curare-like effects of the venom. Systemic manifestations
may be delayed in onset as much as 4 to 13 hours after the occurrence of the bite.[4][13] Nausea and
vomiting, generalized weakness, paresthesias, and dizziness are reported. Patients may be drowsy or
exhibit an uncharacteristic euphoria. Muscle fasciculations and diaphoresis may occur. The most serious
central nervous system signs are due to bulbar paralysis. Diplopia, slurred speech, and trouble swallowing
may mimic botulism, and these patients are at risk for aspiration pneumonia. Most authorities agree that the
central nervous system effects after Sonoran coral snake bites are less severe than those after an eastern
coral snake bite.[8]
Peripheral nervous system effects manifest primarily as weakness, with occasional progression to total
paralysis, including paralysis of the respiratory muscles. In one series of 39 patients, 6 required elective
intubation, although not all of those required mechanical ventilation.[4] In most cases, paralysis lasts 3 to 5
days and total recovery from nervous system effects may take several weeks. If death occurs early in the
course, it is most often due to inadequate treatment of respiratory failure. [4][7]
There is no reliable way of predicting the clinical course of the neurologic symptoms or the ability of
antivenom to reverse them. There may be rapid progression once symptoms appear.
Cardiac effects such as dysrhythmias have not been reported.[4] Hematologic abnormalities such as
hemolysis or clotting disturbances have not been reported.[3]


Differential diagnosis depends on the presence of fang marks (“bite marks”) on physical examination.
Because patients may be asymptomatic on presentation only to develop severe, delayed symptoms, the
following rationale is employed. If there are wounds in the skin and the patient gives a reliable history of a
bite by a multicolored, banded snake consistent with the coral snake, the practitioner must assume a
potentially venomous bite has occurred. The bite is either without systemic envenomation, or the patient has
presented before the appearance of signs and symptoms. It is, of course, possible that the victim has been
bitten by a nonvenomous snake.
If the patient is exhibiting central nervous symptoms of bulbar palsy, then botulism, Guillain-Barré syndrome,
basilar artery stroke, and intoxication with other chemicals that cause bulbar palsy or respiratory paralysis
must be considered ( Table 110–2 ). If a skin wound is present in association with neurologic symptoms,
envenomation by a coral snake must be strongly considered. The reliability of the diagnosis of coral snake
envenomation is increased if the patient reports that the snake had to be forcibly removed. Obtaining
historical information about the patient’s activities before the onset of the symptoms is crucial.
Table 110-2 -- Differential Diagnosis of Coral Snake Envenomation

Bite by other venomous snake without envenomation
Bite of a nonvenomous snake
Botulism
Basilar artery stroke
Chemical/drug intoxication
Paralytic shellfish poisoning
Neuroparalytic drugs
Tetrodotoxin


LABORATORY STUDIES
The lack of hemotoxins in coral snake venom makes laboratory studies in the acute phase of treatment of
little or no value. Baseline complete blood cell count, electrolytes, clotting studies, and urinalysis are not
indicated. If one suspects chemical or drug intoxication as a contributing factor to symptoms, then blood
ethanol testing or urine drug testing might be appropriate. No single laboratory test is diagnostic of
envenomation.
Because respiratory compromise is responsible for morbidity and mortality, periodic measurements of peak
flow, pulmonary tidal volumes, or negative inspiratory flow can be helpful. Pulse oximetry monitoring and
arterial blood gas analysis can be used as adjunct measures of pulmonary status. After the initial treatment
phase, objective measurements of pulmonary function should be continued and chest radiographs assessed
for signs of aspiration pneumonia.


TREATMENT
All patients should be quickly transported to a hospital with capability for appropriate treatment. Prehospital,
initial life support measures should be followed by reassurance that treatment is available. Methods to retard
venom spread should not be used. These include tourniquets, incision and suction in the field, or putting ice
on the extremity. Improperly applied tourniquets may impede arterial flow, whereas loose tourniquets are
ineffective owing to the hematogenous spread of coral snake venom. Applying ice to the envenomated
extremity risks cold-induced injury.
Acute Phase of the Envenomation
In the emergency department a detailed history is obtained if the patient’s vital signs are stable. The
characteristics of the bite (“Was it a multicolored snake?” “Did the snake appear to chew?” “Did the snake
have to be removed?” “How long did the snake have contact?”) are helpful in distinguishing coral snake
bites from pit viper bites. The time since the bite and the therapeutic interventions that have occurred before
arrival at the health care facility should be determined. Identification of the snake should be done without
putting either the victim or a health care provider at risk. The patient’s pertinent past medical historical
information should focus on underlying general state of health, prior pulmonary disease, prior neurologic
disease, previous exposure to horse serum products, and allergies.
The initial physical examination includes measurement of the vital signs, careful inspection of the site of the
bite, and complete pulmonary and neurologic evaluations. Peak flow, tidal volumes, or negative inspiratory
flow measurements can be done at this point. If indicated, a tetanus toxoid booster should be given. Any
drug that causes respiratory depression should be avoided. The most important therapeutic intervention is
good supportive care with respiratory, cardiac, and neurologic monitoring.
Antivenom
The decision for antivenom therapy and hospital admission is straightforward in the patient who, by history,
has been envenomed by a multicolored, banded snake resembling the eastern or Texas coral snake and
who exhibits any sign or symptom consistent with envenomation. If the patient reports that such a snake
“chewed” or needed to be forcibly removed, then antivenom should be given even if the patient exhibits no
signs or symptoms. It is impossible to predict which patients with a history of snake bite have actually been
envenomated or will become symptomatic. As symptoms of coral snake bite may not be evident for 13 or
more hours,[4] early intervention with antivenom has been recommended even in asymptomatic individuals.
This might expose some persons to antivenom who would not have had severe symptomatology from the
bite. However, because antivenom reversal of symptoms is not absolute, most authorities believe such early
treatment has a positive “benefit/risk” ratio. [4][5][9]
Initial Dose
Five vials of Micrurus fulvius fulvius antivenom should be given after appropriate skin testing (see later
protocol). Micrurus fulvius fulvius antivenom (Wyeth Laboratories, Inc., Philadelphia, PA) is a commercially
prepared, horse serum–derived product. It is effective only for the envenomation of Texas and eastern coral
snakes. Antivenom should always be given intravenously, never intramuscularly nor directly in the area of
the bite. Respiratory support should be aggressive. Early, elective intubation at the onset of pulmonary
symptoms before respiratory failure may minimize pulmonary morbidity caused by aspiration ( Table 110–3
).
Table 110-3 -- Treatment of Coral Snake Envenomation

Good supportive care is the hallmark of therapy.
Elective intubation and mechanical ventilation for respiratory insufficiency/failure.
Antivenom use is indicated in patients:
Who have neurologic signs/symptoms at presentation.
Who are asymptomatic but have blood at the site of fang marks that pierce the epidermis and one of the
following:
A bite by a snake confirmed to be a Texas or eastern coral snake or
History that the snake chewed or was difficult to remove.
Micrurus fulvius fulvius antivenom (Wyeth Laboratories) is effective for bites by Texas or eastern coral snakes.
Skin test must be performed using a 1:10 or 1:100 dilution of reconstituted antivenom.
Reconstitute five vials of antivenom.
Add five vials to 250 mL of normal saline.
Administer by continuous intravenous infusion. Start at 3–5 mL/hr; slowly increase to reach a maximum rate of
120–180 mL/hr.
Be prepared to treat anaphylactoid reaction.
Total dose of antivenom is determined empirically. If patients have severe or prolonged sequelae, antivenom in
aliquots of five vials may be infused.
Patients who have been treated with antivenom should be observed for signs of serum sickness and
appropriately treated.
Skin Testing
Skin testing for sensitivity to horse serum is performed once the commitment is made to administer
antivenom and not before. To do so, reconstituted antivenom is further diluted 1:10. Then, 0.01 to 0.02 mL is
injected intradermally on the volar surface of the forearm. Normal saline is used as a control in the same
fashion. If patients have previously received horse serum products and give a history of sensitivity,
reconstituted antivenom might be diluted 1:100 for skin testing. A “positive” test is defined as edema, wheal
formation, or erythema which appears within the first half-hour. If the skin test is negative, antivenom
infusion can proceed.
The patient who has a positive skin test to horse serum–prepared antivenom poses a dilemma. Pretreatment
with H1 (e.g., diphenhydramine) and H2 (e.g., cimetidine) blocking agents and systemic corticosteroids has
been suggested. Although patients with Crotalidae envenomation have received continuous intravenous
infusions of epinephrine to receive antivenom, this cannot be routinely recommended in the case of Elapidae
envenomation. The neurologic consequence of respiratory failure can be adequately treated with elective
intubation and artificial respiration; thus, it is difficult to evaluate the “benefit/risk” ratio of using continuous
epinephrine to give antivenom for Elapidae envenomation. Consultation with a toxicologist or a regional
poison center with expertise in managing these patients is encouraged.
Antivenom Infusion
This is prepared by first reconstituting five vials of antivenom. The reconstituted solution is added to 250 mL
of normal saline. (If the patient has cardiac or renal disease in which volume and salt load would be a
contraindication, 50 mL of reconstituted antivenom can be added to 100 mL normal saline to give a total
volume of 150 mL. Flow rates should be appropriately slowed.) A continuous infusion should be started at 3
to 5 mL/hr; and, if no systemic reaction occurs, the infusion should be increased slowly until a maximal rate
of 120 to 180 mL/hr is reached. Such a rate will deliver two to three diluted vials each hour. Appropriate
medications and equipment for treating anaphylactoid reaction should be readily available. Antivenom
should only be given with medical personnel in attendance.
The dosage of antivenom given in any individual case is empirical. After administration of the first five vials,
persons with more severe symptoms or prolonged duration may require additional doses. Subsequent doses
are usually given in three- to five-vial aliquots.
There is no specific antivenom for the bite of the Sonoran coral snake. Supportive therapy is appropriate.
Because the venom is less toxic, no deaths have been reported.
Subacute Phase of the Envenomation
Patients should be carefully observed for any sign of respiratory compromise. Measurements of pulmonary
function allow for objective monitoring. Aspiration pneumonia and complications from intubation can develop
during this time.[4] Wound and skin infections can occur. Any ensuing diagnosis made during this phase
should be treated as clinically indicated.


DISPOSITION
Any patient with blood at the site of visible fang marks piercing the epidermis who meets one of the following
criteria, even if asymptomatic, should be admitted to the hospital for at least 24 hours of intensive care
monitoring and possible antivenom administration, as discussed earlier[4][5][9]: (1) a confirmed bite from a
snake definitely identified to be an eastern or a Texas coral snake or (2) a history of a snake bite in which a
multicolored, banded snake “chewed” on the person or was difficult to remove.
Patients with neurologic symptoms should only be discharged when there is no concern for respiratory
failure. If the patient has been intubated, a period of observation for postintubation complications is
imperative. Patients may not achieve their baseline muscle strength for 4 to 6 weeks after paralysis.
Outpatient physical therapy may be necessary depending on the patient’s neurologic status. Follow-up visits
should be individualized to the patient’s clinical condition.


SEQUELAE
Subsequent to administration of antivenom, patients are likely to develop serum sickness within 3 weeks of
receiving the horse serum–derived product. An appropriate index of suspicion in patients who present with
urticaria, malaise, arthralgias, lymphadenopathy, or fever will allow timely diagnosis. Most patients respond
to medication regimens of antihistamines and oral corticosteroids. Some centers are currently treating
patients prophylactically at the time of their discharge. There have been no controlled trials proving the
efficacy of this regimen.
Long-term morbidity due to Elapidae envenomation is fortunately rare.


REFERENCES
1. Gold BS, Barish RA: Venomous snakebites: Current concepts in diagnosis, treatment and management.
Emerg Med Clin North Am 1992; 10:249-267.
2. Iyaniwura TT: Snake venom constituents: Biochemistry and toxicology: I and II. Vet Hum
Toxicol 1991; 33:468-480.
3. Kitchens CS: Hemostatic aspects of envenomation by North American snakes. Hematol Oncol Clin
North Am 1992; 6:1189-1195.
4. Kitchens CS, Van Mierop LHS: Envenomation by the eastern coral snake (Micrurus fulvius fulvius): A
study of 39 victims. JAMA 1987; 258:1615-1618.
5. Kurecki BA, Brownlee J: Venomous snakebites in the United States. J Fam Pract 1987; 25:386-392.
6. Minton SA, Minton MR: Venomous Reptiles, New York, Scribner’s, 1969.
7. Norris RL, Dart RC: Apparent coral snake envenomation in a patient without visible fang marks. Am J
Emerg Med 1989; 7:402-405.
8. Russell FE: Bites by the Sonoran coral snake, Micruroides euryxanthus. Toxicon 1967; 5:39-42.
9. Russell FE: Snake venom poisoning in the United States. Annu Rev Med 1980; 21:247-259.
10. Russell FE: Snake Venom Poisoning, Philadelphia, JB Lippincott, 1980.
11. Russell FE: Snake Venom Poisoning, New York, Scholium, 1983.
12. Wingert WA: Poisoning by animal venoms. Top Emerg Med 1980; 2:89-118.
13. Wingert WA, Wainschel J: Diagnosis and management of envenomation by poisonous snakes. South
Med J 1975; 68:1015-1026.
14. Wurstlin CF: Rhymes to meet snakes by, [Letter]. JAMA 1988; 259:218.


Chapter 111 – Brown Recluse and Other Necrotizing Spiders
GARY S. WASSERMAN
Essentials
• Initial bite is often unnoticed, and the spider is rarely identified.
• Dermonecrosis may appear within 24 hours or be delayed for 7 to 14 days.
• Systemic toxicity, if it occurs, usually develops within 4 days and rarely may involve multiple organs.
• Systemic effects may not be proportional to the severity of the local reaction and vice versa.
• Serial clinical and laboratory assessments are necessary to manage potential life-threatening
complications.
INTRODUCTION
Slightly more than a dozen families of spiders in the world have a bite known to cause dermonecrosis. Six of
these families are distributed in the United States ( Table 111–1 ).[11][13][24][28][32][39] The most venomous of
these spiders belongs to the genus Loxosceles, of which L. reclusa is the most prevalent of the 13
Loxosceles species in the United States. Spiders from the family Loxoscelidae are distributed in South,
Central, and North America as well as the Mediterranean area and Europe. [14] Reports of brown spider bites
causing necrotic skin lesions appeared in the U.S. literature as early as 1872, [7] but it was not until 1957 that
L. reclusa was recognized as the probable cause of “necrotic arachnoidism.”[2]
Table 111-1 -- Spiders Causing Necrotizing Bites in the United States

Genus Common Name
Argiope Orbweaver
Chiracanthium Running or sac spider
Loxosceles Brown recluse, fiddle-back, or violin spider
Lycosa Wolf spider
Phidippus Jumping spider
Tegenaria agrestis Northwestern brown spider or hobo spider
Spiders of the Loxosceles species are often called “brown,” “violin,” or “fiddleback” spiders. However, the
term brown recluse should be reserved only for L. reclusa. The name “reclusa” describes its behavior
because it avoids areas of activity, is nocturnal, hides its web, and is seldom seen. The main habitats of
brown recluse spiders are the southern midwestern states, but these spiders can be found coast to coast
because of migration in boxes and baggage. Depending on the temperature, this spider prefers living in
warm, dry, secluded areas either outdoors or in structures such as basements, attics, and storage areas.
Bites usually occur between April to October, may occur anywhere on the body, and seldom occur unless
the spider is threatened. Most victims are bitten while working in the yard or house, dressing, or asleep as
the spider searches its environment.
L. reclusa measures 1 to 5 cm leg to leg, is usually a brownish color, and is characterized by a darker brown
violin-shaped marking (larger end of fiddle toward the head) on the back of its cephalothorax ( Fig. 111–1 ).
Its other body segment is oval with short hairs, and the legs are long and slender. A large spider will have a
total body length of 1 cm and width of 0.5 cm. Another distinctive identifying characteristic are three pairs of
eyes, because most other spiders have four pairs. Hunting spiders like the wolf spider and jumping spider
have a fourth pair of eyes, much larger than the other eyes and often located high. Hunting spiders are one
of the few groups of spiders possessing fangs large enough to pierce human skin and inject a venom that
causes mild dermonecrosis.
Figure 111-1 Loxosceles reclusa (brown recluse, “fiddle-back”) spider showing the classic violin-shaped marking on the back (dorsal
side) of the cephalothorax. Note the long slender legs and oval body segment with short hairs. (Spider tore off one leg during captivity.)
The Pacific Northwest (Idaho, Oregon, Washington, Canada) has seen an increased number of necrotic
bites resulting from Tegenaria agrestis, known as the “hobo spider.” T. agrestis spiders are brown with
nondiscrete gray markings and similar in size, activity, and local effects to L. reclusa. The most common
systemic symptom is a severe headache; other symptoms include nausea, vomiting, weakness, fatigue,
temporary memory loss, impaired vision, pancytopenia, and, rarely, death.[32] Therapy should be the same
as for loxoscelism.


PATHOPHYSIOLOGY
Loxosceles venom contains at least nine proteins, mostly enzymes with cytotoxic activity, of which the
mechanisms of actions are not well established. Venom causes both local and systemic toxicity by means of
endothelial cell damage, lysis of red blood cells, coagulopathy, and complex activations such as calcium-
dependent systems, complement, C-reactive protein, polymorphonuclear leukocytes, serum amyloid P
component, antibodies, and other reactants.[3][8][9][10][17][20][21][22][30] Other important venom components are
hyaluronidase (spreading factor), alkaline phosphatase, 5-ribonucleotide phosphohydrolase, and
sphingomyelinase D. Sphingomyelinase D is unique to Loxosceles venom and appears to be the major
dermonecrotic factor. It reacts with sphingomyelin, a cell membrane component, which releases choline and
N-acylsphingosine phosphate,[8][26] when calcium and serum amyloid protein are present,[8][9] stimulating
platelet aggregation and release of serotonin.[21] Dermonecrosis is additionally enhanced by the resulting
inflammation and ischemia.


The clinical presentation varies tremendously depending on the age of the patient, pre-existing medical
conditions, amount of venom, location of envenomation, and the immune response of the host ( Table 111–2
). Most bitten victims have a relatively benign course.[6] Children and debilitated patients are at greater risk
for severe reactions, but often the elderly are asymptomatic, possibly owing to acquired immunity from bites
earlier in their lives.[35] Few victims receive a “full dose” of venom, and there is usually only one bite site.
Cutaneous and systemic toxicity (loxoscelism) may occur, and the systemic reaction may develop before an
obvious local lesion. The systemic response is not necessarily proportional to the severity of the local
reaction and vice versa ( Fig. 111–2 ). Venomous spider bites are not reportable in the United States, and
because many victims never seek medical attention, toxicity statistics are unreliable.
Table 111-2 -- Presentation of Brown Recluse Spider Bites

Cutaneous Local Effects
Initial pinprick, but often no bite felt
Itching, tingling, swelling, tenderness, pain
Pallor/blanching or redness
Blister, bleb, or purpura
Induration, necrosis, eschar
Ulceration, delayed healing
Systemic Effects
Nausea, vomiting, abdominal tenderness
Fever, chills, or afebrile
Malaise, weakness
Arthralgias, myalgias
Rashes
Discolored serum and/or urine (yellowish to red to black)
Hepatitis
Pancreatitis
Pulmonary edema/effusion
Renal failure, coma, shock, seizures—end-stage effects
Laboratory Findings
Anemia, leukocytosis, thrombocytopenia
Hemolysis, hemoglobinemia, hemoglobinuria
Hematuria
Hyperbilirubinemia
Elevations of liver and renal function tests and amylase
Abnormal clotting studies (prothrombin and partial thromboplastin times, fibrinogen, D-dimers)
Positive antibody studies (IgG, complement, Coombs)
Blood typing/matching interference
Saturated haptoglobin binding capacity or decreased free haptoglobin
Elevated serum/plasma hemoglobin and/or urine hemoglobin
Figure 111-2 A, A 3-year-old female hospitalized on the third day for severe hemolytic anemia, hemoglobinuria, and ecchymosis (note
the vast expansion of ecchymosis secondary to hyaluronidase—“spreading factor”—in the venom). There is no necrosis or ischemia,
but a small bleb/blister is present over the right clavicle that, although not pathogenic, is often present early in lesion progression. Also
note that the cutaneous lesion is mild in comparison with this patient’s systemic presentation. B, On the 15th day post envenomation,
the lesion measures 5 × 2 cm. Multiple small areas of necrosis have manifested in the past week. The largest area indicates the
original bite size. The lesion edges have begun to involute with healing, and ischemia is fading.
Bite
A few patients sense a mild pinprick, but most patients are unaware they have been bitten. Typically, in a
few hours, the bite site progressively begins to itch, tingle, and develop slight swelling or induration. It
becomes tender to the touch and either blanches or becomes erythematous. As toxicity progresses the local
cutaneous lesion becomes painful and purpura may occur ( Fig. 111–3 ). An interesting characteristic is the
appearance often of a blister or bleb that is either flesh colored or deep purple to black. This bleb marks the
site of the fang punctures ( Fig. 111–4 ). Necrotic tissue is almost always located beneath these blebs. Pain
worsens as inflammation and ischemia spread. Eventually, tissue necrosis occurs; eschar may form within
hours or as late as 2 weeks after envenomation. Ultimately, the eschar falls off, leaving an ulceration that
may require months to heal. Occasionally a “halo,” “target,” or “bull’s-eye” lesion develops characterized by
the initial erythematous or violaceous lesion being surrounded by a ring of pallor secondary to spreading of
ischemia.[36] Fatty areas of envenomation such as abdomen, thighs, and buttocks are particularly
susceptible to the most severe necrosis because of the inadequate vascular supply. Neck and facial sites
are particularly prone to develop marked swelling.[35]
Figure 111-3 A 10-year-old with hemolysis from a 3-day-old spider bite. Note the blister and the extensive purpura around the bite.
Figure 111-4 A 9-year-old female was hospitalized for fever, abdominal pain, hemolytic anemia, and left arm tenderness following
brown recluse spider envenomation. Her forearm was edematous. On the eighth day post envenomation, circulation has returned to
the ischemic area, whose border is denoted by the black lines. Necrosis developed beneath the enlarging blister but not in the
remainder of the lesion. At 6 weeks healing was complete, leaving a scar similar to a varicella pox mark.
The spider does not transmit bacteria to the wound, but secondary contamination, usually by streptococcal
or staphylococcal bacteria, may occur 12 to 96 hours after the bite. Rarely does sepsis, toxic shock
syndrome, or necrotizing fasciitis occur.
Systemic Effects
Those effects related to venom toxicity develop within 24 to 96 hours, but indirect venom complications such
as sepsis may occur later. Multiple organ systems, particularly the skin, blood, liver, and pancreas may be
involved. Systemic signs and symptoms include high fever, chills, malaise, weakness, nausea, vomiting,
abdominal discomfort, arthralgias, myalgias, jaundice, abnormal bleeding, and rashes. A full-blown systemic
reaction causes hepatic and pancreatic inflammation, pulmonary edema or effusions, and congestive heart
failure. The most common life-threatening reactions occur from hemolytic anemia, thrombocytopenia, and/or
disseminated intravascular coagulation.[33][34][38] Hemolysis may lead to hemoglobinemia, hemoglobinuria,
shock, renal failure, seizures, and, rarely, death.[31][33][38] Hematuria also may occur as a direct venom effect
to the kidneys, bladder, or urinary tract.
Rashes are puzzling because there may be a scarlatiniform eruption for days with later peeling that may or
may not be related to a streptococcal or staphylococcal infection. Less commonly observed is a diffuse,
faint, either lacelike or macular erythematous rash that erupts transiently for a few hours over the trunk and
flexural surfaces. This rash may be a favorable prognostic sign because immediate cessation in progression
of the local lesion often follows.
Generally, the significance of envenomation is not perceived either by the patient or physician when the
victim first presents for the local cutaneous reaction with vague systemic complaints. Although hemolysis
can occur rapidly, many patients suffer an insidious onset that is not recognized until the third day after
envenomation.


The diagnosis of loxoscelism is usually only presumptive because the spider is rarely identified, and there is
no simple serologic test. The diagnosis is best determined based on the clinical presentation, a consistent
lesion, and the known presence of brown recluse spiders in the area. Without positive identification of the
offending spider, a generic diagnosis such as “necrotizing lesion” or “arthropod bite or sting” should be
considered.
The list of differential diagnoses is virtually endless, especially when considering the cutaneous and
systemic reactions as two separate entities, which unfortunately occurs often ( Table 111–3 ). The total
presentation is not clearly expressed nor recognized when a patient seeks medical care early after
envenomation.[19] When combining the cutaneous and systemic signs and symptoms together, natural
toxins should be highly suspected. Erythema that evolves into a violaceous macule and further darkens
distinguishes a necrotic lesion from a non-necrotic bite or sting. Another hint is that the edge of the necrotic
lesion becomes uneven as the macule widens and the center darkens and sinks below skin level; the non-
necrotic lesion remains edematous, raised, and red.
Table 111-3 -- Differential Diagnosis of Brown Recluse Spider Bite

Bites and stings of many creatures
Dermatoses of many types
Hereditary hemolytic anemias
Acquired hemolytic anemias
Other natural toxins causing hemolysis
Coelenterata (Portuguese man-of-war jellyfish)
Hymenoptera (bees, wasps, etc.)
Snakes (cobra, viper venom)
Spiders (Loxosceles)
Clostridium infections
Streptococcal/staphylococcal infections
Medical conditions
Emboli
Vasculitis
Frostbite
Ischemic vascular ulcers
Fat herniation/infarction
Factitious ulcers (self-inflicted)
Traumatic lesions


LABORATORY STUDIES
Laboratory studies will vary with the clinical presentation and suspected complications. All patients with a
suspicion of loxoscelism should have baseline hemoglobin, hematocrit, and platelet counts and a dipstick
test or urinalysis checking for blood. In children these should be rechecked daily for 3 to 4 days, whereas
observant adults may be rechecked every other day for two visits. Patients with hemolysis or other
significant systemic effects require a more intensive laboratory evaluation focusing on liver and renal
function tests, amylase, blood smear, and coagulation studies. Liver function tests include alanine
aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, and total and
direct bilirubin. Renal function tests include electrolytes, blood urea nitrogen, creatinine, calcium, and
urinalysis. Coagulation studies should be comprehensive, including prothrombin and partial thromboplastin
time (or equivalents), bleeding time, fibrinogen, and D-dimers. An elevated reticulocyte count is an
inexpensive, quick test to verify hemolysis in this circumstance.
Other studies such as blood type and screen/crossmatch, a reticulocyte count, plasma or urine free
hemoglobin levels, direct antiglobulin tests (IgG, complement, Coombs), serum haptoglobin level, or
haptoglobin binding capacity may be helpful as indicated. When hemolysis occurs, initially “free” hemoglobin
will be bound by haptoglobin, forming a complexed molecule too large to pass through the glomeruli and
therefore not appearing in the urine. When the haptoglobin binding capacity is saturated and the renal
tubular resorption capacity is exceeded, however, hemoglobinuria will produce a urine dipstick test positive
for blood with or without red blood cells on the microscopic view. Some patients who present a few days
after envenomation have already stopped hemolyzing but are symptomatic, depending on how anemic they
have become. Coombs tests and other direct antiglobulin tests may only be weakly positive early in the
envenomation and negative by the second or third day and may also revert to negative rapidly after the
administration of corticosteroids. Because blood typing and crossmatching may be difficult secondary to
interfering antibodies, it should be performed as soon as indicated.
Cultures and Gram stains of infected lesions are obtained as needed. A biopsy of a lesion is rarely
necessary except to rule out unusual differential diagnoses. A passive hemagglutination inhibition test
performed from the exudate of the lesion is sensitive, specific, and reproducible for bite diagnosis, but
presently is only used as a research tool because it is cumbersome to prepare.[5]


TREATMENT
Management of necrotic arachnidism is similar regardless of the spider species ( Table 111–4 ). The “benign
neglect” approach is successful in the vast majority of bites. The rare disfiguring lesion cannot be predicted
during early evaluations. An experimental antivenom has been used in research but is not commercially
available.[27] Treatment is subdivided into care of the local wound and management of systemic reactions.
Table 111-4 -- Treatment of Necrotizing Spider Bite

Local Wound Care
Cleansing and topical antimicrobial ointment
Tetanus prophylaxis
Protect area from additional trauma
Immobilization and elevation of bitten extremity as appropriate
Cool compresses (avoid heat)
Antipruritic/antianxiety medication, as needed
Systemic antimicrobial agents only as needed for secondary infection
Serial observations
Culture as needed
Biopsy rarely indicated
Débridement if necrotizing fasciitis suspected
Delay skin grafting as indicated for 4 to 8 weeks
Systemic Reactions to Brown Recluse Spider Bite
Serial clinical and laboratory assessments
Routine: hemoglobin, hematocrit, platelet, urinalysis
Obtained based on clinical picture: type and crossmatch (perform early), liver function tests, renal function
tests, amylase, coagulation studies, haptoglobin, Coombs, chest radiograph, electrocardiogram
Analgesic/antipyretic agents
Systemic antimicrobial agents as indicated for infections
Systemic corticosteroids for hemolysis
Methylprednisolone, 10–40 mg IV q6h for 3–5 days
Disseminated intravascular coagulation—specific management
Packed red blood cell transfusions as needed for anemia
Other blood products/components as indicated
Dialysis as needed for renal failure
Symptomatic and supportive care
Wound Care
Management to minimize dermonecrosis involves routine wound care to prevent further tissue damage and
infection while relieving patient suffering with short-acting opioids. Hot or warm compresses should not be
used because the heat may stimulate activity of sphingomyelinase D. Bacterial infection rarely occurs early.
Analgesics and anti-inflammatory drugs that affect platelet functioning should be avoided because they may
worsen systemic bleeding. Acetaminophen should not be used if hepatotoxicity is known. Corticosteroids or
vasodilators, either injected locally or parenterally, have not been shown to be effective in lessening
dermonecrosis.[1]
Surgical intervention such as early wide excision should be avoided because it is ineffective and may
augment further necrosis by facilitating deeper penetration of venom into tissues. Excision may cause
delayed wound healing, increased infection, disability, and worse scarring.[25][36] Surgery is warranted for
abscess formation and suspicion of necrotizing fasciitis. Corrective surgery, such as skin grafting or
débridement with primary closure, should be delayed for 4 to 8 weeks to allow clear demarcation of necrotic
tissue.[36][37]
There is no specific therapy proven to prevent dermonecrosis. A randomized, blinded, controlled rabbit study
revealed no benefit of hyperbaric oxygen, dapsone, or cyproheptadine (a potent antiserotonergic agent) in
the treatment of Loxosceles deserta envenomation.[23] The use of a leukocyte inhibitor such as dapsone to
limit inflammatory reaction is controversial and not proven effective in any large study with human or animal
control cases. Comparisons of dapsone to electric shock therapy and dapsone to surgical excision were not
convincing.[4][25] Dapsone may produce hemolytic anemia in patients with glucose-6-phosphate
dehydrogenase deficiency or a dose-dependent hemolytic anemia in normal patients; methemoglobinemia
and gastrointestinal distress are not uncommon, especially in children.[18] Patients taking dapsone must also
be closely monitored for leukopenia, superinfection, and rash. Therefore, dapsone therapy, if used at all,
should be closely monitored and should be reserved for nonpregnant patients with presumed L. reclusa
envenomations in cosmetic body areas (i.e., face, digits) demonstrating progressive ischemic necrosis within
24 hours of the bite. The adult dose is 25 to 100 mg orally, twice daily until the lesion stops progressing.
Dapsone should not be used in children due to the incidence of adverse effects and lack of proven efficacy.
Hyperbaric oxygen (HBO) therapy has been used but with no proven benefit.[23][29] The potential benefits of
HBO include promoting neovascularization in necrotic tissue and also inactivating enzymes that contain
sulfhydryl groups such as phospholipids. Whereas HBO is not known to prevent dermonecrosis from
Loxosceles envenomation, it may be beneficial in a subgroup of patients with a history of wound healing
difficulty such as vascular insufficiency (i.e., diabetes). Whether the bite will cause dermonecrosis is
established within minutes of the envenomation and apparently is not prevented by medical care.
Systemic Therapy
Systemic reactions vary from mild aches and malaise to multiorgan involvement and death. Fatalities are
rare and are attributed to complications of hemolysis, disseminated intravascular coagulation, or infection.
Severe systemic reactions require hospitalization for aggressive symptomatic and supportive care.
Corticosteroids appear to prevent and stop hemolysis but are only required for 3 to 5 days. Initially
administer intravenous methylprednisolone, 10 to 40 mg every 4 to 6 hours, and increase the dose if
hemolysis is not controlled in 4 to 8 hours. Other hematologic complications (e.g., anemia, bleeding) should
be treated with component therapy (e.g., packed red cells, platelets) as indicated. Whole blood transfusion
should be avoided because complement or other unknown factors in plasma appear to react with venom,
contributing to red blood cell destruction.[15] Adequate hydration and urine output are essential to ensure
hemoglobinuria and hematuria do not lead to renal failure. Alkalinization of the urine may be indicated for
hemoglobinuria. Dialysis does not remove venom but may be required if renal failure develops.
One should observe closely for the onset of septicemia or toxic shock syndrome, which may occur rapidly in
the first couple of days or later as a variable event.


DISPOSITION
Mildly symptomatic patients presenting immediately after being inflicted with a suspicious Loxosceles and/or
necrotizing bite, and demonstrating a normal laboratory screen, should be closely observed as outpatients
with re-evaluation every 24 to 48 hours for 3 to 5 days. Patients who suffer large ulcerations or develop a
large area of skin discoloration should be referred to a plastic surgeon for follow-up with delayed closure
after demarcation in 4 to 8 weeks. Patients with significant systemic reactions should be hospitalized.
Admitted patients who are observed to have a benign course for 24 to 72 hours may be discharged and re-
evaluated as outpatients within 24 to 48 hours as needed. A liberal admission policy for observation is
warranted for young children, debilitated persons, and those individuals judged to be unreliable regarding
follow-up. Frequent follow-up is necessary because of the unpredictable course and the many controversies
in therapy. Follow-up will also reinforce to the patient and family the inevitability of the resulting
complications.


SEQUELAE
Long-term complications are rare and relate to the involved organ systems. The most common problem
involves resolution of the dermonecrosis, which may, in rare circumstances, be quite extensive and fail to
regenerate after 2 to 3 months without reconstructive plastic surgery depending on the site, depth, and
expansion of necrosis. Rarely, tissue damage may penetrate to muscles or cause neuropathy, resulting in
permanent disability, especially when extensive excisional therapy is performed within days of the bite.
Sepsis and disseminated intravascular coagulation have resulted in extremity and other tissue loss,
especially to distal structures such as fingers, toes, ears, and nose.


SPECIFIC SITUATIONS—PREVENTION
Preventing the spider bite in the first place is not as easy as it may seem. Spiders are abundant and
necessary in nature. Neither the age or construction of a building restricts these spiders, and they can
survive without food or water for up to 6 months.[16] The author had a brown recluse spider survive for a
month in an air-tight sealed 3-ounce jar with no food or water. Although the best prevention is avoidance,
this is not always possible. One can warn the spiders by making noise or vibrations (i.e., foot stomping)
before entering basements, attics, storage areas, seldom-used closets, woodpiles, and so on. This allows
the reclusive creature to avoid you by running away. Shake out items (e.g., boots, shoes, clothing, blankets)
before using them, especially if they have been in storage.
There are only a few reports discussing the use of chemical acaricides against Loxosceles.[12] Available
information and personal experience indicate that chemical prophylaxis is unlikely to control brown recluse
spider activity indoors.[16][36] This ineffectiveness is related to the abundance of spiders both indoors and
outdoors, the hidden locations of their webs, and the concern about short- and long-term pesticide safety to
the human dwellers, as well as the slender legs of the spiders having minimal contact with pesticides. Many
acaricides irritate arthropods, increasing their activity before death.


REFERENCES
1. Anderson PC: Necrotizing spider bites. Am Fam Physician 1982; 26:198-203.
2. Atkins J, Wingo CN, Soderman WA: Probable cause of necrotic spider bites in the Midwest.
Science 1957; 126:73.
3. Babcock JL, Marmer DJ, Steele RW: Immunotoxicology of brown recluse spider (Loxosceles reclusa)
venom. Toxicon 1986; 24:783-790.
4. Barrett SM, Romine-Jenkins M, Fisher DE: Dapsone or electric shock therapy of brown recluse
envenomation?. Ann Emerg Med 1994; 24:21-25.
5. Barrett SM, Romine-Jenkins M, Blick KE: Passive hemagglutination inhibition test for diagnosis of brown
recluse spider bite envenomation. Clin Chem 1993; 39:2104-2107.
6. Berger R: The unremarkable brown recluse spider bite. JAMA 1973; 225:1109-1111.
7. Caverness WA: Insect bite complicated with fever. Nashville J Med Surg 1872; 10:333.
8. Forrester LJ, Barrett JT, Campbell BJ: Red blood cell lysis induced by the venom of the brown recluse
spider: The role of sphingomyelinase D. Arch Biochem Biophys 1978; 187:355-365.
9. Gates CA, Rees RS: Serum amyloid P component: Its role in platelet activation stimulated by
sphingomyelinase D purified from the venom of the brown recluse spider (Loxosceles reclusa).
Toxicon 1990; 28:1303-1315.
10. Gertsch WJ: American Spiders, 2nd ed. New York, Van Nostrand Reinhold, 1979.
11. Geren C, Chan TK, Howell DE, et al: Isolation and characterization of toxins from brown recluse spider
venom (Loxosceles reclusa). Arch Biochem Biophys 1976; 174:90-99.
12. Gladney WJ, Dawkins CC: Insecticidal tests against the brown recluse spider. J Econ
Entomol 1972; 65:1491-1493.
13. Gorham JR, Rheney TB: Envenomation by the spiders Chiracanthium inclusum and Argiope aurantia.
JAMA 1968; 206:1958-1962.
14. Habermehl GG: Venomous Animals and Their Toxins, Berlin: Springer-Verlag; 1981:33-38.
15. Hardman JT, Beck ML, Hardman PK, et al: Incompatibility associated with the bite of the brown recluse
spider (Loxosceles reclusa). Transfusion 1983; 23:233-236.
16. Hite JM, Gladney WJ, Lancaster JL, et al: Biology of the brown recluse spider. Ark Agri Exp Sta
Bull 1966; 711:1-26.
17. Huford DC, Morgan PN: C-reactive protein as a mediator in the lysis of human erythrocytes sensitized
by brown recluse spider venom. Proc Soc Exp Biol Med 1981; 167:493-497.
18. Iserson KV: Methemoglobinemia from dapsone therapy for a suspected brown spider bite. J Emerg
Med 1985; 3:285-288.
19. Knapp JF, Thomas KT, Mathews R, et al: Case 06-1994: A 10-year-old female with fever, jaundice and
orthostatic hypotension. Pediatr Emerg Care 1994; 10:364-368.
20. Kniker WT, Morgan PN, Flanigan WJ, et al: An inhibitor of complement in the venom of the brown
recluse spider, Loxosceles reclusa. Proc Soc Exp Biol Med 1969; 131:1432-1434.
21. Kurpiewski G, Forrester LJ, Barrett JT, et al: Platelet aggregation and sphingomyelinase D activity of a
purified toxin from the venom of Loxosceles reclusa. Biochem Biophys Acta 1981; 678:467-476.
22. Patel KD, Modur V, Zimmerman GA, et al: The necrotic venom of the brown recluse spider induces
dysregulated endothelial cell–dependent neutrophil activation. J Clin Invest 1994; 94:631-642.
23. Philips S, Kohn M, Baker D, et al: Therapy of brown spider envenomation: A controlled trial of
hyperbaric oxygen, dapsone, and cyproheptadine. Ann Emerg Med 1995; 25:363-368.
24. Redman JF: Human envenomation by a Lycosid. Arch Dermatol 1974; 110:111-112.
25. Rees RS, Altenbern DP, Lynch JB, et al: Brown recluse spider bites: A comparison of surgical excision
versus dapsone and delayed surgical excision. Ann Surg 1985; 202:659-663.
26. Rees RS, Nanney LB, Yates RA, et al: Interaction of brown recluse spider venom on cell membranes:
The inciting mechanism?. J Invest Dermatol 1984; 83:270-275.
27. Rees RS, Shack RB, Withers E, et al: Management of the brown recluse spider bite. Plast Reconstr
Surg 1981; 68:768-773.
28. Russell FE: Bite of the spider Phidippus formossus: Case history. Toxicon 1970; 8:193-194.
29. Skinner MW, Butler CS: Necrotising arachnidism treated with hyperbaric oxygen. Med J
Aust 1995; 162:372-373.
30. Smith CW, Micks DW: The role of polymorphonuclear leukocytes in the lesion caused by the venom of
the brown spider, Loxosceles reclusa. Lab Invest 1970; 22:90-93.
31. Taylor EM, Denny W: Hemolysis, renal failure and death, presumed secondary to the bite of brown
recluse spider. South Med J 1966; 59:1209-1211.
32. Vest DK: Necrotic arachnidism in the Northwest United States and its probable relationship to Tegenaria
agrestis (Walckenaer) spiders. Toxicon 1987; 25:175-184.
33. Vorse H, Seccareccio P, Woodruff K, et al: Disseminated intravascular coagulopathy following fatal
brown spider bite (necrotic arachnidism). J Pediatr 1972; 80:1035-1037.
34. Wasserman GS, Mydler TT, Sharma V: Brown recluse envenomation as a cause of hemolysis and
hemoglobinuria. [Abstract]. Vet Hum Toxicol 1991; 33:359.
35. Wasserman GS: Brown recluse spider envenomations. In: Harwood-

Nuss AL, Linden CH, Luten RC, et al ed. The Clinical Practice of Emergency Medicine, 2nd ed.
36. Wasserman GS, Anderson PC: Loxoscelism and necrotic arachnidism. J Toxicol Clin
Toxicol 1983; 84:451-472.
37. Wasserman GS: Wound care of spider and snake envenomations. Ann Emerg Med 1988; 17:1331-
1335.
38. Williams ST, Khare VK, Johnston GA, et al: Severe intravascular hemolysis associated with brown
recluse spider envenomation: A report of two cases and review of the literature. Am J Clin
Pathol 1995; 104:463-467.
39. Wong RC, Hughes SE, Voorhees JJ: Spider bites. Arch Dermatol 1987; 123:98-104.


Chapter 112 – Black Widow Spider Envenomation
G. RANDALL BOND
Essentials
• Prick sensation with bite of the spider
• “Halo” lesion may be present
• Marked muscle cramping and pain
• Autonomic nervous system features, especially hypertension or sweating
INTRODUCTION
The black widow spider, Latrodectus mactans, is part of a family of spiders found throughout temperate
regions of the world, including all of the United States except Alaska.[3][10][12][16][18] Other North American
species include L. hesperus, L. variolus, L. bishopi, and L. geometricus. In most of the United States these
are shiny black spiders.[3][4][18] The ventral aspect of the abdomen of the spider frequently has a red
hourglass marking ( Fig. 112–1 ). When the spider has fasted for a prolonged period, this marking may be
folded up in layers of the exoskeleton. In other parts of the world the distinctive abdominal marking may be
limited to a series of dots or another minor discoloration. Red and brown species are found in some
locations, including Australia, South Africa, and Florida.[12][16][18]
Figure 112-1 Black widow spider.
These spiders prefer dark, hidden places. [3] They frequently inhabit rodent holes, nests, stone walls, and
woodpiles.[3] They may also be found around buildings and in outbuildings (barns, stables, and outdoor
toilets).[3][18] Their natural prey are insects, and they do not bite humans unless provoked.[3][18]
Although folklore suggests that only the female black widow has venom, the male spider also has venom but
has small teeth that cannot penetrate human skin.[3][18]


PATHOPHYSIOLOGY
The venom of spiders of this genus contain at least six proteins. [3] There is great venom similarity between
species within this genus. The most important venom component, the neurotoxin a-latrotoxin, acts at the
presynaptic membrane of the neuronal and the neuromuscular junctions.[2][5][9] Alpha-latrotoxin causes the
opening of nonspecific cation channels, resulting in increased neurotransmitter release and decreased
reuptake of neurotransmitter.[5][9] The primary symptom of envenomation, muscle cramping, is due to
release of acetylcholine at the neuromuscular junction. Latrotoxins from different locales have been noted to
have variable effects on norepinephrine release, but effects on acetylcholine release are constant.[2] This
may explain some of the geographic variation in the frequency of autonomic symptoms.[2][4][10][12][16]


History
A history of recent patient activities should be obtained in someone with suspected Latrodectus
envenomation. A bite occurs when a person disturbs the hidden spider, usually near its web.[18] This often
happens while dressing, gathering wood, or using an outhouse.[3][18] Frequently spiders hide or make their
home in clothes, particularly gloves or shoes that have been left in a garage, basement, or shed. At other
times, shoes or clothing that have been left out overnight, particularly when camping, bring these spiders
into contact with people.[4]
The pattern of symptoms after envenomation is very similar around the world ( Table 112–1 ).[4][10][12][16]
Individual experience of symptoms is variable, both person to person and over time.[4][10]
Table 112-1 -- Clinical Presentation of Black Widow Spider Bite

Pinprick sensation—brief in duration.
Between 30 and 120 minutes later regional lymph node tenderness occurs.
A “target” lesion may appear at the bite site at this time.
Proximal muscle cramping pain begins. Pain in back, chest, or abdomen occurs depending on the anatomic
location of the bite. Pain may wax and wane.
Autonomic nervous system symptoms include nausea, vomiting, sweating, hypertension, tachycardia, and,
rarely, priapism.
These symptoms persist for 36 to 72 hours.
Milder symptoms and a sensation of being “not quite right” may last for 1 to 2 weeks.
Bite
Often, minimal initial pain occurs with the bite.[10][18] The patient may experience a pricking sensation as
from a needle or thorn, but the sensation fades almost immediately.[4][11][18] Over the next 30 minutes to
several hours, the patient may experience an uncomfortable sensation in the bitten extremity and regional
lymph node tenderness.[4][11][16] The venom lacks human cytotoxic agents so there is no local tissue injury
and little to no local tenderness.[3][4][18] A “target” or “halo” lesion may appear at the bite site.[4] This lesion
appears as a flat erythematous ring 5 to 15 mm away from a central macule, the bite site ( Fig. 112–2 ). This
local manifestation is specific for black widow envenomation but fades by 12 hours after envenomation and
may easily be missed.
Figure 112-2 Classic “target” lesion of black widow spider bite. (Courtesy of the Department of Medical Toxicology, Good Samaritan
Medical Center, Phoenix, AZ.)
Anatomic bite sites vary with the mode of exposure.[4][16] In one large study 48 per cent of bites were to the
lower extremity, 28 per cent to the upper extremity, an additional 18 per cent were to the trunk, and 5 per
cent were to the head and neck.[4] Once a frequent site of bites, the penis and scrotum are less frequently
affected due to improvements in plumbing.[10][16][18] Pit toilets at campsites and construction sites account
for recent incidents.
Systemic Manifestations
The onset of significant symptoms may occur within an hour or may be delayed as many as 6 to 12
hours.[4][17] In a large North American series the median time to symptom onset was 1 hour with the median
time to hospital presentation 6 hours. [4]
Symptoms frequently wax and wane.[4] After the pinprick sensation and development of regional lymph node
tenderness, the patient will experience proximal muscle cramping, including pain in the back, chest, or
abdomen, depending on the site of the bite.[3][4][10][11][16][18] A facial grimace or even mild facial swelling may
be noted. The frequency of presenting symptoms noted in one large series is presented in Figure 112–3 .[4]
Patients often experience autonomic symptoms, including nausea, vomiting, malaise, sweating,
hypertension, tachycardia, and a vague feeling of dysphoria. [3][4][10][16][17][18] Sweating patterns may be
remarkably unique, involving just the upper lip or even one side of the upper lip or the tip of the nose.
Priapism and urinary retention are rare manifestations.[10] Leukocytosis may be observed.[4][11]
Rhabdomyolysis is uncommon.[4][6]
Figure 112-3 Clinical presentation. (From Clark RF, Kestner SW, Vance MV: Clinical presentation and treatment of black widow
spider envenomation: A review of 163 cases. Ann Emerg Med 1992; 21:782).
Untreated symptoms will continue to wax and wane over the ensuing 36 to 72 hours.[5][10][17] Although the
pain fades, some patients describe malaise or a sensation of not feeling quite right for a period of 2 to 4
weeks. [10] A patient with underlying heart disease or a small infant may experience such severe
envenomation that symptoms are life threatening, but with modern supportive care death rarely results. In
four reports of envenomation during pregnancy, symptoms were similar to those of nonpregnant
patients.[7][13][14][17] None showed evidence of fetal distress, and two were treated with antivenin without
complication.[7][13] One of these pregnancies and one not treated with antivenin were followed to term, and
both resulted in normal infants.[13][14]


The pain of the black widow bite may be excruciating and can be mistaken for myocardial infarction or acute
abdomen, particularly when the original spider bite was not observed ( Table 112–2 ).[10][18] Rarely, other
conditions such as pulled muscle, food poisoning, meningitis, cocaine intoxication, and psychosis are
considered.[10] Because the bite usually occurs in a circumstance where a spider’s habitat has been
disturbed, a history of recent patient activities should be obtained, particularly in association with a “pinprick”
sensation, and a careful examination made for the halo lesion.
Table 112-2 -- Differential Diagnosis of Black Widow Spider Bite

Acute myocardial infarction
Acute abdomen
Food poisoning
Pulled muscle
Cocaine intoxication
Meningitis
Psychosis


LABORATORY STUDIES
No specific laboratory tests are indicated for Latrodectus envenomation. Mild elevations in leukocyte and
creatine phosphokinase levels may be seen but are usually clinically insignificant.
The cornerstone of treatment for black widow spider envenomation is analgesics in doses adequate to
relieve all pain ( Table 112–3 ). It is always appropriate to provide pain relief for victims. For the patients who
are only experiencing minor discomfort, oral medications such as hydrocodone or oxycodone may be tried.
Intravenous opioid analgesics, such as morphine or meperidine, should be given to all patients who are
experiencing significant pain.[4]
Table 112-3 -- Treatment of Black Widow Spider Bite

Analgesia
Analgesia sufficient to relieve the pain (Often analgesics alone are sufficient to manage the envenomation.)
Intravenous opioids for moderate to severe pain
Oral opioids for mild pain
Benzodiazepines are adjunctive therapy.
Diazepam or lorazepam orally or parenterally
Provide anxiolysis and centrally acting smooth muscle relaxation.
Supportive care
Hydration
Tetanus immunization as needed
Consider black widow spider (Latrodectus) antivenin:
If severe pain is unrelieved by opioid analgesics or
If life-threatening hypertension persists.
Outpatient management
Considered for patients with symptoms controlled by oral analgesics


TREATMENT
Opioids
Muscle Relaxants
Benzodiazepines should be used as second-line therapy even though, because of the prominent role
muscle cramping plays in symptomatology, muscle relaxants have long been suggested as primary therapy.
In one retrospective study more patients who received both analgesics and benzodiazepines had relief of
symptoms than those who received analgesics alone.[4] The perceived benefit of benzodiazepines such as
diazepam may simply be due to anxiolysis. Their use should only be considered adjunctive to the primary
use of analgesics. The centrally acting muscle relaxant methocarbamol has also been tested in the context
of black widow spider envenomation, but it did not reliably produce symptom resolution.[8]
Calcium
Intravenous calcium is not recommended for symptomatic relief. Since at least 1935, calcium gluconate has
been used to treat symptoms. Two studies have examined this phenomenon critically. In a prospective study
of 13 patients, 33 per cent of those who received calcium gluconate 10 per cent solution, 1 g intravenously
over 5 minutes, experienced symptom resolution.[8] Three of 4 other patients who received calcium
gluconate after methocarbamol were described as improved.[8] In a retrospective review, only 1 of 25
patients receiving calcium gluconate as initial therapy was noted to have had significant improvement in
symptoms immediately after calcium administration. [4] Furthermore, if patients do experience improvement,
the effect is often transient.[10] Based on these results, dramatic improvement should not be expected with
calcium gluconate.
Other Measures
Symptomatic care should also include maintaining hydration and treatment of severe hypertension,
particularly in patients with underlying cardiovascular disease. Frequently, adequate analgesia alleviates
hypertension. Dangerous hypertension is rare. When the mean arterial pressure is persistently elevated
more than 30 mmHg above baseline in spite of analgesic therapy, the use of nitroprusside or antivenin
should be considered.
Antivenin
Patients with severe pain that is refractory to opioid analgesics or those with life-threatening hypertension
and tachycardia uncontrolled with supportive care should be considered candidates for antivenin.
Latrodectus antivenin, a horse serum–derived product, has the advantage of offering rapid, complete relief
of pain and the possibility of discharge from the emergency department.[4] It is effective even if more than a
day has elapsed since the bite.[1][15] However, in a review of 58 patients receiving antivenin, acute reaction
occurred in 5, one of whom died.[4] Therefore, its use should be limited to the previously mentioned
indications. When used, one vial is generally sufficient.[4] Contraindications include known allergy to horse
serum and concurrent use of ß-adrenergic receptor antagonists (ß-adrenergic receptor blockade reduces the
efficacy of intervention should anaphylaxis occur). Before administration of antivenin the patient should be
skin tested to horse serum ( Table 112–4 ). If the skin test is positive, antivenin should not be administered.
Antivenin should be diluted and administered over 30 to 60 minutes ( Table 112–5 ).
Table 112-4 -- Procedure for Horse Serum Skin Testing

1. Skin testing should not be done until the decision to administer antivenin has been made.
2. Always perform skin testing in a monitored environment, prepared to treat an immediate hypersensitivity
reaction.
3. Intradermally administer 0.02 mL of a 1:10 dilution of horse serum (provided with each vial of the antivenin)
to the volar aspect of the patient’s forearm.
4. Observe the skin test site for 15 to 20 minutes.
5. Positive reactions include the development of any wheal, erythema, urticaria, or systemic symptoms.
6. Do not administer Latrodectus antivenin if a positive reaction occurs.
Table 112-5 -- Procedure for Administration of Black Widow Spider Antivenin

1. Antivenin should only be administered in a monitored environment (emergency department, intensive care
unit) with physician intervention immediately available.
2. Reconstitute each vial of lyophilized Latrodectus antivenin with 2.5 mL of the diluent. Once the diluent is
added, roll each vial vigorously between the palms for several minutes until no particles of powder can be
observed when the vial is held up to the light. Do not shake. Small globules of lipid may be apparent, but no
powder should be undissolved.
3. Further dilute the antivenin into 100 mL of normal saline.
4. Infuse through an infusion pump and piggyback into a running intravenous line of normal saline.
5. Set the initial infusion rate at 2 mL/hr. Double the rate of infusion every 2 minutes until a rate of 250 mL/hr is
achieved.
6. If an acute reaction occurs, such as itching, hives, hypotension, or respiratory compromise, stop the
antivenin immediately.
a. Administer:
Diphenhydramine IV
Adult: 50 mg
Pediatric: 1 mg/kg (maximum, 50 mg)
Methylprednisolone
Adult: 60 mg IV
Pediatric: 1–2 mg/kg IV (maximum, 60 mg)
Cimetidine
Adult: 300 mg IV over 5–10 minutes
Pediatric: 10 mg/kg IV (maximum, 300 mg) over 5–10 minutes
b. Consider:
Epinephrine 1:1000
Adult: 0.01 mL/kg to maximum 0.5 mL SC
Pediatric: 0.01 mL/kg to maximum 0.3 mL SC
Epinephrine 1:10,000 (for shock state or inadequate response to SC)
Adult: 3–5 mL IV q5–10 minutes prn
Pediatric: 0.1 mL/kg IV q5–10 minutes prn
7. Management should continue with supportive care.


DISPOSITION
When patients present with mild symptoms several hours after the bite, they are likely to respond to oral
analgesic therapy and may be treated as outpatients. Because the natural history of this envenomation is for
symptoms to wax and wane, the patient should be observed for several hours to ensure that symptoms have
been relieved and are unlikely to recur in severe form. These patients may be discharged on analgesics as
required, with instructions to return for recurrent severe symptoms.
Patients who experience pain that is early in onset or more severe at presentation are more likely to have
prolonged, severe pain.[4][8] Pregnant women, young children, the elderly, those with underlying
cardiovascular disease, and those requiring large doses of intravenous analgesics require hospital
admission or prolonged observation in the emergency department.[8]
Patients given antivenin may be discharged 2 hours after completion of the antivenin infusion if symptoms
have resolved.


SEQUELAE
There are no reported long-term sequelae after black widow spider envenomation. Some patients report
mild pain and feeling not totally well, including a lack of their usual energy and appetite for a period of 1 to 2
weeks after the bite.
Those who receive antivenin should be warned of the potential occurrence of delayed serum sickness.
Because the volume of antivenin used to treat black widow spider envenomation is small, delayed serum
sickness is an uncommon complication.[11] Rash, joint aches, joint swelling, low-grade temperature, or
generalized muscle aches can be treated with antihistamines and glucocorticosteroids.


REFERENCES
1. Allen RC, Norris RL: Delayed use of antivenin in black widow spider (Latrodectus mactans)
envenomation. J Wilderness Med 1991; 2:187-192.
2. Baba A, Cooper JR: The action of black widow spider venom on cholinergic mechanisms in
synaptosomes. J Neurochem 1980; 34:1369-1379.
3. Binder LS: Acute arthropod envenomation. Incidence, clinical features and management. Med Toxicol
Adverse Drug Exp 1989; 4:163-173.
4. Clark RF, Kestner SW, Vance MV: Clinical presentation and treatment of black widow spider
envenomation: A review of 163 cases. Ann Emerg Med 1992; 21:782-787.
5. Filippov AK, Tertishnikova AE, Alekseev GP, et al: Mechanism of latrotoxin action as revealed by patch-
clamp experiments on Xenopus oocytes injected with rate brain messenger RNA.
Neuroscience 1994; 61:179-189.
6. Gala S, Katelaris CH: Rhabdomyolysis due to redback spider envenomation. [Letter]. Med J
Aust 1992; 157:66.
7. Handel CC, Izquierdo LA, Curet LB: Black widow spider (Latrodectus mactans) bite during pregnancy.
West J Med 1994; 160:261-262.
8. Key GF: A comparison of calcium gluconate and methocarbamol (Robaxin) in the treatment of
latrodectism (black widow spider envenomation). Am J Trop Med Hyg 1981; 30:273-277.
9. Linial M, Ilouz N, Feinstein N: a-Latrotoxin is a potent inducer of neurotransmitter release in torpedo

electric organ—functional and morphological characterization. Eur J Neurosci 1995; 7:742-752.
10. Maretic Z: Latrodectism: Variations in the clinical manifestations provoked by Latrodectus species of
spiders. Toxicon 1983; 21:457-466.
11. Moss HS, Binder LS: A retrospective review of black widow spider envenomation. Ann Emerg
Med 1987; 16:188-191.
12. Muller GJ: Black and brown widow spider bites in South Africa. S Afr Med J 1993; 83:399-404.
13. Russell FE, Marcus P, Streng JA: Black widow spider envenomation during pregnancy: Report of a
case. Toxicon 1979; 17:188-189.
14. Scalzone JM, Wells SL: Latrodectus mactans (black widow spider) envenomation: An unusual cause for
abdominal pain in pregnancy. Obstet Gynecol 1994; 83:830-831.
15. Suntorntham S, Roberts JR, Nilsen GJ: Dramatic clinical response to the delayed administration of
black widow spider antivenin. Ann Emerg Med 1994; 24:1198-1199.
16. Sutherland SK, Trinca JC: Survey of 2,144 cases of red back spider bites: Australia and New Zealand.
Med J Aust 1978; 2:620-623.
17. Timms PK, Gibbons RB: Latrodectism—Effects of the black widow spider bite. West J
Med 1986; 144:315-317.
18. Wong RC, Hughes SE, Voorhees JJ: Spider bites. Arch Dermatol 1987; 123:98-104.


Chapter 113 – Scorpion Envenomation
RICHARD F. CLARK
Essentials
• Most frequent site of sting is extremity.
• Immediate local pain and tingling are most common symptoms.
• Parasympathetic symptoms of salivation, vomiting, and lacrimation and sympathetic symptoms of
tachycardia, mydriasis, and diaphoresis are common on presentation.
• Severe cases include cranial nerve symptoms such as blurred vision, abnormal eye movements, slurred
speech, drooling, and poor airway control.
• Children younger than age 10 are at highest risk.
INTRODUCTION
Although there are 10 families of arthropods, very few have envenomation apparatuses large or advanced
enough to pierce human skin. Of those capable of human envenomation, scorpions are one of the most
feared by humans. Folklore has largely contributed to much of this distinction, since the American
Association of Poison Control Centers has recorded over 35,000 envenomations by these arachnids in this
country over the past 5 years with no reported fatalities. Significant morbidity, however, can occur after
stings from some scorpions found in other countries, many of which are imported to pet stores in the United
States every year.
Arachnids were among the first animals adapting to life on land. Fossils of creatures resembling scorpions
have been traced back 400 million years.[16] Scorpions are thought to be descendants of Eurypterida, or
“water scorpions,” prehistoric amphibious creatures possessing gills.[19] Scorpions exhibiting book lungs
began appearing in fossils 350 million years ago, and their morphology has not changed significantly since
that time.[19]
Scorpion bodies can be divided into three main sections: cephalothorax, abdomen, and tail. Two pairs of
pedipalps protrude from the cephalothorax and give rise to chelae or pincers, used in catching and holding
prey. The six-segmented tail extends from the posterior section, with the last segment terminating in the
venom apparatus or telson containing a stinger at the tip. Scorpion venom is produced in two glands in the
telson and injected through the stinger into the victim by contraction of gland muscles. The tail thrusts over
the back of the scorpion, striking the victim held in its pincers as venom is injected.
Scorpions are generally nocturnal, preferring to hunt insects such as crickets or small lizards after sunset.
During daylight hours they hide under rocks or logs. Varieties of scorpions are found worldwide, including
mountains, grasslands, and forests. In tropical parts of the world, scorpions may approach lengths in excess
of 20 cm, but the most dangerous varieties found in North America are usually less than 7 cm.
Some 1500 species of scorpion have been identified worldwide. Of these, only 25 species have medical
importance to humans, most of which are members of the Buthidae.[16][18][19] Over 40 species of scorpions
inhabit North America, predominantly in the southern United States and Mexico. Most sightings and stings
by scorpions in the northern United States are thought to occur from “stowaways” exported to these regions
in clothing and furniture. Although all species of scorpions are capable of envenomating humans, in North
America only Centruroides exilicauda, found in Mexico, Arizona, New Mexico, and parts of Texas and
California, possesses venom potent enough to cause systemic toxicity.[7]
Scorpions most often sting humans in the extremities, frequently after hiding in shoes or other
clothing.[7][8][23] Children represent about half of all envenomations, and the vast majority of serious
reactions occur in children 10 years of age or younger.[7][14][22]


PATHOPHYSIOLOGY
Scorpion venom contains several distinct and pharmacologically active protein components. Venom from
most Buthidae act at ion channels on neurons, precipitating massive release of
neurotransmitters.[6][10][13][17][18] After envenomation by Centruroides, for example, significant
parasympathetic stimulation may lead to contraction of visceral smooth muscle, resulting in clinical effects
such as micturition, defecation, and priapism.[18] The yellow scorpion, Leiurus quinquestriatus, found in
Middle Eastern countries, and other members of the Buthidae found in other parts of the world are reported
to cause the release of enormous amounts of catecholamines, precipitating a hyperadrenergic reaction
characterized by hypertension, myocardial injury, dysrhythmias, pulmonary edema, severe hypertension,
and possibly death.[18][22] The North African genus Androctonus, one of the most venomous of that region, is
often reported to cause death in infants and young children from a similar hyperadrenergic syndrome.[1]
Hypotension and shock often follow the hyperadrenergic state and are thought to result from neuronal and
adrenal catecholamine depletion.[12]
Most scorpions found in the United States cause little more than localized pain similar to that seen after
Hymenoptera envenomation. Centruroides exilicauda venom, however, contains at least two types of
neurotoxins, differentiated by their effects on axonal membranes.[15] The first group maintains the sodium
channel in an ion-conducting state by causing incomplete sodium channel inactivation during
depolarization.[24] The effects of these toxins, sometimes referred to as “stabilizers,” is a widening of the
action potential.[24] The second group of neurotoxins initiates a slowly developing inward sodium current
after membrane repolarization. Together, these toxins widen the action potential and enhance membrane
depolarization, causing repetitive firing of axons.[15] All excitable membranes using sodium channels and
undergoing depolarization are susceptible to this toxic effect.
Envenomation from Tityus (found throughout South America), Leiurus, and other Buthidae frequently cause
pulmonary edema from both cardiac and noncardiac factors, again believed to be related to excess
cholinergic and adrenergic stimulation.[1][2][9][11][12] Proposed causes of the pulmonary edema include rapid
increases in peripheral vascular resistance,[13] dysrhythmias,[10] and direct venom-induced depressions in
myocardial contractility.[9][12]
Some scorpion species may cause other specific organ damage after envenomation. Tityus trinitatis, found
in Trinidad and Venezuela, is reported to cause acute pancreatitis in up to 60 per cent of victims.[18] Tissue
destruction, notably absent from most scorpion stings owing to a lack of proteolytic enzymes, can be
produced along with bleeding disorders and hemolysis by Hemiscorpius lepturus and related species found
in the Middle East.[18]


Symptoms occurring after a Centruroides sting can be pronounced and extremely variable ( Table 113–1
). [7][8][14][21]
Table 113-1 -- Clinical Signs and Grading of Envenomation by Centruroides exilicauda

Grade Description
I Local pain or paresthesias at the site of envenomation
Local pain or paresthesias at the site of envenomation accompanied by pain or paresthesias remote
II
from the site
Either cranial nerve or peripheral skeletal neuromuscular dysfunction:
1. Cranial nerve dysfunction such as blurred vision, irregular eye movements, difficulty swallowing,
tongue fasciculations, slurred speech, and occasional upper airway incoordination (especially in
III
children)
2. Peripheral skeletal neuromuscular dysfunction such as jerking of extremities, restlessness, severe
involuntary shaking, and jerking that may be mistaken for seizures
IV Both cranial nerve and peripheral skeletal neuromuscular dysfunction
Adapted with permission from Curry SC, Vance MV, Ryan PJ, et al: Envenomation by the scorpion Centruroides
sculpturatus. J Toxicol Clin Toxicol 1983; 21:417–449. Reprinted by courtesy of Marcel Dekker, Inc.
Sting
Like most scorpions in this country, localized pain and tingling of the stung extremity is the initial complaint
and typically the most common symptom in adults stung by C. exilicauda. Infants may present with
unexplained crying. Because cytotoxicity or inflammation does not occur from Centruroides venom, the
exact site of the sting may not be readily apparent. Symptoms occur immediately and usually resolve over 6
to 12 hours but may persist for up to 24 hours or more.[7]
Systemic Symptoms
Neither children nor adults suffer altered mentation from C. exilicauda envenomation, but both sympathetic
and parasympathetic nervous system stimulation regularly occur in severely envenomated children.[7][18]
Within 1 to 2 hours, infants may demonstrate parasympathetic excitation leading to excessive salivation,
vomiting, and lacrimation, at the same time as sympathetically mediated tachycardia, diaphoresis, and
mydriasis.[7][14][18][20][21]
In more severe cases of C. exilicauda envenomation, both cranial and peripheral neuromuscular junctions
may be affected. [7] Cranial nerve dysfunction may produce blurred vision, slurred speech, tongue
fasciculations, drooling, and poor airway control (especially in infants).[5][7][8][14][21] Abnormal eye
movements, described as involuntary, conjugate, slow, and roving are common, but intermittent
disconjugancy and nystagmus are also reported.[5] Somatic neuromuscular dysfunction may begin as
restlessness, with the victim unable to lie still, and progress to uncontrollable fasciculations and jerking of
the extremities that resembles a seizure.[7] Opisthotonos and hemiballistic movements can occur.


Unless the culprit is seen, the diagnosis of scorpion envenomation can be difficult to recognize. There are
very few clinical aspects of even severe stings that cannot be mistaken for other etiologies ( Table 113–2 ).
Multiple neurologic disorders such as encephalitis, meningitis, tetanus, and cerebrovascular accidents can
present similarly. In addition, sepsis from any source can be accompanied by sympathetic and
parasympathetic stimulation seen with envenomations by C. exilicauda and other species. These autonomic
manifestations can also resemble poisonings from a variety of sympathomimetic and parasympathomimetic
agents. In this country, one of the few differentiating characteristics identified in severe C. exilicauda stings
is the presence of abnormal eye movements. Children with disconjugate gaze, severe nystagmus, or
inability to focus both eyes in the same plane of vision should be suspected of suffering a C. exilicauda
envenomation if residing in the southwestern United States and the rest of the clinical examination is
compatible with this diagnosis.[5] Fortunately, most scorpion stings in this country exhibit only self-limited
localized pain that both resembles and can be managed like a Hymenoptera envenomation.
Table 113-2 -- Differential Diagnosis of Clinical Signs and Symptoms Associated with a Scorpion Sting
Toxins/Drugs Other Disorders
Dystonic reaction to medication Seizures of other etiology
Hymenoptera envenomation Pulmonary edema of other etiology
Lactrodectus envenomation Pancreatitis of other etiology
Sympathomimetic (e.g., cocaine, amphetamine) Cerebrovascular accident
poisoning
Phencyclidine Diseases with cranial nerve dysfunction (multiple sclerosis,
myasthenia gravis, botulism)
Organophosphates/carbamates Infections
Strychnine Sepsis
Withdrawal sedative/hypnotic or ethanol Tetanus
Meningitis
Encephalitis


LABORATORY STUDIES
No laboratory evaluation is uniformly helpful in the diagnosis or management of scorpion envenomation.

Respiratory status can be followed with a pulse oximeter. In severe envenomations by scorpions from Asia,
Africa, or South America, coagulation studies, chemistry tests to evaluate for pancreatitis, and a chest
radiograph to screen for pulmonary edema can be obtained.


TREATMENT
Initial
Treatment of scorpion envenomation should begin by application of ice or a cold compress to the sting site (
Table 113–3 ). Most cases of scorpion envenomation in North America can be successfully observed at
home. Significantly symptomatic individuals, especially children, should be referred to a health care facility
for evaluation.
Table 113-3 -- General Management of Scorpion Sting

1. Provide airway management when indicated.
2. Apply cool compress or ice intermittently to site.
3. Administer oral analgesics such as nonsteroidal anti-inflammatory agents or codeine for mild
envenomations.
4. Give tetanus toxoid as needed.
5. Provide intravenous hydration as needed.
6. Administer anxiolytics such as benzodiazepines for severe agitation or fasciculations.
7. Administer parenteral opioids such as morphine or fentanyl for pain in moderate or severe envenomations.
8. Admit to hospital for most severe envenomations in a monitored setting for at least 24 hours of observation
because symptoms can be delayed.
9. Implement invasive cardiac monitoring (Swan-Ganz catheter) for victims with cardiac dysfunction or
pulmonary edema.
10. Administer vasodilators (nifedipine, nitroprusside), if needed, for severe hypertension.
11. Administer diuretics, dobutamine, and aggressive ventilatory support for pulmonary edema.
12. Where available, consider species-specific antivenom for moderate to severe envenomations by Buthidae
scorpions (including severe Centruroides exilicauda stings in North America). One to two vials should be diluted
in 100 mL of saline and infused over 30 minutes. Skin testing is required before infusion. Dosing can be
repeated in severe or refractory cases. Alternative causes should be considered in individuals who do not
respond to two vials of antivenom.
Severe Envenomations
Severely stung patients, especially children, should be placed on a cardiac monitor with frequent blood
pressure measurements. Sedatives such as benzodiazepines or barbiturates can be administered to help
reduce the anxiety and muscle fasciculations accompanying severe envenomations but should be used
sparingly in individuals whose airway control or function is in doubt. The mainstay of therapy for severe
scorpion envenomation consists of liberal use of analgesics and, when indicated and available, species-
specific antivenoms. Oral anti-inflammatory agents or opioids can be tried, but parenterally administered
analgesics such as morphine or fentanyl may be required for pain relief. Antihistamines such as
diphenhydramine, corticosteroids, and calcium have all been suggested treatment for the varied symptoms
of C. exilicauda envenomation but have never been found to be particularly useful.[7]
Antivenom
In the United States, a Centruroides-specific antivenom is available only in Arizona and is produced from
goat serum. This treatment should be reserved for severely symptomatic individuals, such as those with
intractable pain or agitation or those in whom airway stability is questionable, especially children. This
antivenom should not be used in patients with allergies to goats or in individuals with multiple medical or
environmental allergies. Skin testing, performed by subcutaneously injecting 0.1 mL of the antivenom and
observing for a wheal and flare reaction, is required before antivenom administration, but a negative test
does not absolutely eliminate the possibility of an allergic reaction. The antivenom can be diluted in 100 mL
of saline and infused over 30 minutes. One vial is usually sufficient to permanently relieve symptoms within
1 to 3 hours of infusion. [4][7][8] A second vial may be administered if there is no effect after the first, but
alternate causes for the pain and symptoms should be sought if relief is not obtained after the second vial.


DISPOSITION
Patients exhibiting symptoms of severe scorpion envenomation such as intractable pain requiring frequent
parenteral analgesics or those with significant autonomic findings should be admitted to the hospital. Most
pediatric cases of scorpion stings should be observed by health care providers until symptoms have
diminished or resolved because infants are more prone to airway compromise. Individuals with mild to
moderate pain resulting from envenomations by most varieties of scorpions found in the United States can
be managed at home with over-the-counter analgesics.
Many patients can be discharged after 2 or 3 hours of observation following successful relief of pain with
Centruroides antivenom,[4] but they should be warned about the possibility of goat serum allergy in the
future, as well as the frequent occurrence of delayed hypersensitivity or serum sickness.


SEQUELAE
Delayed hypersensitivity after Centruroides antivenom can occur in up to 60 per cent of cases, and most
often results in pruritic rash, myalgias, and arthralgias up to 14 days after the infusion.[4] Symptoms can be
effectively treated with antihistamines and corticosteroids. No other long-term sequelae are expected after
envenomation by North American varieties of scorpions.


SPECIFIC SITUATIONS
Antivenoms are available for severe cases of envenomation in countries where Buthidae are
endemic.[4][8][18][23] Even individuals who receive adequate antivenom dosing after severe envenomations by
Leiurus, Androctonus, and Tityus scorpions can develop life-threatening cardiac and pulmonary symptoms
that can be delayed several hours.[23] Significant envenomations by these scorpions should therefore be
admitted to a monitored hospital bed for at least 24 hours of observation. Atropine can be used when
cholinergic signs and symptoms predominate. Vasodilators such as nifedipine and nitroprusside have been
used successfully to treat the hypertension after envenomation by species such as L. quinquestriatus.[3][22]
Pulmonary edema from cardiac origin may respond to treatment with diuretics or dobutamine, whereas
those cases exhibiting noncardiogenic pulmonary edema should receive aggressive ventilatory support with
positive end-expiratory pressure.


REFERENCES
1. Abroug F, Boujdaria R, Belghith M, et al: Cardiac dysfunction and pulmonary edema following scorpion
envenomation. Chest 1991; 100:1057-1059.
2. Amaral CFS, de Rezende NA, Freire-Maia L: Acute pulmonary edema after Tityus serrulatus scorpion
sting in children. Am J Cardiol 1992; 71:242-245.
3. Bawasker HS, Bawasker PH: Stings by red scorpions (Buthotus tamulus) in Maharashtra state of India: A
clinical study. Trans R Soc Trop Med Hyg 1989; 83:858-860.
4. Bond GR: Antivenom administration for Centruroides scorpion sting: Risks and benefits. Ann Emerg
Med 1992; 21:788-791.
5. Clark RF, Selden BS, Kunkel DB, Frost MD: Abnormal eye movements encountered following severe
envenomation by Centruroides sculpturatus.. Neurology 1991; 41:604.
6. Corrado AP, Antonio A, Diniz CR: Brazilian scorpion venom—an unusual sympathetic postganglionic
stimulant. J Pharmacol Exp Ther 1978; 164:254-258.
7. Curry SC, Vance MV, Ryan PJ, et al: Envenomation by the scorpion Centruroides sculpturatus.. J
8. Gateau T, Bloom M, Clark RF: Response to specific Centruroides sculpturatus antivenom in 151 cases of
scorpion stings. Clin Toxicol 1994; 32:165-171.
9. Grupp G, Grupp IL, Gueron M, et al: Effects of the venom of the yellow scorpion (Leiurus quinquestriatus)
on the isolated work-performing guinea pig heart. Toxicon 1980; 18:261-270.
10. Gueron M, Yarom R: Cardiovascular manifestations of severe scorpion sting. Chest 1970; 57:156-
162.
11. Gueron M, Adolph RJ, Grupp IL, et al: Hemodynamic and myocardial consequences of scorpion venom.
Am J Cardiol 1980; 45:979-986.
12. Gueron M, Ovsyshcher I: What is the treatment for cardiovascular manifestations of scorpion
envenomation?. Toxicon 1987; 25:121-124.
13. Gueron M, Reuben I, Sofer S: The cardiovascular system after scorpion envenomation. J Toxicol Clin
Toxicol 1992; 30:215-258.
14. Likes K, Banner W, Chavez M: Centruroides exilicauda envenomation in Arizona. West J

Med 1984; 141:634-637.
15. Meves H, Rubly N, Watt DD: Effects of toxins isolated from the venom of the scorpion Centruroides
sculpturatus on the Na currents of the node of Ranvier. Pflugers Arch 1982; 393:56-62.
16. Minton SA: Venom Diseases, Springfield, IL: Charles C Thomas; 1974:27-37.
17. Moss J, Razic T, Henry DP, Ropin IJ: Scorpion venom–induced discharge of catecholamine
accompanied by hypertension. Brain Res 1973; 54:381-385.
18. Peters W: A Colour Atlas of Arthropods in Medicine, London: Wolfe Publishing; 1992:227-235.
19. Polis GA: The Biology of Scorpions, Stanford, CA: Stanford University Press; 1990:1-9.
20. Rachesky IJ, Banner W, Dansky J, Tong T: Treatments for Centruroides exilicauda envenomation. Am
J Dis Child 1984; 138:1136-1139.
21. Rimsza ME, Zimmerman DR, Bergeson PS: Scorpion envenomation. Pediatrics 1980; 66:298-301.
22. Sofer S, Gueron M: Vasodilators and hypertensive encephalopathy following scorpion envenomation in
children. Chest 1990; 97:118-120.
23. Sofer S, Shahak E, Gueron M: Scorpion envenomation and antivenom therapy. J

Pediatr 1994; 124:973-978.
24. Wang GK, Strichartz GR: Purification and physiological characterization of neurotoxins from venoms of
the scorpions Centruroides sculpturatus and Leiurus quinquestriatus.. Mol Pharmacol 1983; 23:519-533.


Chapter 114 – Hymenoptera
WILLIAM J. MEGGS
Essentials
Anaphylaxis to Hymenoptera Envenomation
• History of envenomation
• Tachycardia, hypotension, rarely dysrhythmias and myocardial infarction
• Bronchospasm, tachypnea, hypoxia, bronchorrhea, upper airway obstruction from angioedema
including involvement of tongue and larynx
• Warm flushed skin, urticaria, pruritus, erythema, and pain at site
• Nausea, vomiting, diarrhea, bloating, abdominal pain
Toxic Envenomation
• Multiple stings (50 to 1000 stings common) by many insects
• Pain, edema, and erythema in the areas of envenomation
• Dizziness, malaise, fatigue, and abdominal and muscle pain
INTRODUCTION
Hymenoptera are an order of stinging insects whose venom produces pain and stinging at the site of
injection. Hypersensitivity reactions can produce immediate and severe illness from envenomation by a
single insect, but they require prior sensitization. Toxic envenomations occur with massive envenomations
from multiple stings and are caused by the toxic effects of the venom. A single sting is not sufficient to
produce a systemic toxic reaction. Both toxic and allergic envenomations can be fatal. Over 16,000 stings by
bees, wasps, and hornets are reported to poison centers annually, and approximately 10 per cent require
treatment in a health care facility. About 3000 ant or fire ant stings are reported, of which 300 require
treatment in a health care facility Fortunately, deaths are uncommon.[6]
More than 100,000 species of hymenoptera exist, including honey bees, wasps, yellow jackets, and hornets,
which are the North American vespid species associated with hypersensitivity reactions. Native ants are
rarely, if ever, associated with hypersensitivity. Two non-native fire ant species, Solenopsis invicta and S.
richteri, have spread throughout the southern United States over the past decades and cause anaphylaxis in
sensitized individuals. The Africanized honey bee, or killer bee, is a hybrid of Western and African species.
The bees are progressively moving northward into the southern United States, are known to attack in
swarms, and can produce systemic toxic reactions from multiple stings.


PATHOPHYSIOLOGY
Hypersensitivity Reactions
Hymenoptera venoms contain protein enzymes such as phospholipase and hyaluronidase which can be
immunogenic. If the innoculation by a sting leads to an immune response in which IgE antibody is
manufactured, the individual becomes sensitized. After inoculation, several days are required before
sufficient antibody is manufactured to produce a clinical reaction to subsequent stings. IgE antibodies bind
with high affinity to the surface of mast cells located in tissues. The venom injected in a subsequent sting
binds to IgE molecules on the mast cell surfaces. A cascade of events begins with the release of histamine
and other mediators. Histamine binds to blood vessels, producing vasodilatation and leakage of fluid into the
tissues. Clinically, erythema, angioedema, and urticaria are observed. Histamine binds to sensory nerve
fibers to produce pruritus as well as the release of neuropeptides. It is thought that systemic reactions arise
from a process called neurogenic switching.[11] The central nervous system reroutes the nerve impulses to
other parts of the body, where substance P and other neuropeptides are released from nerve endings.
Substance P binds mast cell receptors to trigger mast cell degranulation. Support for this concept comes
from animal studies, which have shown that systemic anaphylaxis can be ablated by neuronal lesions.[7][16]
The mast cell mediators and neuropeptides produce clinical signs and symptoms by binding to effector cells
such as endothelial, mucus-secreting, and smooth muscle cells. For example, binding to bronchial smooth
muscle cells produces bronchospasm and wheezing. Hypoxia arises from bronchospasm, bronchorrhea,
and upper airway obstruction. Both vasodilation and leakage of fluid from the vasculature lead to
hypotension and shock. Tachycardia compensates for loss of intravascular volume and hypoxia. The direct
effect of mediators on the heart also produces tachydysrhythmias. [11] Cerebral edema and hemorrhage also
occur.[1]
Mast cells release chemotactic factors for neutrophils and eosinophils. These cells are recruited to areas of
anaphylaxis and release factors that degranulate mast cells, leading to a recurrence of the allergic
symptoms, called a late phase reaction. Late phase reactions occur between 4 and 8 hours after the initial
reaction and have been demonstrated experimentally for both asthma and urticaria.
Toxic Envenomations
Bee venom contains a complex mixture of toxins, including vasoactive amines, mellitin, hyaluronidase, and
acid phosphatase. Africanized and Western honey bee venoms are of comparable toxicity. The increased
danger of Africanized bees is their predilection to attack in mass, so that victims may experience a thousand
or more stings. Initial symptoms resembling anaphylaxis can result from the vasoactive amines present in
venom. In high doses venom is directly toxic to many tissues, with manifestations of hypotension, histamine
release, hemolysis, cellular toxicity, and neurotoxicity.
Serum sickness is caused by circulating immune complexes. Immune complexes are large particles that
form when many antigen molecules are linked together by antibody molecules. Formation of immune
complexes occurs when the numbers of antibody molecules and antigen molecules are approximately equal.
When there is a large excess of either kind of molecule, immune complexes will not form. Circulating
immune complexes cause pyrogenic reactions, vasculitis, and glomerulonephritis.


Anaphylaxis to insect stings most commonly occurs within minutes of the sting, and deaths occur within the
first hour.[1] The victim experiences an immediate stinging sensation followed by local pain, redness, and
swelling. The insect is usually seen and can be described, but stings do occur in locations difficult to observe
and the insect may not be identified. A stinging sensation is felt at the site of the sting. Prodromal symptoms
of an anaphylactic reaction include a metallic taste in the mouth, a feeling of impending doom, and pruritus
that is sometimes localized to the groin. Anaphylaxis affects multiple organ systems, but in a given attack,
not all systems may be affected ( Table 114–1 ).
Table 114-1 -- Clinical Presentation of Hymenoptera Envenomation (Hypersensitivity Reactions)

Prodromal:
Pruritus
Metallic taste
Feeling of impending doom
Vital signs:
Tachycardia
Tachypnea
Hypotension
Dermatologic:
Flushing
Warmth
Urticaria
Edema
Respiratory:
Wheezing, bronchospasm
Bronchorrhea
Cough
Laryngeal edema
Angioedema of tongue, upper airway
Hypoxia
Cardiovascular:
Syncope
Tachydysrhythmias
Electrocardiographic changes: ST segment and T wave changes
Abdominal:
Nausea
Vomiting
Diarrhea
Bloating
Crampy pain
Vital signs may show a rapid pulse and respiratory rate. Tachycardia may be primary, as a direct effect of
allergic mediators on the heart, or secondary to hypotension or hypoxia. Blood pressure may be normal or
low. The skin becomes flushed and warm, and palpable urticarial lesions may or may not develop. There is
a sensation of dyspnea, and bronchospasm may be heard on auscultation of the chest. Respiratory
secretions can be copious, and coughing ensues. Upper airway swelling can be remarkable and in some
cases fatal. There may be laryngeal edema and edema of the soft tissues of the upper airway. The tongue
may become swollen to the point that the mouth cannot be closed. Myocardial infarction has been reported
in patients with normal coronary arteries.[4][10][16] Nausea, vomiting, diarrhea, and abdominal bloating can
develop, and there may be crampy abdominal pain. The time to onset of symptoms is variable but typically
occurs within minutes of envenomation and rarely occurs more than 30 minutes after envenomation.
The vast majority of patients will not develop anaphylaxis but will have a limited local reaction of pain, local
swelling, mild pruritus, and erythema. These reactions can be problematic if they occur in the mouth, tongue,
or throat where they can cause rapid airway obstruction. Hymenoptera can settle inside beverage containers
or on food and are apt to sting when eaten.
Toxic Envenomations
There are several cases of toxic reactions to massive envenomations[5][6][13][17]( Table 114–2 ). Victims
experience pain, swelling, and erythema at sites of envenomation. Early symptoms can be similar to a
hypersensitivity reaction, due to vasoactive amines in bee venom. Systemic symptoms of malaise and
dizziness may be present. Blood pressure response is variable, with hypotension and hypertension. Normal
to mildly elevated pulse rate may occur. Hemolysis and rhabdomyolysis develop after 24–48 hours, followed
by renal failure.[2][3][6][15] Dialysis may be required until renal failure resolves, which may take 2 weeks or
longer. Myocardial and hepatocellular necrosis[6] have been reported in fatal cases. Clinical course has been
complicated by thrombocytopenia, disseminated intravascular coagulopathy, and massive hemolysis. [17]
Coma and encephalopathy have been reported. [17] Cardiac findings of wandering atrial pacemaker,
junctional rhythm, and premature ventricular contractions have occurred following multiple stings with no
evidence of anaphylaxis.[13] Multiple hymenoptera stings have been fatal.[2]
Table 114-2 -- Clinical Presentation of Toxic Envenomations

Neurologic:
Coma
Vital signs:
Tachycardia
Tachypnea
Hypotension (early)
Hypertension (late)
Dermatologic:
Pain
Erythema
Edema
Respiratory:
Acute respiratory distress syndrome
Cardiovascular:
Atrial fibrillation
Sinus tachycardia
Ventricular tachycardia
Syncope
Tachydysrhythmias
Myocardial necrosis
Electrocardiographic changes with T wave inversions and ST segment elevations
Abdominal:
Nausea
Vomiting
Hepatic failure
Renal failure
Hematologic:
Hemolytic anemia
Thrombocytopenia
Disseminated intravascular coagulopathy


A history of symptoms in association with a bee sting limits the differential diagnosis. Sometimes patients
present with severe anaphylaxis in extremis, with no history of envenomation. All causes of acute shock
must be considered ( Table 114–3 ). The presence of a sting site can aid in the diagnosis. Warm flushed
skin helps differentiate anaphylactic shock from other forms of shock. Urticarial lesions, if present, and
angioedema of the face, with swelling and puffiness around the eyes, are often a key to the diagnosis.
Table 114-3 -- Differential Diagnosis of Venom Anaphylaxis

Capillary leak syndrome
Cardiogenic shock
Dehydration
Hemorrhagic shock
Hereditary angioedema
Massive pulmonary embolism
Septic shock
Systemic mastocytosis
Tension pneumothorax
Urticaria pigmentosa
Capillary leak syndrome is an idiopathic condition in which recurrent acute leakage of plasma between gaps
in capillary endothelial cells leads to shock and cardiovascular collapse. The findings of flushed skin,
urticaria, bronchospasm, and gastrointestinal symptoms characteristic of anaphylaxis are not present in
capillary leak syndrome. Unlike anaphylaxis, attacks seem to arise spontaneously without ingestion of a
food, drug, or envenomation that initiates anaphylaxis.
Cardiogenic shock usually occurs in the setting of an acute myocardial infarction, with chest pain and
variable associated symptoms such as diaphoresis, pain radiating into the arm, and dyspnea. If a myocardial
infarction is severe enough to produce shock, the electrocardiogram should be diagnostic. However,
myocardial infarction has occurred secondary to anaphylactic shock.
Urticaria pigmentosa is a skin disease with focal salmon-colored to brown macules that produce a wheal-
and-flare reaction when stroked. Biopsy of these lesions shows abnormally high numbers of mast cells.
Patients with urticaria pigmentosa can have acute episodes of mast cell degranulation that are clinically
indistinguishable from allergic anaphylaxis.
Systemic mastocytosis is a disease with increased mast cells throughout the body, including bone marrow,
lymph nodes, spleen, and liver, with or without urticaria pigmentosa. These patients may also have acute
reactions similar to allergic anaphylaxis, and should be treated as for anaphylaxis.
Hypovolemic shock due to hemorrhage or dehydration can be differentiated by the history, laboratory
findings of anemia or elevated blood urea nitrogen (BUN) and creatinine, evidence of bleeding or
dehydration on physical examination, and absence of signs and symptoms associated with anaphylaxis.
Acute massive pulmonary embolism, with sudden onset of tachypnea, tachycardia, hypoxia, and
hypotension, is often difficult to diagnosis at the bedside. Risk factors for pulmonary embolism include
immobilization of an extremity; recent prostate, hip, or other surgery; inactivity; hypercoagulability; and travel
in a confined vehicle.
Toxic Envenomation
The hundreds of bee stings experienced by victims of toxic envenomation limit the differential diagnosis and
make the diagnosis by history straightforward.


LABORATORY STUDIES
Acute anaphylaxis is a clinical diagnosis, and there are no confirmatory laboratory tests. There is a brief
transient rise in plasma histamine levels with acute allergic reactions, but these changes are not helpful in
the clinical setting. The presence of IgE antibody to specific vespid species can be determined by skin
testing or radioallergic sorbent testing (RAST). Though not of immediate benefit, these tests are helpful to
guide preventive therapy.
Toxic Envenomations
Routine laboratory tests are generally normal on presentation but a number of laboratory abnormalities
develop over a few days. Urine may turn red from hemoglobinuria and may test positive for blood on dipstick
analysis. Both free and conjugated bilirubin rise. Red blood cell and platelet counts fall, while creatinine
phosphokinase and myoglobin rise. Coagulation profiles should be followed, as disseminated intravascular
coagulation (DIC) has been reported and may require treatment. BUN and creatinine rise to a plateau after 1
week, then begin falling after 2 weeks. Urine output may decrease after 2 to 3 days, with return of normal
urine flow after 2 to 3 weeks.


The airway may be compromised by angioedema and secretions. Endotracheal intubation or surgical
creation of an airway may be necessary and should be performed early, before swelling obliterates the
airway lumen. Ventilatory effort is usually strong, with tachypnea, so mechanical ventilation is necessary
only in extremis. Hypotension and cardiac arrest may require chest compressions. Oxygen should be given,
and two large-bore intravenous (IV) lines should be established. Bolus infusions of normal saline or lactated
Ringer’s solution should be given for hypotension. Epinephrine 1:1000 at doses of 0.01 mg/kg up to 0.5 mg,
should be administered subcutaneously as soon as possible, ideally before arrival at the hospital.
Epinephrine can be repeated every 15 minutes until symptoms resolve. Intravenous epinephrine is reserved
for patients in extremis because it has been associated with ventricular tachycardia and fibrillation. If the
patient suffers a cardiac arrest, epinephrine 1:10,000 should be given by ACLS protocol, in 1 mg IV boluses
every 3–5 minutes. Epinephrine 1:10,000 may be administered endotracheally. Both H1 and H2
antihistamines should be administered IV or IM, pending establishment of an IV line. Diphenhydramine 1
mg/kg up to 50 mg or hydroxyzine 0.5 mg/kg up to 50 mg are suitable H1 antihistamines. Cimetidine 300 mg
IV should be given as an H2 antihistamine. A corticosteroid should be administered, such as
methylprednisolone 1–2 mg/kg up to 125 mg. Stingers attached to the victim’s skin should be removed.
Some authorities recommend avoiding compression of the gland by sliding a plastic card parallel to and
along the skin surface to remove the stinger. Corticosteroids and cromolyn block late-phase reactions.
Table 114-4 -- Treatment Essentials for Hymenoptera Envenomation

Hypersensitivity reactions:
Intubate and ventilate as needed
Oxygen 100%
IV fluids: normal saline or lactated Ringer’s solution for blood pressure support
Pressors: 1:1000 epinephrine 0.01 mg/kg subcutaneous or endotracheal (1:10,000 epinephrine 0.01 mg/kg IV
if patient is in extremis)
H1 antihistamine: diphenhydramine 1 mg/kg up to 50 mg IV
H2 antihistamine: cimetidine 300 mg IV in adults
Corticosteroids: methylprednisolone 1–2 mg/kg up to 125 mg in adults, IV
Remove stingers attached to the skin
Admit to ICU for severe envenomation
If discharged, 3 day course of H 1 antihistamine and prednisone
Self-administered epinephrine available at all times
Avoidance of high-risk situations:
Walking barefoot outside
Wearing brightly colored clothes or perfumes
Walking in orchards and flower gardens
Referral to allergist for desensitization injections
Toxic envenomations:
Supportive care
IV fluids
Analgesics
Antiemetics
Treatment for hemolytic anemia, hepatic failure, renal failure, myocardial failure, rhabdomyolysis, DIC as
needed
Remove stingers attached to the skin
Patients who present to the emergency department 1–2 days after an insect sting with marked local
inflammation, and sometimes massive angioedema at the site of envenomation, can be treated
symptomatically with analgesics and H1 antihistamines.
Patients who present immediately after a sting with minor local symptoms of burning, itching, and erythema
and no history of anaphylaxis can be discharged after 1 hour of observation. Patients with severe local
reactions are not at risk for anaphylaxis from subsequent stings and do not need to be referred to an allergist
for desensitization. Symptomatic treatment with ice, antihistamines, analgesics, and elevation of the
extremity is helpful.
Toxic Envenomations
Immediate supportive care is given, including intravenous hydration, analgesics, and antiemetics. The
patient should be monitored for hemolytic anemia, which may require blood transfusions. Intravenous
sodium bicarbonate should be used to alkalinize an acidic urine if rhabdomyolysis develops. Because anuria
can develop, fluid status should be monitored closely. Monitoring of renal function and electrolytes is
essential, and peritoneal dialysis or hemodialysis may be necessary. There is no antidote or antivenom
available for toxic envenomations to bees.


DISPOSITION
Patients with mild anaphylactic reactions that resolve after treatment can be discharged with H 1
antihistamines such as diphenhydramine 1 mg/kg up to 50 mg three times a day for 3 days and a short
course of corticosteroids such as prednisone 1 mg/kg every morning for 3 days. Patients with moderate and
severe reactions should be admitted to the hospital for 24 hours, to a monitored bed or intensive care unit,
depending on their clinical condition. Patients who experience anaphylaxis should be given two doses of
self-administered epinephrine, either an Epi-Pen or Anakit, and instructed on its use. They should be
instructed to keep one kit at home and one in the car.
Prevention of future reactions is important. Patients should be instructed about ways of minimizing the risk of
further stings, such as not walking barefoot outside, avoiding orchards and flower gardens, and not wearing
bright flowery clothing and perfumes outside. Every person who has an anaphylactic reaction to an
envenomation should be referred to an allergist for desensitization, which has been proved in rigorous
double-blind studies to prevent allergic reactions to subsequent envenomations.
Toxic Envenomations
All patients with toxic envenomations should be monitored in the intensive care unit for the development of
hemolytic anemia, rhabdomyolysis, renal failure, myocardial infarction, liver failure, and disseminated
intravascular coagulopathy.


SEQUELAE
Acute sequelae of anaphylaxis to bee stings have included myocardial infarction in patients subsequently
shown to have normal coronary arteries at angiography.[4][16] Electrocardiographic abnormalities have been
identified in patients who had electrocardiograms performed before the development of hypotension or the
administration of medications such as epinephrine that could potentially alter electrocardiograms. Acute
tubular necrosis can result from hypotension. Anoxic encephalopathy and adult respiratory distress
syndrome occur in severe cases with shock.
Toxic Envenomations
Patients with severe toxic envenomations can recover without chronic sequelae following successful
treatment for rhabdomyolysis, hemolytic anemia, disseminated intravascular coagulation, and renal failure.


REFERENCES
1. Barnard JH: Studies of 400 hymenoptera sting disease in the United States. J Allergy Clin
Immunol 1973; 52:259.
2. Barss P: Renal failure and death after multiple stings in Papua New Guinea. Ecology, prevention and
management of attacks by vespid wasps. Med J Aust 1989; 151:659.
3. Chugh KS, Sharma BK, Singhal PC: Acute renal failure following hornet stings. J Trop Med
Hyg 1976; 79:42.
4. Engrav MB, Zimmerman M: Electrocardiographic changes associated with anaphylaxis in a patient with
normal coronary arteries. West J Med 1994; 161:602.
5. Hoffman DR: Hymenoptera venom proteins. Adv Exp Med Biol 1996; 391:169.
6. Huang CC, Au C, Chen L, et al: Acute renal failure and hepatic injury following multiple wasp
stings—report of 2 cases. J Formosan Med Assoc 1983; 82:623.
7. Litovitz TL, Smilkstein M, Felbeg L, et al: 1996 Annual Report of the American Association of Poison
10. Levine HD: Acute myocardial infarction following wasp sting Report of two cases and critical survey of
the literature. Am Heart J 1976; 91:365.
11. Meggs WJ: Neurogenic switching: A hypotheses for a mechanism for shifting the site of inflammation in
allergy and chemical sensitivity. Environ Health Perspect 1995; 103:54.
13. Rowe SF, Greer KE, Hodge Jr RH: Electrocardiographic changes associated with multiple yellow jacket
stings. Southern Med J 1979; 72:483.
15. Sakhuja V, Bhalla A, Pereira BJ, et al: Acute renal failure following multiple hornet stings.
Nephron 1988; 49:319.
16. Wagdi P, Mehan VK, Burgi H, et al: Acute myocardial infarction after wasp sting in a patient with normal
coronary arteries. Am Heart J 1994; 128:820.
17. Weizman Z, Mussafi H, Ishay JS, et al: Multiple hornet stings with features of Reyes syndrome.


Uncited references
Levy RM, Rose JE, Johnson JS: Effect of vagotomy on anaphylaxis in rat. Clin Exp Immunol 1976; 24:96.
Leslie CA, Mathe AA: Modification of guinea pig lung anaphylaxis by central nervous system (CNS)
perturbations. J Allergy Clin Immunol 1989; 83:94.
Regal JF, Heller LJ: Cardiac anaphylaxis in isolated guinea pig hearts perfused at constant flow or constant
pressure. Proc Soc Exp Biol Med 1987; 185:193.
Saff R, Nahhas A, Fink JN: Myocardial infarction induced by coronary vasopasm after self-administration of
epinephrine. Ann Allergy 1993; 70:396.


Chapter 115 – Mushrooms
SANDRA M. SCHNEIDER
Essentials
• Gastrointestinal (GI) toxicity that begins within 2 hours of ingestion of a mushroom is almost always self-
limited and benign. GI toxicity that begins more than 5 hours after ingestion may be associated with
severe hepatic or renal dysfunction.
• Amanita species appear in the fall in the Northern Hemisphere. Gyromitra occurs primarily in the spring.
• Never assume that identified mushroom samples are the only ingestants as many foragers mix
mushroom species. When in doubt, believe the patient’s symptoms.
• A disulfiram-type reaction may occur upon consuming alcohol 2–72 hours after the Coprinus mushroom
has been ingested.
EPIDEMIOLOGY
There were 10,477 mushroom exposures reported to poison centers in 1997. Ninety per cent of these
ingestions were inadvertant, with eighty-five per cent occurring in children. Significant toxicity was rare, with
only 0.3 per cent of patients experiencing a major effect, including two deaths.[34a]


PHYSICAL DESCRIPTION
Mushrooms are fungi. The body of a fungus is a dense network of branching filaments called a mycelium. In
the case of the mushroom, the mycelium is largely underground. The visible part of the mushroom is the
fruiting body which contains spores that propagate the species. When two spores of compatible strains
germinate in close proximity their hyphae merge and form a mycelium that produces its own set of
mushrooms. Because of their connection with the mycelium, mushrooms frequently grow in rings.
Accurate description of the characteristic parts of a mushroom facilitates identification. Figures 115–1 and
115–2 show some of the characteristics of the poisonous species Amanita. Important identifying
characteristics include size, color, and shape of the cap, the presence of gills, and whether those gills extend
to the stem. The stem may contain a ring. The stem may widen or taper as it enters the soil, and there may
be a cup, or volva, at its termination. Mushrooms that have been bruised or cut may change colors. Some
mushrooms, such as the common Jack-O-Lantern, are fluorescent.
Figure 115-1 Characteristics of Amanita species.

Figure 115-2 Free gills as seen in cross section.
Spores may also have a characteristic gray, white, or green color that aids in their identification. Spores are
liberated within 1–2 hours following placement of the mushroom, gill side down, on a sheet of white paper in
the dark. They should be examined quickly as drying may alter their color.
Identification of the ingested mushroom is not always possible, nor is it worth the effort and attention it
receives. Mushroom foragers frequently mix several varieties together so that specimens brought in for
identification may not represent those ingested. In addition, characteristic features are often distorted by
cooking or storage. Specimens gathered at the same site may or may not contain the ingested species. It is
most appropriate to treat the patient based on presenting symptoms rather than to conduct an extensive
search for the identity of an implicated mushroom.


CLINCAL SETTINGS
Mushroom poisonings occur in four settings: inadvertent ingestion of mushrooms by children; foragers
looking for a free meal or a delicacy; an attempted homicide or suicide; and persons seeking hallucinatory
effects. Foraging for wild mushrooms is an important activity in certain cultures and the “science” of
identifying mushrooms is often passed down from one generation to another. The location of tasty morel
mushrooms may be a closely guarded family secret. Unfortunately, many mushrooms look alike, and the
clear identification of some species requires a trained mycologist with specialized equipment. Immigrants
may be fooled by look-alike mushrooms that were benign in their home country but are toxic here. In some
areas of Europe the Gyro-mitra species are edible, whereas most species in this country are toxic. Laotians
and other Asians commonly confuse the deadly Amanita phalloides with an edible mushroom of Southeast
Asia. Even regional differences in the appearances of mushrooms may lead to serious inadvertent
poisonings.[42]
Of the 5000–10,000 varieties of mushrooms identified, only 32 have been associated with fatalities and
another 52 cause serious symptoms.[4] Toxic mushrooms found in the United States usually fall into three
groups: (1) those that cause early-onset gastroenteritis, (2) those that cause delayed gastroenteritis and
multisystem organ dysfunction, and (3) those that cause neurologic symptoms. Some European mushrooms
may cause other types of toxicity. This chapter will deal with each of these groups separately.


MUSHROOMS THAT CAUSE EARLY GASTROINTESTINAL SYMPTOMS
A large variety of mushrooms cause GI symptoms within 1–2 hours after ingestion. Symptoms usually
resolve in 12–48 hours. One of the most common mushrooms causing early-onset GI toxicity is
Chlorophyllum molybdites, also known as the green-spored parasol. It grows in the summer in eastern and
southern North America and is particularly common in southern California lawns. Another is the bright
orange-yellow Jack-O-Lantern, a mushroom characterized by a luminescence persisting for 40–50 hours
after collection. It has sharp-edged gills and grows in clusters at the base of stumps or on the buried roots of
deciduous trees. Even the common supermarket mushroom, Agaricus bisporus, causes gastroenteritis in
some susceptible individuals.[49]
Pathophysiology
Several toxins have been isolated. Some are heat-labile, and others cause toxicity even after the
mushrooms are cooked. A hemolysin isolated from R. rhodopolius causes severe diarrhea, hemorrhage,
and lysis of erythrocytes when injected into mice and may be responsible for the diarrhea and abdominal
pain seen following human ingestion of this species.[51] Bolesatine (from Boletus satanes), which causes
mild gastroenteritis and toxic hepatitis in mice, has been shown to inactivate ribosomes and inhibit protein
synthesis in cell culture.[31] None of these toxins has been proved to cause serious toxicity in humans.
Patients present with abdominal pain, cramping, diarrhea, and vomiting shortly after ingesting a mushroom
from this group. All patients develop symptoms before 2 hours and most within the first hour after ingestion.
Symptoms are occasionally severe enough to cause significant dehydration. The gastroenteritis is usually
self-limited, although mild GI upset may continue for 24–48 hours in highly susceptible individuals. Wide
host variability exists; several people may partake of the same meal, but only a few may become ill.
Mushrooms ingested as part of a large communal meal may cause symptoms that are confused with
foodborne gastroenteritis. The time of onset of symptoms following mushroom ingestion is similar to that of
staphylococcal food poisoning. Some patients who present with gastroenteritis and a history of mushroom
ingestion may actually have gastroenteritis of a bacterial etiology. The diagnosis is supported by the clear
temporal relationship of the onset of GI symptoms to the ingestion of a wild mushroom. Prolonged or
worsening symptoms or recurrent symptoms in the setting of a mixed mushroom ingestion should prompt
concern that a more toxic mushroom was also ingested.
Treatment
Gastrointestinal decontamination is unnecessary in these cases, particularly since vomiting and diarrhea are
the prominent toxic manifestations. Patients are rarely able to tolerate oral activated charcoal. Adequate fluid
and electrolyte replacement is essential. Antiemetic drugs such as promethazine may be required.
Antidiarrheal compounds should be avoided.
Laboratory Studies
Laboratory studies are generally not indicated, although severe cases may warrant monitoring of
electrolytes. Liver transaminases or blood coagulation studies in patients who have GI symptoms within 2
hours after ingestion of a single mushroom are unnecessary.
Disposition
Patients who are hydrated and taking oral fluids can be discharged. Other patients may be treated for 12–24
hours in an observation or short stay unit. Prolonged hospitalization is rarely indicated as most patients will
become asymptomatic within 12–18 hours. Follow-up of these patients once they are asymptomatic is not
required.
Sequelae
Prompt treatment of fluid and electrolyte imbalance generally leads to a satisfactory recovery, and most
patients can resume normal daily activities within 48 hours. The rare reports of death in the literature are
most often associated with Chlorophyllum molybdites.[11] Some European varieties of the Jack-O-Lantern
may cause mild elevation of liver transaminases but are rarely of clinical significance.[55]


MUSHROOMS THAT CAUSE DELAYED GASTROENTERITIS WITH MULTIORGAN
DYSFUNCTION
Two distinctly different mushroom groups, the Gyromitra and the Amanita species, cause a similar pattern of
gastroenteritis that develops 6–24 hours after ingestion of the mushroom. The Amanita species (A.
phalloides, A. virosa, and A. verna) grow primarily in the fall throughout North America and Europe. They
carry the common names of “death cap,” “death angel,” and “destroying angel,” respectively. These species
are responsible for 95 per cent of all deaths due to mushrooms. Another amatoxin-producing mushroom,
Lepiota chlorophyllum, has been responsible for severe poisoning in the northeastern United States[16] as
well as in Europe.[38] Amanita smithiana, which causes renal failure, has been mistaken for the edible pine
mushroom by foragers in the Pacific Northwest.[33]
Caps of the Amanita mushrooms are usually white or green with similarly colored free gills that end before
the stem begins. The color may vary owing to local variations in climate and the age of the mushroom. The
stalk has a ring and becomes thicker toward the ground, terminating in a volva (see Fig. 115–1 ). The
characteristic swollen base of the Amanita mushroom is identifiable only when the mushroom is entirely
removed from the ground, rather than being pulled.
Gyromitra esculenta (false morel) grows in the spring throughout North America, Germany, and the Eastern
European countries. It has a brown convoluted and folded cap that resembles a brain, and is frequently
mistaken for the highly prized morel. Gyromitra esculenta contains gyromitrin (N-methyl-N-formylhydrazine),
a volatile heat-labile toxin. It can be removed or inactivated by repeatedly boiling and discarding the cooking
liquid, although this process does not consistently remove all toxin. Most poisonings follow ingestion of raw
or poorly cooked mushrooms. The host response to this toxin is quite variable. Many individuals can eat this
mushroom without difficulty. Some individuals may experience toxic effects following repeated exposures.[35]
Pathophysiology
Amanita Species
Amatoxins contained in the mushrooms Amanita phalloides, A. virosa, A. verna, and Lepiota chlorophyllum
have been well characterized. Amatoxins are heat-stable octapeptides. A wide variety have been isolated;
however, alpha-amanitin appears to be the primary human toxin. Alpha-amanitin is absorbed through the
intestinal mucosa and carried to the liver via the portal vein. There it is actively transported into hepatocytes
where it inhibits protein synthesis by binding to RNA-polymerase II. Hepatocytes, which are dependent on a
high rate of protein synthesis, are rapidly destroyed.[34][59] Some animal studies suggest that the cytochrome
P-450 system modulates the effects of alpha-amanitin.[47][48] Amatoxin undergoes enterohepatic
circulation.[8] In humans it is cleared from the serum within 36 hours through biliary and renal
excretion.[14][27][42]
Phallotoxins are cyclic peptides that are also isolated from A. phalloides. They bind and inactivate F-actin,
leading to disruption of the cell membrane. They are also powerful protein inhibitors. They are not thought to
contribute to serious human toxicity, although they may be responsible for the initial GI irritation. Animals die
promptly following injection of phallotoxin, with hepatocyte vacuolization and intracytoplasmic erythrocyte
accumulation evident on microscopic examination of the liver.[23] Five toxins isolated from A. virosa show a
similar pathologic process following injection into experimental animals.[53]
Gyromitra esculenta
Gyromitrin is hydrolyzed in the stomach to N-methyl-N-formylhydrazine (MFH) that is further metabolized to

N-methylhydrazine (MH), a substance chemically identical to a form of rocket fuel.[39] Workers in rocket
propellant manufacturing plants exposed to the volatile compound MH develop central nervous system
toxicity with manifestations similar to that seen in gyromitrin poisoning.[29][50] MH binds to pyridoxine and
interferes with enzymes that require pyridoxine as a cofactor.[5] This interference results in dramatic lowering
of central nervous system (CNS) levels of GABA ( -aminobutyric acid), an important inhibitory
neurotransmitter.[29] Seizures have been associated with low levels of GABA, although seizures also occur
when GABA levels remain normal.[35] MFH undergoes oxidation in the liver to a free radical form that
appears to have a role in the development of local hepatic necrosis.[39] These two metabolites of gyromitrin
account for the delayed CNS and hepatic toxicity that follows ingestion of Gyromitra. The cause of the initial
GI upset is unknown.
Amanita Species
The severity of toxicity associated with Amanita ingestion is influenced by the quantity of mushrooms
consumed, the preparation of the mushroom, and the age and sex of the individual. Gastrointestinal
symptoms usually begin 5–12 hours after ingestion. Most individuals recover within 2–5 days, although as
many as 25 per cent will go on to fulminant hepatic failure. Toxicity appears related to the time interval
between mushroom ingestion and onset of gastroenteritis; the later the onset of symptoms, the better the
outcome. The gastroenteritis is severe and cholera-like, with watery diarrhea and intractable vomiting.
Hypovolemia and hypoglycemia are common during this phase. After approximately 12 hours the patient
appears to recover. A second latent period extends into the third to fourth day, at which point symptoms of
hepatic dysfunction manifest. [42] Patients initially appear jaundiced and may rapidly progress to fulminant
hepatic failure with an elevated ammonia level, asterixis, and decreased level of consciousness. The
prothrombin time is prolonged. Laboratory evidence of pancreatitis occurs in many patients, although it does
not appear to contribute significantly to the symptomatology.[17] With progression of the illness renal failure
may develop, either as a result of direct renal toxicity or secondary to hepatorenal syndrome. Renal failure is
a primary manifestation of the nephrotoxic effects of amatoxin following the ingestion of Amanita
smithiana.[33]
Table 115-1 -- Clinical Presentation, Differential Diagnosis, and Treatment of Mushroom Poisoning
Mushroom Clinical Onset of Differential
Toxin Treatment
Group Presentation Symptoms Diagnosis
Mushroom R. rhodopolius Vomiting <2 hours Other food-borne Fluid and
causing early hemolysin illness, especially electrolyte
GI symptoms, staphylococcal replacement
e.g.,
Toxin Treatment
e.g.,
Bolesatine Diarrhea Antiemetics, e.g.,
Chlorophyllum
perphenazine
molybdites
Others poorly Abdominal pain,
characterized cramping
Mushrooms
causing
delayed GI
symptoms
Amanita Initial: intractable
Food-borne illness,
phalloides, A. Amatoxins vomiting, watery
viral hepatitis, Multidose activated
virosa, A. (primarily alpha- diarrhea; 5–12 hours
toxin-induced charcoal
verna; Lepiota amanitin) hypoglycemia can
hepatotoxicity
chlorophyllum occur
Delayed:
hepatotoxicity, Penicillin
Phallotoxins fulminant hepatic 300,000–1,000,000
failure and death U/kg/d
can occur.
Monitor LFTs daily
Supportive care
Gyromitra Consider other
Gyromitrins,
esculenta toxin-induced
metabolized to N- Vomiting 5–12 hours Seizures:
seizures and
methylhydrazine
hepatotoxicity
Diarrhea Benzodiazepines
Abdominal pain,
Pyridoxine
cramping
Adult—25 mg/kg
Headache
IV
Pediatric—25
Muscle cramps
mg/kg IV
Loss of
Phenobarbital
coordination
Seizures Other:
Fluid and
Delayed
electrolyte
hepatotoxicity
replacement,
Antiemetics
Toxin Treatment
Supportive care
Mushrooms
Activated charcoal
with Hallucinations—last
15–30 only for large
neurologic Psilocybin 2–6 hours, can Hypoglycemia
minutes ingestions or
toxicity have flashbacks
severe symptoms
Psilocybe spp.
Distorted time CNS trauma, Benzodiazepines,
perception infections e.g., lorazepam
Postictal
Mushroom spiked
with LSD, PCP or
other mind-altering
drug
Nutmeg
Morning glory
seeds
Plants containing
solanine or
anticholinergic
alkaloids
Other toxins
causing CNS
agitation or
depression
Inocybe, Atropine for
Clitocybe spp. excessive
15–30
Muscarine DUMBELS: Organophosphates secretions or
minutes
symptomatic
bradycardia
External cooling for
Diarrhea Carbamates
hyperthermia
Therapeutic
cholinesterase
Urination
inhibitors, e.g.,
neostigmine
Miosis
Bradycardia,
bronchospasm
Emesis
Toxin Treatment
Lacrimation
Salivation
Hyperthermia,
usually mild and in
children
Ibotenic acid Activated charcoal
and Altered sensorium =30 for large ingestions
Muscimol
muscimol- (appear inebriated) minutes or severe
containing symptoms
mushrooms,
Ataxia Benzodiazepines
e.g., Amanita
muscaria, A. Delirium
pantherina
Visual disturbances
Other
mushroom
syndromes
Coprinus spp., Coprine, Disulfiram-like Occurs Disulfiram reaction Fluid and
e.g., C. metabolized to 1- reaction: when electrolyte
atramentarius aminocyclopropanol ethanol replacement
ingested
2–72 hours
after
mushroom
ingestion
Interaction with Nausea MAOI toxicity Hypotension:
ethanol results in crystalloids,
acetaldehyde vasopressors, e.g.,
excess dopamine
Vomiting Scombroid
Flushing Trichloroethylene-
ethanol interaction
Diaphoresis
Headache
Tachycardia
Hypotension
Mushrooms
causing renal
failure
Toxin Treatment
Orellanine- Other toxin and
containing non-toxin causes
Orellanine Renal failure = 11 days Supportive therapy
mushrooms, of renal failure
e.g., (see Chapter 22 )
Cortinarius
orellanus Hemodialysis
Amanita
Renal failure 1–6 days
smithiana
Gyromitra esculenta
Six to 8 hours after ingestion of a gyromitrin-containing mushroom, patients have an abrupt onset of severe
gastroenteritis accompanied by dizziness, nausea, headache, and abdominal cramping. Patients describe
muscle cramps and loss of coordination. In milder cases the patient has the neurologic symptoms for
several hours to days and recovers without sequelae. In severe cases seizures may be prominent. Acute
hepatic failure occurs on day 3 followed by hepatic coma and occasionally death. Patients may develop
hypoglycemia during the transition from gastroenteritis to hepatic failure and during the phase of hepatic
failure. Hypovolemia secondary to the gastroenteritis may complicate the picture of hepatic failure.
Methemoglobinemia and hemolysis occur, although this is more common in the animal models.
Patients who develop delayed gastroenteritis after ingestion of mushrooms may be difficult to distinguish
from those with other foodborne illnesses. The time delay associated with Salmonella is very similar to that
seen with gyromitrin or amatoxin. Patients seek help during the GI phase of their illness, as the symptoms
are quite severe. A patient with Amanita toxicity may be misdiagnosed and treated for gastroenteritis, only to
return later with hepatic failure.
Acute hepatic failure due to gyromitrin or amatoxin must be differentiated from hepatic failure due to other
causes such as acetaminophen toxicity and infectious hepatitis. A unique feature of Amanita mushroom
toxicity is the preceding history of severe gastroenteritis.
Laboratory Studies
Monitoring
Patients who are known to have ingested or are suspected of ingesting amatoxin or gyromitrin-containing
mushrooms should be observed closely for 3–5 days for the development of hepatic failure. During the GI
phase it is important to monitor glucose hourly or every other hour, as hypoglycemia can be abrupt and
severe in both ingestions. Electrolytes should be monitored frequently. Liver transaminases should be
obtained at baseline and then daily. Transaminases begin to rise at 36–72 hours after ingestion. Once an
elevation is present, aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin should be
monitored two to four times per day as the rise in the enzymes can be extremely rapid. Blood coagulation
studies including prothrombin time, partial thromboplastin time, and platelet counts should be monitored.
Amylase is elevated in many cases; however, clinical complications from pancreatitis are rare. Decreases in
neutrophils, lymphocytes, and platelets have been noted without significant clinical consequences.
Endocrine Disturbances
Endocrine abnormalities including decreased thyroid function tests, hypophosphatemia (primarily in

children), hypocalcemia, and elevated insulin levels have been reported following the ingestion of A.
phalloides.[28] The reasons for these laboratory abnormalities are not known; however, most are of no
clinical significance.
Toxin Assay
There are several tests for amatoxins. The Meixner test is a colorimetric test of the mushroom for the
presence of amatoxin. A drop of liquid from the mushroom is expressed onto print-free (ligand-free)
newspaper and allowed to dry; then a drop of concentrated hydrochloric acid (10–12 N) is applied. A blue
color developing within 1–2 minutes indicates the presence of amatoxin.[37][58] False positives are common,
occurring in nearly 20 per cent of gilled mushrooms that do not contain amatoxin.
Thin-layer chromatography can be used to assay urine for amatoxin levels and is sensitive to levels of 50
mg/mL.[44] In addition, radioimmunoassays have been developed to detect amatoxin levels as low as 0.5
mg/mL in gastric, serum, or urine samples.
There are no available assays for gyromitrin or its metabolites.
Micropathologic Changes
Liver biopsy in patients with amatoxin ingestion shows marked fatty degeneration with intranuclear collection
of lipids and carbohydrates. There is extensive hepatic necrosis with yellow atrophy. Electron microscopy
shows marked vacuolization of the mitochondria and clumping of the chromatin in the nucleoli.
Patients with gyromitrin toxicity show diffuse hepatocellular necrosis and severe interstitial nephritis on
biopsy.
Treatment
If the ingestion is known to have occurred within a few hours of presentation, emesis or gastric lavage is
indicated for removal. However, most cases do not come to medical attention until they are symptomatic, 5
or more hours following ingestion. Repeated doses of activated charcoal, 20–40 g every 3–4 hours, may be
effective in Amanita poisoning because of the enterohepatic circulation of the amatoxin, at least for the first
24 hours. Activated charcoal should be given without a cathartic, because most patients are symptomatic
with gastroenteritis during this period. Although there appears to be no enterohepatic circulation of gyromitrin
toxin, an initial dose of activated charcoal should be administered.
During the acute gastroenteritis phase, fluid and electrolyte losses should be replaced and hypoglycemia
promptly treated. Continued monitoring for hypoglycemia is important as hypoglycemia is a frequent cause
of death.
Once the GI phase is over, standard supportive therapy for hepatic failure is indicated. Patients are generally
placed on a low-protein diet and liver function tests are monitored. Patients who have elevations of
prothrombin time may require fresh frozen plasma. Many patients will fail to respond to replacement therapy.
Amanitin-Specific Treatment
Historical Therapies
Many patients with Amanita poisoning do well with supportive care alone, making assessment of potential
therapies difficult in the absence of prospective trials.[25][42] Clearly efficacious therapies for Amanita
poisoning have been difficult to demonstrate as most series are either retrospective, with a significant
potential for selection bias,[19] or have too few patients.[1] Historically, a myriad of treatments for amatoxins,
ranging from the absurd to the anecdotal, have been tried. When it was observed that rabbits eating
mushroom caps did not die, patients were fed raw ground up rabbit without success.[54] Forced diuresis has
some theoretical basis, as the amatoxin is readily cleared by the kidney[57]; however, no clinical trial has
demonstrated efficacy. Disruption of the enterohepatic circulation by continuous duodenal drainage has
been shown to have some benefit in animals; however, this invasive therapy has not been recommended in
humans.[15]
Thioctic acid is a free radical scavenger that has been used throughout Europe as a treatment for amatoxin
poisoning. Some apparent interplay between thioctic acid and glutathione protects the liver against
microsomal lipid peroxidation. Despite potential theoretical utility, neither animal nor human studies have
demonstrated any clinical benefit in the use of thioctic acid to treat Amanita phalloides poisoning.[3][19]
Generally Accepted Therapies
There are two specific therapies whose efficacies are generally accepted based on animal studies and a
single large retrospective study. The administration of silymarin (silybinin), the active compound in the milk
thistle Silybum marianum, inhibits the binding of amatoxin to hepatocytes and interrupts its enterohepatic
circulation.[19][25][38] It is not available in the United States. The administration of repeated doses of activated
charcoal offers a rational alternative means of interrupting the enterohepatic circulation.[42]
A therapy that is more readily available in the United States is high-dose penicillin.[21] Large doses of
penicillin theoretically block the uptake of amatoxin into the liver through a shared active transport system.
This also results in increased renal excretion of amatoxin. Other antibiotics including rifampin and
cephalosporins have also been shown to be effective against amatoxin in animals.[20][41] The recommended
doses of penicillin ranging from 300,000–1,000,000 U/kg/day result in levels that may cause seizures.[38]
One adjunctive therapy, hyperbaric oxygen, has been used in France to decrease the toxicity of Amanita
phalloides ingestion.[32] The mechanism of its benefit is unclear and may be due to an effect on hepatic
regeneration or interference with free radical formation. It has been used most commonly in conjunction with
high-dose penicillin therapy.
Hemodialysis and Charcoal Hemoperfusion: Controversial Therapies
Amatoxins are removed by both dialysis and charcoal hemoperfusion. Charcoal hemoperfusion continues to
be recommended based on the known pharmacokinetics of amatoxin, again without benefit of prospective
controlled studies.[1][16][45] Charcoal hemoperfusion is recommended if it can be instituted within 24 hours of
the ingestion, a time when serum levels of amatoxin are still detectable.[16][40] Because the amatoxin is
cleared from the blood within 36 hours, there is no theoretical rationale for extracorporeal removal after this
time. Hemodialysis is not recommended for amatoxin removal. A large retrospective study of 205 cases
showed that patients who received hemodialysis did significantly worse than those without treatment or with
other forms of treatment.[19] Hemodialysis is clearly beneficial in patients with acute renal failure related to
amatoxin poisoning.
Orthotopic Liver Transplantation
Liver transplantation has been successful in preserving or sustaining life in a number of patients with
fulminant hepatic failure related to amatoxin exposure.[38][46] No firm criteria definitively differentiate patients
who require liver transplantation from those who will recover. One study showed an 84 per cent fatality rate
in patients whose levels of factor V dropped below 10 per cent.[19] This factor V level was used as a
guideline in two reports of liver transplantation for acute hepatic failure related to Amanita toxicity. [38][46]
Others suggest that patients with AST levels greater than 2000 IU, grade 2 hepatic encephalopathy, and
prothrombin time greater than 50 seconds should be considered for emergency liver transplantation.[12] Most
recently, a child received a “temporary” liver transplant to allow time for her own liver to regenerate, after
which the transplanted liver was removed.[26] This approach has much value. Because rapid clinical
deterioration in fulminant hepatic failure may preclude liver transplantation, all seriously poisoned patients
should have early consultation by a transplant center.[43]
Recent work has suggested that certain markers of hepatic regeneration increase in patients with liver
disease who ultimately recover liver function, and do not appear to increase in patients whose liver function
continues to deteriorate. These special biochemical markers may prove useful in the future in differentiating
patients who go on to regenerate their livers from those who will require hepatic transplant to survive.[24a]
Experimental Therapies
Several experimental therapies have been shown to be effective in animals but have yet to be tested in
humans. High-dose cimetidine, which blocks the cytochrome P-450 system, increases survival and
decreases toxicity in animal models.[47] Likewise, vitamin C, zinc, and thiol compounds have also
demonstrated benefit in an animal model.[18][56] Recently, Fab monoclonal antibodies were developed
against amatoxin. These antibodies were effective in preventing hepatic toxicity in mice. However, the renal
toxicity was approximately 50 times greater, and all study animals died of renal failure.[13] Theoretically, if
antibody-antigen complexes are removed immediately by plasmapheresis, such renal toxicity may be
avoided.[10]
Gyromitrin-Specific Treatment
Patients with neurologic toxic effects including recurrent or intractable seizures due to exposure to N-
methylhydrazine or monomethylhydrazine have been successfully treated by high-dose
pyridoxine.[5][29][30][60] Pyridoxine given at doses of 25 mg/kg, up to a maximum of 25 g/day, overcomes the
inhibition of GABA synthesis and permits the regeneration of GABA. Higher doses of pyridoxine (over 40
g/day) have been associated with severe peripheral neuropathy[2] and should be avoided. Pyridoxine does
not alter the course of the hepatotoxicity, for which there are no specific therapies aside from supportive
care.
Disposition
Patients who have ingested one or more mushrooms, either Amanita or Gyromitra, should be observed for
signs and symptoms of toxicity in the hospital for a minimum of 24 hours. Liver function tests should be
performed repeatedly.
Sequelae
Ingestion of A. phalloides carries a mortality rate of 35 per cent, up to 50 per cent in children.[17] The
mortality rate from ingestion of Gyromitra is estimated at 15–35 per cent, although with proper intensive care
the mortality rates can be less than 10%.[22]
Some patients who survive acute hepatic failure from amatoxin have persistent elevation in liver
transaminases. In one study, 8 of 14 patients showed persistent elevation in transaminases with no
normalization over a 1-year follow-up period.[22] These patients had signs of chronic active hepatitis with
positive anti–smooth muscle antibodies and positive cryoglobulins. It is unclear what the long-term
consequences of this finding will be. Long-term consequences of hepatic injury by gyromitrin have not been
described.


NEUROLOGIC TOXINS
Several mushrooms with CNS effects may be inadvertently ingested by foragers or intentionally ingested
specifically for their CNS effects. Mushrooms of the Psilocybe family, which contain the hallucinogen
psilocybin, are cultivated for their hallucinogenic effects. They resemble the common store mushroom
Agaricus bisporus although the flesh of Psilocybe mushrooms characteristically turns blue or green when
bruised or cut. Sometimes ordinary grocery store mushrooms are laced with CNS-active substances such as
LSD (lysergic acid diethylamide) or phencyclidine (PCP) and sold on the street as Psilocybe mushrooms.
Muscarine is the principal toxic component in mushrooms of the Inocybe and the Clitocybe families.
Muscarinic stimulation causes the typical “SLUDGE” syndrome: salivation, lacrimation, urination,
diaphoresis, gastrointestinal upset, and emesis. CNS effects include headache, ataxia, and visual
disturbances. Patients generally have a clear sensorium.
The familiar bright red–capped Amanita muscaria, often depicted in colored plates of “Alice in Wonderland,”
represents a class of mushrooms that contain a mixture of CNS-active substances including ibotenic acid,
muscimol, and lesser amounts of muscarine. Ibotenic acid and muscimol are isoxazole derivatives that
produce CNS excitement and alterations in visual perceptions. Amanita muscaria and A. pantherina are the
most commonly ingested mushrooms containing ibotenic acid. A. muscaria often contains little muscarine in
relation to its content of other CNS-active agents, so that the SLUDGE syndrome may be mild or absent
following its ingestion.
Pathophysiology
Psilocybin, which resembles 5-hydroxytryptamine and LSD, inhibits the firing of serotonin-dependent
neurons, causing alterations in perception, changes in mood, hallucinations, and a distortion of time.
Muscarine is a stimulant of postganglionic cholinergic (muscarinic) receptors. Such stimulation causes

symptoms of cholinergic excess including nausea and vomiting, diarrhea, diaphoresis, salivation, and
lacrimation.
Ibotenic acid undergoes decarboxylation to form muscimol, which acts on GABA receptors as a weak
noncompetitive inhibitor of GABA. Muscimol increases CNS serotonin levels and decreases catecholamine
levels. This leads to visual hallucinations, seizures, and myoclonus.
Patients present to the emergency department with frightening unexpected symptoms if the mushroom
ingestion was inadvertent, or because of excess manifestations of the sought-after CNS effects. The
ingestion of 10 mg of Psilocybe cubensis causes a mild euphoria. Larger doses cause frank hallucinations
and a distorted perception of time. Symptoms develop within 15–30 minutes of ingestion. Hallucinations last
for 2–6 hours, but occasional flashbacks have been reported.[6][36]
Within 15–30 minutes of ingestion of muscarine, a typical cholinergic syndrome may develop. Patients may
have difficulty handling their oral secretions and lacrimation is prominent. Gastrointestinal upset including
vomiting, abdominal pain, and diarrhea occurs. Bradycardia and bronchospasm can be severe. Tachycardia
may supervene due to the sympathetic stimulation caused by hypoxia. Pupils are classically constricted.
Symptoms last up to 6 hours but occasionally may persist up to 24 hours.
After ingestion of isoxazole compounds, patients appear to be somewhat inebriated and ataxic. Visual
disturbances, delirium, and mania develop after large ingestions. Symptoms begin within 30 minutes of
ingestion and generally last no more than 2 hours.
Treatment
Supportive treatment is appropriate for all patients. Attempts at gastric emptying or administration of
activated charcoal add to the distortion of reality that the patient is experiencing, and may be more harmful
than beneficial. These interventions should be considered for patients who have large ingestions or severe
symptoms. Benzodiazepines such as lorazepam or diazepam can be given with caution for agitation or
seizures (rare) and titrated as needed. Atropine will effectively antagonize the cholinergic effects of
muscarine, although these effects are often mild and rarely require specific treatment. Atropine is indicated
in the presence of bronchorrhea or excessive salivation compromising the airway or profound bradycardia.
However, the CNS effects associated with isoxazole may be potentiated by atropine, and this drug should be
used cautiously. The dose of atropine is 0.02 mg/kg for children (minimum dose of 0.1 mg) and 1 mg for an
adult, repeated as necessary until secretions are manageable. Fever is occasionally seen in children and
responds to external cooling. Antipyretic medications are ineffective.
In most cases of CNS alteration related to mushroom ingestion, the symptoms occur so rapidly that there is
little doubt of their cause. The clinical assessment of the patient with altered mental status should always
include consideration of nontoxic etiologies such as hypoglycemia, occult head injury, CNS infection, or a
postictal state (see Chapter 16 ). A variety of other possible plant exposures should be considered in the
differential diagnosis of suspected mushroom-induced mental status alteration. As already mentioned,
Agaricus bisporus, the common grocery store mushroom, may be “spiked” with LSD, PCP, or other mind-
altering substances. Solanine-containing plants (see Chapter 118 ) may cause hallucinations. Similarly, the
anticholinergic alkaloids in Datura species such as jimson weed classically cause hallucinations,
accompanied by anticholinergic signs (see Chapter 116 ). Nutmeg and the seeds of some morning glory
varieties are classic hallucinogens.
Laboratory Studies
In general, laboratory studies are of little or no use except to explore the differential diagnosis, such as the
demonstration of PCP poisoning.
Disposition
Patients with simple hallucinatory effects can be observed until they have cleared and then discharged
provided there is safe monitoring at home. Patients with muscarinic signs and symptoms may require
prolonged observation owing to the duration of effects. Severely agitated patients should be admitted to the
ICU. Symptoms spontaneously remit 6–24 hours after ingestion.
Sequelae
With the exception of flashback hallucinations reported with psilocybin, long-term sequelae are not known.[6]


OTHER MUSHROOM SYNDROMES
Acetaldehyde Dehydrogenase Inhibitors
One of the most interesting mushroom toxins is that contained in the Coprinus family, whose members are
also known as “inky cap” or “shaggy mane” mushrooms. These mushrooms are tall, thin, white mushrooms
with long cylindrical shaggy caps. As the mushroom matures, the cap blackens and black liquid drops from
the cap. These species commonly occur throughout North America and may sprout up literally overnight
after a rain. They contain a toxin, coprine, that is not present in the raw mushroom but is a hydrolate created
during cooking. A metabolite of coprine, 1-aminocyclopropanol, inhibits acetaldehyde dehydrogenase. [52]
This inhibition results in acetaldehyde accumulation when ethanol is ingested and a typical “disulfiram”
reaction of flushing, diaphoresis, headache, tachycardia, nausea, and vomiting. Because of a delay in the
effect of 1-aminocyclopropanol, the mushroom can be ingested concomitantly with ethanol without difficulty.
Two to 6 hours later a period of sensitivity to ethanol begins that can last up to 72 hours. Neither the patient
nor the physician may recognize the link to the previously ingested mushrooms.
Supportive treatment is all that is necessary in most cases. Hypotension generally responds to intravenous
fluid administration. Vasopressors may be indicated in severe cases. Unlike disulfiram, coprine does not
inhibit dopamine ß-hydroxylase,[9] and dopamine can be used as needed for hypotension. There is no role
for GI decontamination.
Renal Failure
The mushroom Cortinarius orellanus was first associated with renal toxicity in the 1950s. [23] Orellanine, the
toxin found in C. orellanus, C. speciosissimus, and C. gentilis, is structurally related to paraquat and diquat.
This heat-stable toxin causes severe delayed interstitial nephritis. The mechanism of injury is unknown.
Patients who ingest the mushroom may remain asymptomatic for up to 20 days. Occasionally paresthesias,
taste impairment, and cognitive dysfunction are reported. Renal failure begins insidiously on or around day
11 after ingestion. Renal function may deteriorate to the point of requiring hemodialysis in as many as 30–46
per cent of patients.[7] Approximately 50 per cent of patients will have spontaneous recovery of renal
function. Renal transplantation has been used in many of those patients whose renal function did not
return.[24] Marked host variability is seen with this mushroom. Some individuals experience no side effects,
yet others eating the same mushroom develop renal failure necessitating dialysis.[24] Renal biopsies in
affected patients show tubular lesions with epithelial necrosis and disruption of tubular basement
membranes.[7]
A recent report linked the mushroom Amanita smithiana, which is indigenous to the Pacific Northwest, with
acute renal failure that presents 1–6 days following ingestion. Patients who developed renal failure had GI
symptoms that began 5–8 hours after the mushroom ingestion. All patients recovered following dialysis and
supportive care. These mushrooms are readily mistaken for the tasty matsutake or pine mushroom
(Tricholoma magnivelare) by foragers.[33]
Patients who develop renal failure due to mushroom toxicity are managed like any patient with acute renal
failure. Urine output, electrolytes, calcium, magnesium, blood urea nitrogen, and creatinine should be
monitored daily. Indications for hemodialysis are the same as for any other cause of renal failure.


CONCLUSION
The spectrum of mushroom toxicity encompasses several unique types of poisonings ranging from simple
GI upset to hallucinations to life-threatening multiorgan failure. Awareness of the spectrum of disease, the
timing of a patient’s symptoms, and knowledge of potential life-threatening sequelae are essential.


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34a. Litovitz TL, Klein-Schwartz W, Dwer KS, et al: 1997 Annual Report of American Association of Poison
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37. Meixner A: Amatoxin Nochwers. Pilzen Z Mykol 1979; 45:137.
38. Meunier BC, Camus CM, Houssin DP, et al: Liver transplantation after severe poisoning due to
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39. Michelot D, Toth B: Poisoning by Gyromitra esculenta—A review. J Appl Toxicol 1991; 11:235.
40. Mydlik M, Derzsiova K, Mizla P, Beno P: Hemoperfusion in mushroom poisoning. Clinical analysis of 58
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41. Neftel K: Sind cephalosporine bei der Intoxikation mit Knollenblatterpilz besser Wirksam als Penicillin
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43. O’Grady JG, Alexander GJ, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure.
44. Rieck W, Platt D: High-performance liquid chromatographic method for the determination of a-amanitin
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45. Sabeel AI, Kurkus J, Lindholm T: Intensive hemodialysis and hemoperfusion treatment of Amanita
mushroom poisoning. Mycopathologia 1995; 131:107.
46. Scheurlen C, Spannbrucker N, Spengler U, et al: Amanita phalloides intoxications in a family of Russian
immigrants Case reports and review of the literature with a focus on orthotopic liver transplantation. J
47. Schneider SM, Borochovitz D, Krenzelok EP: Cimetidine protection against amanitin hepatoxicity in
mice: A potential model for the treatment of Amanita phalloides poisoning. Ann Emerg Med 1987; 16:1136.
48. Schneider SM, Vanscoy GJ, Michelson EA: Penicillin and cimetidine in Amanita toxicity in mice
49. Simons DM: The mushroom toxins. Del Med J 1971; 43:177.
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51. Suzuki K, Une T, Yamazaki M, Takeda T: Purification and some properties of a hemolysin from the
poisonous mushroom Rhodophyllus rhodopolius. Toxicon 1990; 9:1019.
52. Tottmar O, Lindberg P: Effects on rat liver acetaldehyde dehydrogenase in vitro and in vivo by coprine,
the disulfiram-like constituent of Coprinus atramentarius. Acta Pharmacol Toxicol 1977; 40:476.
53. Turcotte A, Gicquaud C, Gendreau M, et al: Separation of the virotoxins of the mushroom Amanita
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56. Vanscoy GJ, Schneider SM: Cimetidine and ascorbic acid in the treatment of amanitin toxicity in mice
57. Vesconi S, Langer M, Iapichino G, et al: Therapy of cytotoxic mushroom intoxication. Crit Care
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pyridoxine chloride. J Food Safety 1981; 3:199.


Chapter 116 – Plants: Central Nervous System Toxicity
CATHLEEN CLANCY WENDY KLEIN-SCHWARTZ
Many different plants contain pharmacologically active substances that cross the blood-brain barrier.
Resultant central nervous system (CNS) effects include delirium, seizures, sedation, and hallucinations.
Many of these substances have medical uses, and some have been used for recreation or for religious
ceremonies. Familiar examples of CNS-active alkaloids include scopolamine from jimson weed (Datura
stramonium), nicotine from the tobacco plant (Nicotiana tabacum), coniine from poison hemlock (Conium
maculatum), cicutoxin from water hemlock (Cicuta maculata), and morphine from the opium poppy (Papaver
somniferum). In 1998 there were 122,578 exposures to plants reported to the American Association of
Poison Control Centers Toxic Exposure Surveillance System (AAPCC TESS) by poison centers in the
United States. None of these exposures were fatal.[39] This chapter highlights common plant species whose
ingestion may result in toxicity to the CNS. Treatment strategies will vary, depending on the mechanism of
toxicity, but are based on the fundamentals of decontamination and supportive care described in earlier
chapters.
PLANTS CONTAINING ATROPINE AND RELATED ALKALOIDS
Essentials
• Populations at risk include young children sampling attractive flowers, leaves, and berries and
adolescents and young adults intentionally abusing these plants for their central nervous system (CNS)
effects.
• Peripheral anticholinergic effects can help differentiate poisoning with these plants from other CNS-
active substances or other pathologic states with CNS manifestations.
• Diagnosis is based on history and physical examination, not laboratory evaluation.
• Physostigmine is not a reliable diagnostic tool, although it may be useful therapeutically.
Introduction
Many members of the Solanaceae family contain the anticholinergic alkaloids hyoscyamine, atropine, and
scopolamine, which are chemically and pharmacologically closely related. These alkaloids are present in all
parts of the plant in varying amounts. In 1998, 1025 exposures to plants with anticholinergic effects were
reported to the AAPCC TESS by poison centers in the United States; 35 resulted in life-threatening
effects.[39]
Atropine is the primary alkaloid in Atropa belladonna (deadly nightshade). It acquired the name belladonna
during the Italian Renaissance when women used it to beautify their eyes by enlarging their pupils. The
seeds and unripe fruits contain l-hyoscyamine.[19][27] Ingestion of ripe berries from Cestrum diurnum (day-
blooming jessamine) and Cestrum nocturnum (night-blooming jessamine) has resulted in poisonings.
Solanine, an alkaloid with gastrointestinal (GI) toxicity, is the predominant alkaloid in unripe berries, while
atropine predominates in ripe berries.[34] The major alkaloid in Hyoscyamus niger (henbane, fetid
nightshade, insane root, poison tobacco) is l-hyoscyamine, although concentrations of scopolamine of up to
40 per cent have been reported.[14]
Scopolamine is the predominant alkaloid in Mandragora officinarum (mandrake, Satan’s apple).[14]

Mandrake is also the common name for Podophyllin peltatum (mayapple), which has different toxicity and
should not be confused with M. officinarum.
Chinese herbal medicines have been implicated in anticholinergic poisonings, either related to use of
yangjinhua (dried flower of Datura metel containing 85 per cent scopolamine and 15 per cent hyoscyamine
and atropine) for the treatment of asthma and bronchitis, or medicines contaminated with atropine-like
substances.[10] Anticholinergic poisoning associated with ginseng use is most likely related to adulteration
with M. officinarum.[10]
The Datura species also include D. arborea (angels trumpet or trumpet lily) and D. stramonium (jimson
weed, Jamestown weed, devil’s weed, locoweed, thornapple). Serious poisonings and fatalities are most
commonly reported following ingestions of plant parts or teas prepared from jimson weed, which flourishes
throughout the United States. Jimson weed grows to 5 feet in height and bears a single erect tubular white
or lavender flower from July through September and a spiny capsule containing 50 to 100 brownish black
kidney-shaped seeds ( Fig. 116–1 ). The majority of exposures are intentional, occurring in adolescents and
young adults.[1][5][12][18][29][53][54][62] Unintentional poisonings in children, as well as poisoning from its use in
homemade toothpaste, and from food prepared from millet contaminated during harvesting, also
occur.[47][50]
Figure 116-1 A–B, Datura stramonium (jimsonweed) foliage and spiny capsule containing seeds. (Courtesy of Neta Reich Nelson.)
Atropine and its related alkaloids are muscarinic receptor antagonists that block the binding of acetylcholine
to muscarinic cholinergic receptors in smooth muscle, cardiac tissue, gland cells, autonomic ganglia, and the
CNS.[8] The sensitivity of muscarinic receptors varies in different organs, resulting in a dose-response
spectrum. At low doses patients present with slight dryness of the mouth, decreased sweating, and
bradycardia. At higher doses they develop tachycardia; mydriasis; dry, hot, flushed skin; hallucinations,
delirium, and coma. There are quantitative differences between the pharmacologic actions of atropine and
scopolamine. Scopolamine penetrates more readily into the CNS, resulting in drowsiness, euphoria,
disorientation, hallucinations, delirium, and amnesia at lower doses. Atropine is less likely to produce CNS
effects with therapeutic doses; however, it does cause CNS excitation following toxic doses. Paradoxically,
low doses of both atropine and scopolamine will slow the heart rate. This transient slowing of the heart rate
by atropine may be related to its blockade of inhibitory postganglionic cholinergic receptors.[8] Although
higher doses of atropine cause persistent tachycardia, scopolamine more often produces transient
tachycardia.
Each 100 seeds of the the jimson weed plant contain the equivalent of approximately 6 mg of atropine. All
parts of the plant are toxic, although the alkaloid content varies depending on the plant part (e.g., roots 0.23
per cent, seeds 0.58 per cent) and age of plant.[14] Young plants contain more scopolamine and old plants
contain more hyoscyamine.
The time of onset of symptoms will vary, depending on the route of exposure. For example, smoking the
leaves or drinking a decoction obtained by boiling the leaves with water would have a rapid onset of action,
but symptoms could be delayed for several hours following ingestion of the leaves or other parts of the plant.
A 68-year-old man experienced delayed CNS symptoms 10 hours after ingestion of deadly nightshade
berries.[61] The usual duration of symptoms is 12–48 hours.
As few as three berries of deadly nightshade have been reported to be fatal in a child.[27] Ingestion of three
to six raw Atropa belladonna berries and approximately 20–200 g of cooked berries produced severe
confusion in two adults and coma with respiratory failure in a third family member.[52] Severe anticholinergic
toxicity followed ingestion of ten mandrake fruits.[63]
Patients with anticholinergic poisoning are aptly described as “hot as a hare, red as a beet, dry as a bone,
blind as a bat, and mad as a hatter.” Clinical effects include mydriasis, dry mucous membranes, flushed
skin, decreased sweating, tachycardia, decreased GI motility, urinary retention, hallucinations, delirium,
seizures, and coma ( Table 116–1 ). The patient may have a wide-eyed, wild stare, be mumbling
incoherently, and appear psychotic, but the presence of peripheral anticholinergic effects suggests
poisoning. Skin moisture is absent, even in the axillae, and the bladder may be distended. Seizures are
generalized and self-limited. Mydriasis may persist long after other symptoms have resolved. As previously
described, pharmacologic differences among these alkaloids produce different dose-response patterns,
depending on the part of the plant ingested, the dose, and the relative concentrations of each alkaloid. Thus,
a patient may present with some, but not all, of the above mentioned signs and symptoms.
Table 116-1 -- Clinical Signs and Symptoms of Atropine and Related Alkaloid Poisoning
Signs and Symptoms Comments
Central nervous Restlessness, agitation, aggressiveness, Hallucinations are of simple objects, not
system irritability, confusion, disorientation, bizarre brilliant colors, and occur in 50–100% of
behavior, myoclonus, hallucinations, delirium, patients in published cases;[15][23][42] patients
coma, seizures, amnesia may pick at imaginary objects
Signs and Symptoms Comments
HEENT Mydriasis, nonreactive pupils, blurred vision Mydriasis may persist up to 2 weeks
Dry, hot, flushed skin and mucous
Dermatologic
membranes
Cardiovascular Sinus tachycardia
Dry mouth, difficulty swallowing, thirst, Seeds may remain in stomach up to 36
Gastrointestinal
diminished bowel motility hours
Genitourinary Urinary retention
Other Fever
The health hazards of jimson weed were highlighted by a report of 24 incidents of jimson weed poisoning,
which occurred in Texas, New York, and California. Two exposures resulted in fatalities.[5] Death may result
from trauma or drowning, rather than from the direct toxic effects of the plants. A shallow water drowning
occurred in one of seven people who suffered severe hallucinations following ingestion of the flowers of
Datura arborea.[22] Toxic delirium from Datura innoxia has been reported, while chronic use of Datura plants
has resulted in a schizophrenia-like syndrome.[16][21]
Human cases of anticholinergic poisoning from henbane include a 20-year-old who intentionally chewed four
henbane flowers to get high, two adults who confused it for “parsnip” from their garden, and a fatality in a
child.[31][51][57]
Diagnosis may be complicated because patients may be unable to provide a coherent history ( Table 116–2;
also see Chapter 56 ). Ataxia and aggression in anticholinergic poisoning may be confused with acute
alcohol intoxication. Likewise patients poisoned with sympathomimetic agents such as amphetamine or
cocaine may be agitated with dilated pupils and hyperthermia. However, the skin is usually moist and bowel
sounds are active. Patients intoxicated with LSD (lysergic acid diethylamide) or mescaline describe more
brilliant, colorful hallucinations, are generally more passive than patients with anticholinergic poisoning, and
are better oriented to time, place, and person than the patient with a complete anticholinergic syndrome.
Anticholinergic effects are also associated with intoxication with other agents such as cyclic antidepressants
(see Chapter 62 ) or antihistamines (see Chapter 56 ). Patients with encephalitis or meningitis frequently
present with fever and agitated delirium. These diagnoses should be excluded by lumbar puncture when the
diagnosis of poisoning is not clear. Physostigmine has been used as a diagnostic test to confirm
anticholinergic poisoning in some patients when the diagnosis is suspected. Complete normalization of the
mental status following the administration of physostigmine, including return of full orientation, does
implicate the presence of an anticholinergic toxin. However, physostigmine has an analeptic effect and can
cause arousal in patients with disorders that do not involve anticholinergic poisoning. In general,
physostigmine should not be used as a diagnostic agent in routine evaluation of delirium and coma.
Table 116-2 -- Differential Diagnosis of Atropine and Related Alkaloid Poisoning

Drugs Plants Medical Conditions
Amphetamines Conium maculatum (poison Cerebrovascular
hemlock) accident
Antihistamines Lantana camara (lantana) Electrolyte imbalances
Cyclic antidepressants Encephalitis
LSD Hepatic encephalopathy
Mescaline Hypoglycemia
Mushrooms (psilocybin) Meningitis
Phencyclidine Psychosis
Sedative hypnotic (including ethanol)
Schizophrenia
withdrawal
Uremia
Laboratory Studies
Laboratory evaluation is generally not of value in the management of these patients. Although atropine can
be detected i

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Ford: Clinical Toxicology, 1st ed.

MARSHA D. FORD, KATHLEEN A. DELANEY, L OUIS J. LING , TIMOTHY ERICKSON

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