Вы находитесь на странице: 1из 2979

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.


Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/4.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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

For our patients, whose lives are entrusted to us and to whom we owe intelligent, informed medical care
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
To all my students, from whom I continue to learn
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
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

W.B. Saunders Company

A Harcourt Health Sciences Company

The Curtis Center

Independence Square West

Philadelphia London New York St. Louis Sydney Toronto

Philadelphia, Pennsylvania 19106

Library of Congress Cataloging-in-Publication Data

Clinical Toxicology/Marsha D. Ford.—[et al.]—1st ed.


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]


RA1211.C587 2001515.9—dc21

Publisher's Team

Project Manager: Gina Scala

Production Manager: Peter Faber

Illustration Specialist: Robert Quinn

Book Interior Designer: Ellen Zanoll


ISBN 0-7216-5485-1

Copyright © 2001 by W.B. Saunders Company

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval
system, without permission in writing from the publisher.

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/1.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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,

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
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
Pulmonary Abnormalities

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
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
Assistant Director, Medical Toxicology Fellowship, University of Texas Southwestern Medical Center, Dallas,

Kathleen Birnbaum, Pharm.D., C.S.P.I.

Poison Specialist II, University of New Mexico, Albuquerque, New Mexico

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,
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,

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

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

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,
Medical Director, Maryland Poison Center, Baltimore, Maryland;
Attending Physician, Department of Emergency Medicine, Georgetown University Medical Center, Washington,
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,
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,
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
Associate Residency Director, Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North

Merilyn J. Crittenden, R.N., C.S.P.I.

Certified Specialist in Poison Information, Carolinas Poison Center, Carolinas Medical Center, Charlotte, North
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

Suzanne Doyon, M.D.

Medical Director, Maryland Poison Center, School of Pharmacy, Baltimore, Maryland

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

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

Fun H. Fong Jr., M.D., F.A.C.E.P.

Assistant Medical Director, Emory Adventist Hospital, Smyrna, Georgia

Show H. Fong, Ph.D.

Senior Health Physicist, Atlanta, Georgia

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

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

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,
Philadelphia, Pennsylvania

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
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

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
Indiana Poison Center, Emergency Medicine and Trauma Center, Clarian/Methodist Hospital, Indianapolis,
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
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,
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

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,
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,

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

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
Pulmonary Abnormalities

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,
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,

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,
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,

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

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

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,
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

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

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

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
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

Dirk C. Schrader, M.D.

Emergency Department, Athens Regional Medical Center, Athens, Georgia

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,
Philadelphia, Pennsylvania
Plants: Gastrointestinal Toxicity; Scombroid, Ciguatera, and Other Seafood Intoxications; Plant Poisoning:

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,
Philadelphia, 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
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

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

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

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
Pulmonary Abnormalities

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

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

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,

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,
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,

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/2.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/3.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

Chapter 1 – Initial Approach to the Poisoned Patient

Marsha Ford Kathleen A. Delaney


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/5.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/6.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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).

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/7.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/8.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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 .

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/9.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.)
Antivenom, loxosceles
Brown recluse spider (Loxosceles reclusa)
Antivenom, scorpion (goat) Scorpions (Centruroides spp.)
Botulinum antitoxin
Clostridium botulinum
Calcium channel antagonists
Hydrofluoric acid
Calcium Hyperkalemia (except cardiac glycosides)
Hypocalcemia (e.g., ethylene glycol)
Calcium disodium edetate Lead
Cyanide antidote kit: Cyanide
Amyl nitrite
Sodium nitrite
Deferoxamine Iron
Antidote Indication for Use
Ackee fruit (hypoglycin)
Other (e.g., salicylates, pentamidine)

Digoxin-specific antibody Digitalis

fragments (Fab) Other cardiac glycosides, e.g., bufodienalides (Bufo toads)
Dimercaprol Lead
Diethylene glycol
Ethylene glycol
Experimental: sodium monofluoroacetate

Folic acid/tetrahydrofolic Methanol

acid (leucovorin) Methotrexate
Ethylene glycol
Beta-adrenergic receptor antagonists
Calcium channel antagonists
Carbon monoxide
Hyberbaric oxygen Experimental: carbon tetrachloride
Cyanide, hydrogen sulfide
Methylene blue Methemoglobin-producing agents
Experimental: carbon tetrachloride, chloroform, pennyroyal oil
Naloxone, nalmefene,
Anticholinergic agents, e.g., diphenhydramine, Jimsonweed (Datura spp.),
Antidote Indication for Use
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
Succimer Lead
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

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 .

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/10.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/11.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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.


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

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
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

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

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
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

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.
hypnotics Propofol 0.5–2 mg/kg
Etomidate 0.2–0.4 mg/kg
Methohexital 0.5–2.5 mg/kg
Ketamine 1–1.5 mg/kg 1 mg/kg if compromised hemodynamics.
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.
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
* 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
0.1 mg/kg IV titrated to effect; no
Methohexital N/A 1–2 mg/kg IV
0.1 mg/kg IV titrated to effect; no
Propofol N/A 1–2 mg/kg IV
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
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
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
Globe trauma or glaucoma
Increased intracranial pressure
Depolarizer Succinylcholine
mg/kg Recent major burns, soft tissue
Spinal cord injuries with paraplegia
or quadriplegia
Muscular dystrophies
Rocuronium Rapid onset
0.2 “Prime” with 0.02 mg/kg 3 minutes
mg/kg before endotracheal intubation
Nondepolarizers (pretreatment dose is 10% of
paralyzing dose given 3 minutes before Curare (dTc) Histamine release
intubation) Class Drug Dose Comments
Atracurium Elimination neither renal nor hepatic
Pancuronium Moderate sympathomimetic effects
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

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

Sellick’s maneuver (10 lb pressure to the cricoid ring unless there is a potentially unstable C-spine) is

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/12.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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

• 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
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
• 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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/13.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Adnet F, Borron SW, Finot M-A, et al: Intubation difficulty in poisoned patients: Association with initial
Glasgow Coma Scale score. Acad Emerg Med 1998; 5:123.

2. Berk WA, Andersen JC: Salicylate-associated asystole: Report of two cases. Am J Med 1989; 86:505.

3. Chapman BJ, Proudfoot AT: Adult salicylate poisoning: Deaths and outcome in patients with high plasma
salicylate concentrations. Q J Med 1989; 72:699.

4. Clemessy JL, Taboulet P, Hoffman JR, et al: Treatment of acute chloroquine poisoning: A 5-year
experience. Crit Care Med 1996; 24:1189.

5. di Constanzo J, Noirclerc M, Jouglard J, et al: New therapeutic approach to corrosive burns of the upper
gastrointestinal tract. Gut 1980; 21:370.

6. Ferguson MK, Migliore M, Staszak VM, et al: Early evaluation and therapy for caustic esophageal injury.
Am J Surg 1989; 157:116.

7. Gabow PA, Anderson RJ, Potts DE, et al: Acid-base disturbances in the salicylate-intoxicated adult.
Arch Intern Med 1978; 138:1481.

8. Gerkin R, Sergen KC, Curry SC, et al: Life-threatening airway obstruction from rattlesnake bite to the
tongue. Ann Emerg Med 1987; 16:813.

9. Gronert GA, Theye RA: Pathophysiology of hyperkalemia induced by succinylcholine.

Anaesthesiology 1975; 43:89.

10. Hawkins DB, Demeter MJ, Barnett TE: Caustic ingestion: Controversies in management: A review of
214 cases. Laryngoscope 1980; 90:98.

11. Hoffman RS, Morasco R, Goldfrank LR: Administration of purified human plasma cholinesterase
protects against cocaine toxicity in mice. J Toxicol Clin Toxicol 1996; 34:259.

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/14.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 3 – Advanced Life Support in the Poisoned Patient (TOX ACLS)



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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/15.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/16.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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.


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)


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

Astemizole, terfenadine, terodiline
Droperidol, haloperidol
Class Ia antidysrhythmics
Disopyramide, N-acetyl-procainamide (NAPA), procainamide, quinidine
Class III antidysrhythmics
Amiodarone, almokalant, sotalol
Antimony, arsenic
Erythromycin, clarithromycin, spiramycin
Chlorpromazine, mesoridazine, thioridazine
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]


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.


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]


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

Drug-induced (typical)
Distributive ( vasodilation)
Cardiogenic ( contractility)
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
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 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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/17.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/18.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Agura ED, Wexler LF, Witzburg RA: Massive propranolol overdose: Successful treatment with high-dose
isoproterenol and glucagon. Am J Med 1986; 80:755-757.

2. Antman EM, Wenger TL, Butler Jr 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; 81:1744-1752.

3. Assimes TL, Malcolm I: Torsades de pointes with sotalol overdose treated successfully with lidocaine.
Can J Cardiol 1998; 14:753-756.

4. Barat SA, Abdel-Rahman MS: Cocaine and lidocaine in combination are synergistic convulsants. Brain
Res 1996; 742:157-162.

5. Beckman KJ, Parker RB, Hariman RJ, et al: Hemodynamic and electrophysiological actions of cocaine.
Effects of sodium bicarbonate as an antidote in dogs. Circulation 1991; 83:1799-1807.

6. Benowitz NL, Rosenberg J, Becker CE: Cardiopulmonary catastrophes in drug-overdosed patients. Med
Clin North Am 1979; 63:267-296.

7. Billman GE: The effect of adrenergic receptor antagonists on cocaine-induced ventricular fibrillation:
Alpha but not beta adrenergic receptor antagonists prevent malignant arrhythmias independent of heart rate.
J Pharmacol Exp Ther 1994; 269:409-416.

8. Bismuth C, Gaultier M, Conso F, et al: Hyperkalemia in acute digitalis poisoning: Prognostic significance
and therapeutic implications. J Toxicol Clin Toxicol 1973; 6:153-162.

9. Boehrer JD, Moliterno DJ, Willard JE, et al: Influence of labetalol on cocaine-induced coronary
vasoconstriction in humans. Am J Med. 1993; 94:608-610.

10. Brady WJ, DeBehnke DJ, Laundrie D: Prevalence, therapeutic response, and outcome of ventricular
tachycardia in the out-of-hospital setting: A comparison of monomorphic ventricular tachycardia,
polymorphic ventricular tachycardia, and torsades de pointes. Acad Emerg Med 1999; 6:609-617.

11. Brogan WC, Lange RA, Kim AS, et al: Alleviation of cocaine-induced coronary vasoconstriction by
nitroglycerin. J Am Coll Cardiol 1991; 18:581-586.

12. Brown TCK: Tricyclic antidepressant overdosage: Experimental studies on the management of
circulatory complications. Clin Toxicol 1976; 9:255-272.

13. Callaham M, Schumaker H, Pentel P: Phenytoin prophylaxis of cardiotoxicity in experimental

amitriptyline poisoning. J Pharmacol Exp Ther 1988; 245:216-220.

14. Carlon GC, Howland WS, Goldiner PL, et al: Adverse effects of calcium administration: Report of two
cases. Arch Surg 1978; 113:882-885.

15. Chalak W, Taha A, Araoya M, et al: Torsades de pointes: Report of 18 cases. J Med
Liban 1993; 41:62-68.discussion 68–69.

16. Citrin DL, O’Malley K, Hillis WS: Cardiac standstill due to digoxin poisoning successfully treated with
atrial pacing. Br Med J. 1973; 2:526-527.

17. Clark RF, Vance MV: Massive diphenhydramine poisoning resulting in a wide-complex tachycardia:
Successful treatment with sodium bicarbonate. Ann Emerg Med 1992; 21:318-321.

18. Cranefield PF, Aronson RS: Torsades de pointes and early afterdepolarizations. Cardiovasc Drug
Ther 1991; 5:531-538.

19. Cronk JD: Phenol with glucagon in cardiotherapy. N Engl J Med 1971; 284:219-220.

20. Cummins RO: Toxicologic Cardiac Emergencies in Advanced Cardiac Life Support, Dallas, American
Heart Association, 1997.

21. Derlet RW, Albertson TE, Tharratt RS: Lidocaine potentiation of cocaine toxicity. Ann Emerg
Med 1991; 20:135-138.

22. Domenighetti GM, Savary G, Stricker H: Hyperadrenergic syndrome in severe tetanus: Extreme rise in
catecholamines responsive to labetalol. Br Med J (Clin Res Ed) 1984; 288:1483-1884.

23. Doyon S, Roberts JR: The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg
Med 1993; 22:1229-1233.

24. Dusenberry SJ, Hicks MJ, Mariani PJ: Labetalol treatment of cocaine toxicity. Ann Emerg
Med 1987; 16:235.

25. Farrell M, Heinrichs M, Tilelli JA: Response of life-threatening dimenhydrinate intoxication to sodium
bicarbonate administration. J Toxicol Clin Toxicol 1991; 29:527-535.

26. Freedberg RS, Friedman GR, Palu RN, et al: Cardiogenic shock due to antihistamine overdose.
Reversal with intra-aortic balloon counterpulsation. JAMA 1987; 257:660-661.

27. Frierson J, Bailly D, Shultz T, et al: Refractory cardiogenic shock and complete heart block after
unsuspected verapamil-SR and atenolol overdose. Clin Cardiol 1991; 14:933-935.

28. Friesen RM, Bonet JF: The antiarrhythmic effects of verapamil and propranolol in aminophylline toxic
dogs. Can Anaesth Soc J 1983; 30:124-131.

29. Gantenberg NS, Hageman GR: Cocaine-enhanced arrhythmogenesis: Neural and nonneural
mechanisms. Can J Physiol Pharmacol 1992; 70:240-246.

30. Gay GR, Loper KA: The use of labetalol in the management of cocaine crisis. Ann Emerg
Med 1988; 17:282-283.

31. Glick G, Parmley WW, Wechsler AS, et al: Glucagon. Its enhancement of cardiac performance in the
cat and dog and persistence of its inotropic action despite beta-receptor blockade with propranolol. Circ
Res 1968; 22:789-799.

32. Goenen M, Col J, Compere A, et al: Treatment of severe verapamil poisoning with combined amrinone-
isoproterenol therapy. Am J Cardiol 1986; 58:1142-1143.
33. Golsousidis H, Kokkas V: Use of 19,590 mg of atropine during 24 days of treatment after a case of
unusually severe parathion poisoning. Hum Toxicol 1985; 4:339-340.

34. Goodwin DA, Lally KP, Null DM: Extracorporeal membrane oxygenation support for cardiac dysfunction
from tricyclic antidepressant overdose. Crit Care Med 1993; 21:625-627.

35. Grawe JJ, Hariman RJ, Winecoff AP, et al: Reversal of the electrocardiographic effects of cocaine by
lidocaine. Part 2. Concentration-effect relationships. Pharmacotherapy 1994; 14:704-711.

36. Haberl R: Medicamentous anti-arrhythmia therapy. Is oral adjuvant therapy with electrolytes of value?
Herz 1997; 22(Suppl 1):77-80.

37. Hantson P, Vekemans MC, Squifflet JP, et al: Outcome following organ removal from poisoning donors:
Experience with 12 cases and a review of the literature. Transpl Int 1995; 8:185-189.

38. Hebert MJ, Boucher A, Beaugage G, et al: Transplantation of kidneys from donor with carbon monoxide
poisoning. N Engl J Med 1992; 326:1571.

39. Heit J, Hoffman RS, Goldfrank LR: The effects of lidocaine pretreatment on cocaine neurotoxicity and
lethality in mice. Acad Emerg Med 1994; 1:438-442.

40. Hendren WG, Schieber RS, Garrettson LK: Extracorporeal bypass for the treatment of verapamil
poisoning. Ann Emerg Med 1989; 18:984-987.

41. Henry M, Kay MM, Viccellio P: Cardiogenic shock associated with calcium-channel and beta blockers:
Reversal with intravenous calcium chloride. Am J Emerg Med 1985; 3:334-336.

42. Hicks PR, Rankin AP: Massive adrenaline doses in labetalol overdose. Anaesth Intensive
Care 1991; 19:447-449.

43. Hii JT, Wyse DG, Gillis AM, et al: Precordial QT interval dispersion as a marker of torsades de pointes:
Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 1992; 86:1376-1382.

44. Hurwitz MD, Kallenbach JM, Pincus PS: Massive propranolol overdose. Am J Med 1986; 81:1118.

45. Immonen P, Linkola A, Waris E: Three cases of severe verapamil poisoning. Int J
Cardiol 1981; 1:101-105.

46. Jolly SR, Kipnis JN, Lucchesi BR: Cardiovascular depression by verapamil: Reversal by glucagon and
interactions with propranolol. Pharmacology 1987; 35:249-255.

47. Kalman S, Berg S, Lisander B: Combined overdose with verapamil and atenolol: Treatment with high
doses of adrenergic agonists. Acta Anaesthesiol Scand 1998; 42:379-382.

48. Kenyon CJ: Successful resuscitation using external cardiac pacing in ß-adrenergic antagonist induced
bradyasystolic arrest. Ann Emerg Med 1988; 17:711-713.

49. Keren A, Tzivoni D: Torsades de pointes: Prevention and therapy. Cardiovasc Drugs
Ther 1991; 5:509-513.

50. Kerns W, Kline J, Ford MD: ß-Blocker and calcium channel blocker toxicity. Emerg Clin North
Am 1994; 12:365-390.

51. Kerns W, Ransom M, Tomaszewski C, et al: The effect of hypertonic sodium and dantrolene on
propranolol cardiotoxicity. Acad Emerg Med 1997; 4:545-551.

52. Kerns W, Schroeder D, Williams C, et al: Insulin improves survival in lethal canine propranolol toxicity.
Ann Emerg Med 1996; 27:154.

53. Kerns W, Schroeder D, Williams C, et al: Insulin improves survival in a canine model of acute ß-blocker
toxicity. Ann Emerg Med 1997; 29:748-757.

54. Keyler DE, Pentel PR: Hypertonic sodium bicarbonate partially reverses QRS prolongation due to
flecainide in rats. Life Sci 1989; 45:1575-1580.

55. Kim SY, Benowitz NL: Poisoning due to class IA antiarrhythmic drugs. Quinidine, procainamide and
disopyramide. Drug Saf 1990; 5:393-420.

56. Kline JA, DeStefano AA, Schroeder JD, et al: Magnesium potentiates imipramine toxicity in the isolated
rat heart. Ann Emerg Med 1994; 24:224-232.

57. Kline JA, Leonova E, Raymond RM: Beneficial myocardial metabolic effects of insulin during verapamil
toxicity in the anesthetized canine. Crit Care Med 1995; 23:1251-1263.

58. Kline JA, Leonova E, Williams TC, et al: Myocardial metabolism during graded intraportal verapamil
infusion in awake dogs. J Cardiovasc Pharmacol 1996; 27:719-726.

59. Kline JA, Raymond RM, Leonova ED, et al: Insulin improves heart function and metabolism during non-
ischemic cardiogenic shock in awake canines. Cardiovasc Res 1997; 34:289-298.

60. Kline JA, Raymond RM, Schroeder JD, et al: The diabetogenic effects of acute verapamil poisoning.
Toxicol Appl Pharmacol 1997; 145:357-362.

61. Kline JA, Tomaszewski CA, Schroeder DJ, et al: Insulin is a superior antidote for cardiovascular toxicity
induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993; 267:744-750.

62. Knudsen K, Abrahamsson J: Effects of magnesium sulfate and lidocaine in the treatment of ventricular
arrhythmias in experimental amitriptyline poisoning in the rat. Crit Care Med 1994; 22:494-498.

63. Kollef MH: Labetalol overdose successfully treated with amrinone and alpha-adrenergic receptor
agonists. Chest 1994; 105:626-627.

64. Koppel C, Oberdisse U, Heinemeyer G: Clinical course and outcome in class IC antiarrhythmic
overdose. J Toxicol Clin Toxicol 1990; 28:433-444.

65. Kosinski EJ, Malindzak GS: Glucagon and isoproterenol in reversing propranolol toxicity. Arch Intern
Med 1973; 132:840-843.

66. Krukenkamp I, Sorlie D, Silverman N, et al: Direct effect of high-dose insulin on the depressed heart
after beta blockade or ischemia. Thorac Cardiovasc Surg 1986; 34:305-309.

67. Lane AS, Woodward AC, Goldman MR: Massive propranolol overdose poorly responsive to
pharmacologic therapy: Use of the intra-aortic balloon pump. Ann Emerg Med 1987; 16:1381-1383.
68. Lange RA, Cigarroa RG, Clyde WY, et al: Cocaine-induced coronary-artery vasoconstriction. N Engl J
Med 1989; 321:1557-1562.

69. Lange RA, Cigarroa RG, Flores ED, et al: Potentiation of cocaine-induced coronary vasoconstriction by
beta-adrenergic blockade. Ann Intern Med 1990; 112:897-903.

70. Larkin GL, Graeber GM, Hollingsed MJ: Experimental amitriptyline poisoning: Treatment of severe
cardiovascular toxicity with cardiopulmonary bypass. Ann Emerg Med 1994; 23:480-486.

71. Lewis M, Kallenbach J, Germond C, et al: Survival following massive overdose of adrenergic blocking
agents (acebutolol and labetalol). Eur Heart J 1983; 4:328-332.

72. Liu D, Hariman RJ, Bauman JL: Cocaine concentration-effect relationship in the presence and absence
of lidocaine: Evidence of competitive binding between cocaine and lidocaine. J Pharmacol Exp
Ther 1996; 276:568-577.

73. Love JN, Hanfling D, Howell JM: Hemodynamic effects of calcium chloride in a canine model of acute
propranolol intoxication. Ann Emerg Med 1996; 28:1-6.

74. Love JN, Howell JM: Glucagon therapy in the treatment of symptomatic bradycardia. Ann Emerg
Med 1997; 29:181-183.

75. Love JN, Leasure JA, Mundt DJ: A comparison of combined amrinone and glucagon therapy to
glucagon alone for cardiovascular depression associated with propranolol toxicity in a canine model. Am J
Emerg Med 1993; 11:360-363.

76. Love JN, Leasure JA, Mundt DJ, et al: A comparison of amrinone and glucagon therapy for
cardiovascular depression associated with propranolol toxicity in a canine model. J Toxicol Clin
Toxicol 1992; 30:399-412.

77. MacLeod KM, Rodgers RL, McNeil JH: Characterization of glucagon-induced changes in rate,
contractility and cyclic AMP levels in isolated cardiac preparations of the rat and guinea pig. J Pharmacol
Exp Ther 1981; 217:798-804.

78. Mariani PJ: Pseudoephedrine-induced hypertensive emergency: Treatment with labetalol. Am J Emerg
Med 1986; 4:141-142.

79. Martin TG, Klain MM, Molner RL, et al: Extracorporeal life support vs thumper after lethal desipramine
OD. [Abstract.] Vet Hum Toxicol 1990; 32:349.

80. Martin TG, Menegazzi JJ, Perel HM, et al: Extraordinary medical therapy for severe verapamil overdose.
[Abstract]. Ann Emerg Med 1992; 21:627.

81. Martin TG, O’Connell JJ, Pentel P, et al: Resuscitation from severe cyclic antidepressant toxicity using
cardiopulmonary bypass. [Abstract.] Vet Hum Toxicol 1988; 30:354.

82. Mayer DB, Miletich DJ, Feld JM, et al: The effects of magnesium salts on the duration of epinephrine-
induced ventricular tachyarrhythmias in anesthetized rats. Anesthesiology 1989; 71:923-928.

83. Mayron R, Ruiz E: Phenytoin: does it reverse tricyclic-antidepressant–induced cardiac conduction

abnormalities?. Ann Emerg Med 1986; 15:876-880.
84. McVey FK, Corke CF: Extracorporeal circulation in the management of massive propranolol overdose.
Anaesthesia 1991; 46:744-746.

85. Nattel S, Mittleman M: Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in
dogs. J Pharmacol Exp Ther 1984; 231:430-435.

86. Nickalls RW, Nickalls EA: The first use of physostigmine in the treatment of atropine poisoning.
[Translation.] Anaesthesia 1988; 43:776-779.

87. O’Mahony D, O’Leary P, Molloy MG: Severe oxprenolol poisoning: The importance of glucagon infusion.
Hum Exp Toxicol 1990; 9:101-103.

88. Orr DA, Bramble MG: Tricyclic antidepressant poisoning and prolonged external cardiac massage
during asystole. Br Med J 1981; 282:1107-1108.

89. Pentel P, Benowitz N: Efficacy and mechanism of action of sodium bicarbonate in the treatment of
desipramine toxicity in rats. J Pharmacol Exp Ther 1984; 230:12-19.

90. Perticone F, Ceravolo R, De Novara G, et al: New data on the antiarrhythmic value of parenteral
magnesium treatment: Magnesium and ventricular arrhythmias. Magnes Res 1992; 5:265-272.

91. Peterson CD, Leeder JS, Sterner S: Glucagon therapy for beta-blocker overdose. Drug Intell Clin
Pharm 1984; 18:394-398.

92. Prasad K: Glucagon-induced changes in the action potential, contraction, and Na+-K+-ATPase of
cardiac muscle. Cardiovasc Res 1975; 9:355-365.

93. Prasad K: Electrophysiologic effects of glucagon on human cardiac muscle. Clin Pharmacol
Ther 1975; 18:22-30.

94. Prasad K: Use of glucagon in the treatment of quinidine toxicity in the heart. Cardiovasc
Res 1977; 11:55-63.

95. Prasad K, Desousa HH: Glucagon in the treatment of ouabain-induced cardiac arrhythmias in dogs.
Cardiovasc Res 1972; 6:333-343.

96. Prasad K, Weckworth P: Glucagon in procainamide-induced cardiac toxicity. Toxicol Appl

Pharmacol 1978; 46:517-528.

97. Ramoska E, Sacchetti AD: Propranolol-induced hypertension in treatment of cocaine intoxication. Ann
Emerg Med 1985; 14:1112-1113.

98. Ramoska EA, Spiller HA, Winter M, et al: A one-year evaluation of calcium channel blocker overdoses:
Toxicity and treatment. Ann Emerg Med 1993; 22:196-200.

99. Ramsey ID: Survival after imipramine poisoning. Lancet 1967; 2:1308-1309.

100. Reikeras O, Gunnes P, Sorlie D, et al: Metabolic effects of low and high doses of insulin during beta-
receptor blockade in dogs. Clin Physiol 1985; 5:469-478.

101. Reikeras O, Gunnes P, Sorlie D, et al: Haemodynamic effects of insulin and beta receptor blockade
during acute left ventricular failure in dogs. Eur Heart J 1986; 7:227-233.

102. Sand C, Brody SL, Wrenn KD, et al: Experience with esmolol for the treatment of cocaine-associated
cardiovascular complications. Am J Emerg Med 1991; 9:161-163.

103. Sangster B, de Groot G, Borst C, et al: Dopamine and isoproterenol in imipramine intoxication in the
dog. J Toxicol Clin Toxicol 1985; 23:407-420.

104. Sasyniuk BI, Jhamandas V, Valois M: Experimental amitriptyline intoxication: Treatment of cardiac
toxicity with sodium bicarbonate. Ann Emerg Med 1986; 15:1052-1059.

105. Sener EK, Gabe S, Henry JA: Response to glucagon in imipramine overdose. J Toxicol Clin
Toxicol 1995; 33:51-53.

106. Shih RD, Hollander JE, Burstein JL, et al: Clinical safety of lidocaine in patients with cocaine-
associated myocardial infarction. Ann Emerg Med 1995; 26:702-706.

107. Shub C, Gau GT, Sidell PM, et al: The management of acute quinidine intoxication.
Chest 1978; 73:173-178.

108. Southall DR, Kilpatrick SM: Imipramine poisoning: Survival of a child after prolonged cardiac massage.
Br Med J 1974; 4:508.

109. Stinson J, Walsh M, Feely J: Ventricular asystole and overdose with atenolol. Br Med
J 1992; 305:693.

110. Stork CM, Redd JT, Fine K, et al: Propoxyphene-induced wide QRS complex dysrhythmia responsive
to sodium bicarbonate—a case report [see comments]. J Toxicol Clin Toxicol 1995; 33:179-183.

111. Strubelt O, Diederich KW: Experimental treatment of the acute cardiovascular toxicity of caffeine. J
Toxicol Clin Toxicol 1999; 37:29-33.

112. Totterman KJ, Turto H, Pellinen T: Overdrive pacing as treatment of sotalol-induced ventricular
tachyarrhythmias (torsades de pointes). Acta Med Scand Suppl 1982; 668:28-33.

113. Tynan RF, Fisher MM, Ibels LS: Self-poisoning with propranolol. Med J Aust 1981; 1:82-83.

114. Tzivoni D, Keren A, Cohen AM, et al: Magnesium therapy for torsades de pointes. Am J
Cardiol 1984; 53:528-530.

115. Vernon DD, Banner Jr W, Garrett JS: Efficacy of dopamine and norepinephrine for treatment of
hemodynamic compromise in amitriptyline intoxication. Crit Care Med 1991; 19:544-549.

116. Vick JA, Kandil A, Herman EH, et al: Reversal of propranolol and verapamil toxicity by calcium. Vet
Hum Toxicol 1983; 25:8-10.

118. Weinstein RS: Recognition and management of poisoning with beta-adrenergic blocking agents. Ann
Emerg Med. 1984; 13:1123-1131.

119. White RD, Goldsmith RS, Rodriguez R, et al: Plasma ionic calcium levels following injection of
chloride, gluconate, and gluceptate salts of calcium. J Thorac Cardiovasc Surg 1976; 71:609-613.
120. Winecoff AP, Hariman RJ, Grawe JJ, et al: Reversal of the electrocardiographic effects of cocaine by
lidocaine. Part 1. Comparison with sodium bicarbonate and quinidine. Pharmacotherapy 1994; 14:698-

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/19.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Uncited reference

Visscher MB, Muller EA: The influence of insulin upon the mammalian heart. J Physiol 1927; 62:341-348.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/20.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 4 – Focused Physical Examination/Toxidromes


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.


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.


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
Cyclic antidepressants
Lysergic acid diethylamide (LSD)
Methylenedioxymethamphetamine (MDMA), other designer amphetamines
Monoamine oxidase inhibitors (MAOIs)
Phencyclidine (PCP)
Withdrawal from ethanol and sedative-hypnotics
Uncoupling of oxidative phosphorylation
Increased metabolic rate
Thyroid hormones
Decreased Heat Loss
Impaired sweating
Cyclic antidepressants
Malignant hyperthermia
Neuroleptic malignant syndrome
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
Lamp oil

Table 4-2 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hypothermia
Cyclic antidepressants
Impaired perception of cold
Carbon monoxide
Depressed hypothalamic/central nervous system function
Substrate depletion
Oral hypoglycemics
Decreased heat production or metabolic activity
Beta-adrenergic receptor antagonists
Hydrogen sulfide



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

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, 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.


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.


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
Methylenedioxymethamphetamine (MDMA), other designer amphetamines
Phencyclidine (PCP)
Withdrawal from ethanol, barbiturates, and sedative-hypnotics
Acetylcholine excess
Therapeutic cholinesterase inhibitors (e.g., physostigmine, pyridostigmine, neostigmine)
Anticholinergic-muscarinic blockade
Belladonna-containing plants
Cyclic antidepressants
Lomotil (atropine and diphenoxylate)
Calcium channel antagonists
Cyclic antidepressants
Disulfiram reactions
Volume loss
Arsenic (acute)
Disulfiram-ethanol interaction
Mushrooms (e.g., Amanita phalloides)
Opioid withdrawal
Increased metabolic rate
Thyroid hormones
Increased sensitivity to catecholamines
Halogenated hydrocarbons
Chloral hydrate
Cyclic antidepressants
Digitalis glycosides
Halogenated hydrocarbons
Cellular asphyxia
Carbon monoxide
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.


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
Calcium channel antagonists
Cardiac glycoside-containing plants (e.g., lily of the valley, oleander, foxglove) and toads
Reflex mechanisms
Alpha-adrenergic receptor agonists (phenylpropanolamine)
CNS depressants
Decreased sympathetic outflow
Beta-adrenergic receptor antagonists
Imidazoline, topical
Cholinomimetic agents
Mushrooms containing muscarine (Clitocybe and Inocybe spp.)
Physostigmine, other medicinal cholinesterase inhibitors
Antidysrhythmics—membrane depressant effects
Beta-adrenergic receptor antagonists
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.


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
Clonidine (early intoxication)
Cyclic antidepressant overdoses (early)
Imidazolines (naphazoline, oxymetazoline, tetrahydrozoline)
Monoamine oxidase inhibitors
Thyroid hormones
Withdrawal from ethanol, barbiturates, sedative-hypnotics
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.

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
Calcium channel antagonists
Clonidine, guanfacine, guanabenz, imidazolines (oral)
Cyclic antidepressants
Disulfiram-ethanol interaction
Decreased myocardial contractility
Beta-adrenergic receptor antagonists
Calcium channel antagonists
Cyclic antidepressants
Hypovolemia or third spacing of intravascular volume
Caustic injuries
Colchicine, other antimitotics
Coprinus-ethanol interaction
Disulfiram-ethanol interaction
Lithium (diabetes insipidus)
Mercury salts
Plants (e.g., pokeweed)
Rattlesnake envenomation
Theophylline (late)
Zinc phosphate
Monoamine oxidase inhibitors

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

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

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 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

Table 4-7 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Hyperventilation
(Tachypnea or Hyperpnea)
Stimulation of the central nervous system
Nicotine (early)
Metabolic acidosis
Arsenic (acute)
Ethylene glycol
Hydrogen sulfide
Ketoacidosis (alcoholic)
Nonsteroidal anti-inflammatory drugs (propionic acid class)
Sodium azide
Sodium monofluoroacetate
Hyperadrenergic stimulation
Aspiration of gastric contents
Noncardiogenic pulmonary edema
Carbon monoxide
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, 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

Table 4-8 -- Mechanisms and Common Examples of Drug- and Toxin-Induced Respiratory Depression
Depression of central respiratory drive
Cyclic antidepressants
Ethanol and other alcohols
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)
Poison hemlock (conine)
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/21.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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
Disulfiram reaction
Ethanol, sedative-hypnotic, barbiturate withdrawal
Meperidine (normeperidine)
Monoamine oxidase inhibitors
Neuroleptic malignant syndrome
Nonsteroidal anti-inflammatory drugs (phenylbutazone, diclofenac, fenoprofen)
Propoxyphene (norpropoxyphene)
Serotonin syndrome
Hypoglycemic agents
Akee fruit
Antidysrhythmic agents
Hypoxia-producing agents
Carbon monoxide
Simple asphyxiant hydrocarbons
Ibotenic acid, muscimol-containing mushrooms
Khat, methcathinone
Lysergic acid diethylamide (LSD)
Other psychoactive agents
Black widow spiders
Pit vipers
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
Carbon monoxide
Hydrogen sulfide
Methemoglobin-producing drugs and toxins
Simple asphyxiants (methane, ethane, butane, propane)
Acetylcholinesterase inhibitors
Central nervous system depression
Anticonvulsants (carbamazepine, phenytoin, valproic acid, ethosuximide)
Clonidine, guanfacine, imidazolines
Cyclic antidepressants


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
Clonidine, other central a 2 agonists
Cyclic antidepressants
Ethanol, sedative-hypnotic, barbiturate withdrawal
Meperidine (normeperidine)
Monoamine oxidase inhibitors
Phenylbutazone (especially in children)
Propoxyphene (norpropoxyphene)
Quinine (cinchonism)
Quinolones (enoxacin, norfloxacin, ofloxacin)
Water hemlock (cicutoxin)
Akee fruit
Cerebral edema
Ethylene glycol
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]

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.


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 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 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

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

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/22.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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).


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.


Anticoagulant toxicity may inhibit clotting and present with ecchymosis.


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 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 (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]


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).
Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/23.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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


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

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


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 ).


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

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/24.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/25.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Ackerman A, Mandy S: Skin lesions in barbiturate poisoning [letter]. N Engl J Med 1970; 283:764.

2. Ahmad S: Amidarone and reversible alopecia. Arch Intern Med 1995; 155:1106.

3. Aitken M, Martin T: Life-threatening theophylline toxicity is not predictable by serum levels.

Chest 1987; 91:10.

4. Alexander G: Skin lesions in barbiturate poisoning [letter]. N Engl J Med 1970; 283:764.

5. Appenzeller O: The normal pupil and some pupillary abnormalities. In: Appenzeller O, ed. The
Autonomic Nervous System, 3rd ed. New York: Elsevier; 1982:319.

6. Armstrong LE, Epstein Y, Greenleaf JE, et al: American College of Sports Medicine position stand: Heat
and cold illnesses during distance running. Med Sci Sports Exerc 1996; 28:i.

7. Baden M: Bullous skin lesions in barbiturate overdosage and carbon monoxide poisoning [letter].
JAMA 1970; 213:2271.

8. Benzinger T, Pratt A, Kitzinger C: The thermostatic control of human metabolic heat production.
Physiology 1961; 47:730.

9. Blanc P, Boushey H, Wong H, et al: Cytokines in metal fume fever. Am Rev Respir Dis 1993; 147:134.

10. Boyd RE, Brennan PT, Deng JF, et al: Strychnine poisoning: Recovery from profound lactic acidosis,
hyperthermia, and rhabdomyolysis. Am J Med 1983; 74:507.

11. Browne B, Linter S: Monoamine oxidase inhibitors and narcotic analgesics: A critical review of the
implications for treatment. Br J Psychol 1987; 151:210.

12. Brubacher J, Ravikumar P, Bania T, et al: Treatment of toad venom poisoning with digoxin-specific Fab
fragments. Chest 1996; 110:1282.

13. Burrows N, Grant J, Crisp A, et al: Scarring alopecia following gold therapy [letter]. Acta Derm
Venereol 1994; 74:486.

14. Campbell BC, Meredith PA, Scott JJ: Lead exposure and changes in the renin-angiotensin-aldosterone
system in man. Toxicology 1985; 25:25.

15. Chrousos G, Cowdry R, Schuelein M, et al: Two cases of downbeat nystagmus and oscillopsia
associated with carbamazepine. Am J Ophthalmol 1987; 103:221.

16. Corbett J, Jacobson D, Thompson H, et al: Downbeating nystagmus and other ocular motor defects
caused by lithium toxicity. Neurology 1989; 39:481.

17. Cucco R, Yoo O, Cregler L, et al: Nonfatal pulmonary edema after “freebase” cocaine smoking. Am
Rev Respir Dis 1987; 136:179.
18. Curry S: Methemoglobinemia. Ann Emerg Med 1982; 11:214.

19. Danzl D, Pozos R: Multicenter hypothermia survey. Ann Emerg Med 1987; 16:1042.

20. Dunn C, Held J, Spitz J, et al: Coma blisters: Report and review. Cutis 1990; 45:423.

21. Edgren B, Tilelli J, Gehrz R: Intravenous lidocaine overdose in a child. Clin Toxicol 1986; 24:51.

22. Ellison D, Pentel P: Clinical features and consequences of seizures due to cyclic antidepressant
overdose. Am J Emerg Med 1989; 7:5.

23. El-Mallakh R, Lee R: Seizures and transient cognitive deterioration as sequelae of acute lithium
intoxication. Vet Hum Toxicol 1987; 29:143.

24. Ernst A, Sanders W: Unexpected cocaine intoxication presenting as seizures in children. Ann Emerg
Med 1989; 18:774.

25. Feldman J, Levisohn D: Acute alopecia: Clue to thallium toxicity. Pediatr Dermatol 1993; 10:29.

26. Gibson D, Moore G, Pfaff J: Camphor ingestion. Am J Emerg Med 1989; 7:41.

27. Ginsberg MD, Hertzman M, Schmidt-Nowara WV: Amphetamine intoxication with coagulopathy,
hyperthermia and reversible renal failure. Ann Intern Med 1970; 73:81.

28. Glazener F, Blake K, Gradman M: Bradycardia, hypotension, and near-syncope associated with Afrin
(oxymetazoline) nasal spray. N Engl J Med 1983; 309:731.

29. Goodman J, Bischel M, Wagers P, et al: Barbiturate intoxication morbidity and mortality. West J
Med 1976; 124:179.

30. Gould D, Slater D, Durrant T: A case of green hair—a consequence of exogenous copper deposition
and permanent waving. Clin Exp Dermatol 1984; 9:545.

31. Grabert B, Conner C, Rumack B, et al: Clonidine-recurrent apnea following overdose. Drug Intelligence
Clin Pharmacy 1979; 13:778.

32. Granville-Grossman K, Sergeant H: Pulmonary oedema due to salicylate intoxication.

Lancet 1960; 1:575.

33. Gustavson E, Levitt C: Physical abuse with severe hypothermia. Arch Pediatr Adolesc
Med 1996; 150:111.

34. Hall C, Hall W, Speers D: Clinical and physiological manifestations of bronchiolitis and pneumonia. Am
J Dis Child 1979; 133:798.

35. Heffner J, Sahn S: Salicylate-induced pulmonary edema. Ann Intern Med 1981; 95:405.

36. Henry J, Jeffreys K, Dawling S: Toxicity and deaths from 3,4-methylenedioxymethamphetamine

(“ecstasy”). Lancet 1992; 340:384.

37. Horowitz J, McNeil J, Sweet B, et al: Hypertension and postural hypotension induced by
phenylpropanolamine (Trimolets). Med J 1979; 1:175.
38. Howrie D, Wolfson J: Phenylpropanolamine-induced hypertensive seizures. J Pediatr 1983; 102:143.

39. Hurwitz M, Burney R, Howatt W, et al: Clinical scoring does not accurately assess hypoxemia in
pediatric asthma patients. Ann Emerg Med 1984; 13:1040.

40. Johnson RP, Mellors JW: Arteriolization of venous blood gases: A clue to the diagnosis of cyanide
poisoning. J Emerg Med 1988; 6:401.

41. Karjalainen J, Viitasalo M: Fever and cardiac rhythm. Arch Intern Med 1986; 146:1169.

42. Kedes L, Field J: Hypothermia—a clue to hypoglycemia. N Engl J Med 15:785.

43. Kew M, Hopp M, Rothberg A: Fatal heart-stroke in a child taking appetite-suppressant drugs. S Afr
Med J 1982; 62:905.

44. Kiyama S: A simple test for scopolamine mydriasis [letter]. Anesth Analg 1991; 73:824.

45. Kjeldgaard J, Hahn G, Heckenlively J, et al: Methadone-induced pulmonary edema.

JAMA 1971; 218:882.

46. Kluger M: Fever. Pediatrics 1980; 66:720.

47. Kulick R: Pulse oximetry. Pediatr Emerg Care 1987; 3:127.

48. Kuschner W, D’Alessandro A, Wintermeyer S, et al: Pulmonary responses to purified zinc oxide fume.
J Investig Med 1995; 43:371.

49. Lampe R, Henderson A, Hansen G: Green hair. JAMA 1977; 237:2092.

50. Lev R, Clark R: Visine overdose: Case report of an adult with hemodynamic compromise. J Emerg
Med 1995; 13:649.

51. Lifshitz M, Rotenberg M, Sofer S, et al: Carbamate poisoning and oxime treatment in children: A clinical
and laboratory study. Pediatrics 1994; 93:652.

52. Lipsky B, Hirschmann J: Drug fever. JAMA 1981; 245:851.

53. Lowe-Ponsford F, Henry J: Clinical aspects of carbon monoxide poisoning. Adverse Drug React Acute
Poisoning Rev 1989; 8:217.

54. Ludwig S, Warman M: Shaken baby syndrome: A review of 20 cases. Ann Emerg Med 1984; 13:104.

55. Mahieu L, Rooman R, Goossens E: Imidazoline intoxication in children. Eur J Pediatr 1993; 152:944.

56. Maickel R: Interaction of drugs with autonomic nervous function and thermoregulation. Federation
Proceedings 1970; 29:1973.

57. Mandy S, Ackerman A: Characteristic traumatic skin lesions in drug-induced coma.

JAMA 1970; 213:253.

58. Merigian K, Roberts J: Cocaine intoxication: Hyperpyrexia, rhabdomyolysis and acute renal failure. Clin
Toxicol 1987; 25:135.
59. Mofenson H, Greensher J: The unknown poison. Pediatrics for the Clinician 1974; 54:336.

60. Morgan R, King D: Urban hypothermia. BMJ 1996; 312:124.

61. Muly E, McDonald W, Steffens D, et al: Serotonin syndrome produced by a combination of fluoxetine
and lithium [letter]. Am J Psychol 1993; 150:1565.

62. Pappas P, Kauffman C, Perfect J, et al: Alopecia associated with fluconazole therapy. Ann Intern
Med 1995; 123:354.

63. Parrish J, Arndt K: Skin lesions in barbiturate poisoning [letter]. N Engl J Med 1970; 43:764.

64. Plum F, Posner J: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia: Davis; 1982:87-151.

65. Restek-Samarzija N, Momcilovic B: Delayed effects of lead on the kidney-factor analysis. Arh Hig
Rada Toksikol 1993; 44:9.

66. Reuler J: Hypothermia: Pathophysiology, clinical settings, and management. Ann Intern
Med 1978; 89:519.

67. Ross J: Deficient activity of DPNH-dependent methemoglobin diaphorase in cord blood erythrocytes.
Blood 1963; 21:51.

68. Rubin M, Sadoff R, Cozzi G: Unilateral mydriasis caused by transdermal scopolamine. Oral Surg Oral
Med Oral Pathol 1990; 70:569.

69. Sanchez-Fructuoso A, Torralbo A, Arroyo M, et al: Occult lead intoxication as a cause of hypertension
and renal failure. Nephrol Dial Transplant 1996; 11:1775.

70. Schillinger B, Berstein M, Goldberg L, et al: Boric acid poisoning. Am Acad Dermatol 1982; 7:667.

71. Srivastava A, Gupta B, Bihari V, et al: Generalized hair loss and selenium exposure. Vet Hum
Toxicol 1995; 37:568.

72. Steinberg A, Karliner J: The clinical spectrum of heroin pulmonary edema. Arch Intern
Med 1968; 122:122.

73. Trabulsy M: Cocaine washed out syndrome in a patient with acute myocardial infarction. Am J Emerg
Med 1995; 13:538.

74. Uehlinger C, Barrelet L, Touabi M, et al: Alopecia and mood stabilizers: Two case reports. Eur Arch
Psychiatry Clin Neurosci 1992; 242:85.

75. Vernon D, Banner W, Dean J: Hemodynamic effects of experimental iron poisoning. Ann Emerg
Med 1989; 18:863.

76. Wahl N, Woodall B: Hypothermia in shaken infant syndrome. Pediatr Emerg Care 1995; 11:233.

77. Weaver D, Camfield P, Fraser A: Massive carbamazepine overdose: Clinical and pharmacologic
observations in five episodes. Neurology 1988; 38:755.

78. Weinstein R: Recognition and management of poisoning with beta-adrenergic blocking agents. Ann
Emerg Med 1984; 13:1123.

79. Welch M, Correa G: PCP intoxication in young children and infants. Clin Pediatr 1980; 19:510.

80. Yelderman M, New W: Evaluation of pulse oximetry. Anesthesiology 1983; 59:349.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/26.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 5 – Gastrointestinal Decontamination


“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
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.
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.


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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/27.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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]
Decker 1968[31]
Lithium Favin 1988[38]
Decker 1968[31]
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]
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/28.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
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
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
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

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

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/29.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/30.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/31.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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 ).

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/32.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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.
Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/33.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/34.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Abdallah AH, Tye A: A comparison of the efficacy of emetic drugs and stomach lavage. Am J Dis
Child 1967; 113:571.

2. Aks SE, Vander Hoek TL, Hryhorczuk DO, et al: Cocaine liberation from body packets in an in vitro
model. Ann Emerg Med 1992; 21:1321.

3. Albertson TE, Derlet RW, Foulke GE, et al: Superiority of activated charcoal alone compared with ipecac
and activated charcoal in the treatment of acute toxic ingestions. Ann Emerg Med 1989; 18:56.

4. Andersen AH: Experimental studies on the pharmacology of activated charcoal. III. Adsorption from
gastro-intestinal contents. Acta Pharmacol 1948; 4:275.

5. Andersen AH: Experimental studies on the pharmacology of activated charcoal. II. The effect of pH on
the adsorption by charcoal from aqueous solutions. Acta Pharmacol 1946; 3:199.

6. Andersen AH: Experimental studies on the pharmacology of activated charcoal. I. Adsorption power of
charcoal in aqueous solutions. Acta Pharmacol 1946; 2:69.

7. Arimori K, Deshimaru M, Furukawa E, Nakano M: Adsorption of mexiletine onto activated charcoal in

macrogol-electrolyte solution. Chem Pharm Bull 1993; 41:766.

8. Arimori K, Furukawa E, Nakano M: Adsorption of imipramine onto activated charcoal and a cation
exchange resin in macrogol-electrolyte solution. Chem Pharm Bull 1992; 40:3105.

9. Arnold FJ, Hodges JB, Barta PA, et al: Evaluation of the efficacy of lavage and emesis in the treatment of
salicylate poisoning. Pediatrics 1959; 23:286.

10. Atkinson SW, Young Y, Trotter GA: Treatment with activated charcoal complicated by gastrointestinal
obstruction requiring surgery. BMJ 1992; 305:563.

11. Beerman R, Nunez Jr D, Wetli CV: Radiographic evaluation of the cocaine smuggler. Gastrointest
Radiol 1986; 11:351.

12. Boxer L, Anderson FP, Rowe DS: Comparison of ipecac-induced emesis with gastric lavage in the
treatment of acute salicylate ingestion. J Pediatr 1969; 74:800.

13. Buck WB, Bratich PM: Activated charcoal: Preventing unnecessary death by poisoning. Vet
Med 1986; 73(Jan):

14. Buckley N, Dawson AH, Howarth D, Whyte IM: Slow-release verapamil poisoning: Use of polyethylene
glycol whole-bowel irrigation lavage and high-dose calcium. Med J Aust 1993; 158:202.

15. Burkhart KK, Kulig KK, Rumack B: Whole-bowel irrigation as treatment for zinc sulfate overdose. Ann
Emerg Med 1990; 19:1167.

16. Burkhart KK, Martinez MA: The adsorption of isopropanol and acetone by activated charcoal. Clin
Toxicol 1992; 30:371.

17. Burkhart KK, Wuerz RC, Donovan JW: Whole-bowel irrigation as adjunctive treatment for sustained-
release theophylline overdose. Ann Emerg Med 1992; 21:1316.

18. Burton BT, Bayer MJ, Barron L, et al: Comparison of activated charcoal and gastric lavage in the
prevention of aspirin absorption. J Emerg Med 1984; 1:411.

19. Caruana DS, Weinbach B, Goerg D, et al: Cocaine-packet ingestion. Ann Intern Med 1984; 100:73.

20. Chin L, Picchioni AL, Bourn WM, et al: Optimal antidotal dose of activated charcoal. Toxicol Appl
Pharmacol 1973; 26:103.

21. Chin L, Picchioni AL, Duplisse BR: The action of activated charcoal on poisons in the digestive tract.
Toxicol Appl Pharmacol 1970; 16:786.

22. Chin L, Picchioni AL, Duplisse BR: Comparative antidotal effectiveness of activated charcoal, Arizona
montmorillonite, and evaporated milk. J Pharm Sci 1968; 58:1353.

23. Comstock EG, Boisaubin EV, Comstock BS, et al: Assessment of the efficacy of activated charcoal
following gastric lavage in acute drug emergencies. Clin Toxicol 1982; 19:149.

24. Cooney DO: Activated Charcoal: Antidotal and Other Medical Uses, New York, Marcel Dekker, 1980.

25. Corby DC, Decker W: Clinical comparison of pharmacologic emetics in children.

Pediatrics 1968; 42:361.

26. Corby DC, Lisiandro RC, Lehman RH, et al: The efficacy of methods used to evacuate the stomach
after acute ingestions. Pediatrics 1967; 40:871.

27. Cranston PE, Pollack Jr CV, Harrison RB: CT of crack cocaine ingestion. J Comput Assist
Tomogr 1992; 16:560.

28. Curtis RA, Barone J, Giacona N: Efficacy of ipecac and activated charcoal/cathartic: Prevention of
salicylate absorption in a simulated overdose. Arch Intern Med 1984; 144:48.

29. Curt-Sneed CD, Parks KS, Bordelon JG, et al: In vitro adsorption of sodium pentobarbital by superchar,
USP and Darco G-60 activated charcoals. Clin Toxicol 1987; 25:1.

30. Davis GR, Santa Ana CA, Morawski SG, et al: Development of a lavage solution associated with
minimal water and electrolyte absorption or secretion. Gastroenterology 1980; 78:991.

31. Decker WJ, Combs HF, Corby DG: Adsorption of drugs and poisons by activated charcoal. Toxicol
Appl Pharmacol 1968; 13:454.

32. 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.

33. Derlet RW, Albertson RE: Activated charcoal—past, present, and future. West J Med 1986; 145:493.

34. Edwards DG, McCredie M: Binding properties of acidic, basic, and neutral drugs to anion and cation
exchange resins and charcoal in vitro. Med J Aust 1967; 1:535.
35. Elliot CG, Colby TV, Kelly TM, et al: Charcoal lung: Brochiolitis obliterans after aspiration of activated
charcoal. Chest 1989; 96:672.

36. Ernstoff JJ, Howard DA, Marshall JB, et al: A randomized blinded clinical trial of a rapid colonic lavage
solution (GoLYTELY) compared with standard preparation for colonoscopy and barium enema.
Gastroenterology 1983; 84:1512.

37. 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.

38. Favin FD, Klein-Schwartz W, Oderda GM, Rose SR: In vitro study of lithium carbonate adsorption by
activated charcoal. J Toxicol Clin Toxicol 1988; 26:443.

39. Fishbain DA, Wetli CV: Cocaine intoxication, delirium, death in a body packer. Ann Emerg
Med 1981; 10:531.

40. Gherardi R, Marc B, Alberti X, et al: A cocaine body packer with normal abdominal plain radiograms:
Value of drug detection in urine and contrast study of the bowel. Am J Forensic Med Pathol 1990; 11:154.

41. Gomez HF, Brent JA, Munoz DC, et al: Charcoal stercolith with intestinal perforation in a patient treated
for amitriptyline ingestion. J Emerg Med 1994; 12:57.

42. Greensher J, Mofenson HC, Picchioni AL, et al: Activated charcoal updated. J Am Coll Emerg
Phys 1979; 8:261.

43. Guven H, Tuncok Y, Gidener S, et al: In vitro adsorption of dichlorvos and parathion by activated
charcoal. Clin Toxicol 1994; 32:157.

44. Harris CR, Filandrinos D: Accidental administration of activated charcoal into the lung: Aspiration by
proxy. Ann Emerg Med 1993; 22:1470.

45. Harsch HH: Aspiration of activated charcoal. N Engl J Med 1986; 314:318.

46. Hayden JW, Comstock EG: Use of activated charcoal in acute poisoning. Clin Toxicol 1975; 8:515.

47. Hoffman RS, Chiang WK, Howland MA, et al: Theophylline desorption from activated charcoal caused
by whole bowel irrigation solution. J Clin Toxicol 1991; 29:191.

48. Hoffman RS, Chiang WK, Weisman RS, et al: Prospective evaluation of “crack-vial” ingestions. Vet
Hum Toxicol 1990; 32:164.

49. Hoffman RS, Smilkstein MJ, Goldfrank LR: Whole bowel irrigation and the cocaine “body-packer”: A
new approach to a common problem. Am J Emerg Med 1990; 8:523.

50. Holt LE, Holz PH: The black bottle. Pediatrics 1963; 63:306.

51. Hulton BA, Heath A, Mellstrand T, et al: Does alcohol adsorb to activated charcoal?. Hum
Toxicol 1985; 5:211.

52. Jackson JE, Picchioni AL, Chin L: Contraindications for activated charcoal use. Ann Emerg
Med 1980; 9:599.
53. Justiani FR, Hippalgaonkar R, Martinez LO: Charcoal containing empyema complicating treatment for
overdose. Chest 1985; 87:404.

54. Kaczorowski JM, Wax PM: Five days of whole-bowel irrigation in a case of pediatric iron ingestion. Ann
Emerg Med 1996; 27:258.

55. Katona BG, Siegel EG, Cluxton RJ, et al: The new black magic: Activated charcoal and new therapeutic
uses. J Emerg Med 1987; 5:9.

57. 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.

58. Kirshenbaum LA, Sitar DS, Tenenbein M: Interaction between whole-bowel irrigation solution and
activated charcoal: Implications for the treatment of toxic ingestion. Ann Emerg Med 1990; 19:1129.

59. Kornberg AE, Dolgin J: Pediatric ingestions: Charcoal alone versus ipecac and charcoal. Ann Emerg
Med 1991; 20:648.

60. Kulig K, Bar-Or D, Cantrill SV, et al: Management of acutely poisoned patients without gastric emptying.
Ann Emerg Med 1985; 14:562.

61. Lambert RJ, Kindler BL, Schaeffer DJ: The efficacy of superactivated charcoal in treating rats exposed
to a lethal oral dose of potassium cyanide. Ann Emerg Med 1988; 17:595.

62. Lee DC, Roberts JR, Kelly JJ, Fishman SM: Whole-bowel irrigation as an adjunct in the treatment of
radiopaque arsenic. Am J Emerg Med 1995; 13:244.

63. Levy G, Tsuchiya T: Effect of activated charcoal on aspirin absorption in man. Clin Pharmacol
Ther 1972; 13:317.

64. Linden CH: Ipecac for ingested drug packets [abstract A-29]. Vet Hum Toxicol 1984; 26:404.

65. Makosiej FJ, Hoffman RS, Howland MA, et al: An in vitro evaluation of cocaine hydrochloride adsorption
by activated charcoal and desorption upon addition of polyethylene glycol electrolyte lavage solution. J
Toxicol Clin Toxicol 1993; 31:381.

66. Mann KV, Picciotti MA, Spevack TA, Durbin DR: Management of acute iron overdose. Clin
Pharm 1989; 8:428.

67. Marc B, Baud FJ, Aelion MJ, et al: The cocaine body-packer syndrome: Evaluation of a method of
contrast study of the bowel. J Forensic Sci 1990; 35:345.

68. Marc B, Gherardi RK, Baud FJ, et al: Managing drug dealers who swallow the evidence.
BMJ 1989; 299:1082.

69. Mariani PJ, Pool N: Gastrointestinal tract perforation with charcoal peritoneum complicating orogastric
intubation and lavage. Ann Emerg Med 1993; 132:606.

70. McCarron MM, Wood JD: The cocaine bodypacker syndrome. JAMA 1983; 250:1417.

71. McKinney PE, Phillips S, Gomez HF, et al: Corneal abrasions secondary to activated charcoal. Am J
Emerg Med 1993; 11:562.
72. McNamara RM, Aaron CK, Gemborys M, et al: Efficacy of charcoal and cathartic versus ipecac in
reducing serum acetaminophen in a simulated overdose. Ann Emerg Med 1989; 18:934.

73. Melandri R, Re G, Morigi A, et al: Whole bowel irrigation after delayed release fenfluramine overdose.
J Toxicol Clin Toxicol 1995; 33:161.

74. Menzies DG, Busuttil A, Prescott LF: Fatal pulmonary aspiration of oral activated charcoal.
BMJ 1988; 297:459.

75. Merigian KS, Woodard M, Hedges JR, et al: Prospective evaluation of gastric emptying in the self
poisoned patient. Am J Emerg Med 1990; 8:479.

76. Minocha A, Herold DA, Barth JT, et al: Activated charcoal in oral ethanol absorption: Lack of effect in
humans. J Toxicol Clin Toxicol 1986; 24:225.

77. Minocha A, Krenzolek EP, Spyker DA: Dosage recommendations for activated charcoal-sorbitol
treatment. J Toxicol Clin Toxicol 1985; 23:579.

78. Mizutani T, Yamashita M, Okubo N, et al: Efficacy of whole bowel irrigation using solutions with or
without adsorbent in the removal of paraquat in dogs. Hum Exp Toxicol 1992; 11:495.

79. Neuvonen PJ: Clinical pharmacokinetics of oral activated charcoal in acute intoxications. Clin
Pharmacokinet 1982; 7:465.

80. Neuvonen PJ, Elonen E: Effect of activated charcoal on absorption and elimination of phenobarbitone,
carbamazepine, and phenylbutazone in man. Eur J Pharmacol 1980; 17:51.

81. Neuvonen PJ, Kannisto H, Alanen T et al. Effect of activated charcoal on the absorption of tolbutamide
and valproate in man [abstract]. Joint meeting of the British and Scandinavian Pharmacological Societies,
July 4–6, 1982.

82. Neuvonen PJ, Karkkainen S: Effects of charcoal, sodium bicarbonate, and ammonium chloride on
chlorpropamide kinetics. Clin Pharmacol Ther 1983; 33:386.

83. Neuvonen PJ, Olkkola KT: Oral activated charcoal in the treatment of intoxications: Role of single and
repeated doses. Med Toxicol 1988; 3:33.

84. Neuvonen PJ, Olkkola KT: Activated charcoal and syrup of ipecac in prevention of cimetidine and
pindolol absorption in man after administration of metoclopramide as an antiemetic agent. Clin
Toxicol 1984; 22:103.

85. Neuvonen PJ, Variainen M, Tokola O: Comparison of activated charcoal and ipecac syrup in prevention
of drug absorption. Eur J Clin Pharmacol 1983; 24:557.

86. Oderda GM, Klein-Schwartz W, Insley BM: In vitro study of boric acid and activated charcoal. Clin
Toxicol 1987; 25:13.

87. Olsen KM, Ma FH, Ackerman BH, Stall RE: Low-volume whole bowel irrigation and salicylate
absorption: A comparison with ipecac charcoal. Pharmacotherapy 1993; 13:229.

88. Orisakwe OE, Obi N: In vitro and in vivo adsorption studies of diazinon. Hum Exp
Toxicol 1993; 12:301.

90. Picchioni AL, Chin L, Laird HE: Activated charcoal preparations— relative antidotal efficacy. Clin
Toxicol 1974; 7:97.

91. Picchioni AL, Chin L, Verhulst HL, et al: Activated charcoal vs. universal antidote as an antidote for
poisons. Toxicol Appl Pharmacol 1966; 8:447.

92. Pollack MM, Dunbar BS, Holbrook PR, et al: Aspiration of activated charcoal and gastric contents. Ann
Emerg Med 1981; 10:528.

93. Pond SM, Lewis-Driver DJ, Williams GM, et al: Gastric emptying in acute overdose: A prospective
randomised controlled trial. Med J Aust 1995; 163:345.

94. Rau NR, Nagara MV, Prakesh PS, et al: Fatal pulmonary aspiration of activated charcoal.
BMJ 1988; 297:918.

95. Ray MJ, Padin R, Condie JD, et al: Charcoal bezoar: Small bowel obstruction secondary to amitriptyline
overdose therapy. Dig Dis Sci 1988; 33:106.

96. Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg
Med 1992; 10:577.

97. Roberts JR, Price D, Goldfrank L, et al: The bodystuffer syndrome: A clandestine form of drug overdose.
Am J Emerg Med 1986; 4:24.

98. Rose SR, Gorman RL, Oderda GM, et al: Simulated acetaminophen overdose: Pharmacokinetics and
effectiveness of activated charcoal. Ann Emerg Med 1991; 20:1064.

99. Rosenberg PJ, Livingstone DJ, McLellan BA: Effect of whole-bowel irrigation on the antidotal efficacy of
oral activated charcoal. Ann Emerg Med 1988; 17:681.

100. Scharman EJ, Lembarsky R, Krenzelok EP: Efficacy of whole bowel irrigation with and without
metoclopramide pretreatment. Am J Emerg Med 1994; 12:302.

102. Smith RP, Gosselin RE, Henderson JA, et al: Comparison of the adsorptive properties of activated
charcoal and Alaskan montmorillonite for some common poisons. Toxicol Appl Pharmacol 1967; 10:95.

103. Smith SW, Ling LJ, Halstenson CE: Whole-bowel irrigation as a treatment for acute lithium overdose.
Ann Emerg Med 1991; 20:536.

104. Suarez CA, Arango A, Lester III JL: Cocaine-condom ingestion: Surgical treatment.
JAMA 1977; 238:1391.

105. Szabuniewicz M, Bailey EM, Wiersig DO: A new regimen for the treatment of ethylene glycol
poisoning. IRCS Medical Science 1975; 3:102.

106. Tenenbein M: Whole bowel irrigation as a gastrointestinal decontamination procedure after acute
poisoning. Med Toxicol 1988; 3:77.

108. Tenenbein M: Whole bowel irrigation for toxic ingestions. Clin Toxicol 1985; 23:177.
109. Tenenbein M, Cohen S, Sitar DS: Whole bowel irrigation as a decontamination procedure after acute
drug overdose. Arch Intern Med 1987; 147:905.

110. Tenenbein M, Cohen S, Sitar DS: Efficacy of ipecac-induced emesis, orogastric lavage, and activated
charcoal for acute overdose. Ann Emerg Med 1987; 16:838.

111. Tomaszewski C, McKinney P, Phillips S, et al: Prevention of toxicity from oral cocaine by activated
charcoal in mice. Ann Emerg Med 1993; 22:1804.

112. Trent MS, Kim U: Cocaine packet ingestion. Arch Surg 1987; 122:1179.

113. Vale JA, Proudfoot AT: How useful is activated charcoal?. BMJ 1993; 306:78.

114. Watson WA, Cremer KF, Chapman JA: Gastrointestinal obstruction associated with multiple dose
activated charcoal. J Emerg Med 1986; 4:401.

115. Welch DW, Johnson PN, Driscoll JL, et al: In vitro potassium binding: A comparison, of activated
charcoal and sodium polystyrene sulfonate. Vet Hum Toxicol 1986; 28:495.

116. Wetli CV, Mittleman RE: The “body packer syndrome”—toxicity following ingestion of illicit drugs
packaged for transportation. J Forensic Sci 1981; 26:492.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/35.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Uncited references

Katona BG, Siegel EG, Roberts JR, et al: The effect of “superactive” charcoal and magnesium citrate
solution on blood ethanol concentration and area under the curve in humans. J Toxicol Clin
Toxicol 1989; 27:129.

Palatnick W, Tenenbein M: Activated charcoal in the treament of drug overdose. Drug Safety 1992; 7:3.

Schneider SM, Michelson EA: Enhanced activated charcoal delivery through small-bore tubing. Vet Hum
Toxicol 1993; 35:503.

Tenenbein M: Whole bowel irrigation in iron poisoning. J Pediatr 1987; 111:142.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/36.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 6 – Extracorporeal Removal of Drugs and Toxins


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
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

Weight Volume of
Toxin Serum Level (Daltons) Distribution (L/kg) Protein Binding Modality
Ethylene 50 mg/dL 62 0.6–0.7 Negligible HD
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
Methotrexate (high flux)
Paraquat (very early)
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

ß-Adrenergic receptor antagonists (atenolol, sotalol)
Thyroid hormone
Valproic acid

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


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
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

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 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

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

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 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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/37.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.


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 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


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 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.

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/38.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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, 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.


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

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]


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/39.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Alvan G, Bergman U, Gustafsson LL: High unbound fraction of salicylate in plasma during intoxication.
Br J Clin Pharmacol 1981; 11:625.

2. Arnow PM, Bland LA, Garcia-Houchins S, et al: An outbreak of fatal fluoride intoxication in a long-term
hemodialysis unit. Ann Intern Med 1994; 121:339.

3. Aronoff GR, Berns JS, Brier ME, et al: Drug Prescribing in Renal Failure, Philadelphia: American
College of Physicians; 1999.

4. Bellomo R, Kearly Y, Parkin G, et al: Treatment of life-threatening lithium toxicity with continuous arterio-
venous hemodiafiltration. Critical Care Med 1991; 19:836.

5. Brent J, McMartin K, Phillips S, et al: Fomepizole treatment of ethylene glycol poisoning. N Engl J
Med 1999; 340:832.

6. Burwen DR, Olsen SM, Bland LA, et al: Epidemic aluminum intoxication in hemodialysis patients traced
to use of an aluminum pump. Kidney Int 1995; 48:469.

7. Cutler RE, Forland SC, John St, Hammond PG, Evans JR: Extracorporeal removal of drugs and poisons
by hemodialysis and hemoperfusion. Annu Rev Pharmacol Toxicol 1987; 27:169.

8. Eaton JW, Kolpin CF, Swofford HS, et al: Chlorinated urban water: A cause of dialysis-induced hemolytic
anemia. Science 1973; 181:463.

9. Ekins BR, Rollins DE, Duffy DP, et al: Standardized treatment of severe methanol poisoning with ethanol
and hemodialysis. West J Med 1985; 142:337.

10. Fine RN, Tejani A: Dialysis in infants and children. In: Daugirdas JT, Ing TS, ed. Handbook of Dialysis,
Boston: Little, Brown; 1994:553-568.

11. Ford MD, Sivilotti MLA: Alcohols and glycols. In: Irwin RS, Cerra FB, Rippe JM, ed. Irwin and Rippe’s
Intensive Care Medicine, 4th ed. Philadelphia: Lippincott-Raven; 1999:1478-1493.

12. Freeman RM, Lawton RL, Chamberlain MA: Hard-water syndrome. N Engl J Med 1967; 276:1113.

13. Garella S: Extracorporeal techniques in the treatment of exogenous intoxications. Kidney

Int 1988; 33:735.

14. Garrettson LK, Geller RJ: Acid and alkaline diuresis: When are they of value in the treatment of
poisoning. Drug Safety 1990; 5:220.

15. Gentilello LM, Cobean RA, Offner PJ, et al: Continuous arteriovenous rewarming: Rapid reversal of
hypothermia in critically ill patients. J Trauma 1992; 32:316.

16. Gordon SM, Bland LA, Alexander SR, et al: Hemolysis associated with hydrogen peroxide at a pediatric
dialysis center. Am J Nephrol 1990; 10:123.
17. Gordon SM, Drachman J, Bland LA, et al: Epidemic hypotension in a dialysis center caused by sodium
azide. Kidney Int 1990; 37:110.

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:
Plasmapheresis and hemoperfusion.
In: Jacob C, Kjellstrand CM, Kock KM, Winchester JF, ed. Replacement of Renal Function by Dialysis,
Dordrecht: Kluwer Academic; 1996.

20. Hansen HE, Amdisen A: Lithium intoxication: Report of 23 cases and review of 100 cases from the
literature. Q J Med 1978; 186:123.

21. Hoy RH: Accidental systemic exposure to sodium hypochlorite (Chlorox) during hemodialysis. Am J
Hosp Pharm 1981; 38:1512.

22. Jacobsen D, Jansen H, Wilk-Larsen E, et al: Studies on methanol poisoning. Acta Med
Scand 1982; 212:5.

23. Jacobsen D, McMartin KE: Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin
Toxicol 1997; 35:127.

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
intoxication. Med Toxicol 1988; 3:418.

26. Jacobsen D, Wilk-Larsen E, Dahl T, et al: Pharmacokinetic evaluation of haemoperfusion in

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
hemodialysis. Am J Kidney Dis 1999; 33:786.

29. Kerns W, Tomaszewski C, McMartin K, et al: Formate kinetics in methanol poisoning [abstract]. J
Toxicol Clin Toxicol 1999; 37:669.

30. Larsen LS, Sterrett JR, Whitehead B, Marcus SM: Adjunctive therapy of phenytoin overdose: A case
report using plasmapheresis. J Toxicol Clin Toxicol 1986; 24:37.

31. Leblanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance

continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996; 27:365.

32. Lim PS, Lim JL: Continuous arteriovenous hemoperfusion in acute poisoning. Ann Emerg
Med 1995; 26:725.

33. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 Annual Report of the American Association of
Poison Control Centers. Am J Emerg Med 1999; 17:435.
34. Malluche HH, Smith AJ, Abreo K, Faugere MC: The use of desferoxamine in the management of
aluminum accumulation in bone in patients with renal failure. N Engl J Med 1984; 311:140.

35. Manns M, Sigler MH, Teehan BP: Continuous renal replacement therapies: An update. Am J Kidney
Dis 1998; 32:185.

36. Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia: A new complication of
hemodialysis. Ann Intern Med 1970; 73:409.

37. Mehta RL, Dobos GJ, Ward DM: Anticoagulation in continuous renal replacement therapy. Semin
Dial 1992; 5:61.

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
ethylene glycol poisoning. J Toxicol Clin Toxicol 1998; 36:659.

40. Nickey WA, Chinitz VL, Kim DE, et al: Hypernatremia from water softener malfunction during home
dialysis. JAMA 1970; 214:915.

41. Orringer EP, Mattern WD: Formaldehyde-induced hemolysis during chronic hemodialysis. N Engl J
Med 1976; 294:1416.

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.

44. Petrie JJB, Row PG: Dialysis anaemia caused by subacute zinc toxicity. Lancet 1977; 1:1178.

45. Pond SM: Extracorporeal techniques in the treatment of poisoned patients. Med J Aust 1991; 154:617.

46. Roberts M, Daugirdas JT: REDY sorbent hemodialysis. In: Daugirdas JT, Ing TS, ed. Handbook of
Dialysis, Boston: Little, Brown; 1994.

47. Sabeel AI, Kurkus J, Lindholm T: Intensified dialysis treatment of ethylene glycol intoxication. Scand J
Urol Nephrol 1995; 29:125.

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,
Rockville, MD, USDHHS, 1986.

50. Vaziri ND, Upham T, Barton CH: Hemodialysis clearance of arsenic. J Toxicol Clin
Toxicol 1980; 17:451.

51. Winchester JF: Use of dialysis and hemoperfusion in treatment of poisoning.

In: Daugirdas JT, Ing TS, ed. Handbook of Dialysis, Boston: Little, Brown; 1994.
52. Woo OF, Pond SM, Benowitz NL, Olson KR: Benefit of hemoperfusion in acute theophylline intoxication.
J Toxicol Clin Toxicol 1984; 22:411.

53. Yip L, Dart RC, Gabow PA: Concepts and controversies in salicylate toxicity. Emerg Med Clin North
Am 1994; 12:351.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/40.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 7 – Laboratory Testing in Emergency Toxicology



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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/41.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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
Spectrometric †
Immunoassay †
Some ‡
Thin-layer chromatography
Gas chromatography
Yes ‡
High-performance liquid chromatography
Yes ‡
Gas chromatography–mass spectrometry
Yes ‡
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.


Table 7-2 -- Qualitative Toxicologic Methods Used in Urine

Spot, SC
TD (<1 d), OD
Salicylamide, diflunisal, ketonuria, phenylketonuria, proteinuria, sulfonamides, hippuric acids (from toluene,
xylene ‡ )
Acetaminophen (p -aminophenol detected)
Spot, SC
TD (<1 d), OD
N -acetylcysteine, phenols from throat lozenges and mouthwashes ‡ , proteinuria
Phenothiazines (metabolites)
Forrest or ferric-perchlorate-nitric (FPN)
TD for some (<3 d), OD
Salicylates, ketonuria ‡ , proteinuria
Spot, SC
OD (<3 d)

Tetrabromophenophthalein ethyl ester
Other opiates, antihistamines, antipsychotics ‡
Chloral hydrate (trichloroethanol)
OD (<2 d)
Chlorinated hydrocarbons ‡
Opiates (morphine, codeine)
RD (<3 d), OD
Other opiates (hydrocodone, hydromorphone, oxycodone, dihydrocodeine), morphine from poppy seeds,
adulterants § , rifampin, ofloxacin
RD (<4 d), OD
Other less used barbiturates, NSAIDs # ¤ , adulterants §
Benzodiazepine (metabolites)
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)
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)
RD (<2 wk, <2 mo (if chronic), OD
Adulterants §
Cocaine (benzoylecgonine)
RD (<2 d), OD
Few; teas made from coca leaf, adulterants §
RD (<1 wk), OD
PCP analogs, chlorpromazine, diphenhydramine, dextromethorphan
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-

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
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
Cephalosporins; sulfonamides
Fetal hemoglobin
Bromide (0.8 mEq Cl = 1 mEq Br)
SC *
Ketoacidosis (may increase creatinine up to 2–3 mg/dL); cephalosporins; creatine (e.g., with rhabdomyolysis),
Lidocaine metabolite, 5-fluorouracil
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)
Ethylene glycol
SC *
Other glycols; elevated triglycerides
Propylene glycol
Deferoxamine causes 15% lowering of total iron-binding capacity (TIBC); Lavender-top Vacutainer tube contains
EDTA, which lowers total iron
Skin disinfectant containing isopropyl alcohol used before venipuncture (highly variable, usually trivial, but up to
40 mg/dL)
Green-top Vacutainer specimen tube (contains lithium heparin) may cause marked elevation (up to 6–8 mEq/L)
Quinidine, procainamide
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
Falsely decreased level with in vitro spontaneous reduction to hemoglobin in Vacutainer tube (~10%/hr); analyze
within 1 hr
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)
Diflunisal > ketosis, salicylamide; accumulated salicylate metabolites in patients with renal failure (~10%
Decreased or altered salicylate level with bilirubin; phenylketones
SC *
Diazepam; caffeine; accumulated theophylline metabolite
Acetazolamide; cephalosporins; endogenous xanthines; theophylline metabolites in renal failure (minor effect)
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.


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
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 ]
R, chart review
Helliwell (1979)[19 ]
P, verbal, chart
ED coma
Bury (1981)[6 ]
R, chart review
OD *
Mahoney (1987)[29 ]
Kellermann (1987)[24 ]
4.4 (66.3) †
P, questionnaire before/after
Brett (1988)[4 ]
R, records review
Intentional OD
ED, emergency department patients suspected of drug toxicity; OD, overdosed patients; P, prospective; R,
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

Bookmark URL: /das/book/0/view/1013/42.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Concentration Rationale for
Drug/Toxin Clinical Presentation * Criteria Therapy † Intervention
Acetaminophen History or none >150 µg/mL @ 4 NAC Prevent hepatotoxicity
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

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/43.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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]


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
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/44.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Auerbach PS, Osterloh J, Braun O, et al: Efficacy of gastric emptying: Gastric lavage vs. emesis induced
with ipecac. Ann Emerg Med 1986; 15:692.

2. Bailey DN: Changing trends in drug abuse [abstract]. California Association of Toxicologists Newsletter,
winter 1990, p 20.

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; 313:474.

4. Brett AS: Implications of discordance between clinical impression and toxicology analysis in drug
overdose. Arch Intern Med 1988; 148:437.

5. Brett AS, Rothschild N, Gray R, et al: Predicting the clinical course in intentional drug overdose:
Implications for use of the intensive care unit. Arch Intern Med 1987; 147:133.

6. Bury RW, Mashford ML: Use of a drug-screening service in an inner-city teaching hospital. Med J
Aust 1981; 1:132.

7. California Association of Toxicologists Newsletter, summer 1995, pp 13–16.

8. Callahan M: Tricyclic antidepressant overdose. JACEP 1979; 8:413.

9. Caplan YH, Ottinger WE, Park J, et al: Drug and chemical related deaths: Incidence in the state of
Maryland—1975 to 1980. J Forensic Sci 1985; 30:1012.

10. College of American Pathologists—CAP Surveys; Urine Toxicology Survey 1995 Set UT-B; Therapeutic
Drug Monitoring Survey 1995 Set Z-B; Chemistry Survey 1995 Set C4–B., Northfield, College of American
Pathologists, 1995.

12. Ellenhorn MJ, Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning, New
York, Elsevier, 1988.

13. Fazen LE, Lovejoy FH, Crone RK, et al: Acute poisoning in a children’s hospital: A 2-year experience.
Pediatrics 1986; 77:144.

14. Ferrara SD, Tedeschi L, Frison G, et al: Drugs-of-abuse testing in urine: Statistical approach and
experimental comparison of immunochemical and chromatographic techniques. J Anal
Toxicol 1994; 18:278.

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
immunoassay. Clin Chem 1994; 40:1606.
18. Griner PF, Glaser RJ: Misuse of laboratory tests and diagnostic procedures. N Engl J
Med 1982; 307:1336.

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.
Study of an integrated approach. J Toxicol Clin Toxicol 1984–1985; 22:503.

21. Jacobsen D, Fredericksen PS, Knutsen KM, et al: A prospective study of 1212 cases of acute poisoning:
General epidemiology. Hum Toxicol 1984; 3:93.

23. Kellerman AL, Fihn SD, Logerfro JP, et al: Utilization and yield of drug screening in the emergency
department. Am J Emerg Med 1988; 6:14.

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.

26. Kulig K: Utilization of emergency toxicology screens. Am J Emerg Med 1985; 6:573.

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.

28. Litovitz TL, Felberg L, White S, Klein-Schwartz W: 1995 annual report of the American Association of
Poison Control Centers: Toxic Exposure Surveillance System. Am J Emerg Med 1996; 14:487.

29. Mahoney JD, Gross PL, Stern TA: The use of the toxic screen in the management of overdosed patients
[abstract]. Vet Hum Toxicol 1987; 29:474.

30. Mikkelsen SL, Ash KO: Adulterants causing false negatives in illicit drug testing. Clin
Chem 1988; 34:2333.

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.

32. Norton LE, Garriott JC, Di Maio VJM: Drug detection at autopsy: A prospective study of 247 cases. J
Forensic Sci 1982; 27:61.

33. Olson KR: Comprehensive evaluation and treatment of poisoning and overdose. In: Olson KR, et
al ed. Poisoning and Drug Overdose, 2nd ed. Norwalk, CT: Appleton and Lange; 1994:1-58.

34. Osterloh JD: Utility and reliability of emergency toxicologic testing. Emerg Med Clin North
Am 1990; 8:693.

35. Prescott LF: Limitations of hemodialysis and forced diuresis. In: Curry AS, ed. Symposium on the
Poisoned Patient—Role of the Laboratory. CIBA Foundation Symposium, New York: Elsevier; 1974:278-

36. Rosenberg J, Benowitz NL, Pond S: Pharmacokinetics of drug overdose. Clin

Pharmacokinet 1981; 6:161.

37. Rygnestad T, Berg KJ: Evaluation of benefits of drug analysis in the routine clinical management of
acute self-poisoning. J Toxicol Clin Toxicol 1984; 22:51.

38. Sanguineti VR, Samuel SE: Comorbid substance abuse and recovery from acute psychiatric relapse.
Hosp Community Psych 1993; 44:1073.

39. Schwartz JG, Stuckey JH, Prihoda TJ, et al: Hospital-based toxicology: Patterns of use and abuse. Tex
Med 1990; 86:44.

40. Schwarzhoff R, Cody JT: The effects of adulterating agents on FPIA analysis of urine for drugs of
abuse. J Anal Toxicol 1993; 17:14.

41. Spiehler VR, O’Donnell CM, Gokhale DV: Confirmation and certainty in toxicologic screening. Clin
Chem 1988; 34:1535.

42. Tarcher AB: Principles and Practice of Environmental Medicine, New York, Plenum Medical Book
Company, 1992.

43. Teitelbaum DT, Morgan J, Gray G: Nonconcordance between clinical impression and laboratory findings
in clinical toxicology. Clin Tox 1977; 10:417.

44. Trinkoff AM, Baker SP: Poisoning hospitalizations and deaths from solids and liquids among children
and teenagers. Am J Public Health 1986; 76:657.

45. Wiltbank TB, Sine HE, Brody BB: Are emergency toxicology measurements really used?. Clin
Chem 1974; 20:116.

46. Wu AH, Forte E, Casella G, et al: CEDIA for screening drugs of abuse in urine and the effect of
adulterants. J Forensic Sci 1995; 40:614.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/45.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Uncited references

Dalrymple RW, Sterns FM: Diflunisal interferes with determination of salicylate by Trinder, Abbott TDx and
Dupont aca methods. Clin Chem 1986; 32:230.

Frings CS, Battaglia DJ, White RM: Status of drug-of-abuse testing in urine under blind conditions: An
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/46.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 8 – Radiology


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.

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
Iron tablets (except chewable vitamins with iron)
Contraband drug packets
Lead-containing products
Zinc sulfate tablets
Thallium-tainted foods
Elemental mercury
Button batteries
Paradichlorobenzene deodorizers/moth repellents
Carbon tetrachloride
Methylene iodide
Indirect Clues
Colonic Ileus
Cyclic antidepressants
Antiparkinsonian drugs
Anticholinesterase insecticides
Multiple-dose activated charcoal
Small Bowel Obstruction
Activated charcoal
Aluminum hydroxide antacids
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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/47.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Hydrochloric acid
Hydrofluoric acid
Sulfur dioxide
Sulfuric acid
Water Insoluble
Methyl bromide
Nitrogen dioxide
Carbon tetrachloride
Freon 11 (fluorocarbon 11)
Mineral seal oil
Gold salts
Cromolyn sodium
Metal Fumes
Nickel carbonyl
Polydimethylsiloxane (silicone)
Radiation therapy
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/48.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.


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
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]


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/49.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

Table 8-4 -- Toxins Causing Radiographic CNS Abnormalities

Phenytoin intoxication
Phenytoin therapy
Lithium therapy
Methyl mercury
Radiation therapy
Adrenocorticotropic hormone (ACTH)
Cerebral Ischemia
Ergot derivatives
High-dose oral contraceptives
Sympathomimetic nasal decongestants
Carbon monoxide
Subarachnoid Hemorrhage
Cerebral Edema
Carbon monoxide
Ethylene glycol
Pentachlorophenol insecticides
Sodium valproate
Pseudotumor Cerebri
Vitamin A
Oral contraceptive agents
Nalidixic acid
Intracranial Hemorrhage
Anticoagulant drugs
Scorpion envenomation
Subdural Hematoma

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/50.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Amitai Y, Silver B, Leikin JB, et al: Visualization of ingested medications in the stomach by ultrasound.
Am J Emerg Med 1992; 10:18-23.

2. Ansell G: Radiology of Adverse Reactions to Drugs and Toxic Hazards, Rockville, MD, Aspen Systems
Corporation, 1985.

3. Aquilonius SM, Bergstrom K, Enoksson P, et al: Cerebral computed tomography in methanol intoxication.
J Comput Assist Tomogr 1980; 4:425-428.

4. Bagnasco FM, Stringer B, Muslim AM: Carbon tetrachloride poisoning—radiographic findings. NY State
J Med 1978; 78:646-647.

5. Balthazar EJ, Lefleur R: Abdominal complications of drug addiction: Radiologic features. Semin
Roentgenol 1983; 18:213-220.

6. Beerman R, Nunez D, Wetli CV: Radiographic evaluation of the cocaine smuggler. Gastrointest
Radiol 1986; 11:351-354.

7. Blickman JG, Wilkinson RH, Graef JW: The radiologic “lead band” revisited. AJR 1986; 146:245-247.

8. Brown JI, Coyne TJ, Hurlbert RJ, et al: Deep cerebral venous system thrombosis: Case report.
Neurosurg 1993; 33:911-913.

9. Bruns BR, Tytle T: Skeletal fluorosis: A report of two cases. Orthopedics 1988; 11:1083-1087.

10. Burkhart KK, Kulig KW, Rumack B: Whole-bowel irrigation as treatment for zinc sulfate overdose. Ann
Emerg Med 1990; 19:1167-1170.

11. Byrd RP, Morris CJ, Roy TM: Drug-induced pleural effusions. Kans Med Assoc J 1991; 89:71-73.

12. Cagin CR, Diloy-Puray M, Westerman MP: Bullets, lead poisoning, and thyrotoxicosis. Ann Intern
Med 1978; 89:509-511.

13. Caruana DS, Weinback B, Goerg D, et al: Cocaine-packet ingestion: Diagnosis, management, and
natural history. Ann Intern Med 1984; 100:73-74.

14. Chan YW: Magnetic resonance imaging in toxic encephalopathy due to podophyllin poisoning.
Neuroradiology 1991; 33:372-373.

15. Chastre J, Basset F, Viau F, et al: Acute pneumonitis after subcutaneous injection of silicone in
transexual men. N Engl J Med 1983; 30:764-767.

16. Crystal RG: Interstitial lung disease. In: Wyngaardern JB, Smith Jr LH, ed. Cecil Textbook of Medicine,
18th ed. Philadelphia: WB Saunders; 1988:432.

17. Daffner RH, Jimenez JP: The double gastric fluid level in kerosene poisoning.
Radiology 1973; 106:383-384.

18. Dally S, Garnier R, Bismuth C: Diagnosis of chlorinated hydrocarbon poisoning by xray examination.
Br J Indust Med 1987; 44:424-425.

19. Dillman RO, Crumb CK, Lidsky MJ: Lead poisoning from a gunshot wound: Report of a case and review
of the literature. Am J Med 1979; 66:509-514.

20. Douglass RE, Levison MA: Pneumothorax in drug abusers: An urban epidemic?. Am
Surg 1986; 52:377-380.

21. Everson GW, Oudjhane K, Young LW, et al: Effectiveness of abdominal radiographs in visualizing
chewable iron supplements following overdose. Am J Emerg Med 1989; 7:459-463.

22. Gadaleta D, Hall MH, Nelson RL: Cocaine-induced acute aortic dissection. Chest 1989; 96:1203-

23. Goulbourne KB, Cisek JE: Small bowel obstruction secondary to activated charcoal and adhesions.
Ann Emerg Med 1994; 24:108-110.

24. Graham JB: Doctor’s diplomacy. NC Med J 1992; 53:33-40.

25. Handy CA: Radiopacity of oral nonliquid medications. Radiology 1971; 98:525-533.

26. Hantsen P, Duprez T, Mahieu P: Neurotoxicity to the basal ganglia shown by magnetic resonance
imaging (MRI) following poisoning by methanol and other substances. Clin Toxicol 1997; 35:151-161.

27. Hart RG, Boop BS, Anderson DC: Oral anticoagulants and intracranial hemorrhage: Facts and
hypotheses. Stroke 1995; 26:1471-1477.

28. Haubek A, Lee K: Computed tomography in alcoholic cerebellar atrophy. Neuroradiology 1979; 18:77-

29. Hillbom M, Muuronen A, Holm L, et al: The clinical versus radiological diagnosis of alcoholic cerebellar
degeneration. J Neurol Sci 1986; 73:45-53.

30. Hoffman RS, Smilkstein MJ, Goldfrank LR: Whole bowel irrigation and the cocaine body-packer: A new
approach to a common problem. Am J Emerg Med 1990; 8:523-527.

31. Jones G, Sambrook PN: Drug-induced disorders of bone metabolism: Incidence, management and
avoidance. Drug Safety 1994; 10:480-489.

32. Kikano GE, Stange KC: Lead poisoning in a child after a gunshot injury. J Fam
Practitioner 1992; 34:498-500.

33. King TE: Bronchiolitis obliterans. Lung 1989; 167:69-93.

34. Kram HB, Hardin E, Clark SR, et al: Perforated ulcers related to smoking “crack” cocaine. Am
Surgeon 1992; 58:293-294.

35. Litovitz TL: Button battery ingestions: A review of 56 cases. JAMA 1983; 249:2495-2500.
36. Masur H, Fahrendorf G, Oberwittler C, et al: Cerebellar atrophy following acute intoxication with
phenytoin. Neurology 1990; 40:1800-1801.

37. Matsumoto SC, Okajima T, Inayoshi S, et al: Minamata disease demonstrated by computed
tomography. Neuroradiology 1988; 30:42-46.

38. McCarron MM, Wood JD: The cocaine body packer syndrome: Diagnosis and treatment.
JAMA 1983; 250:1417-1420.

39. Meggs WJ, Gerr F, Aly MH, et al: The treatment of lead poisoning from gunshot wounds with succimer
(DMSA). Clin Toxicol 1994; 32:377-385.

40. Messing B, Storch B: Computer tomography and magnetic resonance imaging in cyanide poisoning.
Eur Arch Psychiatr Neurol Sci 1988; 237:139-143.

41. Miura T, Mitomo M, Kawai R, et al: CT of the brain in acute carbon monoxide intoxication: Characteristic
features and prognosis. AJNR 1985; 6:739-742.

42. Morgan BW, Tomaszewski CA, Rotker I: Spontaneous hemoperitoneum from Brodifacoum overdose.
Am J Emerg Med 1996; 14:656-659.

43. Ng RC, Perry K, Martin DJ: Iron poisoning: Assessment of radiography in diagnosis and management.
Clin Pediatr 1979; 18:614-646.

44. O’Brien RP, McGeehan PA, Helmeczi AW, et al: Detectability of drug tablets and capsules by plain
radiography. Am J Emerg Med 1986; 4:302-312.

45. Ohri SK, Patel T, Desa L, et al: Drug-induced colonic pseudo-obstruction. Report of a case. Dis Colon
Rectum 1991; 34:347-351.

46. Pollack CV, Biggers DW, Carlton FB, et al: Two crack cocaine body stuffers. Ann Emerg
Med 1992; 21:1370-1380.

47. Reed CR, Glauser FL: Drug-induced noncardiogenic pulmonary edema. Chest 1991; 100:1120-1124.

48. Resnick D: Heavy metal poisoning and deficiency. In: Resnick D, Niwayama G, ed. Diagnosis of Bone
and Joint Disorders, 2nd ed. Philadelphia: WB Saunders; 1988:3102-3114.

49. Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg
Med 1992; 10:577-583.

50. Roberts JR, Price D, Goldfrank L, et al: The bodystuffer syndrome: A clandestine form of drug overdose.
Am J Emerg Med 1986; 4:24-27.

51. Rosenberg NL, Kleinschmidt-DeMasters BK, Kavis KA, et al: Toluene abuse causes diffuse central
nervous system white matter changes. Ann Neurol 1988; 23:611-614.

52. Savitt DL, Hawkins HH, Roberts JR: The radiopacity of ingested medications. Ann Emerg
Med 1987; 16:331-339.

53. Schwartz DT, Goldfrank L: Toxicologic imaging. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et
al ed. Toxicologic Emergencies, 5th ed. Norwalk, CT: Appleton & Lange; 1994:110.
54. Sinner WN: The gastrointestinal tract as a vehicle for drug smuggling. Gastrointest
Radiol 1981; 6:319-323.

55. Sogge MR, Griffith JL, Sinar DR, et al: Lavage to remove enteric-coated aspirin and gastric outlet
obstruction. Ann Intern Med 1977; 87:721-722.

56. Stromberg BV: Symptomatic lead toxicity secondary to retained shotgun pellets: Case report. J
Trauma 1990; 30:356-357.

57. Sussman S, Goldberg RP, Glotzer DJ: Aluminum hydroxide gel bezoar—CT diagnosis. J Can Assoc
Radiol 1985; 36:148-149.

58. Walters JS, Woodring JH, Stelling CB, et al: Salicylate induced pulmonary edema.
Radiology 1983; 146:289-293.

59. Weimerskirch PJ, Burkhart KK, Bono MJ, et al: Methylene iodide poisoning. Ann Emerg
Med 1990; 19(10):1171-1176.

60. Woolf AD, Saperstein A, Zawin J, et al: Radiopacity of household deodorizers, air fresheners, and moth
repellents. Clin Toxicol 1993; 31:415-428.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/51.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 9 – Pharmacokinetics and Toxicokinetics


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 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]


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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/52.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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 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
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 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
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/53.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/54.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/55.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/56.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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.

15. Rose SR, Gorman RL, Oderda GM, et al: Simulated acetaminophen overdose: Pharmacokinetics and
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/57.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 10 – Fluids and Electrolytes


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.


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,

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.



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
Other or Unknown Mechanism
Tricyclic antidepressants (amitriptyline)
Nontricyclic antidepressants
MAO inhibitors
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.


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 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.

Clinical Presentation

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.

Differential Diagnosis

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]


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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/58.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.



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.

Clinical Presentation

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]

Differential Diagnosis
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
Beta-adrenergic agonists
Other, Unknown, or Mixed Mechanisms
Barium (soluble salts)
Clay (geophasia)
Methyl mercury
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.


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 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

Clinical Presentation

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]

Differential Diagnosis

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.


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/59.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.



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.

Clinical Presentation

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]

Differential Diagnosis

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

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)
Microsomal Oxidizing System Induction
Hypercalcemia Hypocalcemia
Inhibition of Bone Resorption
Other or Unknown Mechanism
Foscarnet *

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.


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



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]

Clinical Presentation

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]

Differential Diagnosis

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]


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/60.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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]



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.

Clinical Presentation

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.

Differential Diagnosis

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
Diuretics (loop, thiazide, osmotic)
Growth hormone
Thyroid hormone
Increased Gastrointestinal Loss
Transcellular Shift into Cells
Cardiac glycosides
Other or Unknown Mechanism
Fluoride poisoning
Data from references 1 , 2 , 41 , 45 , 61 and 64 .


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]


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]

Differential Diagnosis

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]


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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/61.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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]



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]

Clinical Presentation

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]

Differential Diagnosis

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
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
Bicarbonate salts
Steroids (chronic)
Transcellular Shift into Cells
Other or Unknown Mechanism
Ethanol (chronic, withdrawal)
Data from references 12 , 22 , 34 , 41 , 55 , 61 , 62 , 66 , 72 , 78 and 96 .


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]


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]

Differential Diagnosis

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]


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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/62.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Gastrointestinal Decontamination

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]


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]


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.


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/63.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Al-Harbi NN, Domrongkitchaiporn S, Lirenman DS: Hypocalcemia and hypomagnesemia after ibuprofen
overdose. Ann Pharmacother 1997; 31:432-434.

2. Agus ZS, Wasserstein A, Goldfarb S: Disorders of calcium and magnesium homeostasis. Am J

Med 1982; 72:473-488.

3. Allerton JP, Strom JA: Hypernatremia due to repeated doses of charcoal-sorbitol. Am J Kidney
Dis 1991; 17:581-584.

4. Allon M, Dunlay R, Copkney C: Nebulized albuterol for acute hyperkalemia in patients on hemodialysis.
Ann Intern Med 1989; 110:426-429.

5. Alpern RJ, Saxton CR, Seldin DW: Clinical interpretation of laboratory values.
In: Tannen R, Kokko JP, ed. Fluid and Electrolytes, Philadelphia: WB Saunders; 1990:3-58.

6. American Academy of Clinical Toxicology, European Association of Poison Centres and Clinical
Toxicologists: Position statement: Gastric lavage. Clin Toxicol 1997; 35:711-719.

7. Antman EM, Wenger TL, Butler VP, et al: Treatment of 150 cases of life-threatening digitalis intoxication
with digoxin-specific fab antibody fragments. Circulation 1990; 81:1744-1752.

8. Barer J, Hill LL, Hill RM, Martinez WM: Fatal poisoning from salt used as an emetic. Am J Dis
Child 1973; 125:889-890.

9. Beck DE, Harford FJ, DiPalma JA, et al: Bowel cleansing with polyethylene glycol electrolyte lavage
solution. South Med J 1985; 78:1414-1416.

10. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 1992; 326:1196-1203.

11. Blevins LS, Wand GS: Diabetes insipidus. Crit Care Med 1992; 20:69-79.

12. Bourke E, Yanagawa N: Assessment of hyperphosphatemia and hypophosphatemia. Clin Lab

Med 1993; 13:183-207.

13. Bradberry SM, Vale JA: Disturbances of potassium homeostasis in poisoning. Clin
Toxicol 1995; 33:295-310.

14. Brass EP, Thompson WL: Drug-induced electrolyte abnormalities. Drugs 1982; 24:207-228.

15. Brown RS: Potassium homeostasis and clinical implications. Am J Med 1984; 77(5A):3.

16. Chipperfield B: Magnesium and the heart. Am Heart J 1972; 93:679.

17. Chisholm MA, Mulloy AL, Taylor AT: Acute management of cancer-related hypercalcemia. Ann
Pharmacother 1996; 30:507-513.

18. Clemessy J, Favier C, Borron SW, et al: Hypokalaemia related to acute chloroquine ingestion.
Lancet 1995; 346:877-880.

19. Cluitmans FHM, Meinders AE: Management of severe hyponatremia: Rapid or slow correction?. Am J
Med 1990; 88:161-166.

20. Connelly DM: Silver nitrate: Ideal burn wound therapy?. NY State J Med 1970; 70:1642-1644.

21. Davies DL, Fraser R: Do diuretics cause magnesium deficiency?. Br J Clin Pharmacol 1993; 36:1-10.

22. Davis RF, Eichner JM, Bleyer WA, et al: Hypocalcemia, hyperphosphatemia, and dehydration following
a single hypertonic phosphate enema. J Pediatr 1977; 90:484-485.

23. Delaney V, dePertuz Y, Nixon D: Indomethacin in streptozocin-induced nephrogenic diabetes insipidus.

Am J Kidney Dis 1987; 9:79-83.

24. DiPalma JR, Ritchie DM: Vitamin toxicity. Annu Rev Pharmacol Toxicol 1977; 17:133-148.

25. Douglas PS, Carmichael KA, Palevsky PM: Extreme hypercalcemia and electrocardiographic changes.
Am J Cardiol 1984; 54:674.

26. Eisenbud E, LoBue CC: Hypocalcemia after therapeutic use of magnesium sulfate. Arch Intern
Med 1976; 136:688-691.

27. Elisaf M, Merkouropoulos M, Tsianos EV, et al: Acid-base and electrolyte abnormalities in alcoholic
patients. Miner Electrolyte Metab 1994; 20:274-281.

28. Ettinger PO, Regan TJ, Oldewurtel HA: Hyperkalemia, cardiac conduction, and the electrocardiogram: A
review. Am Heart J 1974; 88:360-371.

29. Flink EB: Therapy of magnesium deficiency. Ann NY Acad Sci 1969; 162:901-905.

30. Forman J, Baluarte HJ, Gruskin AB: Hypokalemia after hypertonic phosphate enemas. J
Pediatr 1979; 94:149-151.

31. Foy A: Magnesium the neglected cation. Med J Aust 1980; 1:305-306.

32. Gabow PA: How to avoid overlooking salicylate intoxication. J Crit Care 1986; 1:77-85.

33. Gayet S, Ville E, Durand JM, et al: Foscarnet-induced hypercalcaemia in AIDS [letter].
AIDS 1997; 11:1068-1070.

34. Gerard JM, Luisiri A: A fatal overdose of arginine hydrochloride. Clin Toxicol 1997; 35:621-625.

35. Goldsmith RS: Multiple effects of phosphate therapy. N Engl J Med 1970; 282:927.

36. Gonzalez JJ, Owens W, Ungaro PC, et al: Clay ingestion: A rare cause of hypokalemia. Ann Intern
Med 1982; 97:65-66.

37. Guillaume MP, Karmali R, Bergmann P, Cogan E: Unusual prolonged hypocalcemia due to foscarnet in
a patient. Clin Infect Dis 1997; 25:932-933.

38. Guyton AC, Hall JE: Textbook of Medical Physiology, 9th ed. Philadelphia, WB Saunders, 1996.
39. Hoffman RS, Smilkstein MJ, Rubenstein F: An “amp” by any other name: The hazards of intravenous
magnesium dosing. JAMA 1989; 261:557.

40. Howes LG: Which drugs affect potassium?. Drug Safety 1995; 12:240-244.

41. Janson CL, Marx JA: Fluid and electrolyte balance. In: Rosen P, Barkin RM, ed. Emergency Medicine
Concepts and Clinical Practice, St. Louis: Mosby–Year Book; 1992:2132-2175.

42. Jones AF, Harvey JM, Vale JA: Hypophosphataemia and phosphaturia in paracetamol poisoning.
Lancet 1989; 2:608-609.

43. Jones J, Heiselman D, Dougherty J, et al: Cathartic-induced magnesium toxicity during overdose
management. Ann Emerg Med 1986; 15:1214-1218.

44. Kazal LA, Hall DL, Miller LG, et al: Fluoxetine-induced SIADH: A geriatric occurrence?. J Fam
Pract 1993; 36:341-343.

45. Kirkpatrick JJR, Enion DS, Burd DAR: Hydrofluoric acid burns: A review. Burns 1995; 21:483-493.

46. Kirschbaum B: The acidosis of exogenous phosphate intoxication. Arch Intern Med 1998; 158:405-

47. Kline JA, Tomaszewski CA, Schroeder JD, et al: Insulin is a superior antidote for cardiovascular toxicity
induced by verapamil in the anesthetized canine. J Pharm Exp Ther 1993; 267:744-767.

48. Knochel JP: The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern
Med 1977; 137:203-220.

49. Knochel JP: Diuretic-induced hypokalemia. Am J Med 1984; 77:11.

50. Knochel JP: Interactions of drugs with alcohol. Ann NY Acad Sci Med 1975; 242:272.

51. Leaf A: The clinical and physiologic significance of the serum sodium concentration. N Engl J
Med 1962; 267:24.

52. Lemann J, Pleuss JA, Gray RW: Potassium causes calcium retention in healthy adults. J
Nutr 1993; 123:1623-1626.

53. Lindeman RD, Papper S: Therapy of fluid and electrolyte disorders. Ann Intern Med 1975; 82:64-70.

54. Marsden PA, Halperin ML: Pathophysiological approach to patients presenting with hypernatremia. Am
J Nephrol 1985; 5:229-235.

55. Martin RR, Lisehora GR, Braxton M, et al: Fatal poisoning from sodium phosphate enema.
JAMA 1987; 257:2190-2192.

56. Masson A: Mesalazine associated nephrogenic diabetes insipidus presenting as a weight loss.
Gut 1992; 33:563-564.

57. Mizrahi A, London RD, Gribetz D: Neonatal hypocalcemia—its causes and treatment. N Engl J
Med 1968; 278:1163-1165.
58. Moder EG, Hurley DL: Fatal hypernatremia from exogenous salt intake: Report of a case and review of
the literature. Mayo Clin Proc 1990; 65:1587-1594.

59. Mofenson HC, Caraccio RR: Magnesium intoxication in a neonate from oral magnesium hydroxide
laxative. J Toxicol Clin Toxicol 1991; 29:215-222.

60. Moses AM, Miller M: Drug-induced dilutional hyponatremia. N Engl J Med 1974; 291:1234-1239.

61. Murray SS, Kramlinger KG, McMichan JC, et al: Acute toxicity after excessive ingestion of colchicine.
Mayo Clin Proc 1983; 58:528-532.

62. Narins RG, Jones ER, Stom MC, et al: Diagnostic strategies in disorders of fluid, electrolyte and acid-
base homeostasis. Am J Med 1982; 72:496-518.

63. Navarro JF, Quereda C, Quereda C, et al: Nephrogenic diabetes insipidus and renal tubular acidosis
secondary to foscarnet therapy. Am J Kidney Dis 1996; 27:431-434.

64. Nordt SP, Williams SR, Turchen S, et al: Hypermagnesemia following an acute ingestion of epsom salts
in a patient with normal renal function. Clin Toxicol 1996; 34:735-739.

65. Olinger ML: Disorders of calcium and magnesium metabolism. Emerg Med Clin North
Am 1989; 7:795-822.

66. Peppers MP, Geheb M, Desai T: Hypophosphatemia and hyperphosphatemia. Crit Care
Clin 1991; 7:201-214.

67. Peterson CD: Electrolyte depletion following emergency stomach evacuation. Am J Hosp
Pharm 1979; 36:1366-1369.

68. Ponce SP, Jennings AE, Madias NE, et al: Drug-induced hyperkalemia. Medicine 1985; 64:357-370.

69. Ramsahoye BH, Davies SV, El-Gaylani N, et al: The mineralocorticoid effects of high dose
hydrocortisone. BMJ 1995; 310:656-657.

70. Ramsay LE, Yeo WW, Jackson PR: Metabolic effects of diuretics. Cardiology 1994; 84(suppl 2):48-

71. Reber PM, Heath HI: Hypocalcemic emergencies. Med Clin North Am 1995; 79:93-106.

72. Reedy JC, Zwiren GT: Enema-induced hypocalcemia and hyperphosphatemia leading to cardiac arrest
during induction of anesthesia in an outpatient surgery center. Anesthesiology 1983; 59:578-579.

73. Rose BD: Clinical Physiology of Acid-Base and Electrolyte Disorders, 4th ed. New York, McGraw-
Hill, 1994.

74. Royston A, Prout BJ: Carbenoxolone-induced hypokalaemia simulating Guillain-Barre(c) syndrome.

BMJ 1976; 2:150-151.

75. Sacchetti A, Brilli R, Barkin RM: Fluid and electrolyte balance. In: Barkin RM, ed. Pediatric Emergency
Medicine: Concepts and Clinical Practice, St. Louis: CV Mosby; 1997:166.

76. Sakane N, Yoshida T, Umekawa T, Miyazaki R: Nephrogenic diabetes insipidus induced by lobenzarit
disodium treatment in patients with rheumatoid arthritis. Intern Med 1996; 35:119-122.

77. Scott R, Haywood JK, Buddy K, et al: Whole body calcium deficit in cadmium-exposed workers with
hypercalciuria. Urology 1980; 15:356.

78. Shields HM: Rapid fall of serum phosphorus secondary to antacid therapy.
Gastroenterology 1978; 75:1137-1141.

79. Shires T, Williams J, Brown F: Acute change in extracellular fluids associated with major surgical
procedures. Ann Surg 1961; 154:803-810.

80. Smilkstein MJ, Steedle D, Kulig KW, et al: Magnesium levels after magnesium-containing cathartics. J
Toxicol Clin Toxicol 1988; 26:51-65.

81. Smith TW, Antman EM, Friedman PL, et al: Digitalis glycosides: Mechanisms and manifestations of
toxicity. Prog Cardiovasc Dis 1984; 27:21-56.

82. Soreensen E, Tougaard L, Brochner-Mortensen J: Iatrogenic magnesium intoxication during 1-alpha-

hydroxycholecalciferol treatment. BMJ 1976; 2:215.

83. Soriano J: Potassium homeostasis and its disturbances in children. Pediatr Nephrol 1995; 9:364-374.

84. Sotos JF, Cutler EA, Finkel MA, et al: Hypocalcemic coma following two pediatric phosphate enemas.
Pediatrics 1977; 60:305-307.

85. Spencer H, Lender M: Adverse effects of aluminum-containing antacids on mineral metabolism.

Gastroenterology 1979; 76:603-606.

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
hyponatremia. N Engl J Med 1986; 314:1535-1542.

90. Stoff JS: Phosphate homeostasis and hypophosphatemia. Am J Med 1982; 72:495.

91. Streicher HZ, Gabow PA, Moss AH, et al: Syndromes of toluene sniffing in adults. Ann Intern
Med 1981; 94:758-762.

92. Szylman P, Benzakin A, Szjnader Y, Taitelman U: Potassium-wasting nephropathy in an outbreak of

chronic organic mercurial intoxication. Am J Nephrol 1995; 15:514-520.

93. Vamvakas S, Teschner M, Bahner U, Heidland A: Alcohol abuse: Potential role in electrolyte
disturbances and kidney diseases. Clin Nephrol 1998; 49:205-213.

94. Van Amelsvoort T, Bakshi R, Devaux CB, et al: Hyponatremia associated with carbamazepine and
oxcarbazepine therapy: A review. Epilepsia 1994; 35:181-188.
95. Vianna NJ: Severe hypophosphatemia due to hypokalemia. JAMA 1971; 215:1497.

96. Voigts A, Kaufman J, Christian E: Acidosis and other metabolic abnormalities associated with paint
sniffing. S Med J 1983; 76:443-452.

97. Walker WC: The biochemistry of magnesium. Ann NY Acad Sci 1969; 162:717.

98. Wax PM, Yang RY, Hoffman RS, et al: Prevalence of sorbitol in multiple-dose activated charcoal
regimens in emergency departments. Ann Emerg Med 1993; 22:1807-1812.

99. Weiner M, Epstein FH: Signs and symptoms of electrolyte disorders. Yale J Biol Med 1970; 43:76-

100. Zaloga GP: Hypocalcemia in critically ill patients. Crit Care Med 1992; 20:251-262.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/64.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 11 – Acid-Base Disturbances in the Poisoned Patient


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.


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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/65.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/66.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/67.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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

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]

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/68.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Small bowel fluid losses
Ileal-loop bladder
Acetazolamide (inhibition of carbonic anhydrase)
Chronic toluene use (renal losses of hippurate with retention of chloride)
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]
Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/69.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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)

Table 11-6 -- Causes of Metabolic Alkalosis

Licorice (chronic ingestion)
Sodium bicarbonate (chronic use)
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

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/70.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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)
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.
Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/71.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Sympathomimetics (e.g., theophylline, amphetamine, cocaine)
Hepatic insufficiency
Pericardial effusion/tamponade
Heart failure
Increased intracranial pressure

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/72.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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
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
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!)


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


Non–anion gap metabolic acidosis (chronic toluene abuse)

Respiratory acidosis (hypokalemic myopathy, also due to

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.
1. Calculate the anion gap: 145 - (96 + 19) = 30 mEq/L
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


Metabolic alkalosis (vomiting, delta AG > delta BC)

Anion gap metabolic acidosis (likely alcoholic ketoacidosis, given the clinical
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.
1. Calculate the anion gap: 140 - (106 + 9) = 25 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


Anion gap metabolic acidosis (probably lactic acidosis from

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
1. Calculate the anion gap: 150 - (86 + 24) = 40 mEq/L
2. Calculate the delta BC: 0
3. Calculate the delta AG: 40 - 7 = 33 mEq/L


Anion gap metabolic acidosis (hypotension with shock, delta AG > delta
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.
1. Calculate the anion gap: 150 - (100 + 20) = 30 mEq/L
2. Calculate the delta BC: 24 - 20 = 4 mEq
3. Approximate the delta AG: 30 - 7 = 23 mEq


Anion gap metabolic acidosis (diabetic

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/73.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Adrogue HJ, Wilson H, Boyd AE, et al: Plasma acid-base patterns in diabetic ketoacidosis. N Engl J
Med 1982; 307:1603-1610.

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
acidosis. Ann Intern Med 1967; 66:32.

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.
Nephron 1988; 49:210-218.

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-

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.

40. Vogel SN: Lactic acidosis in acute cyanide poisoning. In: Ballantyne B, ed. Clinical and Experimental
Toxicology of Cyanide, Bristol, England: Wright; 1987.

41. Williams RH, Palmer JP: Farewell to phenformin for treating diabetes mellitus. Ann Intern
Med 1975; 83:567-568.

42. Winter SD, Pearson R, Gabow PA, et al: The fall of the serum anion gap. Arch Intern
Med 1990; 150:311-313.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/74.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/75.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 12 – Special Considerations in the Pregnant Patient


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
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
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
Case report data suggest 10–15% of cases were malformed by different drugs; this may be an overinflated

* 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


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

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

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

(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
The rem (roentgen-equivalent man) causes the same biologic effect as 1 R of X/gamma ray: 100 rem = 1 sv

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

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
* 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

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
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
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
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
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.


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

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

Multidisciplinary teamwork among the clinician, obstetrician, perinatologist, and toxicologist can optimize patient

Copyright © 2007 Elsevier Inc . All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/76.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Abel EL: Smoking and pregnancy. J Psychoactive Drugs 1984; 16:327.

2. Angell NF, Lavery JP: The relationship of blood lead levels to obstetric outcome. Am J Obstet
Gynecol 1982; 142:40.

3. Baghurst PA, Robertson EF, Oldfield RK, et al: Lead in the placenta, membranes and umbilical cord in
relation to pregnancy outcome in a lead-smelter community. Environ Health Perspect 1991; 90:315.

4. Blanc P, Hryhorczuk D, Danel I: Deferoxamine treatment of acute iron intoxication in pregnancy. Obstet
Gynecol 1984; 64:125.

5. Book SA, Goldman M: Thyroidal radioiodine exposure to the fetus. Health Phys 1975; 29:874.

6. Buchanan CK: Helpful sources of information. In: Turner DJ, Finnell RH, Chernoff GF, et al ed. Peace of
Mind During Pregnancy, New York: Facts on File; 1988:356-360.

7. In: Cherry SH, Berkowitz RL, Kase NG, ed. Medical, Surgical and Gynaecological Complications of
Pregnancy, 3rd ed. Baltimore: Williams & Wilkins; 1985.

8. Clarren SK, Smith DW: The fetal alcohol syndrome. N Engl J Med 1978; 298:1063.

9. Cohlan SQ: Tetracycline staining of the teeth. Teratology 1977; 15:127.

10. Czeizel A: Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. Reprod

Toxicol 1988; 1:183.

11. Dansky L, Andermann F, Sherwin AL, et al: Maternal epilepsy and congenital malformations:
Correlation with maternal plasma anticonvulsant levels during pregnancy. In Janz D, Bossi L, Dain M (eds):
Epilepsy, Pregnancy and the Child. New York, Raven Press, p 251.

12. Davidson JM, Hytten FE: Glomerular filtration during and after pregnancy. J Obstet
Gynecol 1974; 81:588.

13. Dettli L: Elimination kinetics and drug dosage in renal insufficiency patients. Triangle 1975; 14:116.

14. Dugdale AE, Powell LW: Acute iron poisoning: Its effects and treatment. Med J Aust 1964; 2:990.

15. Ellenhorn MJ: Toxic exposure in pregnancy. In: Ellenhorn MJ, Barceloux DG, ed. Medical Toxicology,
1st ed. New York: Elsevier; 1988:132-152.

16. Foreman H, Trüjillo TT: The metabolism of C-14-labeled ethylene diaminetetra-acetic acid in human
beings. J Lab Clin Med 1954; 43:566.

17. Friedman JM: Teratogen update: Anesthetic agents. Teratology 1988; 37:69.

18. Gaily E, Kantola-Sorsa E, Granstrom MZ: Specific cognitive dysfunction in children with epileptic
mothers. Dev Med Child Neurol 1990; 32:403.
19. Gershanik JJ, Brooks GG, Little JA: Blood lead values in pregnant women and their offspring. Am J
Obstet Gynecol 1974; 119:508.

20. Goldfrank LR, Howland MA, Weisman RS, et al: Acetaminophen. In: Goldfrank LR, et
al ed. Goldfrank’s Toxicologic Emergencies, 4th ed. East Norwalk, CT: Appleton and Lange; 1990:251-260.

21. Goldfrank LR, Kulberg AG, Kirstein RH: Iron. In: Goldfrank LR, et al ed. Goldfrank’s Toxicologic
Emergencies, 4th ed. East Norwalk, CT: Appleton and Lange; 1990:277-288.

22. Gossel AT, Bricker JD: Carbon monoxide, cyanides, and sulfides.
In: Gossel AT, Bricker JD, ed. Principles of Clinical Toxicology, 1st ed. New York: Raven Press; 1984:84-

23. Graham K, Koren G, Klein J, et al: Determination of gestational cocaine exposure by hair analysis.
JAMA 1989; 262:3328.

24. Graziano JH, Siris ES, La Iancono N, et al: 2,3-Dimercaptosuccinic acid as an antidote for lead
intoxication. Clin Pharmacol Ther 1985; 37:431.

25. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J
Med 1980; 68:122.

26. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 1974; 87:285.

27. Hu H: Knowledge of diagnosis and reproductive history among survivors of childhood plumbism. Am J
Public Health 1991; 81:1070.

28. Ishiyama J, Nagai T, Toshida S: Detection of basic drugs (methamphetamines, antidepressants and
nicotine) from human hair. J Forensic Sci 1983; 28:380.

29. Jacobson SJ, Jones K, Johnson K, et al: Prospective multicentre study in pregnancy outcome after
lithium exposure during first trimester. Lancet 1992; 339:530.

30. Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2:999.

31. Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in offspring of chronic alcoholic
mothers. Lancet 1973; 1:1267.

32. Kerr MG: Cardiovascular dynamics in pregnancy and labour. Br Med Bull 1968; 24:19.

33. Kimmel CA: Critical periods of exposure and developmental effects of lead.
In: Kacew S, Reasor MJ, ed. Toxicology and the Newborn, New York: Elsevier; 1984:217-236.

34. Koren G, Bologa M, Pastuszak A: The way women perceive teratogenic risk: The decision to terminate
pregnancy. In: Koren G, ed. Maternal-Fetal Toxicology, 1st ed. New York: Marcel Dekker; 1990:373-381.

35. Koren G, Cheng M, Klein J, et al: Lead exposure in mothers and infants in Toronto, 1989. Can Med
Assoc J 1990; 142:1241.

36. Kyriakou D, Papanicalaou C, Gyparaki M, et-al.: Absence of desferrioxamine teratogenicity in a

thalassemic patient [abstract]. Second International Conference on Thalassemia and the
Haemoglobinopathies, Herakleion (Crete), Greece, October 21–24, 1987, p 106.

37. Lammer EJ, Chen DJ, Hoar RM, et al: Retinoic acid embryopathy. N Engl J Med 1985; 313:837.

38. Lander CM, Edwards VE, Eadie MJ, et al: Plasma anticonvulsant concentrations during pregnancy.
Neurology (Minneapolis) 1977; 27:128.

39. Lewander WJ, Gaudreault P, Einhorn A, et al: Acute pediatric digoxin ingestion—a ten-year experience.
Am J Dis Child 1986; 140:770.

40. Lindbohm ML, Taskinen H, Sallmen M, et al: Spontaneous abortions among women exposed to organic
solvents. Am J Ind Med 1990; 17:449.

41. Longo LD: The biological effects of carbon monoxide on the pregnant woman, fetus and newborn infant.
Am J Obstet Gynecol 1977; 129:69.

42. Luxford AME, Kellaway GSM: Pharmacokinetics of digoxin in pregnancy. Eur J Clin
Pharmacol 1983; 25:117.

43. Lynd PA, Andreasen AC, Wyatt RJ: Intrauterine salicylate intoxication in a newborn. Clin Pediatr
(Phila) 1976; 15:912.

44. Martin K: Successful pregnancy in ß-thalassemia major. Aust Paediatr J 1983; 19:182.

45. Martin TR, Bracken ME: Association of low birth-weight with passive smoke exposure in pregnancy.
Am J Epidemiol 1986; 124:633.

46. Newman CGH: Clinical aspects of thalidomide embryopathy—a continuing preoccupation.

Teratology 1985; 32:133.

47. Nimmo WS, Wilson JE, Prescott LF: Narcotics analgesics and delayed gastric emptying during labour.
Lancet 1975; 1:890.

48. Okita GT, Plotz EJ, Dans ME: Placental radioactive digitoxin in pregnant women and its fetal
distribution. Circ Res 1956; 4:376.

49. Olenmark M, Biber B, Dottori O, et al: Fatal iron intoxication in late pregnancy. Clin
Toxicol 1987; 25:347.

50. Palmisano PA, Polhik RB: Fetal pharmacology. Pediatr Clin North Am 1972; 19:3.

51. Palmisano PA, Sneed RC, Cassady G: Untaxed whisky and fetal lead exposure. J
Pediatr 1969; 75:869.

52. Papadopoulou-Tsoukali H, Njau S: Mother-fetus postmortem toxicologic analysis in a fatal overdose

with mecarbam. Forensic Sci Int 1987; 35:249.

53. Parry E, Shields R, Turnbull AC: Transit time in the small intestine in pregnancy. J Obstet Gynaecol Br
Com 1970; 77:900.

54. Pastuszak AL, Schick-Boschetto B, Zuber C, et al: Pregnancy outcome following first trimester exposure
to fluoxetine (Prozac). JAMA 1993; 269:2246.
55. Perez V, Gorodisch S, Casavilla F, et al: Ultra structure of human liver at the end of normal pregnancy.
Am J Obstet Gynecol 1971; 110:428.

56. Philipson A: Pharmacokinetics of antibiotics in pregnancy and labour. Clin

Pharmacokinet 1979; 4:297.

57. Pirani BBK, Campbell DM, MacGillivray I: Plasma volume in normal first pregnancy. J Obstet Gynaecol
Br Com 1973; 80:884.

58. Rabinowitz M, Bellinger E, Leviton A, et al: Pregnancy hypertension, blood pressure during labour, and
blood lead levels. Hypertension 1987; 10:447.

59. Rayburn WF, Donn SM, Wulf ME: Iron overdose during pregnancy: Successful therapy with
deferoxamine. Am J Obstet Gynecol 1983; 147:717.

60. Reboud P, Groulade J, Groslambert P, et al: The influence of normal pregnancy and the post partum
state on plasma proteins and lipids. Am J Obstet Gynecol 1963; 86:820.

61. Richards R, Brooks SEH: Ferrous sulphate poisoning in pregnancy (with afibrinogenaemia as a
complication). West Indian Med J 1966; 15:134.

62. Rowland AS, Baird DD, Weinberg CR, et al: Reduced fertility among women employed as dental
assistants exposed to high levels of nitrous oxide. N Engl J Med 1992; 327:993.

63. Rush D, Callahan KR: Exposure to passive cigarette smoking and child development. Ann N Y Acad
Sci 1989; 562:74.

64. Saarikoski S: Placental transfer and fetal uptake of H-digoxin in humans. Br J Obstet
Gynaecol 1976; 83:879.

65. Schou M, Amdisen A, Steenstrap DR: Lithium and pregnancy. II. Hazards to women given lithium during
pregnancy and delivery. BMJ 1973; 2:137.

66. Sherman Jr JL, Locke RV: Transplacental neonate digitalis intoxication. Am J Cardiol 1960; 6:834.

67. Shilalukey K, Robieux I, Spino M, et al: Are current pediatric dose recommendations for intravenous
theophylline appropriate?. J Asthma 1993; 30:109.

68. Smith EM, Warner GG: Estimates of radiation dose to embryo from nuclear medicine procedures. J
Nucl Med 1979; 17:836.

69. Swiet de M, Dorrington Ward P, Fidler J, et al: Prolonged heparin therapy in pregnancy causes bone
demineralization. Br J Obstet Gynaecol 1983; 90:1129.

70. Taskinen H, Anttila A, Lindbohm ML, et al: Spontaneous abortions and congenital malformations among
the wives of men occupationally exposed to organic solvents. Scand J Work Environ Health 1989; 15:346.

71. Thomas RM, Skalioka AE: Successful pregnancy in transfusion dependent thalassemia. Arch Dis
Child 1980; 55:572.

72. Turk J, Aks S, Ampuero F, et al: Successful therapy of iron intoxication in pregnancy with intravenous
deferoxamine and whole bowel irrigation. Vet Hum Toxicol 1993; 35:441.

73. Van Amyde KJ, Tenenbein M: Whole bowel irrigation during pregnancy. Am J Obstet
Gynecol 1989; 160:646.

74. Weis OF, Muller FO, Lyell H, et al: Materno-fetal cholinesterase inhibitor poisoning. Anesth
Analg 1983; 62:233.

75. Zelterlund B, Winberg J, Lundgren G, et al: Lead in umbilical cord blood correlated with the blood lead
of the mother in areas of low, medium or high atmospheric pollution. Acta Paediatr Scand 1977; 66:169.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/77.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 13 – Poison Centers


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
• 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
• 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

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)
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
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

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

† 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.

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
Hum Toxicol 1992; 34:319.

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

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-

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/78.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 14 – Managing Patients with Hazardous Chemical Contamination


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]


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
Chemical manufacturing plant
Hazardous waste site
Transportation accidents
Train derailment
Tanker truck
Plane (crop duster)
Barges and cargo ships
Farm accidents
Type of incident
Ruptured tank
Structural collapse
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
Overdoses of cleaning or agricultural chemicals

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/79.html
Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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

Table 14-2 -- Information Resources for Chemical Identification

Container labels
Department of Transportation (DOT) placard categories
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
Sweet, ether-like
Ethylene oxide
Methylene chloride
Hydrochloric acid
Sharp, choking
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,
Rom WN: Environmental and Occupational Medicine. 3rd ed. Philadelphia, Lippincott Williams & Wilkins,
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
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)
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
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

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.


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


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

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 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


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
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

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)

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/80.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Mucous membrane irritation
Systemic toxic effects
Ammonia, chlorine, isocyanates,
Mucous membrane irritation acrolein, sulfur dioxide, hydrogen
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
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,
Nerve agents: sarin, soman, tabun,
Pinpoint pupils and eye pain VX, organophosphate, carbamate
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]


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/81.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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?
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
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
Soft brushes
Shower nozzle
Containment vessels for water run-off
Containment vessels for contaminated clothing
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?
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

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


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/82.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
1. Abrams J, El-Mallakh RS, Meyer R: Suicidal sodium azide ingestion. Ann Emerg Med 1987; 16:1378.

3. Agency for Toxic Substances and Disease Registry : Managing Hazardous Materials Incidents.
Washington, D.C., U.S. Department of Health and Human Services, 1991.

4. Aghababian RV: Hospital disaster planning. Top Emerg Med 1986; 7:46.

5. Alexeeff GV, Lipsett MJ, Kizer KW: Problems associated with the use of immediately dangerous to life
and health (IDLH) values for estimating the hazard of accidental chemical releases. Am Ind Hyg Assoc
J 1989; 50:598.

6. Auf der Heide E: Community medical disaster planning and evaluation guide, Dallas, American College
of Emergency Physicians, 1995.

7. Auf der Heide E: Disaster planning, part II: Disaster problems, issues, and challenges identified in the
research literature. Emerg Med Clin North Am 1996; 14:453.

8. Bertazzi PA: Industrial disasters and epidemiology. Scand J Work Environ Health 1989; 15:85.

9. Boxer PA: Occupational mass psychogenic illness. J Occup Med 1985; 27:867.

10. Bresnitz EA, Rest KM, Miller N: Clinical industrial toxicology: An approach to information retrieval. Ann
Intern Med 1985; 103:967.

11. Bromberg BE: Hydrotherapy of chemical burns. Plast Reconstr Surg 1965; 35:85.

12. Bunner BL, Wannemacher RW, Broski FH: Cutaneous absorption and decontamination of (3H)T-2 toxin
in the rat model. J Toxicol Environ Health 1989; 26:413.

13. Burgess JL, Keifer MC, Barnhart S, et al: Hazardous materials exposure information service:
Development, analysis, and medical implications. Ann Emerg Med 1997; 29:248.

14. Burkle FM: Acute-phase mental health consequences of disasters: Implications for triage and
emergency medical services. Ann Emerg Med 1996; 28:119.

15. California Emergency Medical Services Authority, Toxics Epidemiology Program: Hazardous materials
medical management protocols. California Emergency Medical Services and the Toxics Epidemiology
Program, Los Angeles County Department of Health Services, 1989.

16. Cancio LC: Chemical casualty decontamination by medical platoons in the 82nd Airborne Division. Milit
Med 1993; 158:1.

17. Carter BJ, Cammermeyer M: Emergence of real casualties during simulated chemical warfare training
under high heat conditions. Milit Med 1985; 150:657.

18. Charan NB, Lakshminarayan S, Meyers G, et al: Effects of accidental chlorine inhalation on pulmonary
function. West J Med 1985; 143:333.

19. Cox RD: Decontamination and management of hazardous materials exposure victims in the emergency
department. Ann Emerg Med 1994; 23:761.

20. Curreri PW, Asch MJ, Pruitt BA: The treatment of chemical burns: Specialized diagnostic, therapeutic,
and prognostic considerations. J Trauma 1970; 10:634.

21. Dart RC, Stark Y, Fulton B, et al: Insufficient stocking of poisoning antidotes in hospital pharmacies.
JAMA 1996; 276:1508.

22. DeAtley C: Hazardous materials exposure mandates integrated patient care. Occup Health Saf 1991;
March 40.

23. Doyle CJ: Mass casualty incident: Integration with prehospital care. EMS/Prehosp Care 1990; 8:163.

24. Durham TW, McCammon SL, Allison EJ: The psychological impact of disaster on rescue personnel.
Ann Emerg Med 1985; 14:664.

25. Edwards JG: Psychiatric aspects of civilian disasters. Br Med J 1976; 1:944.

26. El Sanadi N, Grove C, Takacs M, et al: A hospital-based, hazardous materials decontamination and
treatment unit: Utilization patterns over a nine-month period. Prehosp Disaster Med 1993; 8:337.

27. Feldman RJ, Maibach HI: Percutaneous penetration of some pesticides and herbicides in man. Toxicol
Appl Pharmacol 1974; 28:126.

28. Fiserova-Bergerova V, Pierce JT, Droz PO: Dermal absorption potential of industrial chemicals: Criteria
for skin notation. Am J Ind Med 1990; 17:617.

29. Fredriksson T: Percutaneous absorption of parathion and paraoxon: IV. Decontamination of human skin
from parathion. Arch Environ Health 1961; 3:185.

30. Fullerton CS, Ursano RJ: Behavioral and psychological responses to chemical and biological warfare.
Milit Med 1990; 155:54.

31. Gough AR, Markus K: Hazardous materials protections in ED practice: Laws and logistics. J Emerg
Nurs 1989; 15:477.

32. Greenberg MI, Cone DC, Roberts JR: Material Safety Data Sheet: A useful resource for the emergency
physician. Ann Emerg Med 1996; 27:347.

33. Gruber RP, Laub DR, Vistnes LM: The effect of hydrotherapy on the clinical course and pH of
experimental cutaneous chemical burns. Plast Reconstr Surg 1975; 55:200.

34. Hall EM, Johnson JV: A case study of stress and mass psychogenic illness in industrial workers. J
Occup Med 1989; 31:243.

35. Hall HI, Haugh GS, Price-Green PA, et al: Risk factors for hazardous substance releases that result in
injuries and evacuations: Data from 9 states. Am J Public Health 1996; 86:855.

36. Harris JC, Rumack BH, Peterson RG: Methemoglobinemia resulting from absorption of nitrates.
JAMA 1979; 242:2869.

37. Himmelstein JS, Frumkin H: The right to know about toxic exposures: Implications for physicians. N
Engl J Med 1985; 312:687.

38. Hodson PB: Assessment of casualties in a chemical environment. JR Army Med Corps 1985; 131:116.

39. King JM, Frelin AJ: Impact of the chemical protective ensemble on the performance of basic medical
tasks. Milit Med 1984; 149:196.

40. Koehler GA, Van Ness C: The emergency medical response to the Cantara hazardous materials
incident. Prehosp Disaster Med 1993; 8:359.

41. Kolka MA, Cadarette BS: Heat exchange after cholinolytic and oxime therapy in protective clothing.
Milit Med 1990; 155:390.

42. Lanese TR, Slattery J: Preparing for a hazardous materials incident. Firehouse 1991; 12:74.

43. Lavoie FW, Coomes T, Cisek JE, et al: Emergency department external decontamination for hazardous
chemical exposure. Vet Hum Toxicol 1992; 34:61.

44. Leonard LG, Scheulen JJ, Munster AM: Chemical burns: Effect of prompt first aid. J
Trauma 1993; 22:420.

45. Leonard RB: Community planning for hazardous materials disasters. Top Emerg Med 1986; 7:55.

46. Leonard RB, Ricks RC: Emergency department radiation accident protocol. Ann Emerg
Med 1980; 9:462.

47. Leonard RB, Teitelman U: Manmade Disasters. Crit Care Clin 1991; 7:293.

48. Lerman SE, Kipen HM: Material Safety Data Sheets: Caveat emptor. Arch Intern Med 1990; 150:981.

49. Lorin HG, Kulling PE: The Bhopal tragedy—What has Swedish disaster medicine planning learned from
it?. J Emerg Med 1986; 4:311.

50. Merchant JA: Preparing for disaster. Am J Public Health 1986; 76:233.

51. Merrit NL, Anderson MJ: Malathion overdose: When one patient creates a department hazard. J Emerg
Nurs 1989; 15:463.

52. Misra NP, Pathak R, Gaur JJBS, et al: Clinical profile of gas leak victims in acute phase after Bhopal
episode. Indian J. Med Res 1987; 86(suppl):11.

53. Mitchell GW: The triage process. Top Emerg Med 1986; 7:34.

54. Moran KD, O’Reilly T, Munster AM: Chemical burns: A ten-year experience. Am Surg 1987; 11:652.

55. Moylan JA, Chan C: Inhalation injury—An increasing problem. Ann Surg 1977; 188:34.

56. Mozingo DW, Smith AA, McManus WF, et al: Chemical burns. J Trauma 1988; 28:642.
57. Mullett T, Zoeller T, Bingham MD, et al: Fatal hydrofluoric acid cutaneous exposure with refractory
ventricular fibrillation. J Burn Care Rehabil 1987; 8:216.

58. Nantel AJ: The role of the clinical toxicologist in chemical and environmental accidents. Clin
Toxicol 1995; 33:603.

59. Ohbu S, Yamashina A, Takasu N, et al: Sarin poisoning on Tokyo subway. South Med J 1997; 90:587.

60. Okumura T, Takasu N, Ishimatsu S, et al: Report on 640 victims of the Tokyo subway sarin attack. Ann
Emerg Med 1996; 28:129.

61. Plante DM, Walker JS: EMS Response at a hazardous material incident: Some basic guidelines. J
Emerg Med 1989; 7:55.

62. Saenger EL: Radiation accidents. Ann Emerg Med 1986; 15:1061.

63. Sandman P: Explaining environmental risks—Some notes on environmental risks communication. U.S.
Environmental Protection Agency, 1986; Nov.

64. Savelkousl TJF, Leenhouts HP, Sangster B: The role of poison control centers in radiation accidents.
Clin Toxicol 1989; 27:305.

65. Sawhney CP, Kaushish R: Acid and alkali burns: considerations in management. Burns 1989; 15:132.

66. Schultz M, Cisek J, Wabeke R: Simulated exposure of hospital personnel to solvent vapors and
respirable dust during decontamination of chemically exposed patients. Ann Emerg Med 1995; 26:324.

67. Selden BS: Adolescent epidemic hysteria presenting as a mass casualty, toxic exposure incident. Ann
Emerg Med 1989; 18:892.

68. Sidell FR: What to do in case of an unthinkable chemical warfare attack or accident. Postgrad
Med 1990; 88:70.

69. Silverman JJ, Hart RP, Garrettson LK, et al: Posttraumatic stress disorder from pentaborane
intoxication. JAMA 1985; 254:2603.

70. Simpson LA, Cruse CW: Gasoline immersion injury. Plast Reconstr Surg 1981; 67:54.

71. Singer TJ: An introduction to disaster: Some considerations of a psychological nature. Aviat Space
Environ Med 1982; 53:245.

72. Slovic P: Perception of risk. Science 1987; 236:280.

73. Summers GM, Cowan ML: Mental health issues related to the development of a National Disaster
Response System. Milit Med 1991; 156:30.

74. Tepperman PB: Fatality due to acute systemic fluoride poisoning following a hydrofluoric acid skin burn.
J Occup Med 1980; 22:691.

75. Vicas IM: Poison center participation in a municipal chemical disaster exercise (abstract). Prehospital
and Disaster Medicine 1993; 8:S98.
76. Waeckerle JF: Disaster planning and response. N Engl J Med 1991; 324:815.

77. Walter FG, Dedolph R, Kallsen GW, et al: Hazardous materials incidents: A one-year retrospective
review in central California. Prehosp Disaster Med 1992; 7:151.

78. Weber LW, Zesch A, Rozman K: Decontamination of human skin exposed to 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) in vitro. Arch Environ Health 1992; 47:302.

79. Wester RC, Maibach HI: In vivo percutaneous absorption and decontamination of pesticides in humans.
J Toxicol Environ Health 1985; 16:25.

80. Wiener RK, Shaver DK: The applications of toxicologic parameters in emergency response planning.
Toxicol Lett 1989; 49:361.

81. Wing JS, Sanderson LM, Brender JD, et al: Acute health effects in a community after a release of
hydrofluoric acid. Arch Environ Health 1991; 46:155.

82. Woolf AD, Chrisanthus K: On-site availability of selected antidotes: Results of a survey of
Massachusetts hospitals. Am J Emerg Med 1997; 15:62.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/83.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Uncited reference

Agency for Toxic Substances and Disease Registry : Managing Hazardous Materials Incidents.
Washington, D.C., U.S. Department of Health and Human Services, 1994.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/84.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company
Chapter 15 – Drug Testing in the Workplace


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.


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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/85.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Probation and parole 5
Suspicious activity
Table 15-3 -- Positive Drug Test Results by Testing Category, for Safety-Sensitive Transportation
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%
From Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beecham
data shows. Collegeville, PA, SmithKline Beecham Clinical Laboratories, 1996.
* 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
From Johnson T: Press release: Drug detection in workplace continues downward trend, SmithKline Beecham
data shows. Collegeville, PA, SmithKline Beecham Clinical Laboratories, 1996.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/86.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/87.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/88.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/89.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/90.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/91.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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
Mefenamic acid
Salicyluric acid
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
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
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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/92.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

Apple juice
Drano (sodium hydroxide)
Goldenseal tea
MJ Super Clean 13
Mountain Dew
Pyridine (pyridium chlorochromate)
Salt (sodium chloride)
Sodium bicarbonate
Soft drinks

Table 15-8 -- Common Adulteration Checks Done by Laboratories on Urine Specimens

Appearance (precipitate at bottom or bubbles)
Specific gravity

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/93.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/94.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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.

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/95.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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

Copyright © 2007 Elsevier Inc. All rights reserved. - www.mdconsult.com

Bookmark URL: /das/book/0/view/1013/96.html

Use of this content is subject to the Terms and Conditions

Ford: Clinical Toxicology, 1st ed.

Copyright © 2001 W. B. Saunders Company

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)
Benzodiazepines “Black pearls” (Asian product)
Cocaine Coca leaf teas (Health Inca Tea)
Dronabinol (Marinol)
Hemp-containing foods:
Seedy Sweeties
Cranberry Coconut Hemp Bar
Opiates Poppy seeds
* Chiral separation of isomers required.


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 (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.


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

Other opioids do not cross react with current immunoassays for opiates. These substances include
dihydrocodeine, oxycodone, hydrocodone, oxymorphone, hydromorphone, propoxyphene, methadone,
meperidine, and fentanyl.


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 t