Latifi 2003

V m
Rifat Latifi
Stanley J. Dudrick
a d e m e c u V a d e m e c u m
Table of contents
1. Clinical Implications
of Carbohydrate, Proteins,
Lipids, Vitamins and Trace
Elements in Nutrition Support
2. Current Nutrient Substrates
3. Biochemistry of Amino Acids:
Clinical Implications
4. Acute Phase Proteins
in Critically Ill Patients
5. Arginine Metabolism
in Critical Care and Sepsis
6. Wound Healing and the Role
of Nutrient Substrates
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LANDES
B I OS C I E NC E
I SBN 1- 57059- 595- X
LANDES
B I OS C I E NC E
The Biology and Practice
of Current Nutritional
Support
2nd edition
7. Protein Metabolism in Liver
and Intestine During Sepsis:
Mediators, Molecular Regulation,
and Clinical Implications
8. Biochemical Assessment and
Monitoring of Nutritional Status
9. Optimizing Drug Therapy
and Enteral Nutrition: Detecting
Drug-Nutrient Interactions
10. Techniques and Monitoring
of Total Parenteral Nutrition
11. Radiologic Assessment
of Nutritional and Metabolic
Status
12. Enteral Nutrition: Indications,
Monitoring and Complications
(excerpt)
Rifat Latifi, M.D.
Department of Surgery
University of Arizona
Tucson, Arizona, U.S.A.
Stanley J. Dudrick, M.D.
Yale University School of Medicine
St. Marys Hospital/Yale Affiliate
Waterbury, Connecticut, U.S.A.
of Current Nutritional Support
2nd Edition
GEORGETOWN, TEXAS
U.S.A.
v a d e m e c u m
L A N D E S
B I O S C I E N C E
VADEMECUM
The Biology and Practice of Current Nutritional Support, 2nd Edition
LANDES BIOSCIENCE
Georgetown, Texas U.S.A.
Copyright 2003 Landes Bioscience
All rights reserved.
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ISBN: 1-57059-595-X
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Dedication
Jonathan Evans Rhoads, M.D.
1907-2002
Dedicated to the surgeon of the century, whose extraordinary personal at-
tributes and countless professional, educational and scientific contributions
serve as the quintessential model that has greatly influenced and inspired the
editors and will continue to endure for future generations.
Rifat Latifi, M.D. and Stanley J. Dudrick, M.D.
Contents
Foreword ....................................................................... xvii
1. Clinical Implications of Carbohydrate, Proteins,
Lipids, Vitamins and Trace Elements
in Nutrition Support ......................................................... 1
Larry H. Bernstein
Overview .................................................................................................... 1
Stress Hypermetabolism and the Nutritionally-Dependent
Adaptive Dichotomy .............................................................................. 2
Energy Requirements of Injured Man ......................................................... 3
Nutritional Requirements ........................................................................... 6
Clinical vs. Laboratory Information ............................................................ 8
Information Model ................................................................................... 10
Length of Stay (LOS) ................................................................................ 11
Improving Correction of Malnutrition...................................................... 11
Nutrition Support Monitoring .................................................................. 12
Quality Management ................................................................................ 13
2. Current Nutrient Substrates ............................................ 17
Wendy Swails Bollinger, Timothy J. Babineau
and George L. Blackburn
Introduction ............................................................................................. 17
Hepatic Disease and Stress: Branched-Chain Amino Acid
Enriched Diets ..................................................................................... 17
Arginine .................................................................................................... 24
Glutamine ................................................................................................ 27
Nucleotides ............................................................................................... 33
Lipids ....................................................................................................... 35
Conclusion ............................................................................................... 43
Clinical Implications....................................................... 52
Rifat Latifi, Khawaja Aizimuddin
Introduction ............................................................................................. 52
Structure of Amino Acid and Proteins ....................................................... 52
Amino Acid and Protein Synthesis ............................................................ 53
Post-Synthetic Modification...................................................................... 54
Protein Function ....................................................................................... 54
Classification of Amino Acids ................................................................... 55
Amino Acids in Critical Illness and Injury ................................................ 58
Amino Acids in Circulation ...................................................................... 59
Digestion of Amino Acids ......................................................................... 59
Absorption of Amino Acids ....................................................................... 60
Biochemical Transformation of Amino Acids ............................................ 61
4. Acute Phase Proteins in Critically Ill Patients ................. 63
Khawaja Azimuddin, Rifat Latifi and Rao R. Ivatury
Role of the Acute Phase Response ............................................................. 63
Physiology ................................................................................................ 63
Sequence of Events During Acute Phase Response .................................... 65
Modulation of the Acute Phase Response .................................................. 65
The Acute Phase Proteins .......................................................................... 65
Albumin ................................................................................................... 66
Prealbumin ............................................................................................... 67
Retinol-Binding Protein ............................................................................ 67
Transferrin ................................................................................................ 67
C-Reactive Protein .................................................................................... 67
Ceruloplasmin .......................................................................................... 68
Fibrinogen ................................................................................................ 68
Complement ............................................................................................. 68
Amyloid.................................................................................................... 68
Alpha 1 Acid Glycoprotein ....................................................................... 68
Alpha-1 Protease Inhibitor ........................................................................ 68
Monitoring Nutrition in the Critically Ill Patient ...................................... 69
5. Arginine Metabolism in Critical Care and Sepsis ............ 72
Rima I. Kandalaft, V. Bruce Grossie, Jr.
Pathways of Arginine and Ornithine Metabolism...................................... 72
Fate of Exogenous Arginine ...................................................................... 80
Nitric Oxide in Critical Care .................................................................... 81
Conclusion ............................................................................................... 83
6. Wound Healing and the Role of Nutrient Substrates ...... 88
David A. Lanning, Rifat Latifi
Basic Principles of Wound Healing ........................................................... 88
Malnutrition and Wound Healing ............................................................ 89
Nutritional Supplementation and Wound Healing ................................... 91
Specific Nutrients, Vitamins, and Trace Elements ..................................... 92
Conclusion ............................................................................................... 98
7. Protein Metabolism in Liver and Intestine
During Sepsis: Mediators, Molecular Regulation,
and Clinical Implications .............................................. 103
Timothy A. Pritts, Eric Hungness and Per-Olof Hasselgren
Introduction ........................................................................................... 103
Liver ....................................................................................................... 103
Intestine .................................................................................................. 113
8. Biochemical Assessment and Monitoring
of Nutritional Status ..................................................... 126
Robert S. DeChicco, Laura E. Matarese, Douglas Seidner and Ezra Steiger
The Incidence of Malnutrition ............................................................... 126
Methods of Nutrition Assessment ........................................................... 126
9. Optimizing Drug Therapy and Enteral Nutrition:
Detecting Drug-Nutrient Interactions .......................... 145
Marcia L. Brackbill, Gretchen M. Brophy
Introduction ........................................................................................... 145
Avoiding Tube Occlusions ...................................................................... 145
Pharmacokinetic Interactions .................................................................. 148
Pharmacodynamic Interactions ............................................................... 150
Influence of Tube Placement on Drug Efficacy ....................................... 151
Optimizing Tolerance to Enteral Nutrition and Drug Therapy ............... 152
Summary ................................................................................................ 153
10. Techniques and Monitoring of Total
Parenteral Nutrition...................................................... 158
Renee Piazza-Barnett, Laura E. Matarese, Douglas L. Seidner
and Ezra Steiger
Introduction ........................................................................................... 158
Macronutrients ....................................................................................... 158
Micronutrients/Additives ........................................................................ 159
Access/Delivery ....................................................................................... 162
Monitoring Parameters ........................................................................... 163
Complications of Parenteral Nutrition Therapy ...................................... 165
Cycling Total Parenteral Nutrition .......................................................... 177
Conclusion ............................................................................................. 177
11. Radiologic Assessment of Nutritional
and Metabolic Status ..................................................... 181
Diane R. Horowitz, Rifat Latifi
Introduction ........................................................................................... 181
Ultrasound Use in Assessing Body Composition ..................................... 181
Conclusion ............................................................................................. 190
12. Enteral Nutrition: Indications, Monitoring
and Complications ........................................................ 192
Gayle Minard
Introduction ........................................................................................... 192
Indications .............................................................................................. 192
Contraindications ................................................................................... 194
Monitoring ............................................................................................. 194
Complications ........................................................................................ 195
Conclusion ............................................................................................. 198
13. Enteral Access: Open, Endoscopic
& Laparoscopic Techniques .......................................... 199
Keith Zuccala, John M. Porter
Gastrostomy ........................................................................................... 199
Jejunostomy ............................................................................................ 203
Conclusion ............................................................................................. 206
14. Total Parenteral Nutrition: Current Concepts
and Indications ............................................................. 208
Rifat Latifi, Stanley J. Dudrick
Introduction ........................................................................................... 208
General Indications for Use of TPN........................................................ 209
Specific Indications for Total Parenteral Nutrition .................................. 210
Short Bowel Syndrome ........................................................................... 210
Enterocutaneous Fistula .......................................................................... 211
Inflammatory Bowel Disease ................................................................... 212
Liver Failure ............................................................................................ 212
Acute Pancreatitis .................................................................................... 214
Cancer and TPN: To Feed or Not to Feed? ............................................. 215
15. Intestinal Adaptation: New Insights .............................. 219
Jon S. Thompson
Introduction ........................................................................................... 219
Structural Changes .................................................................................. 219
Functional Adaptation ............................................................................ 220
Summary ................................................................................................ 230
Systemic Factors ...................................................................................... 230
Clinical Implications ............................................................................... 235
16. Intestinal Regeneration and Nutrition .......................... 250
Jon S. Thompson, Shailendra K. Saxena and John G. Sharp
Introduction ........................................................................................... 250
Mechanism ............................................................................................. 250
Clinical Implications ............................................................................... 253
17. Nutritional and Metabolic Management
of Short Bowel Syndrome ............................................. 261
Stanley J. Dudrick, Frizan Abdullah and Rifat Latifi
Introduction ........................................................................................... 261
Pathophysiology ...................................................................................... 263
Nutritional and Metabolic Management ................................................. 265
Immediate Postoperative Period .............................................................. 265
Bowel Adaptation Period ........................................................................ 268
Long-Term Management Period ............................................................. 270
Growth Hormone, Glutamine, and Hormone Modified Diet ................. 270
Surgical Considerations ........................................................................... 271
18. Pharmacologic Aspects of Short Bowel Syndrome ........ 275
Patricia Pecora Fulco, Donald F. Kirby
Physiologic Considerations ..................................................................... 275
Site Specific Contributions ..................................................................... 276
Adaptation .............................................................................................. 278
Intravenous Access in SBS Patients ......................................................... 278
Conclusion ............................................................................................. 296
19. Nutritional Support in Inflammatory Bowel Disease.... 306
John H. Seashore, Melissa F. Perkal
Introduction ........................................................................................... 306
Malnutrition in Inflammatory Bowel Disease ......................................... 306
Nutritional Support in Inflammatory Bowel Disease............................... 309
Summary ................................................................................................ 314
20. Nutrition Support of Acute Pancreatitis........................ 320
Introduction ........................................................................................... 320
Pathophysiology of Acute Pancreatitis ..................................................... 320
Alcohol and Biliary Disease ..................................................................... 322
Oxygen-Derived Free Radicals ................................................................ 322
Pancreatic Ischemia in Experimental Acute Pancreatitis .......................... 323
Metabolic Changes and Other Complications
in Acute Pancreatitis ........................................................................... 323
Biochemical Abnormalities ..................................................................... 325
Lung Injury ............................................................................................ 326
Nutritional Management in Acute Pancreatitis ....................................... 326
The Effects Of Nutrient Substrates ......................................................... 327
Inhibition of Pancreatic Secretion ........................................................... 328
Rationale for TPN in Acute Pancreatitis ................................................. 329
Dextrose and Amino Acids ..................................................................... 329
Lipids ..................................................................................................... 330
Administration and Monitoring of TPN................................................. 330
21. Nutritional Management of Chronic Pancreatitis:
Current Concepts .......................................................... 334
Rifat Latifi, Paul G. Perch and Stanley J. Dudrick
Introduction ........................................................................................... 334
Etiologic and Risk Factors of Chronic Pancreatitis .................................. 335
Nutritional Deficiencies in Chronic Pancreatitis ..................................... 335
Pancreatic Diabetes ................................................................................. 336
Diagnosis of Malabsorption in Chronic Pancreatitis ................................ 336
Principles of Clinical Management of Chronic Pancreatitis ..................... 337
Enteral Feeding ....................................................................................... 338
Total Parenteral Nutrition ....................................................................... 339
Nutrient Substrates in Chronic Pancreatitis ............................................ 339
Enzyme Treatment of Exocrine Pancreatic Insufficiency .......................... 340
The Role of Exogenous Pancreatic Enzymes in Pain Management .......... 341
The Effect of Exogenous Enzymes in Gastrointestinal Hormones ........... 342
Conclusion ............................................................................................. 342
22. Nutritional Support in Liver Failure
and Liver Transplantation ............................................. 346
Rifat Latifi
Introduction ........................................................................................... 346
Malnutrition in Patients with Chronic Liver Disease .............................. 347
Hepatic Encephalopathy ......................................................................... 347
Amino Acids in Hepatic Encephalopathy ................................................ 349
Nutritional Assessment ........................................................................... 350
Peritransplant Nutrition: Support ........................................................... 352
Metabolic Changes ................................................................................. 353
Nutrition Status of Donors ..................................................................... 353
How to Feed Liver Transplant Patients .................................................... 354
Conclusion ............................................................................................. 356
23. Nutritional Support in Renal Transplantation .............. 360
Susan T. Crowley, Richard Formica and Antonio Cayco
Introduction ........................................................................................... 360
Protein Malnutrition and Nitrogen Balance ............................................ 360
Dyslipidemia .......................................................................................... 362
Vitamin Supplementation....................................................................... 364
Bone Metabolism.................................................................................... 365
Summary ................................................................................................ 366
24. Biology of Nutrition Support
in the Critically Ill Patient ............................................ 369
Rifat Latifi, Selman Uranes
Introduction ........................................................................................... 369
Protein and Nitrogen Metabolism in Critically Ill Patients ...................... 370
Amino Acid Metabolism......................................................................... 370
Branched-Chain Amino Acids (BCAA) ................................................... 372
Nucleotides and Nucleic Acids in Nutritional Support ............................ 372
Omega 3-Fatty Acids .............................................................................. 375
Growth Hormone ................................................................................... 375
Immune-Enhancing Enteral Nutrition: Clinical Evidence ....................... 376
Summary ................................................................................................ 378
Selected References ................................................................................. 379
25. Nutrition Support in Patients with Pulmonary
Failure and ARDS ......................................................... 384
Vanessa Fuchs, A.K. Malhotra and Rifat Latifi
Malnutrition and Lung Functions ........................................................... 384
Anatomy of Respiratory Failure .............................................................. 384
Acute Respiratory Distress Syndrome (ARDS) ........................................ 385
Nutritional Assessment ........................................................................... 387
Molecular Basis Nutritional Management ............................................... 389
Summary ................................................................................................ 392
26. Nutritional Support for the Burned Patient .................. 395
G.J.P Williams, Michael J. Muller and David N. Herndon
Introduction ........................................................................................... 395
Hypermetabolism in Burns ..................................................................... 395
Physiologic Responses to Burn Injury ..................................................... 397
Nutritional Support ................................................................................ 399
Hormonal Manipulation of Burn Hypermetabolism............................... 406
Summary ................................................................................................ 409
27. Nutritional Support after Small Bowel
Transplantation ............................................................. 418
S. Janes, S.V. Beath
Introduction ........................................................................................... 418
Recovery from Ischemia and Preservation ............................................... 419
Weaning off Parenteral Nutrition ............................................................ 420
Establishment of Normal Diet ................................................................ 424
Monitoring ............................................................................................. 424
Complications after Intestinal Transplant and Implications
for Nutritional Support ...................................................................... 425
Conclusion ............................................................................................. 426
28. Nutritional Support in Patients with Head
and Neck Cancer ........................................................... 430
Matthew E. Cohen, Rosemarie L. Fisher
Introduction ........................................................................................... 430
Risk Factors for Malnutrition.................................................................. 430
Malnutrition and Clinical Outcome ....................................................... 432
Surgery, Nutritional Support and Clinical Outcome ............................... 434
Radiotherapy, Nutritional Support and Clinical Outcome ...................... 439
Chemotherapy, Nutritional Support and Clinical Outcome .................... 440
Enteral Nutrition Delivery ...................................................................... 441
Surgical Gastrostomy or Jejunostomy...................................................... 444
Conclusion ............................................................................................. 445
29. Nutritional Support in Patients with Gastrointestinal,
Pancreatic and Liver Cancer .......................................... 449
Matthew E. Cohen
Esophageal Cancer .................................................................................. 453
Gastric Cancer ........................................................................................ 455
Colon Cancer ......................................................................................... 456
Pancreatic Cancer ................................................................................... 459
Liver Cancer ........................................................................................... 460
Cost Effectiveness ................................................................................... 463
Conclusion ............................................................................................. 464
30. The Treatment of Obesity ............................................. 473
Souheil Abou-Assi, Rifat Latifi and Stephen J.D. OKeefe
Epidemiology.......................................................................................... 473
Measurements of Obesity ........................................................................ 473
Health Risks Associated with Obesity ..................................................... 474
Can Obesity and Its Co-Morbid Diseases Be Reversed? .......................... 475
Summary of Interventions, and Results of Randomized
Controlled Trials ................................................................................ 475
Bariatric Surgery ..................................................................................... 481
Current Operations ................................................................................ 481
Nutritional Complications Following Bariatric Surgery........................... 484
Index ............................................................................. 489
Editors
Rifat Latifi, M.D.
Associate Professor of Clinical Surgery
University of Arizona
Tucson, Arizona, U.S.A.
Chapters 3, 6, 11, 17, 20, 24, 25, 30
Professor of Surgery
St. Marys Hospital/Yale Affiliate
Waterbury, Connecticut, U.S.A.
Chapters 14, 17, 20, 21
Frizan Abdullah
Yale University
New Haven, Connecticut, U.S.A.
Chapter 17
Souheil Abou-Assi
Section of Nutrition
Division of Gastroenterology
Department of Internal Medicine
Richmond, Virginia, U.S.A.
Chapter 30
Khawaja Azimuddin
University of New Mexico
Espanola Hospital
Espanola, New Mexico, U.S.A.
Chapters 3, 4
Timothy J. Babineau
Minimally Invasive Surgery
Boston Medical Center
Boston University School
of Medicine
Boston, Massachusetts, U.S.A.
Chapter 2
S. V. Beath
The Birmingham Children's
Hospital and
University of Birmingham
Birmingham, U.K.
Chapter 27
Larry H. Bernstein
Yale University Pathology
Bridgeport, Connecticut, U.S.A.
Chapter 1
George L. Blackburn
Division of Nutrition
Beth Israel Deaconess Medical
Center
Harvard Medical School
Chapter 2
Wendy Swails Bollinger
Department of Health Matters
Pennsylvania State University
University Park, Pennsylvania, U.S.A.
Chapter 2
Contributors
Marcia Brackbill
Department of Pharmacy
Shenandoah University
Winchester, Virginia, U.S.A.
Chapter 9
Gretchen M. Brophy
Department of Pharmacy
and Neurosurgery
Virginia Commonwealth University
Medical College of Virginia
Chapter 9
Antonio Cayco
Section of Nephrology
Chapter 23
Matthew E. Cohen
Section of Digestive Diseases
Chapters 28, 29
Susan T. Crowley
New Haven, Conneticut, U.S.A.
Chapter 23
John M. Daly
Weill Medical College of Cornell
University
New York, New York, U.S.A.
Forward
Robert S. Dechicco
The Cleveland Clinic Foundation
Cleveland, Ohio, U.S.A.
Chapter 8
Rosemarie L. Fisher
Section of Digestive Diseases
Chapter 28
Richard Formica
New Haven, Conneticut, U.S.A.
Chapter 23
Vanessa Fuchs
Hospital General de Mxico
The American British Cowdray
Medical Center
Mxico DF, Mexico
Chapter 25
Bruce Grossie
Department of Nutrition and Food
Sciences
Texas Woman's University
Denton, Texas, U.S.A.
Chapter 5
Per-Olof Hasselgren
Beth Israel Medical Center
Harvard Medical School
Chapter 7
David N. Herndon
Galveston Shriners Hospital
Blocker Burn Unit
Galveston, Texas, U.S.A.
Chapter 26
Diane R. Horowitz
Radiologist
Private Practice
Orlando, Florida, U.S.A.
Chapter 11
Eric Hungnness
University of Cincinnati
Cincinnati, Ohio, U.S.A.
Chapter 7
Rao R. Ivatury
Hospitals and Physicians
Chapter 4
S. Janes
The Birmingham Children's
Hospital and
University of Birmingham
Birmingham, U.K.
Chapter 27
Rima I. Kandalaft
Department of Nutrition and Food
Sciences
Texas Woman's University
Denton, Texas, U.S.A.
Chapter 5
Donald F. Kirby
Hospitals
Chapter 18
David A. Lanning
Childrens Hospital of Michigan
Wayne State University
Detroit, Michigan, U.S.A.
Chapter 6
A. K. Malhotra
Hospitals and Physicians
Chapter 25
Laura E. Matarese
Chapters 8, 10
Gayle Minard
The University of Tennessee
Memphis, Tennessee, U.S.A.
Chapter 12
Michael M. J. Muller
South Auckland Burn Service
Middlemore Hospital
Otahuhu, Auckland, New Zealand
Chapter 26
Stephen J. D. O'Keefe
Division of Gastroenterology
Department of Internal Medicine
Chapter 30
Patricia Pecora Fulco
Medical College of Virginia Hospitals
Chapter 18
Paul G. Perch
Hospitals and Physicans
Chapter 21
Melissa F. Perkal
Chapter 19
Renee Piazza-Barnett
Chapter 10
John M. Porter
University of Arizonia
Tucson, Arizona
Chapter 13
Timothy A. Pritts
University of Cincinnati
Cincinnati, Ohio, U.S.A.
Chapter 7
Shailendra K. Sazena
University of Nebraska Medical
Center
Omaha, Nebraska, U.S.A.
Chapters 15, 16
John H. Seashore
Chapter 19
Douglas L Seidner
Chapters 8, 10
Ezra Steiger
Cleveland Clinic Hospital
Chapter 8
John G. Sharp
Department of Anatomy
Center
Surgical Services at the Omaha VA
Medical Center
Chapters 15, 16
Jon S. Thompson
Center
Chapter 15, 16
Selman Uranues
AustriaGraz University
Graz, Austria
Chapter 24
G.J.P. Williams
Clinical Burns Fellow
Shriners Burns Hospital
Galveston, Texas, U.S.A.
Chapter 26
Abdulmasih Zarif
St. Mary's Hospital
Waterberry, Connecticut, U.S.A.
Chapter 17
Keith Zuccala
Danbury Hospital
Danbury, Connecticut, U.S.A.
Chapter 13
Foreword
It has been over 35 years since Dudrick et al described the growth of
beagle puppies fed intravenously demonstrating normal weight gain and
normal growth compared to their orally fed counterparts. This major achieve-
ment is worthy of all the accolades that have been heaped on Drs. Dudrick,
Rhoades and Vars for this work done at the University of Pennsylvania.
These studies demonstrated for the very first time that one could grow an
animal from a young age by administration of all nutrients by vein. This
study in animals was followed shortly thereafter in 1967 by the birth of a
young child with intestinal atresia. She was treated for well over a year with
intravenous nutrition demonstrating normal growth. Studies such as these
were replicated in a whole variety of clinical situations such as trauma, can-
cer, inflammatory bowel disease, radiation enteritis, G-I fistula and poor
wound healing.
Major achievements by Dr. Dudrick were not only to initiate a new therapy
and bring it from the laboratory to the clinical bedside but also to refine the
technique such that it could be applied with low morbidity. The develop-
ment of nutrition support teams and the development of the American So-
ciety of Parenteral and Enteral Nutrition were created by the concept of
teaching proper nutritional support throughout the world. Teams of doc-
tors, nurses, dietitians and pharmacists as well as others came together in
hospitals to administer parenteral and enteral nutrition. Utilization of teams
minimized complications and maximized effectiveness.
The decade of the 1970s was marked by the ever-increasing use of
parenteral nutrition demonstrating its metabolic efficacy in terms of weight
gain, serum protein metabolism, wound healing and improvement in out-
come. Prospective randomized trials were then begun and carried through
into the 1980s evaluating the use of parenteral nutrition compared with
other modalities in situations of cancer treatment.
The use of crystalline amino acids replaced protein hydrolysates. Fat emul-
sions were refined and brought into general use. Multi-vitamin preparations
were better defined along with micronutrient requirements. These studies
were painstaking occurring in both animal models and in humans, but they
were necessary as new nutrient administration techniques gave rise to vita-
min and mineral deficiencies. Early recognition of these problems led to
their solution.
The decades of the 1980s and 1990s demonstrated efficacy of certain
specific amino acids that would provide either metabolic fuels such as
glutamine for the intestinal track and for muscle as well as specific amino
acids such as arginine that might enhance immune effector cell function.
Omega-3 fatty acids, use of RNA and use of specific vitamins and minerals
were demonstrated to enhance immunological cell function. We entered an
age of nutrient pharmacology as noted by Dr. J. Wesley Alexander. Prospec-
tive randomized trials of enteral and parenteral nutrition were carried out in
elective surgery patients as well as critically ill patients in the intensive care
unit. These studies focused not only on clinical outcome measures but also
focused on cost efficiencies. Again, use of nutritional support teams in hos-
pitals minimized morbidity using nutritional support.
Drs. Latifi and Dudrick have superbly put this text, The Biology and
Practice of Current Nutrition Support, together. The chapters vary from
methods of assessing and monitoring nutritional status to those of the use of
intravenous and enteral nutritional support. Practical chapters define
laparoscopic placement of feeding tubes as well as the use of a variety of nutri-
tional substrates, which can be administered in different clinical scenarios.
Of particular importance, is the chapter on nutritional metabolic man-
agement of the short bowel syndrome. Dr. Dudrick was the first to propose
the use of long-term intravenous nutritional support for patients with short
gut syndrome and defined quite well the metabolic needs of these patients.
Many were kept alive for long periods of time by their intestinal tract to adapt
and finally giving way to combinations of enteral and parenteral nutrition.
There is no question that the discovery, implementation and utilization of
total parenteral nutritional support have made enormous benefits to our
patients; saving lives and improving clinical outcome. The recent death of
Dr. Jonathan E. Rhoads, former Chairman of the Department of Surgery at
the University of Pennsylvania and mentor to Dr. Stanley J. Dudrick exem-
plifies the value of an inquisitive mind and the strength of working in part-
nership with many others to achieve beneficial outcomes.
John M. Daly, M.D.
Lewis Atterbury Stimson Professor
Chairman, Department of Surgery
Weill Medical College of Cornell University
Surgeon-in-Chief
New York Presbyterian Hospital-Weill Cornell Center
CHAPTER 1
CHAPTER 1
Clinical Implications of Carbohydrate,
Proteins, Lipids, Vitamins and Trace
Larry H. Bernstein
Overview
Malnutrition occurs in 30-50% of hospitalized patients admitted to acute care
hospitals.
1
Patients who are malnourished or are at malnutrition risk usually have
risk factors or disease co-morbidities, any and all of which, unattended, may ad-
versely affect the outcomes of the surgical patient. Severe malnutrition is usually
easily recognized merely by extreme or significant weight loss, loss of strength, and
loss of function. Identifying severe malnutrition in a timely manner, then, should
lead to appropriate intervention.
1,2
Nevertheless, that is not always the case, and
malnutrition of moderate degree is often unnoticed at the time of admission. It is
especially important for surgeons to be aware of the risk of malnutrition, particu-
larly in the geriatric patient, because of the very strong association between malnu-
trition and postoperative complications.
3,4
Malnutrition occurs with co-morbidities
and is a significant co-morbidity. The surgeon also has to be concerned with the
effects of the metabolic requirements for acute injury independent of and interact-
ing with a malnourished state.
The Malnutrition Risk
The problem of unrecognized patient risk is tied to our conception and defini-
tion of the malnutrition risk. Increasingly, the risk of malnutrition is viewed in
terms of unexpected complications, such as, pneumonia, urinary infection, sepsis,
systemic inflammatory response syndrome (SIRS), which lends itself to expression
in statistical terms. That has not always been the case.
Definitions of Malnutrition
We traditionally make a distinction between marasmus, or chronic inanition
and kwashiorkor. Marasmus is starvation with loss of fat stores and skeletal muscle,
but sparing of circulating transport proteins produced by the liver. Kwashiorkor is
defined by the decrease in circulating plasma proteins. These concepts fit neatly into
measurement criteria using anthropometrics and the laboratory, but they dont em-
body the dynamic changes of the critically-ill patient. We refine our concept of the
high risk surgical patient, in particular, by reviewing the metabolic response to stress
injury.
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
2
The Biology and Practice of Current Nutritional Support
1
Imperative for Nutritional Intervention
The identification of geriatric surgical patients at high risk for malnutrition and
initiating their timely nutritional support is a critical standard of care issue used by
the Joint Commission for Accreditation of Healthcare Organizations. This can be
achieved by a systematized program for identifying patients who might need either
nutritional supplements or aggressive nutritional support. The program has to iden-
tify chronic losses and an acute stress state by both clinical and laboratory charac-
teristics and allow for timely correction of deficits.
5,6
Stress Hypermetabolism and the Nutritionally-Dependent
Adaptive Dichotomy
Stress Injury
Stress injury is described in three stages: the ebb phase, the catabolic flow phase,
and the anabolic flow phase.
7,8
The ebb phase is dominated by circulatory changes
that requires fluid resuscitation over a period of 8-24 hours. The catabolic flow
phase is dominated by catabolism with initial liver glycogenolysis over the first 24
hours concomitant with skeletal muscle proteolysis to provide gluconeogenic sub-
strates, and lipolysis to provide fatty acid fuel for energy after enzyme induction.
This phase lasts for three to 10 days, but may be extended. The anabolic flow phase
emerges as metabolism shifts to synthetic activities and reparative processes.
Cytokine and Hormonal Events
It is essential to control the hormonal and metabolic balances in these phases for
the metabolic management of the stressed patient. The catabolic flow phase is driven
by cytokine mediators released by lymphocytes and macrophages in the cellular
immune reaction, dominated by interleukin-6 (IL-6).
9
The release of these media-
tors is proportionate to the amount of the injury. The release of cytokines is linked
to upregulation of hormonal and humoral events.
9
The hormonal events include
the release of glucagon and catecholamines, thyroid hormone, growth hormone,
and cortisol, and their effectshyperglycemia, metabolic rate, release of free fatty
acids and associated ketosis, insulin growth factor 1 (IGF1), and negative nitrogen
balance from gluconeogenesis.
Catabolic Reactions
The principal action of glucagon is on the conversion of hepatic glycogen to
glucose, thereby, raising the plasma glucose level. Thyroid hormone (T
4
) has an
effect on target organs through the free hormone (FT
4
). The catabolic effect of
growth hormone on lipid metabolism is reciprocal to an anabolic effect through
IGF1. An adrenal cortisol secretory response opposes the action of insulin and
promotes a diabetogenic response. Hypercortisolemia results in muscle proteolysis.
Amino acids, especially branch chains amino acids from skeletal muscle, provide
the gluconeogenic precursors through alanine. These hormones are released by the
stress response and drive the metabolic pathways necessary for the use of carbohy-
drate and fatty acid fuels, and necessary to support the repair of damaged tissue.
The humoral events include the changes in and interactions between serum pro-
teins in the inflammatory response. The systemic effects of fever, tachycardia, in-
creased energy expenditure, muscle weakness and wasting are associated with the
elevations of acute phase reactants (APRs) (C-reactive protein, tumor necrosis
factor-alpha, alpha-1 acid glycoprotein) and hormonal changes.
7,8
3
Clinical Implications of Nutrition Elements
1
Suppressed Syntheses
The stress response immediately suppresses synthetic activity by the liver,
9
an
organ that has a sole synthetic function with NADP dominated pathways. The se-
rum cholesterol decreases as does the production of essential transport proteins,
such as, albumin, transferrin, cortisol-binding globulin (CBG), thyroxine-binding
globulin (TBG), transthyretin or thyroxine-binding prealbumin (TTR), insulin
growth-factor 1 (IGF1).
9
While the transport proteins decline abruptly by as much
as 40%, the synthesis of APRs is unaffected. Their essentially controlling and adap-
tive role they exert through their binding to and effects on active ligands.
Nutritionally-Dependent Adaptive Dichotomy (NDAD)
The above relationship, under the influence of cytokines, Ingenbleek refers to as
the nutritionally-dependent adaptive dichotomy (NDAD).
9
One has to also con-
sider that this adaptive relationship in stress injury is affected by protein malnutri-
tion prior to the injurious state. Why? Because the basal level of binding proteins is
set low and the adaptive response is blunted.
Free Ligands and the Adaptive State
The metabolic effect of stress injury in the catabolic phase increases the flow of
fuel substrates for energy using processes by its effect on the liver. The decrease in
CBG, TBG, TTR and RBP increases the hypermetabolic effect. The free hormone
hypothesis states that hormonal effect on target tissue is a result of the free hormone.
The adrenal gland is releasing increased cortisol which has an amplified effect with
its binding to a lower plasma concentration of CBG. The liver is the repository for
extrathyroidal T
4
. The extrathyroidal T
4
is released with a decreased circulating TBG
and TTR.
9
The result is an increased thyroidal activity measured by an increased
free T
4
(FT
4
). This is actually what is referred to as the sick euthyroid syndrome. The
TSH is not affected or slightly decreased, but not in the hyperthyroid range. Vita-
min A is stored in the liver, and it is transported in the circulation in a complex with
TTR and RBP. The vitamin A and RBP are dependent on the level of TTR.
Effect of Stress Injury on Liver Syntheses
The metabolic effect of stress injury on the liver is coupled with the reciprocal
effect of GSH.
9
The decreased synthesis of GSH dependent IGF1 occurs with a
high level of GSH. The IGF1 promotes anabolism and protein retention. The result
is an increase of lipid utilization with a breakdown of lean body mass to support
gluconeogenesis. The IGF1 is bound to IGF1 binding protein-3 (IGFBP-3), which
is unaffected by stress. The decreased level of IGF1, which has a short halflife of 8
hours, results in a decrease in the free and active protein, supporting the increased
catabolism.
Energy Requirements of Injured Man
Proteolysis and Nitrogen Loss
The hypermetabolism as it affects protein metabolism is measured by the break-
down of skeletal muscle and the oxidation of amino acids through alanine to
alpha-ketoglutarate in the Krebs cycle.
7,8
This results in the release of the amino
group and the production of urea nitrogen through the urea cycle. The somatic
protein loss is also associated with the release of 3-methyl histidine, an amino acid
specific for skeletal muscle that is excreted into the urine with urea nitrogen.
4
1
Cuthbertson described the catabolic loss of nitrogen that cccurs with severe
injury and is associated with skeletal muscle wasting, loss of strength, and attrib-
uted to extensive breakdown of muscle.
7,8
The increased rate of metabolism in stress
injury is measured by the rate of protein oxidation and by the rate of CO
2
produc-
tion. The rate of protein oxidation is measured by the rate of nitrogen appearance
in the urine. There is normally 4 grams of unmeasured nitrogen to be accounted for
in 24 hours, so the total nitrogen is calculated from urinary urea nitrogen by adding
4 grams, assuming that the nonurea nitrogen is negligible.
Nitrogen Loss and Gluconeogenesis
The rate of gluconeogenesis is decreased in normal man, a nitrogen sparing
effect, when 6-10 grams of carbohydrate is provided. The rate of gluconeogenesis is
not increased in starvation as the body economy relies on lipolysis and fatty acid
fuels associated with ketogenesis. These patients have a normal or decreased urinary
nitrogen. The rate of gluconeogenesis is accelerated during the acute catabolic state,
even when glucose is provided. This is unabated, though, by providing exogenous
glucose.
10
The loss of nitrogen with trauma or sepsis is related to the extent of the
injury.
7,8
Nitrogen balance studies measure nitrogen equilibrium, which is the net
loss or gain of protein from the body.
11
The nitrogen loss after severe injury is
proportional to the severity and extent of trauma, and it tapers off in days. Indeed,
the nitrogen loss is greatest with severe trauma and delayed refeeding. The net ac-
cretion of body protein in the reparative phase is slow in the post-injury phase and
has been measured by Hill and associates using whole body neutron activation
analysis.
12
Anabolism with refeeding occurs at a constant rate of 3 gm of nitrogen
(20 gm protein) per 70 kg body weight per day, but muscle activity is required for
rebuilding the loss.
12
Stress Metabolism of Carbohydrate and Fat
Stress injury results in alterations in carbohydrate and fat utilization. Adipose
tissue is converted to fatty acids and glycerol as described above. Fatty acids are
oxidized by non glucose-dependent tissues. The glycerol is and unoxidized ketones
are used as a glucose fuel. As the concentration of plasma glucose rises in severe
injury, the hyperglycemia is related to crude muscle losses with increased urinary
nitrogen loss. The site of injury is supported by the breakdown of whole body
protein to support the immune response. This is not associated with a lack of insu-
lin, but with increased activities of counterregulatory hormones opposing the insu-
lin action.
9
Fat is not utilized as the primary fuel in the extensively injured extremity
because of the shift to glycolytic metabolism in the injured tissue associated with
increased production of lactate.
7-9
A significant amount of glucose production by
the liver is from lactate and pytuvate as the wound metabolizes glucose.
Measuring Energy Expenditure
Indirect calorimetry and tracer techniques are used to study substrate oxidation
in vivo.
10,13,14
The latter requires blood sampling and is only used in the research
setting. CO
2
production is used to measure substrate oxidation and energy expen-
diture by indirect calorimetry from measurement of respiratory gas exchange rates.
The method assumes the CO
2
expired is proportional to the rate of respiration.
The assumption depends on the O
2
disappearing from the inspired air being used
exclusively for biological oxidations so that all the CO
2
expired is derived from
5
1
combustion of substrates. It is also assumed that all of the nonprotein nitrogen
excreted into the urine is derived only from the oxidation of free amino acids, which
is 16% of the nitrogen content. Indirect calorimetry measures the net loss of sub-
strate by oxidation, regardless of cycling that may occur along the way. The method
of indirect calorimetry and the Fick principle both measure the oxygen consump-
tion (VO
2
) and the carbon dioxide production (VCO
2
). Indirect calorimetry mea-
sures the oxygen consumption (VO
2
) and the transpulmonary O
2
gradient from the
respiratory gas exchange. Fick proposed to measure the VO
2
and VCO
2
from gas
exchange and the transpulmonary O
2
and CO
2
gradient by heart catheterization. In
this idealized model, the O
2
input and CO
2
output is measured, and the cardiac
output (CO) provides the flow rate. The result is:
VO
2
= CO (arterial O
2
mixed venous O
2
)
VCO
2
= CO (arterial CO
2
mixed venous CO
2
)
Assuming that ambient air is the only source for O
2
and the only sink for meta-
bolic CO
2
, the VO
2
and the VCO
2
are measured from the fractional concentrations
of O
2
and CO
2
concentrations in the inspired (FI) and the expired (FE) air flows.
The calculation is:
VO
2
= (FIO
2
FEO
2
)Ve
VCO
2
= (FICO
2
FECO
2
)Ve, where Ve is the ventilatory rate.
The only significant difference between these is that the measures of VCO
2
are
12% lower and less accurate with Fick than with indirect calorimetry.
13
Energy of Fuels
The respiratory quotient (RQ), defined as VCO
2
/VO
2
, is the measure of
efficiency of respiration.
10
The calorimetric RQ is between 0.69 and 1.00. The en-
ergy expenditure being measured by the VO
2
, a value of less than 1.0 is incomplete
combustion. RQ is important for calculating the nutritional requirements in pro-
viding assisted nutritional support. The RQ for fat is 0.7, whereas the RQ for carbo-
hydrate is 1.0. We have to weigh the advantage of the administration of fat versus
carbohydrate energy sources. Fat has an advantage over carbohydrate because it is a
dense calorie source and it is efficiently oxidized based on its low RQ. The effect of
excessive carbohydrate calories is excessive CO
2
production, which drives a hyperp-
nea, detrimental to the pulmonary compromized patient. Lipid has a rate of admin-
istration that is rate limited by its clearance. Excessive fat administration is
immunosuppressive.
Harris-Benedict Equation
The use of indirect calorimetry is limited in most clinical settings, except for
intensive care units, because of cost requirements for the technology and for the
staffing. The Harris-Benedict equation is most commonly used to calculate the esti-
mated calorie and protein needs with reasonable agreement with actual needs.
Males BEE = 66.47 + 13.75 W + 5.0 H6.76 A
Females BEE = 655.10 + 9.56 W + 1.85 H4.68 A, where W is weight in
kg, H is height in cm and A is age in years.
Consideration must be given to existing energy needs that go beyond basal or
resting needs. This basic estimate of energy needs (BEE/REE) is often increased to
reflect the energy required for physical activity and any anticipated hypermetabolic
response to injury or illness.
BEE x (activity factor) x (injury factory) = TEE (total energy expenditure)
6
1
Nutritional Requirements
Energy Requirements Under Stress
The calorie and protein requirements for stressed patients are shown in Table
1.1. For normal energy needs 100-150 g of CHO must be furnished daily. Glucose
oxidation under normal conditions is at approximately 2-4 mg/kg/min, and in
severe stress is only slightly greater at 3-5 mg/kg/min. Catabolism of peripheral
muscle and lipolysis release carbohydrate and lipid substrates in severe stress (14).
An excess of 400-500 g of glucose per day is not used. However, administration of
carbohydrate as a sole energy source has a calorigenic effect, increasing the utiliza-
tion of fuel by about 20% over REE. Protein sparing by glucose is abrogated by
severe stress.
Protein Requirements
Protein is required for growth, maintenance and repair of tissue. 6.25 grams of
protein has one gram of nitrogen. Nitrogen balance occurs when protein synthesis
and breakdown are in equilibrium. Dietary protein contains 20 common amino
acids of which nine are essential. The recommended dietary allowance of protein
for an adult (non pregnant or lactating) is 0.8 g/kg/day. In the catabolic phase of
acute stress or trauma, protein requirements are increased at 1.5 to 2.0 g/kg/day or
more for wound repair, or to replace protein lost in drainage of exudate. The provi-
sion of adequate calories and protein is mandatory.
Fat Requirements
35% of diet intake as fat is required for energy and for essential fatty acids.
EFAD occurs at a ratio of 0.4 or greater. Linolenic acid deficiency is characterized
by: growth retardation, scaly dermatitis, and alteration of the normal triene:tetrene
ratio. Linoleic acid is derived from linoleic and may be derived exogenously. Oils as
corn, soy and safflower contain 50-70% of their fat as linolenic. Linoleic acid is a
precursor of arachidonic acid, which is needed for prostaglandin and thromboxane
synthesis. Most lipid emulsions presently available are composed for the most part
of long chain triglycerides (LCT). Complications from use of LCTs include com-
promised immune function, hyperlipidemia, impaired alveolar diffusion capacity,
and reduced function of the reticulo-endothelial system.
Minerals and Trace Elements
The macronutrients, water and electrolytes constitute the major part of nutri-
ent intake, regardless of the route of administration. The major mineralscalcium,
phosphorus, and magnesium, and electrolytessodium, potassium and chloride
must be provided. They are essential for neuromuscular, cardiac, endocrine and
skeletal function. Potassium is the main intracellular cation and it is in equilibrium
with sodium, divalent cations, and anions. Its intracellular concentration is 140
mmol/L. The total body potassium is 71 mmol/kg. The total body potassium is
depleted in malnourished surgical patients, and it is disproportionately reduced
compared with nitrogen. It is increased with short term TPN without increasing
the total body nitrogen, but long term feeding also increases nitrogen.
11
It is impor-
tant to keep in mind the following:
1. glucose infusions increase the need for K
+
;
2. there is a retention of 3 meq K
+
per gm of nitrogen;
7
1
3. infusion of about 80-120 meq K
+
per day is required to replenish stores in
patients receiving TPN.
The most important divalent cation is magnesium, important for membrane,
mitochondrial, and nuclear metabolic functions. The extracellular magnesium ac-
counts for only 3% of the total body magnesium. Magnesium becomes depleted
with protein-energy malnutrition, and it has to be increased to about 15 mmol per
day to improve nitrogen balance. Phosphate is the main intracellular anion. It is
critical for buffering systems, energy linked nucleotide reactions, membrane func-
tion, oxygen transfer systems, and neuromuscular function. The majority of phos-
phorus is in bone matrix with calcium. The serum phosphorus falls rapidly during
TPN, and it is extremely sensitive to the administration of glucose and insulin and
less sensitive to use of a mixed substrate. As with magnesium and potassium, phos-
phorus promotes nitrogen retention. The importance of monitoring for adequate
blood levels of magnesium and phosphate is covered later.
Vitamins
Beyond maintenance requirements, little of a definitive nature is known regard-
ing the needs for vitamins and minerals in critical illness or injury, except for the
nutrients involved in wound repair, as Vit A, Vit C and Zinc.
11
The most important
trace elements for our consideration include iron, zinc, chromium, copper, manga-
nese, iodide, selenium and molybdenum, and cobalt. These are required for meta-
bolic function and their deficiency is associated with specific biochemical change
and functional abnormality that is relieved by giving these nutrients. Of these, co-
balt is associated with vitamin B
12
. These are absorbed in bound and elemental
forms, and they circulate as protein-bound complexes or ligands that are not in free
equilibrium with tissue stores. These are usually incorporated as cofactors of en-
zymes or proteins in tissue. In relationship to this dissociation of plasma level and
tissue stores, the plasma concentration is not a measure the total body stores. For
example, zinc plasma concentration is normal in the hypercatabolic state as zinc is
being lost and the patient is in negative zinc balance. The plasma zinc is maintained
by a net outflow from tissue stores. A positive zinc balance occurs with provision of
nutritional support as there is a net inflow of zinc into tissue with anabolism, and
the plasma level falls unless exogenous zinc is given. Vitamins are active in minute
quantities and have to be provided in any regimen of TPN to avoid deficiency.
Patients with steatorrhea, short bowel, and pancreatic insufficiency require increased
fat soluble vitamins, including 10,000-30,000 IU per day of vitamin A. Patients
with chronic liver disease will have reduced vitamin A stores. Those receiving TPN
may need 3300 IU per day.
Table 1.1. Calorie and protein needs in stress
Stress Clinical Setting CHO% NPC:N Stress
0 Simple starvation 28 150:1 1.0
1 Elective Surgery 32 100:1 1.5
2 Polytrauma 40 100:1 2.0
3 Sepsis 50 180:1 2.5
8
1
Clinical vs. Laboratory Information
Clinical and Functional Status
The importance of clinical indicators is correlation with functional status and
identification of prior co-morbidities, i.e., cancer, sepsis, major surgical procedure,
prolonged vomiting or diarrhea, fistula, inability to take in or utilize nutrients.
15
These are associated with depletion from hypo- and/or hypermetabolism. Clinical
indicators are excellent categorical criteria for risk assessment, but they can by them-
selves, contribute to over- and underutilization (malutilization) of nutritional sup-
port. Table 1.2 lists clinical risk factors for malnutrition.
Laboratory Evaluation
Laboratory indicators are objective and may be used for measuring calorie and
protein needs, for identifying serious clinical risk of malnutrition, for documenting
agreement between clinical criteria and actual deficits, for documenting anabolic
response from nutrient repletion, and for assessing prognosis.
5,6
These are shown in
Table 1.3. The finding that the laboratory is no better than subjective global assess-
ment is expected concordance between two types of observations. The sensitivity
and onespecificity of a test is actually fitted to a receiver-operator characteristic
curve to remove, as much as possible, the effect of decision value selection, but it is
affected by the choice of the dependent variable that is used to define the outcome.
We have to put into context additional value provided by the laboratory. Agree-
ment between SGA and severe losses for at least two laboratory measures confirms
correlation between clinical and laboratory tests. On the other hand, there are unique
patient (sub)groups (syndromic classes) that have incongruously depressed serum
proteins either because of early protein depletion or repletion that may or may not
agree with clinical assessment.
16
Redundant Laboratory Abnormals
Syndromic classes is treated in the information-based definition of decision-values
proposed by Spiekerman, Rudolph and Bernstein.
16
A simple example of this con-
cept is the observation that a patient has an albumin of 2.7 g/dl AND and lympho-
cyte count of 1,080. In a more formal way, one takes the tests and scales them for
intervals, assigning values in the assigned ranges from 1 to k. The test combinations
form pattern classes, which group into the malnourished and nonmalnourished
groups with frequencies related to risk. The existence of three groups (non-disease,
moderate, severe) requires a multivalued logic with at two decision-values for a
laboratory test. In the absence of a gold standard test to use as a supervisory vari-
able, it would be possible to determine the correct assignment of laboratory data to
each group only if sufficient variables are used to form a classification.
Tests to Monitor
Test selection has a basis in pathophysiology. Hypermetabolism increases pro-
teolysis and gluconeogenesis with loss of muscle mass and amino acid oxidation
resulting in urinary loss of nitrogen as 3-methyl histidine, creatinine, and urea.
Nitrogen loss is a primary measure of stress. The greatest nitrogen losses in trauma
occur in the first few days, at a time when total urinary nitrogen reflects the cata-
bolic phase more accurately than urinary urea nitrogen.
9
1
Liver transport proteins are characterized by different rates of production and
degradation, and short halflife is a useful characteristic for following catabolism and
anabolic response. The acute phase proteins, C-reactive protein (CRP) and alpha-1
antitrypsin are elevated with the inflammatory response (ceruloplasmin and trans-
ferrin are also) even when other proteins are severely depressed. CRP is a particularly
good indicator of bacterial infection. CRP and TNF- are increased associated with
the cytokine mediated response, particularly interleukin-6.
Table 1.4 is a comparison of the plasma proteins that are used to assess protein
energy malnutrition (PEM). The phenomenon of protein depletion is referred to as
an inverted acute phase response. Serum albumin, with a halflife of 21 days, is in-
sensitive for measuring anabolism, and its volume distribution makes it a popula-
tion rather than an individual measure of nutrition. It is unsuitable for the dynamic
evaluation of nutritional repletion. Albumin increases by only 0.2 g/dl a week with
aggressive nutrition support. Transferrin, with a halflife of 8 days, is somewhat bet-
ter than albumin, but it is affected by iron balance. Table 1.5 shows the features of
an ideal nutritional marker.
Rapid Turnover Proteins
Proteins with short halflifes less than 2 days, such as transthyretin (prealbumin,
thyroxine-binding prealbumin, TBPA, TTR), are needed to measure the anabolic
response. TTR increases at an expected rate of 1 g/dl a day, or doubles in a week
with nutrition support.
5,16
It may be halved after a week to 10 days NPO. It may be
elevated by corticosteroid therapy after a few days. Retinol-binding protein (RBP),
which has a half-life of 36 hours, circulates bound with vitamin A to TTR in a 1:1:1
molar ratio. The complex is elevated in patients with renal failure on dialysis and
RBP is excreted in the urine. RBP and TTR are both measured easily by nephelom-
etry. Insulin growth-factor 1 (IGF1) or somatomedin C is the best measure of ana-
bolic response because it has the insulin effect without the lipolytic effect of growth
hormone. It is bound to the IGFBP3 receptor and it is difficult to measure because
of an extraction and long incubation time. The method has been improved by an
automated column methodology (Nichols). Arguments have been made for mea-
suring fibronectin, which may have a role in wound healing. Fibronectin is de-
creased in burn patients and appears to be a predictor of sepsis. The most easily
measured of this class of tests is TTR. A TTR of less than 8.5 mg/dl is a critical
Table 1.2. Clinical risk factors
inadequate nutrient intake for 5 days or more
recent unexplained weight loss
surgery or disease of the gastrointestinal tract
unwillingness or inability to eat or eat enough
Table 1.3. Laboratory risk factors
Total lymphocyte count < 1200/mm
2
Pre-Albumin < 11 mg/dl
Transferrin < 150 mg/dl
Albumin < 3.0 g/dl
10
1
finding for a burn patient because the patient cant hold a graft. A TTR of less than
5 mg/dl is severe protein depletion. A case study illustrates its advantage.
Case Example
An 88-year old woman with lower GI bleeding associated with perforated di-
verticulitis had a surgical resection and proximal diverting colostomy with a some-
what complicated recovery. She was maintained on PPN initially and changed to
central TPN day 13 when she had an obstruction that resolved by day 20 after the
small bowel was decompressed.
Postoperative Day
Test 1 13 16 26 Reference range
ALB, g/L 27 25 25 27 35-55
TTR, mg/L 72 121 160 205 160-350
Information Model
Getting the Most Out of Information
I previously referred to the concept of syndromic classes.
16,17
Even though it is a
formal idea that is measurable, it is not important for surgeons to feel a deficiency
of knowledge with unfamiliarity with this. The truth of the matter is that you use it
often in practice. Clinical decisions are made by observing data from laboratory
and clinical findings together.
The evaluation of nutritional status is somewhat refined by an information model.
The model is derived from the fundamental theory of communication, which uses
Table 1.5. Features of an ideal marker
Identify clinically significant depletion
Reflects severity of deficits
Indicator of current status and change in status
Sensitive to decline
Sensitive to improvement
Minimal interference
Table 1.4. Plasma protein used in nutrition assessment
Albumin: limited value for detecting acute changes in nutritional status.
3.0-3.5 g/dl Mild depletion
2.5-2.9 g/dl Moderate depletion
2.4 or less Severe depletion
Transferrin: half-life of 8 days
Affected by iron metabolism
TTR: half-life is 1.9 days
Early predictor of protein malnutrition
Measures response to nutritional support
A serum TTR < 11 mg/dl is protein malnutrition
TTR decreases at a rate of 0.8 to 1.5 mg/dl per day, depending on the level of stress with no
oral feeding. It doubles in a week with nutritional support.
11
1
redundancy to minimize the effects of noise in message transmission. We use an
information model for medical decision-making by treating disease as a symptom
complex that is a coded-message (each coded-message is a syndromic class). The
message transmission can be interpreted from the redundant information (correla-
tion) in the message. Regression is the most common approach to continuous data.
It is a smoothing function and carries a risk of loosing information. It does not
reveal the structure of the data. There are approaches that learn and classify data
(clinical and laboratory) based on analysis of the information content of the data,
such as, recursive partitioning and amalgamation, Rypkas truth table comprehen-
sion,
17
Rudolphs group-based reference,
16
and neural networks. These are based on
classification matrices that are formed by similarities and differences of features that
define data sets. Normal-reference is defined by Rudolph and Bernstein
18
as the set
having no information. That is a departure from distance from the center.
Length of Stay (LOS)
Association between Malnutrition and Length of Hospital Stay
Clinical and laboratory indicators of nutritional status are associated with excess
LOS.
19
The best predictor of nutritional class is a combination of tests.
20
Use of the
chemistry profile can take into account the information in: albumin, total protein,
cholesterol. TTR (prealbumin, transthyretin, thyroxine-binding prealbumin), with
its short halflife (1.9 days), is sensitive to changes in nutrititional status and is an
indication of severity of deficits. It is not affected by hydration status in the way that
albumin is. Serum TTR can be combined with the chemistry panel. These tests may
be scored and used to predict LOS. Although the information model can be used to
examine the relationship between malnutrition and LOS, it can be used to examine
the effects of an implementation program, which includes early feeding, but may
include other measures. In this case LOS becomes an outcome variable and inter-
ventions become inputs.
Improving Correction of Malnutrition
Identify Malnutrition Risk and Intervene
The ability to identify malnourished patients and to implement early interven-
tion has implications for continuous quality improvement.
1
Using laboratory as well
as clinical indicators of malnutrition should allow identification of all patients at
risk within 24 hours of admission. Laboratory tests can be triggered by admission
criteria, such as weight loss, decreased food intake, or medical condition, or they can
be added to a standard admission profile. Advanced age over 65 years or serum
albumin concentration below 3.2 g/dl can be used as automatic criteria for obtain-
ing TTR.
Monitoring Effectiveness of Feeding
The greatest value of TTR is its measure of current nutritional status.
5,6,21
Thereby,
it allows determination of adequacy of feeding, and it should reduce the discharge of
wasted patients who are at risk of readmission. Its physiological range is 16-35 mg/
dl. Serious malnutrition is reflected by a serum concentration < 11 mg/dl, severe at
< 7 mg/dl. It increases at a rate of 1 mg/dl per day with adequate nutritional sup-
port. A TTR concentration of less than 11 mg/dl after a week of nutrition support
or a daily increase of less than 0.5 mg/dl is a reasonable indication that the feeding is
12
1
inadequate or that the patient is unresponsive. Serum TTR concentration is a prog-
nostic indicator.
Clinical Processes Incorporating Transthyretin (Prealbumin)
A profile including TTR can be incorporated into a clinical practice guideline
implemented through a critical pathway. Although TTR acts as an acute phase
reactant, it can be used to establish a baseline for nutritional support. Urinary ni-
trogen excretion is often used to assess the amount of protein deficit prior to feed-
ing. Failure to increase TTR is an indication of inability to provide adequate nutrients
by method of feeding. Systematic identification of patients at risk, appropriate tim-
ing and mode of feeding, and monitoring effectiveness are essential elements for
such a guideline.
Nutrition Support Monitoring
TTR a Measure of NDAD
We have seen how the use of a short halflife protein, such as TTR can be used
alone, or in combination with serum albumin and clinical indicators for identify-
ing serious risk. TTR is a measure of the NDAD, so the decrease in TTR is associ-
ated with changes in CRP, TNF
alpha
, RBP and IGF1.
9
In some patients who have
recieved high dose corticosteroids, the TTR is elevated, but it is possible to trend
patients as they receive nutritional support. In these patients it might be argued
that urinary nitrogen excretion is done weekly.
Nitrogen Loss
Nitrogen balance is daily intake of nitrogen minus the excretion. The intake
represents nutritional nitrogen and the excretion consists of measured urinary ni-
trogen plus a factor for unmeasured gastrointestinal and cutaneous losses, usually 2
to 4 grams. Nitrogen balance is calculated as:
N intake(urinary N + change BUN + 4)
change in BUN (g) = (0.6 weight) (SUNfSUNi),
where i and f are the initial and final values in the measurement period, SUN is
serum urea nitrogen (g/l), and weight is body weight in kilograms. A positive bal-
ance indicates an anabolic state with an overall gain in body protein for the day. A
negative nitrogen balance indicates a catabolic state with a net loss of protein. Uri-
nary nitrogen excretion may rise to 30-50 g/day with severe stress, which is the
equivalent of 1 to 1.5 kg of lean body mass.
Overfeeding and Monitors
We have already considered the consequence of lipids versus carbohydrate as an
energy source. The effects of excess carbohydrate are hyperglycemia and on driving
pCO
2
production with CO
2
retention. Carbohydrate also leads to fatty liver. This
necessitates the close monitoring of pCO
2
measurement for patients on nutritional
support and less frequent evaluation of liver function, such as the alkaline phos-
phatase. Table 1.6 lists the complications of overfeeding. The electrolytes have to be
monitored because of losses from fluid loss. The fluid associated electrolyte losses
are listed in Table 1.7.
We have to add to the complications the serious effect of hypophosphatemia.
Hypophosphatemia and hypokalemia can both occur as a result of the refeeding
syndrome. They have to be watched as closely as the pCO
2
, the glucose, and the
13
1
TTR. The K
+
, Mg
2+
and H
2
PO
3
2-
are intracellular cations and anion, respectively.
They move into the cell and out of the circulation with refeeding. They are critical
for excitation-contraction coupling, and failure to monitor these can result in sud-
den death. In the case of magnesium, the serum level is not an accurate measure of
the total body load. A patient with tetany may have low calcium concentration, but
if the calcium fails to resolve this, than administration of magnesium is the best test.
Table 1.8 lists the requirements for monitoring phosphate levels. The lowering of
serum phosphorus levels leads to a decrease in ATP and other phosphorylated com-
pounds in the tissues and blood. When the serum level falls to 1.0 mg/dl or lower,
leukocyte dysfunction and a potential for sepsis occurs. In addition, reduced nucle-
otide production due to hypophosphatemia can result in hemolytic anemia, neuro-
muscular dysfunction, myocardial depression and respiratory failure. Adequate
treatment of the severely malnourished patient requires adequate nutritional sup-
port with careful monitoring. Repletion must be initiated slowly while monitoring
serum phosphorus, along with serum electrolytes, glucose, and magnesium levels.
Quality Management
Excess LOS variation is a global outcome variable. It is dependent on extended
period after surgery without oral intake (Meguids IONIP), initial condition, unex-
pected complication (wound site infection, pneumonia), and malnutrition. The ef-
fect of nutritional status is independent and interacts with the other factors. The
laboratory tests predict outcome by forming severity classes. Mozes et al
22
recently
classified surgical and nonsurgical major diagnostic categories into groups homoge-
neous with respect to LOS from seven laboratory values (wbc, Na, K, CO
2
, BUN,
HCT, ALB) for 73,117 admissions at UCSF and Stanford. Studies have shown that
Hb, cholesterol
23
and insulin-like growth factor 1 (IGF1)
24
are predictors of mortal-
ity. Nutritional markers are important tests in any analysis.
Quality Management has to focus on medical outcomes of alternative strategies,
i.e., feeding, not feeding, delayed intervention, and the costs of interventions. Policy
considerations are the organizational purview of a Nutrition Committee and the
Nutrition Support Team. The cost of data collection can be significant. The cost of
prevention, with an effect on under- and over-utilization, can be less than the cost of
failure to develop a system. The use of the laboratory has a low cost in supporting a
system of quality management.
The information model has been used to determine optimum decision-values
for tests, and has been used to examine the relationship between tests, malnutrition
and LOS. It can be used to examine differences in the effects of interventions. Not
all interventions can be assumed to be equivalent. Preoperative feeding for five days
before a major procedure assumes utilization costs that have a different significance
for marginally than severely at risk patients. Perioperative interventions, intrave-
nous and enteral, are uniquely identified input variables. In addition to the assign-
ment of treatment effects, it is necessary to identify the initial pretreatment condition
as distinguished from the treatment effects. Therefore, laboratory data need to be
adequate to examine post-treatment status. These can be described in the form of a
truth table with each defining variable as a column and each patient as a row.
It is important to recognize that a quality improvement model for nutritional
interventions has to take into account the expectations of costs to do nothing, the
expected costs of alternative interventions, and the costs reduced by failure avoid-
ance. Traditional cost accounting models are not adequate for the complexity
of the issues.
14
1
The ability to identify malnourished patients and to implement early interven-
tion has implications for continous quality improvement (1). Using laboratory as
well as clinical indicators of malnutrition should allow identification of all patients
at risk within 24 hours of admission. Laboratory tests can be triggered by admis-
sion criteria, such as weight loss, decreased food intake, or medical condition, or
they can be in a standard admission profile.
Transthyretin (prealbumin, thyroxine-binding prealbumin, TBPA, TTR) is a
transport protein with a short halflife (1.9 days) that is sensitive to changes in
nutrititional status and is an indication of severity of deficits. It allows determina-
tion of adequacy of feeding, and it should reduce the discharge of wasted patients
who are at risk of readmission. It has a physiological range of 16-35 mg/dl. Serious
Table 1.6. Problems of overfeeding
excess CO
2
production
fat deposition
hyperglycemia
pulmonary edema
worsening of existing congestive heart failure
hepatic complications
Table 1.7. Etiology of common electrolyte deficiencies
Electrolyte Cause of Deficiency
Sodium Loss of skin, GI tract, lungs or kidney
Kidneydiuretic use, renal damage, adrenal insuffic
Potassium Starvation, loss from skin, bile, lower GI tract or fistula.
Renal: diuretics, alkalosis, Amphotericin
Bicarbonate Diarrhea, pancreas or small bowel loss, renal tubular acidosis,
mineralcorticoid deficiency
Chloride Diuretics, gastric loss, intestinal loss, secretory loss, renal
reabsorption due to drug therapy-carbenicillin, sulfate, phosphate
Magnesium starvation, intestinal loss, malabsorption, diarrhea, laxative abuse,
diuretics, cyclosporin
Phosphorus starvation, alkalosis, glucose administration, diabetic keto
acidosis, GI tract losses, aluminum containing antacids.
Table 1.8. Clinical conditions for which phosphorus levels should
be monitored during treatment
Refeeding phase for the malnourished patient
Alcohol withdrawal and nutritional support
Insulin therapy with diabetic keto-acidosis
Phosphate binding antacid therapy
Recovery diuretic phase after severe burns
Severe respiratory alkalosis
15
1
malnutrition is reflected by a serum concentration < 11 mg/dl, severe at < 7 mg/dl.
It increases at a rate of 1 mg/dl per day with adequate nutritional support. The table
of ranges shows the effect of nutrition support on TBPA. Moderately malnourished
patients with low ALB have increased TBPA with nutrition support.
A profile including TTR can be incorporated into a clinical practice guideline
implemented through a critical pathway. Although TTR acts as a acute phase reac-
tant, it can be used to establish a baseline for nutritional support. Urinary nitrogen
excretion is often used to assess the amount of protein deficit prior to feeding. Fail-
ure to increase TTR is an indication of inability to provide adequate nutrients by
method of feeding. Systematic identification of patients at risk, appropriate timing
and mode of feeding, and monitoring effectiveness are essential elements for such a
guideline.
Selected References
1. Brugler L, DiPrinzio MJ, Bernstein L. The five-year evolution of a malnutrition
treatment program in a community hospital. J Qual Imp. 1999; 25:191-206.
2. Bernstein LH, Shaw-Stiffel TA, Schorow M et al. Financial implications of malnu-
trition. In: Labbe R, ed. Clinics in laboratory medicine. Nutition support. Vol 13.
Philadelphia: Saunders, June 1993:491-506.
3. Meguid MM, Mughal MM, Meguid V et al. Risk-benefit analysis of malnutrition
and preoperative nutrition support: a review. Nutr Int 1987; 3:25-34.
4. Meguid MM, Campos ACL, Meguid V et al. IONIP: a criterion of surgical out-
come and patient selection for preoperative nutritional support. Br J Clin Pract
1988; 42(suppl 63):8-14.
5. Bernstein LH, Leukhardt-Fairfield CJ, Pleban W et al. Usefulness of data on albu-
min and prealbumin concentrations in determining effectiveness of nutritional
support. Clin Chem 1989; 35:271-274.
6. Bernstein LH. Utilizing laboratory parameters to monitor effectiveness of nutri-
tional support. Nutr Int 1994; 10:58-60.
7. Kinney JM. Metabolic Responses to Injury. Chapter 2. In: Winters RW, Greene
HL, eds. Nutritional Support of the Seriously Ill Patient. New York: Academic
Press, 1983:5-12.
8. Wilmore DW, Black PR, Muhlbacher F. Injured Man: Trauma and Sepsis. Chap-
ter 4. In: Winters RW, Greene HL, eds. Nutritional Support of the Seriously Ill
Patient. New York: Academic Press, 1983:33-52.
9. Ingenbleek Y, Bernstein L. The stressful condition as a nutritionally dependent
adaptive dichotomy. Nutrition 1999; 15:305-320.
10. Kinney JM. Energy Metabolism: Heat, Fuel and Life. Chapter 1. In: Kinney JM,
Jeejeebhoy KN, Hill GL et al, eds. Nutrition and Metabolism in Patient Care.
Philadelphia: W.B. Saunders, Harcourt Brace Jovanovich, 1988:3-34.
11. Jeejeebhoy KN. Nutrient Metabolism. Chapter 3. In: Kinney JM, Jeejeebhoy KN,
Hill GL et al, eds. Nutrition and Metabolism in Patient Care. Philadelphia: W.B.
Saunders, Harcourt Brace Jovanovich, 1988:60-88.
12. Hill GL, King RFGJ, Smith RC et al. Multi-element analysis of the living body by
neutron activaion analysisapplication to critically ill patients receiving intrave-
nous nutrition. Br J Surg 1979; 66:868-72.
13. Ferrannini E. Equations and Assumptions of Indirect Calorimetry: Some Special
Problems. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determi-
nants and Cellular Corollaries. New York: Raven Press, 1992:1-17.
14. Young VR, Yong-Ming Y, Fukagawa NK. Whole Body Energy and Nitrogen (Pro-
tein) Relationships. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue
Determinants and Cellular Corollaries. New York: Raven Press, 1992:139-161.
16
1
15. Jeejeebhoy KN, Baker JP, Wolman SL et al. Critical evaluation of the role of clini-
cal assessment and body composition studies in patients with malnutrition after
total parenteral nutrition. Am J Clin Nutr 1982;35:1117-27.
16. Spiekerman AM, Rudolph RA, Bernstein LH. Determination of malnutrition in
hospitalized patients with the use of group-based reference. Arch Path Lab Med
1993; 117:184.
17. Rypka EW. Methods to evaluate and develop the decision process in the selection
of tests. In: McPherson RA, Nakamura RM, eds. Clinics in laboratory medicine.
Laboratory immunology II. Strategies for clinical laboratory management. Vol 12.
Philadelphia: Saunders, June 1992:351.
18. Rudolph RA, Bernstein LH, Babb J. Information-Induction for the diagnosis of
myocardial infarction. Clin Chem 1988; 34:2031-2038.
19. Shaw-Stiffel TA, Zarny LA, Pleban WE et al. Effect of nutrition status and other
factors on length of hospital stay after major gastrointestinal surgery. Nutr Int
1993; 9:140-145.
20. Bernstein LH, Shaw-Stiffel T, Zarny L et al. An information approach to likeli-
hood of malnutrition. Nutrition 1996; 12(9/10):772-776.
21. Bernstein LH (Chairman). Prealbumin in Nutritional Care Consensus Group. Mea-
surement of visceral protein status in assessing protein and energy malnutrition:
Standard of care. Nutrition 1995; 11:169-171.
22. Mozes B, Easterling MJ, Sheiner LB et al. Case-mix adjustment using objective
measures of severity: The case for laboratory data. Health Services Research 1994;
28[6]:689-712.
23. Verdery RB, Goldberg AP. Hypocholesterolemia as a predictor of death: a prospec-
tive study of 224 nursing home residents. J Gerontol:Med Sci 1991; 46:M84-M90.
24. Sullivan DH. The role of nutrition in increased morbidity and mortality. (Review)
Clin Geriatric Med 1995; 11:661-74.
CHAPTER 1
CHAPTER 2
Current Nutrient Substrates
Wendy Swails Bollinger, Timothy J. Babineau and George L. Blackburn
Introduction
Traditionally, nutrition support was simply the provision of calories and protein.
More recently, however, we have discovered that manipulation of certain nutrients
may significantly alter the response to illness and facilitate the healing process. These
findings suggest that patient-specific feeding with nutrient-specific formulas may
hold promise for improved patient outcome. This chapter discusses some of the
advantages and disadvantages of administering certain nutrient substrates, specifically
branched-chain amino acids, arginine, glutamine, nucleotides, and lipids.
Hepatic Disease and Stress: Branched-Chain Amino Acid
Enriched Diets
Hepatic Disease
The discovery of altered plasma amino acid concentrations (low branched-chain
amino acids and high aromatic and sulfur- containing amino acids) in patients with
hepatic encephalopathy prompted the development of branched-chain enriched
parenteral and enteral formulas. These formulas differ from conventional amino
acid formulas in that they contain a greater concentration of the branched-chain
amino acids (BCAA) leucine, valine, isoleucine and a lower amount (or none) of the
aromatic amino acids (AAA) phenylalanine, tyrosine, tryptophan and the
sulfur-containing amino acid methionine. The modified amino acid profile in these
solutions is thought to counterbalance the altered plasma amino acid concentra-
tions seen in patients with hepatic encephalopathy. These plasma amino acid alter-
ations are a result of an increased utilization of BCAA by the peripheral muscles and
a decreased metabolism of the AAA by the failing liver.
The use of BCAA-enriched formulas in patients with encephalopathy is based
predominantly upon the AAA/false neurotransmitter theory.
1
Fischer postulated that
the decrease in BCAA and increase AAA plasma concentrations seen in patients
with hepatic dysfunction allows a disproportionate amount of AAA to cross the
blood brain barrier. As a result, there is an increase in serum levels of false neu-
rotransmitters (octopamine and phenyethylanine) and a concomitant decrease in
the levels of normal neurotransmitters (dopamine and norepinephrine). In addition,
there is an increased serum serotonin concentration (physiologic neuroinhibitor)
due to excess tryptophan. This altered ratio of BCAA to AAA is believed to contribute,
in part, to the development of encephalopathy. It was Fisher and colleagues who
first noted that the administration of BCAA-enriched, low AAA solutions to animals
18
2
and humans with hepatic encephalopathy resulted in more normal patterns of plasma
amino acid concentrations and an improvement in encephalopathy.
2,3
A number of prospective, randomized clinical trials have investigated the use of
parenteral BCAA solutions when hepatic encephalopathy is present.
3,4-6
Most of
these trials have shown no significant change in mental status. It is important to
note, however, that many of the early trials used solutions containing only BCAA as
opposed to the BCAA-enriched, low AAA formulas typically used today. In an early
multicenter, prospective, randomized trial, 34 patients with cirrhosis of the liver
(predominantly cryptogenic) and grade III to IV hepatic encephalopathy received
either an intravenous solution containing 60 g of BCAA only in 20% dextrose or
lactulose (30-40 g every 4 hours via a nasogastric tube or 200-300 g/day via in-
termittent rectal enemas) plus 20% dextrose.
4
Seventy percent of the patients
receiving the BCAA solution regained consciousness (defined as grade 0 hepatic
encephalopathy) within 48 hours compared to only 47% in the lactulose group.
Although this difference was not statistically significant, the authors concluded that
parenteral administration of BCAA is at least as effective as lactulose in ameliorating
the symptoms of hepatic encephalopathy. Interestingly, these authors found no cor-
relation between the modifications in plasma amino acid levels and an improvement
in the patients mental status. Instead, they noted a significant decrease in plasma
ammonia levels in both groups at the time of mental recovery. Since lactulose is
believed to work by binding excess ammonia, these results suggest that BCAA may
favorably impact on hepatic encephalopathy, at least in part, by decreasing free
plasma ammonia levels.
Wahran, et al
5
also noted a slight improvement in responsiveness in patients
with hepatic encephalopathy who received a BCAA parenteral solution. In this
prospective, double-blind trial, 50 cirrhotic patients with acute hepatic encephal-
opathy (grade II to IV) were randomized to receive either an amino acid free
parenteral solution consisting of dextrose and lipids or the same solution with the
addition of 40 g of a 100% BCAA solution. The carbohydrate and fat portions of
each parenteral solution were isocaloric and provided 30 kcal/kg. In addition, all
patients were prohibited from taking any food by mouth. Although the patients in
the BCAA-treated group showed a statistically significant improvement in their
plasma BCAA to AAA ratios (1.10 0.08 to 1.96 0.22), this ratio never returned
to a normal ratio of 3.0 to 3.5. Fifty-six percent of the patients receiving the BCAA
solution demonstrated an improvement in encephalopathy compared to 48% in
the control group. This difference, however, was not statistically significant. As the
authors readily pointed out, this study had two major shortcomings. First, patients
with active gastrointestinal bleeds were not excluded from the study; a complication
that may worsen encephalopathy. Second, twice as many patients in the control
group received systemic antibiotics which would theoretically decrease the amount
of enteric bacteria and their byproducts and subsequently ameliorate hepatic en-
cephalopathy.
The largest and most complete prospective, double-blind trial was a multicenter
study done by Cerra and colleagues.
6
Seventy-five patients with acute hepatic en-
cephalopathy (grade II or higher; average grade 2.65) due to chronic hepatic disease
(85% alcoholic cirrhosis) were randomized to receive either oral neomycin or a
branched-chain enriched (36%) parenteral solution low in AAA and methionine.
Patients with acute viral hepatitis, acute fulminant hepatitis, hepatorenal syndrome,
significant gastrointestinal bleeding, nonhepatic coma and patients requiring
19
2
severe fluid restriction were excluded from the study. The control group received
25% dextrose intravenously plus oral neomycin (4 g daily divided into 4 doses)
whereas the treatment group received a daily infusion of the branched-chain en-
riched parenteral solution plus placebo tablets. Oral intake was restricted in both
groups until the encephalopathy had resolved. A maximum daily protein intake of
1.1 g/kg was reached by day 3 and was well tolerated in the group receiving the
BCAA-enriched solution. Despite receiving what some clinicians would consider a
high protein load for this patient population, 53% of the patients in the BCAA
group demonstrated complete resolution of their encephalopathy compared to only
17% of the patients in the control group (p<0.05). Not suprisingly, net protein
catabolism was decreased in the group being fed as evidenced by a positive nitrogen
balance by day 4. The group not being fed protein remained in negative nitrogen
balance throughout the study. Moreover, 55% of the patients in the control group
died whereas only 17% of the patients receiving the BCAA-enriched solution died
(p<0.01). These results suggest that administration of BCAA-enriched parenteral
solutions in amounts that provide at least 1 g protein/kg/day is well tolerated in
cirrhotic patients with hepatic encephalopathy, and may improve mental status and
survival. There are, however, some researchers who contend that the improved sur-
vival may have been a result of providing nutritional support in these critically ill
patients rather than due to the BCAA-enriched solution itself.
7
The disparity between the results of these clinical trials may be partially due to
differences in experimental design, patient population, type and amount of BCAA
solution administered, as well as diversity of the control group (Table 2.1). It has
been suggested that because Cerra and collegues
6
excluded patients with serious
complications (i.e., fulminant hepatitis, hepatorenal syndrome, etc.) that would not
be expected to improve by changing the serum BCAA to AAA ratio that this may
explain why the results of their study differed from others.
8
Interestingly, none of
the studies shown in Table 2.1 compared a BCAA solution to a conventional parenteral
amino acid solution. There are, however, several enteral studies that have addressed
this issue.
Eriksson and collegues
9
were among the first to investigate the use of a BCAA
formula delivered orally. Seven patients with liver cirrhosis and chronic hepatic en-
cephalopathy (grade I to II) participated in a 28 day study with a cross-over design.
Patients received each of the following oral supplements, in addition to their regular
diet, for a 14 day period: a BCAA solution containing BCAA only (30 g protein/
day) or a placebo solution devoid of amino acids. The results failed to demonstrate
a significant improvement in mental status when patients consumed the BCAA
solution instead of the placebo (43% vs 29%, respectively). These findings have
been substantiated by several other small, prospective cross-over studies.
10,11
In contrast, Horst, et al
12
noted a significant worsening of mental status in cir-
rhotic patients with encephalopathy receiving a standard oral diet containing a maxi-
mum of 80 g protein/day compared to those receiving a standard oral diet, restricted
to 20 g protein/day, supplemented with an oral BCAA-enriched (35% BCAA) solu-
tion, low in AAA that provided up to a maximum of 60 g protein/day.
Most of the clinical trials using oral BCAA examined the efficacy of using these
formulas over a short time period (i.e. less than one month). Thus, in an attempt to
evaluate the long-term effects of using BCAA during hepatic encephalopathy,
Marchesini, et al
13
conducted a multicenter prospective, randomized, double-blind
trial in which patients were followed for a three-month period. Sixty-four cirrhotic
2
0
T
h
e

B
i
o
l
o
g
y

a
n
d

P
r
a
c
t
i
c
e

o
f

C
u
r
r
e
n
t

N
u
t
r
i
t
i
o
n
a
l

S
u
p
p
o
r
t
2
Table 2.1. Parenteral BCAA clinical trials
Author Patients Experimental Group Control Group Results/Conclusions
Rossi-Fanelli, et al
4
34 patients with liver 100% BCAA (57 g protein/day) Lactulose No significant change in
cirrhosis/grade III to + 20% dextrose + 20% dextrose encephalopathy. BCAA
IV encephalopathy are as effective as lactulose
in reversing hepatic
encephalopathy.
Wahran, et al
5
50 patients with liver 100% BCAA (40 g protein/day) Dextrose + lipid No significant change in
cirrhosis/grade II to + dextrose + lipid encephalopathy.
IV encephalopathy
Cerra, et al
6
75 patients with liver 35% BCAA-enriched (maximum 25% dextrose + Significant improvement in
cirrhosis/grade II to of 85 g protein/day) oral neomycin encephalopathy and survival
IV encephalopathy + placebo tablets in BCAA-enriched group.
21
2
patients (66% alcoholic) with hepatic encephalopathy were randomized to receive
either a 100% BCAA oral supplement or a casein-based oral supplement in addition
to an oral diet containing 45-65 g protein daily. Patients were randomized to receive
either one packet of BCAA/kg body weight (0.24 g 100% BCAA/packet) or one
packet of casein/kg body weight (0.17 g casein/packet: 22% BCAA). Since all pa-
tients weighed between 60 and 80 kg, the oral supplements provided between 14 to
19 g BCAA or 10 to 14 g casein daily. After three months, twice as many patients
receiving the BCAA supplement demonstrated an improvement in mental status
(defined by the portal-systemic encephalopathy index) when compared to those
patients receiving the casein-based supplement (p<0.01). In addition, when the ten
casein-treated patients who showed no improvement in mental status were given the
BCAA supplement, eight of them demonstrated a rapid improvement in their
neuropsychologic function. These results suggest that long-term supplementation
(i.e., 3 months or more) of oral BCAA is superior to casein in terms of improving
mental status in cirrhotic patients with chronic encephalopathy.
The results of these enteral BCAA studies are summarized in Table 2.2. As was
the case with the parenteral BCAA studies, there are several factors which may ac-
count for the different results seen in the enteral studies. First, of the studies re-
ported here, those which failed to demonstrate any difference between BCAA and
standard amino acid solutions had a sample size of less than ten patients. Thus, they
may have been unable to detect any significant differences due to a Type II error.
Second, not all of the studies used the same experimental design (i.e., cross-over
design versus parrallel group comparison) nor did they administer the diets in the
same fashion. Several of the studies gradually increased the daily protein intake until
encephalopathy developed, whereas others adminstered a constant amount of protein
throughout the study. Finally, all of the diets differed in regard to the total percentage
of BCAA, as well as the ratio of each BCAA. Taken together, therefore, it is difficult
to compare the studies or to draw any definite conclusion.
The primary goal of nutrition support during hepatic dysfunction is to provide
sufficient protein in order to support protein synthesis and to promote regeneration
of liver cells. In view of this, perhaps the most important finding of these clinical
trials is that BCAA formulas can be safely administered to this patient population in
amounts that provide 1.0 to 1.5 g protein/kg/day without exacerbating preexisting
encephalopathy. Thus, encephalopathic, cirrhotic patients who are unable to tolerate
low to moderate intakes of standard protein sources may benefit from receiving
BCAA-enriched solutions. In 1997 the European Society for Parenteral and enteral
nutrition published guidelines recommending the aforementioned.
14
In addition,
there is evidence to suggest that administration of BCAA-enriched solutions are
better utilized by cirrhotic patients and can improve hepatic protein synthesis.
15
Stress
The metabolic response to injury is characterized, in part, by an increase in lean
body mass catabolism, a reduction in total body protein synthesis, and an increase
in the use of BCAA by the skeletal muscle. The result is an obligatory negative
nitrogen balance. In view of this, numerous investigators have examined the
protein-sparing effects of administering BCAA-enriched formulas in the setting of
stress, sepsis or trauma. The results of these clinical trials suggest that administration
of BCAA-enriched solutions can reduce nitrogen loss and support protein synthesis
better than standard amino acid solutions in critically ill patients.
2
2
T
h
e

B
i
o
l
o
g
y

a
n
d

P
r
a
c
t
i
c
e

o
f

C
u
r
r
e
n
t

N
u
t
r
i
t
i
o
n
a
l

S
u
p
p
o
r
t
2
Table 2.2. Enteral BCAA clinical trials
Author Patients Experimental Group Control Group Results/Conclusions
Ericksson, et al
9
7 patients with liver 100% BCAA oral supplement Oral supplement No significant improvement
cirrhosis/grade I to II (30 g protein/day) devoid of amino acids) in mental status.
encephalopathy + oral diet + oral diet
McGhee, et al
10
4 patients with liver 35% BCAA oral supplement Oral casein modular No significant improvement
cirrhosis/grade II to + casein based protein module supplement (50 g in mental status.
IV encephalopathy protein)
Christie, et al
11
8 patients with liver 50% BCAA oral supplement Casein-based oral No significant improvement
cirrhosis/grade 0 to II + 40 g protein oral diet supplement (18% in mental status.
encephalopathy BCAA) + 40 g protein
oral diet
Horst, et al
12
37 patients with liver 35% BCAA oral supplement 80 g (maximum) Mental status worsened in
cirrhosis/grade 0 to I (maximum of 60 g protein/day) protein oral diet patients receiving oral
encephalopathy + 20 g protein oral diet diet alone.
23
2
Most of the studies in this area have used 24-hour urinary urea nitrogen excretion
to assess protein catabolism and nitrogen balance. Clinically, this test is an inexpensive
and quick tool for assessing the degree of catabolism a patient is experiencing. The
disadvantage, however, is that it does not allow one to determine whether nitrogen
balance fluctuations are due to changes in the rate of protein synthesis or the rate of
protein breakdown.
16
While being able to make this distinction is not critical in the
clinical setting, it is important in the setting of a clinical trial that is comparing
differences in the protein-sparing effects of various amino acid solutions. Thus, several
researchers have used isotopic kinetic studies in order to determine whole body pro-
tein turnover.
Using this technique, Echenique, et al
17
assessed the value of administering
BCAA-enriched solutions in five critically ill patients, in the intensive care unit,
who had catabolic indexes ranging from 0 to 3 (indicative of moderate stress). Two
different parenteral solutions were compared in each patient: a BCAA-enriched
parenteral solution (50% BCAA) and a standard parenteral solution containing 15.6%
BCAA. Both solutions were isocaloric and isonitrogenous and were administered
over two consecutive 24-hour periods. During the last ten hours of each infusion, an
isotopic tracer (L-[1-
14
C] Leucine) was added in order to estimate protein kinetics (i.e.,
total body leucine oxidation, incorporation of leucine during protein synthesis, and
release of leucine during protein breakdown). Results showed a significant increase
in plasma leucine, isoleucine, and valine concentrations, as well as an increase in
leucine oxidation and net balance (i.e., the difference between the rate of leucine
incorporation into protein and the rate of release from protein). These results suggest
that administration of a BCAA-enriched solution containing 50% BCAA may result
in a significant improvement in amino acid utilization in critically ill patients.
Similarly, Bonau and collegues
18
used an isotopic tracer (
15
N glycine) to determine
whole body protein turnover in surgical patients receiving BCAA-enriched solutions.
Twenty-five patients undergoing elective radical cystectomies for bladder cancer re-
ceived one of four parenteral infusions: 5% dextrose alone (n=4); dextrose plus a
standard amino acid mixture containing 7% amino acids (n=9); dextrose and a
low-leucine, BCAA-enriched solution (45% BCAA; 22 mmol leucine/L) (n=6); or
dextrose and a high-leucine, BCAA-enriched solution (45% BCAA; 120 mmol leu-
cine/L) (n=6). All dextrose and amino acid solutions provided 30 kcal/kg/day and
1.5 g protein/kg/day. Administration of the low leucine, BCAA-enriched solution re-
sulted in a significant decrease in mean cumulative nitrogen balance (1.67 0.74 g
nitrogen/day versus 3.80 1.01 for the high leucine, BCAA-enriched group and
4.38 0.99 for the standard amino acid group) and an increased rate of mean whole
body protein catabolism compared to the other two amino acid groups. The authors
concluded that the optimal dose of leucine required by this patient population in
order to achieve protein sparing effects was 0.13 g/kg/day. In comparison, normal,
healthy subjects only require 11 mg of leucine/kg/day.
19
These results suggest that
the ability of BCAA-enriched solutions to reduce postsurgical muscle catabolism is
related more to the amount of leucine in the solution than to the total percentage
of BCAA.
Renal Failure
Another controversial area in the use of BCAA-enriched solutions is in the setting
of renal failure. The use of BCAA-enriched solutions in renal failure patients with
severe azotemia (i.e., blood urea nitrogen greater than 100 mg percent) may aid in
24
2
reducing urea and acid production from proteolysis since BCAA are preferentially
used by the body for protein synthesis.
20,21
The ability of BCAA to affect overall patient outcome remains controversial.
However, it is clear that the administration of BCAA does not exacerbate preexisting
encephalopathy. Moreover, BCAA are more efficiently used, promote better nitro-
gen retention, and are less ureagenetic than conventional amino acid formulas.
Thus, when protein intake must be restricted due to encephalopathy or uremia, then
BCAA-enriched solutions may potentially offer certain neurologic and metabolic
advantages over conventional amino acid solutions.
21
Arginine
Traditionally, arginine has been considered to be a semi-essential amino acid.
22
In normal, unstressed adult subjects, arginine requirements can be met through
tissue synthesis. Early animal studies established that arginine was not an essential
amino acid for maintaining nitrogen balance in healthy adult rats. In con-
trast, it was noted that immature growing rats required arginine for optimal
nitrogen balance.
23
Most conventional adult parenteral and enteral formulas contain only a small
amount of arginine (<0.5% of total calories). However, some researchers suggest
that arginine requirements are increased during periods of injury or stress.
24
This
suggestion has been substantiated by a number of animal and human studies dem-
onstrating that supplemental dietary arginine improves nitrogen retention, and
enhances wound healing and immune response following injury.
25-32
These findings
suggest that supplemental arginine may have a potential theurepeutic role in the
clinical setting.
Laboratory Studies
Barbul and collegues conducted many of the early studies that evaluated the
effects of arginine supplementation. In a series of animal studies, supplemental
arginine resulted in increased thymic weight, increased thymocyte response to mi-
togens, and improved wound healing and nitrogen retention.
29,33-35
These experi-
ments prompted other investigators to further explore the relationship between
supplemental arginine and immune response following injury.
Saito and colleges
30
studied the effect of supplemental arginine on immunity in
burned guinea pigs. After receiving a 30% total body surface area burn, animals
were intragastrically fed one of four diets containing either 0%, 1%, 2%, or 4%
arginine. Animals receiving the 2% arginine supplementation demonstrated the
most significant improvement in their cell-mediated immunity and ability to clear
staphylococcus aureus from intradermal injection sites. In addition, those ani-
mals receiving the 1% and 2% arginine supplemented diets had a lower mortality
rate than those receiving the 0% and 4% arginine supplemented diets, although
this difference was not statistically significant. Interestingly, these investigators noted
that 4% arginine supplementation did not result in any beneficial effects which
suggests that administration of excess arginine may, in fact, be detrimental. Thus,
the authors concluded that arginine supplementation in the amount of 2% of total
calories may help to prevent sepsis after burn injury.
Since burn injury is responsible for increased gut permeability to enteric bacteria,
Gianotti, et al
36
conducted a series of experiments to investigate the effects of an
arginine enriched diet on resistance of gut-origin sepsis (i.e., bacterial translocation)
25
2
and survival after peritonitis in the burned animal model. In one experiment, animals
were randomized to receive one of the following diets: rat chow, semipurified diet,
semipurified diet plus 2% arginine, or semipurified diet plus 4% glycine. After 14
days of feeding, the animals were subjected to an injection of E. coli followed by a
20% burn injury. Animals fed with the semipurified diet demonstrated significantly
more bacterial translocation to the mesenteric lymph nodes (as measured by radio-
nuclide counts) compared to all of the other diets. Moreover, analysis of the number
and percentage of viable translocated bacteria in the mesenteric lymph nodes and
spleen showed that the arginine enriched diet significantly improved the animals
ability to kill translocated organisms compared to the other three diets. In another
experiment, animals were fed either the arginine enriched diet, the semipurified
diet, or rat chow for 15 days prior to being subjected to cecal ligation and puncture
followed by a 20% burn injury. Following this, all animals were allowed to feed on
their designated diets ad libitum. Although the arginine enriched group showed a
45% improvement in survival when compared to the animals receiving the
semipurified diet and the rat chow, this difference was not statistically significant.
However, when this experiment was repeated and the animals were transfused with
allogenic blood five days prior to the injury, there was a significant improvement in
survival in the group receiving the arginine enriched diet. Fifty-six percent of the
arginine supplemented animals survived compared to 28% in the semipurified diet
group and 20% in the chow fed group (p<0.02). These experiments suggest that
diets supplemented with arginine may favorably affect survival when provided prior
to the onset of infection.
In order to better define the mechanism by which arginine alters immune function,
Reynolds, et al
31
examined the effects of supplemental arginine on specific components
of the immune response. In this study, mice received an oral diet containing either
1% arginine supplementation or an isonitrogenous glycine supplemented diet for at
least 10 days. Arginine supplementation was noted to significantly enhance cyto-
toxic T-lymphocyte development, increase endotoxin-induced natural killer cell ac-
tivity, and augment interleukin-2 (IL-2) receptor activity on T-lymphcytes stimulated
with the mitogen, conconavalin A. However, basal- and endotoxin-induced mac-
rophage IL-1 and superoxide production were not significantly influenced by supple-
mental arginine. These results suggest that arginine supplementation directly
modulates T-lymphocyte activation which may result in an enhanced production of
cytotoxic T-lymphocytes.
More recently, investigators have explored the ability of arginine to alter the
mRNA expression of inflammatory cytokines in organs. In this study, animals re-
ceiving an enteral diet supplemented with arginine (2.3% of total energy intake) for
seven days after receiving a 30% burn injury demonstrated a significant decrease in
mRNA expression for TNF- in the spleen and lung, IFN- in the lung, IL-1 in
the spleen, and IL-6 in the thymus and liver compared to those animals receiving no
supplemental arginine. In addition, the arginine supplemented animals showed a
significant improvement in survival rate after thermal injury compared to the control
group (100% versus 66.6%;p<.05).
37
Another aspect of arginines ability to modulate immune function relates to its
effects on tumor development. Over the past few decades, there have been numerous
studies demonstrating the anti-tumor properties of arginine in animals with either
chemically induced or transplanted tumors.
38-40
In addition to decreasing tumor
growth in these animal models, arginine supplementation has also been noted to
26
2
prolong survival. These findings, coupled with the fact that cancer patients are
frequently immunosuppressed, prompted several investigators to examine the
potential clinical applicability of administering arginine in this patient population.
Clinical Trials
In 1988, Daly and collegues
32
conducted the first clinical trial to evaluate the
immunologic effects of arginine supplementation in the surgically stressed patient.
Thirty adults with gastrointestinal malignancies undergoing major surgery were
randomized to receive either an enteral diet supplemented with 25 g arginine daily
(7% of maximum caloric intake) or the same enteral diet supplemented with an
isonitrogenous amount of glycine. Mean daily nitrogen balance was not significantly
different between the two groups, however, a positive nitrogen balance was only
achieved in the arginine supplemented group. There was, however, a statistically
significant improvement in immune function in those patients receiving the arginine
supplementation as compared to the glycine group. Specifically, the arginine supple-
mented group demonstrated a significantly enhanced T-lymphocyte response to
the mitogens, conconavalin A (ConA) and phytohemagglutinin (ConA), as well as
an increase in CD4 (helper T-cells) levels from postoperative day 1 to postoperative
day 7 when compared to the glycine supplemented group. Encouraged by these
results but unsure whether the administration of arginine alone would still cause
the increase in peripheral blood monocyte mitogenesis, the investigators conducted
another clinical trial in an attempt to answer this question.
Thirty adult patients undergoing surgery for lower gastrointestinal malignancy
were randomized to receive intravenously either 20 g arginine hydrochloride in 5%
dextrose and water or one liter of a standard 10% amino acid solution (3.7 g arginine
hydrochloride) daily for 7 days postoperatively. Additional dextrose containing so-
lutions were administered as clinically indicated. Postoperative mean daily nitrogen
balance was similar between the two groups (-8.8 g/day for arginine group versus
-9.2 g/day for mixed amino acid group). There was no significant difference between
the two groups in terms of peripheral blood mononuclear cell proliferative responses
to ConA. In the arginine group, mitogen-stimulated lymphocyte response levels
returned to preoperative levels by postoperative day 7 while the standard amino
acid groups levels were actually below their preoperative levels by postoperative day 7.
In contrast, when peripheral monocytes were stimulated with ConA, the mixed
amino acid group demonstrated a significantly higher stimulation level on postop-
erative day 4 than the arginine group. These results suggest that when arginine is
administered parenterally as the sole nitrogen source with minimal additional calo-
ries, there is no significant enhancement of mitogen-stimulated lymphocyte prolifera-
tion. Thus, arginine may require supplemental protein and calories in order to exert
its maximum effect.
41
While it appears that delivery of some arginine may be beneficial in the clinical
setting, Sigal, et al
41
have suggested that the immunostimulatory effects of arginine
may be due to an interaction between arginine and other dietary substrates rather
than the arginine itself. This point is exemplified in a study by Van Buren, et al
42
in
which mice who were fed a nucloetide-free casein-based diet containing 4% arginine
showed no improvement in allogeneically stimulated lymphocytes responses. In
contrast, those animals receiving the arginine diet supplemented with RNA or fish
oil demonstrated a significant improvement in lymphocyte proliferative responses.
Whether or not these same findings are applicable to humans remains unanswered.
27
2
Moreover, it is not clear if enhanced stimulation of lymphocytes translates into im-
proved clinical outcome. To date, there have been no clinical trials examining the
effects of an arginine supplemented diet versus an arginine supplemented diet that
also contains one or more of the so-called immuno-stimulatory nutrients (i.e.,
RNA, fish oil, or glutamine). There are however, a number of clinical trials comparing
an enteral formula that is enriched with arginine in addition to one or more of these
immuno-stimulatory nutrients to a standard enteral formula that is devoid of
supplemental arginine, RNA, fish oil, or glutamine.
43-51
Although arginine is not an essential amino acid in unstressed adult animals and
humans, it appears to become a conditionally essential amino acid during periods
of injury or stress. Supplementation with arginine has been shown to promote wound
healing, enhance immune function, and improve nitrogen retention in both animals
and humans. In addition, animal studies have shown that supplemental arginine
retards growth in animals with chemically induced or transplanted tumors, and
improves survival by modulating bacterial clearance in animals with gut-derived
sepsis and peritonitis. While the animal studies appear to suggest that a diet containing
2% of total calories as arginine provides the most beneficial effects, the optimal dose
in stressed humans remains unclear. The clinical trials discussed here have adminis-
tered doses ranging from approximately 10 to 25 grams per day. This dose would be
the equivalent of 2 to 6 % of total calories for a 70 kg man receiving 25 kcal/kg. It is
quite possible that the optimal dose will vary depending on the severity of illness,
type of injury, or surgery. One potential complication of arginine administration is
its competition with the essential amino acid lysine for tubular reabsorption.
52
Large
doses of arginine may, therefore, theoretically induce lysine deficiency by increasing
its renal excretion.
53
Thus, additional clinical trials are clearly needed in order to
determine the optimal dose of arginine for a variety of clinical settings. Moreover,
investigators need to pursue the question of whether or not the immunostimulatory
effects of arginine are due to the arginine itself or whether they are a result of inter-
actions with other dietary substrates.
Glutamine
Glutamine is currently classified as a nonessential amino acid because sufficient
quantities can be synthesized by the body in healthy subjects.
19
However, during
periods of stress, the bodys requirement for glutamine exceeds its production.
54-56
Animal studies suggest that provision of glutamine-enriched parenteral and enteral
nutrition maintains gut epithelial structure and integrity, enhances nitrogen retention
and intestinal mucosal immune function, decreases the incidence of bacterial trans-
location and improves survival following injury.
57-59
Furthermore, glutamine-enriched
nutrition administered to surgical and bone marrow transplant patients has been
shown to reduce losses of free glutamine in skeletal muscle tissue,
60,61
reduce infectious
complications,
62,63
decrease length of hospital stay
62,64
and improve six month sur-
vival in critically ill patients.
65
Thus, glutamine, like arginine, may be regarded as a
conditionally essential amino acid.
66
Traditionally, it was thought that glucose was the main source of fuel for the
enterocytes, however, there is now evidence that glutamine is actually the preferred
fuel of the enterocytes, as well as the colonocytes.
67,68
This finding coupled with the
observation of intestinal atrophy in animals receiving parenteral nutrition,
69
prompted
investigators to examine the effects of glutamine supplementation on intestinal
mucosal structure and function.
28
2
Laboratory Studies
ODwyer, et al
57
performed a series of animal experiments to examine the effects of
glutamine supplementation on the intestine. In the first experiment, rats were in-
travenously fed a standard 10% amino acid solution that was enriched with either
gutamine or glycine in amounts of either 1 or 2 g/100 mL. Animals receiving 2 g
glutamine/100 mL demonstrated a significant increase in intestinal weight, DNA
and protein content, and villus height when compared to the group receiving 2 g
glycine/100 mL (p<0.01). No increase in intestinal parameters was noted in the
group receiving 1 g glutamine/100 mL. The authors then investigated the
dose-response effects of glutamine by feeding the animals an isonitrogenous, isocaloric
solution containing either 0, 2, or 3 g glutamine/100 mL. Increasing the glutamine
intake from 0 to 3 g/100 mL led to a significant increase in intestinal mucosal
weight, DNA and protein content, and villus height. Interestingly, the animals
receiving 2 g glutamine/100 mL demonstrated a significantly greater nitrogen re-
tention compared to the animals receiving 0 or 3 g glutamine/100 mL. These re-
sults suggest that glutamine, an amino acid that is not currently contained in
commercially available parenteral amino acid solutions, may be important for main-
taining intestinal integrity. In addition, there is evidence to suggest that glutamine
may also be essential for maintaining intestinal function following mucosal injury.
Fox and collegues
58
investigated the effects of a 2% glutamine supplemented
elemental diet on nutritional status, intestinal morphology, bacterial translocation,
and survival in rats with methotrexate-induced enterocolitis. Rats receiving the
glutamine supplemented diet exhibited significantly less intestinal damage, less
weight loss, a lower incidence of bacterial translocation, and an improved nitrogen
balance and survival compared to the animals receiving the control diet (2% glycine
supplemented elemental diet). Similar benefits have been reported by ODwyer, et
al
70
and Jacobs, et al
71
who demonstrated that both enteral and parenteral glutamine
supplementation resulted in a rapid regeneration of enterocytes in rats receiving the
chemotherapeutic agent 5-fluoruracil. In addition, provision of oral glutamine has
been shown to accelerate healing of the small intestine and improve outcome in
animals undergoing whole abdominal radiation.
72
However, since glutamine is the
principle fuel used by most rapidly proliferating tumors,
73
it raises the question of
whether or not providing exogenous glutamine during chemo- or radiation therapy
might present more of a risk (promote tumor growth) rather than a benefit (intestinal
preservation).
In an attempt to answer this question, Austgen, et al
74
studied the effects of
administering glutamine supplemented TPN in tumor-bearing rats. The addition
of glutamine to the TPN did not appear to increase tumor size, DNA content, or
glutamine metabolism. Glutamine supplementation did, however, cause a significant
increase in the intratumor ratio of aneuploid cells to diploid cells suggesting a more
aggressive cell variant. Thus, the authors speculated that glutamine supplemented
TPN caused an increase in the number of differentiated tumor cells within a specified
amount of tumor mass without yielding a measurable increase in tumor size.
However, Klimberg and collegues
75,76
have demonstrated in two separate animal
studies that supplemental glutamine does not stimulate tumor growth. In fact,
enteral glutamine supplementation was actually noted to increase the effectiveness
of methotrexate while reducing its morbidity and mortality in cachectic
tumor-bearing animals.
76
29
2
The ability of glutamine supplemented nutrition to attenuate intestinal atrophy
and decrease the incidence of bacterial tranlocation may be, in part, due to changes
in intestinal immune function. Alverdy, et al
59
randomized rats to receive one of
three diets: rat chow, a standard parenteral solution, or a standard parenteral solution
supplemented with 2% glutamine. After one week of feeding, the animals receiving
the standard parenteral solution demonstrated a significant decrease in biliary secretory
immunoglobulin A (S-IgA) levels and intestinal lamina propria IgA-synthesizing
plasma cell (IgA+) levels compared to the chow fed animals. This finding is of par-
ticular importance because S-IgA prevents bacteria from adhering to the intestinal
mucosa which may, in turn, help to decrease the incidence of bacterial translocation. In
addition, there was a significant decrease in CD4 (helper T-cells) and CD8 (sup-
pressor T-cells) levels in the standard parenteral diet group compared to the chow
group. In contrast, animals receiving the glutamine supplemented solution had CD4
and CD8 levels comparable to those of the chow fed animals. These findings suggest
that glutamine may be an essential amino acid for the maintenance of intestinal
immune function during parenteral feeding. Taken together, these animal studies
suggest that the provision of glutamine either enterally or parenterally may increase
the function of various immune cells and therefore potentially lead to enhanced
resistance to infection.
Clinical Trials
Over the past decade, the potential therapeutic use of glutamine supplementation
in humans has been an area of intense research. Ziegler and collegues
77
were the first
to evaluate the safety of administering the free amino acid glutamine to humans. In
a series of dose-response studies, these investigators demonstrated that glutamine
administration in healthy volunteers at daily doses of 0.3 g/kg enterally and 0.57 g/kg
parenterally was well tolerated. The safety of glutamine administration was subsequently
confirmed in the clinical setting when eight patients undergoing bone marrow trans-
plantation recieved glutamine-enriched TPN solution without evidence of adverse
clinical or metabolic effects. Moreover, nitrogen retention was enhanced in this patient
population when glutamine was administered at a dose of 0.57 g/kg/day compared
to a lower dose (0.285 g/kg/day). These findings subsequently spurred researchers
to investigate the efficacy of parenteral glutamine supplementation in patients under-
going elective surgery.
In a randomized, prospective trial conducted by Stehle, et al,
60
twelve patients
undergoing surgical resection for colonic or rectal carcinoma received either standard
TPN or glutamine enriched TPN. The addition of approximately 12 g of glutamine
per day, provided as the dipeptide L-alanyl-L-glutamine, resulted in a diminished
loss of free glutamine in skeletal muscle tissue and improved nitrogen retention.
Similar benefits were reported by Hammarqvist and collegues
61
who administered
TPN supplemented with approximately 20 g of free glutamine daily to patients
undergoing cholecystectomies. More recently, investigators have examined the effects
of administering glutamine supplemented TPN in bone marrow transplant patients.
Ziegler, et al
62
conducted a prospective, randomized, double-blind trial in which
45 patients undergoing allogeneic bone marrow transplantation for hematologic
malignancies were randomized to receive either standard TPN or TPN supplemented
with 0.57 g of free glutamine/kg body weight per day. Based on a mean body weight
of 67.2 kg, patients in the glutamine supplemented TPN group received approximately
38 g glutamine per day for an average of 26 days. The mean duration of parenteral
30
2
feeding was comparable for patients in the standard TPN group (28 days). Despite an
equivalent caloric and nitrogen intake in both groups, the glutamine supplemented
patients demonstrated a significant improvement in their mean daily nitrogen balance
in comparison to the standard TPN group (-1.4 0.5 g/d versus -4.2 1.2 g/d,
respectively; p=0.002). In addition, fewer patients receiving the glutamine supple-
mented TPN developed infections (13% versus 43% in the standard TPN group;
p=0.041) even though antibiotic administration was similar in both groups. More-
over, the average length of hospital stay following transplantation was 29 1 days
in the glutamine supplemented group compared to 36 2 days in the standard
TPN group (p=0.017). This study demonstrated that the administration of glutamine
supplemented TPN in this patient population resulted in improved nitrogen bal-
ance, decreased incidence of infectious complications, and shortened length of hos-
pital stay compared to patients receiving standard TPN. A subsequent study by this
group showed that bone marrow transplant patients receiving glutamine- supple-
mented TPN had greater numbers of circulating total lymphocytes, T lymphocytes,
and CD4
+
lymphocytes after discharge than patients receiving standard TPN.
78
Schloerb and Amare
64
published results of clinical trial with a protocol similar
to that of Ziegler, et al.
62
Twenty-nine patients undergoing either allogeneic or autolo-
gous bone marrow transplantations were randomized to receive either standard TPN
solution or TPN supplemented with approximately 40 g of free glutamine per day
for approximately one month. One of the parameters that was assessed in the current
trial that was not investigated by Ziegler, et al
62
was the effect of glutamine on total
body water and extracellular water. Total body water, as measured by deuterium
oxide dilution and bioimpedance, was significantly decreased from baseline (before
TPN) to end of study (after TPN) in patients receiving the glutamine supplemented
TPN (p<0.05). This finding suggests that the provision of glutamine may help to
maintain vascular endothelial integrity and prevent the extreme fluid shifts fre-
quently seen during critical illness. In contrast, patients receiving standard TPN
showed a significant increase in the change in their total body water.
In terms of infectious complications, the researchers did not note any significant
difference between the two feeding groups; thirty-eight percent of the patients in
each group developed clinical infections. Patients were then subdivided into those
with hematologic malignancies versus those with solid tumors. In patients with
hematologic malignancies, clinical infections occured in only 20% of those patients
receiving the glutamine supplemented TPN compared to 50% of those receiving
the standard TPN. This difference, however, was not statistically significant. Although
this observation is in contrast to that of Ziegler, et al
59
the authors do not dispute
Ziegler and collegues conclusion that glutamine supplemented TPN decreased the
incidence of clinical infections in patients with hematologic malignancies. Instead,
the authors suggest that differences in patient population may have precluded them
from observing all of the same benefits as Ziegler, et al.
62
In particular, the authors
suggest that they had a patient population with a higher severity of illness than
Ziegler, et al
62
as demonstrated by a higher mortality rate (14% versus 0%, re-
spectively). Schloerb and Amare
64
were, however, able to confirm the finding of
Ziegler, et al
62
that patients receiving the glutamine supplemented TPN had a sig-
nificant reduction in length of hospital stay following transplantation compared to
patients receiving standard TPN.
The use of glutamine-enriched TPN has also been investigated in critically ill
patients. Griffiths, et al
65
reported improved six-month survival in critically ill patients
31
2
receiving glutamine-enriched TPN (an average intake of 21 g glutamine/day) com-
pared to those patients receiving conventional TPN (24/42 patients versus 14/42 pa-
tients; p=.049) The aforementioned studies have yielded promising results with respect
to providing glutamine-enriched parenteral nutrition in select patient populations.
However, some researchers have speculated that in order to meet the glutamine
requirements of the enterocytes and gut-associated lymphoid tissue it might be more
beneficial to provide glutamine enterally rather than parenterally.
Gottschlich, et al
79
were among the first to study the effects of providing glutamine
enterally rather than parenterally in a clinical setting. In a study of 90 burn patients
who were randomized to receive an enteral formula supplemented with either 2, 4,
or 6 g free glutamine/L, serial measurements of plasma glutamine were obtained
during the first four weeks post burn. Results showed that plasma glutamine levels
remained depressed (i.e., < 400 nmol/mL) throughout the four week period in all
feeding regimens. These findings suggest that plasma glutamine levels may be mar-
ginal in burn patients and that enteral glutamine supplementation in excess of 6 g/
L of enteral formula may be warranted in this patient population.
Jensen, et al
80
conducted a prospective, double-blind trial in which 28 critically
ill patients were randomized to receive one of two isocaloric, isonitrogenous enteral
fromulas differing only in glutamine concentration (i.e., six-fold difference). Data
was analyzed for all patients receiving at least 50 cc/hr by day 5 (n=19). Results
demonstrated that the plasma phenylalanine to tryrosine ratio, an indicator of ca-
tabolism, was significantly decreased by day 5 in patients receiving the glutamine
enriched enteral formula. Moreover, immune function, as assessed by CD4/CD8
ratios, was significantly improved in the glutamine enriched group compared to the
standard feeding. A subsequent study by these investigators compared
glutamine-enriched parenteral nutrition with glutamine-enriched enteral nutrition
(isocaloric, isonitrogenous formulas that provided 0.3 g glutamine/kg body weight)
in 17 patients undergoing surgery for gastric or pancreatic carcinomas. Results showed
that both types of feeding resulted in similar amino acid profiles although there was
a trend for serum glutamine levels to recover more slowly in the enterally fed group
compared to the parenterally fed group.
81
More recently, Houdijk and colleagues
63
have investigated the effects of
glutamine-enriched enteral nutrition on the incidence of infectious complications.
In a study of 60 multiple trauma patients, those patients who received the enteral
formula supplemented with glutamine (30.5 g glutamine/100 g protein) within 48
hours of trauma showed a significant reduction in pneumonia (17% versus 45% for
the control group; p<.02), bacteremia (7% versus 42%; p<.005), and sepsis (4% -check
this versus 25%; p<.02) compared to the patients receiving an isocaloric,
isonitrogenous control formula containing 3.5 g glutamine/100 g protein. The
patients receiving the glutamine-enriched enteral formula (an average intake of 31 g
glutamine/day by study day 7) also demonstrated a decrease in TNF-soluble receptors
compared to the patients receiving the control formula. Whether the decrease in
TNF-soluble receptor suggests a modulation of the immune response to the trauma
or is the result of a decrease in the number of infections remains unanswered. A later
study by this same group of investigators
82
suggested that the reduction in infectious
morbidity seen in the glutamine-supplemented trauma patients could not be ex-
plained by a modulation of the humoral stress response and its metabolic consequences.
A study by Aosasa, et al
83
in fifteen patients with colorectal cancer demonstrated
that oral glutamine supplementation (30 g L-glutamine/day) in patients receiving
32
2
TPN significantly suppressed cytokine production from LPS-stimulated mesenteric
blood mononuclear cells (M-MNC) compared to patients receiving conventional
glutamine-free TPN. There were, however, no significant differences in cytokine
production from LPS-stimulated M-MNC between patients receiving the oral
glutamine supplementation and TPN and those patients consuming a regular diet.
Administration
Although it is too early to define the optimal dose or route of glutamine, these
clinical trials have prompted much discussion regarding the different routes (i.e.,
enteral versus parenteral) and types (i.e., free glutamine versus glutamine as a
dipeptide) of glutamine supplementation. Currently, commercially available
parenteral amino acid solutions do not contain the free amino acid glutamine for
several reasons. First, glutamine was traditionally considered to be a nonessential
amino acid. Second, the free amino acid glutamine has a shorter shelf-life than
the amino acids commonly used in commercially available parenteral amino acid
solutions. However, glutamines stability in parenteral formulas appears to be better
than previously thought. Schloerb and Amare
61
recently reported that their free
glutamine supplemented parenteral solution was able to be stored at 5C for up to
six weeks without loss of more than 5% of the glutamine.
In terms of enteral formulas, almost all commercially available enteral formulas
contain glutamine. The exceptions are a few free amino acid based diets which
contain the amino acid glutamate rather than glutamine, and several products spe-
cifically designed for hepatic and renal failure which contain neither glutamate nor
glutamine. Glutamine in enteral products can exist in two forms: protein bound (in
whole proteins or in peptides) or as the free amino acid. Manufacturers of formulas
containing the free amino acid glutamine list the glutamine content of the formulas
on the product label. In comparison, the glutamine content of enteral formulas
containing whole or partially hydrolyzed protein (peptides) can only be estimated.
Thus, the glutamine content of these formulas is not listed on the product label.
The amount of glutamine present in whole protein or peptide based enteral
formulas depends upon the protein source and amount of protein, as well as the
processing conditions. Whole protein based formulas contain glutamine in amounts
characteristic of their original protein source (casein, whey, soy, etc.) because protein
bound glutamine is stable and will not degrade during processing or storage. In
contrast, enteral formulas containing partially hydrolyzed proteins (so-called peptide
based diets) contain less glutamine than was present in their original intact protein
because hydrolysis of the intact protein to peptides leads to the degradation of a
portion of the glutamine originally present in the intact protein to glutamate
(glutamic acid) and ammonia. The greater the degree of protein hydrolysis of a
peptide based diet, the less peptide bound glutamine remains.
In view of this, it is difficult to estimate the amount of glutamine in peptide
based formulas. Although, it has been reported that more than half of the original
glutamine in these formulas may be converted to glutamate and ammonia during
processing and storage.
84
The amount of protein-bound glutamine in selected com-
mercially available whole protein formulas has been estimated to range from 2.80
to 7.99 g/1000 kcal.
85
In comparison, there are several commercially available en-
teral formulas enriched with free glutamine in amounts that range from 4.9 to 14.2
g/1000 kcal (Table 2.3).
33
2
The animal and human data presented herein strongly suggest that glutamine
should be classified as a conditionally essential amino acid rather than as a non-
essential amino acid. Plasma and skeletal muscle concentrations of free glutamine
which have been shown to be markedly diminished during periods of stress, infection,
and injury can be restored with parenteral and enteral glutamine supplementation.
In addition, there is increasing evidence that glutamine has beneficial effects on
nitrogen balance, lean tissue mass, gut integrity, and immune function. To date,
clinical trials suggest that glutamine supplementation has been shown to have some
beneficial effects after major surgery, after bone marrow transplantation, in critically
ill patients, and in patients with multiple traumas.
Nucleotides
Nucleotides are an important component of a wide variety of biochemical pro-
cesses. These molecules which consist of three main components: a nitrogenous
base (either purine or pyrimidine), a pentose sugar (either ribose or 2-deoxyribose),
and one or more phosphate groups, are perhaps best known for their role in deoxyri-
bonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. However, nucleotides
are also present in adenine triphosphate (ATP), as well as a number of coenzymes
which participate in carbohydrate, protein, and lipid synthesis. In addition, nucle-
otides are required by T-lymphocytes in order to maintain normal cellular immune
responses.
Various tissues in the body, such as the liver, are capable of synthesizing nucleotides
from other substrates. However, certain rapidly dividing cells, such as intestinal epi-
thelial cells and T-lymphocytes, appear to be unable to produce nucleotides. More-
over, during severe metabolic stress, such as sepsis, trauma, and burns, de novo
nucleotide synthesis is not sufficient to meet the needs of these rapidly dividing
cells. Some investigators have subsequently suggested that this is the mechanism for
the immune dysfunction which is often present in stressed patients. This theory
coupled with the fact that standard parenteral and enteral diets, except those made
from blenderized protein-containing food sources, do not contain nucleotides has
prompted some investigators to suggest that the provision of exogenous nucleotides
to stressed, immunocompromised patients may be beneficial.
Laboratory Studies
The role of dietary nucleotides on immune function, specifically lymphocyte
metabolism, has been the focus of intense research. Van Buren and collegues have
pioneered much of the work in this area, and were among the first to demonstrate
that helper/inducer T-lymphocytes require exogenous nucleotides in order to respond
normally following immune stimulation.
86
In addition, there have been numerous
studies demonstrating that a nucleotide-free diet suppresses a variety of T-cell
Table 2.3. Commercially available enteral formulas containing free glutamine
Product Manufacturer g Free Glutamine/1000 kcal
Vivonex Novartis Nutrition 4.9
Immun-Aid B. Braun/McGaw 9.0
Vivonex Plus Novartis Nutrition 10.0
Alitraq Ross Laboratories 14.2
34
2
mediated immune responses, such as delayed cutaneous hypersensitivity,
87
cardiac
allograft rejection,
88
in vitro response to T-cell mitogens,
89
and production of
interleukin-2.
86
Furthermore, animals receiving a nucleotide-free diet demonstrated
a significantly higher mortality rate following intravenous injections of staphylococ-
cus aureus or candida albicans compared to animals fed diets supplemented with
either 0.25% RNA (a nucleotide) or 0.06% uracil (a pyrimidine nucleotide base).
89-92
However, it is worth mentioning that in all three of these studies there was also a
fourth group of animals who received a diet supplemented with 0.06% adenine (a
purine nucleotide base). Interestingly, in all instances, the adenine supplementation
had no beneficial effect in terms of survival following bacterial or fungal infection.
Thus, it appears that RNA or pyrimidine bases are the key substrates for maintaining
normal cellular immunity.
Numerous investigators have demonstrated that malnutrition can profoundly
suppress immune function. In view of this relationship, Pizzini and co-workers
93
designed several studies to examine the effect of dietary nucleotide deprivation in
both the protein malnourished, as well as the starved animal model. Animals were
randomized to receive one of four diets: standard rodent chow, protein-free,
nucleotide-free, or nucleotide-free supplemented with 0.25% yeast RNA. The pro-
vision of dietary nucleotides in the form of yeast RNA resulted in the reversal of
immunosuppression in both protein malnourished and starved animals. These results
suggest that nucleotides are required to maintain cellular immune function during
times of nutritional stress.
Clincal Studies
The idea that dietary nucleotides could be used to modulate cellular immunity
in humans initally arose from the observation that renal allograft patients supported
by conventional intravenous nutrition, which is devoid of nucleotides, displayed a
suppressed immune response even when traditional pharmacologic immunosup-
pressive agents (i.e. cyclosporin) had been reduced.
94
Despite this observation, there
are no prospective, randomized clinical trials that have examined the singular effect
of nucleotides. Instead, the clinical trials have compared an enteral formula that
contains nucleotides (1.2 g yeast RNA/1000 kcal), in addition to other
immunostimulatory substrates (i.e., fish oil, arginine, glutamine) to a standard
commercially available enteral formula.
44-51
Thus, clinicians are left wondering
whether the addition of nucleotides alone would produce the same results.
Dietary sources of nucleotides appear to be important for maintaining optimal
growth and function of metabolically active cells such as lymphocytes, macroph-
ages, and intestinal cells. The daily requirement for purines and pyrimidines com-
bined is estimated to be 450-700 mg/day in healthy adults.
95,96
However, this
requirement may be increased during periods of stress. Moreover, animal studies
have demonstrated that the use of a nucleotide-free diet results in a decrease in
cellular immune function and a diminished resistance to infection. These effects
were able to be reversed with the provision of a diet containing 0.25% yeast RNA,
and subsequently lead to the incorporation of yeast RNA into several commercially
available enteral formulas. Although preliminary animal data suggests that the pro-
vision of exogenous nucleotides is necessary to support optimum immune func-
tion, the clinical data is less definative. Clearly, further prospective, randomized
clinical trials are warrented to determine whether or not nucleotides require the
presense of other immunostimulatory substrates in order to be of benefit in the
35
2
clinical setting. It is quite possible that the additional nutrients cause a further im-
provement in immunocompetence (synergism) that translate into fewer infectious
complications and, ultimately, a shorter length of hospital stay. However, to be sure,
one would need to conduct a trial using an enteral formula that differed only with
respect to the immunostimulatory nutrients; that is, both formulas would be
isonitrogenous and isocaloric but one formula would contain just nucleotides where
as the other would contain nucleotides as well as to one or more additional
immunostimulatory nutrients (i.e. fish oil, arginine, glutamine).
Lipids
Lipids are an essential component in enteral and parenteral formulas because
they provide energy and essential fatty acids, as well as function as carriers of fat-soluble
vitamins and precursors of hormones. For years, long-chain triglycerides were the
standard source of fat in enteral formulas, and, in fact, they are still the sole source of
fat in commercially available intravenous lipid emulsions. In the past two decades,
the role of fat in the diet has been elucidated. There is now compelling evidence to
suggest that manipulation of dietary nutrients such as lipids can have a profound
effect upon serum and cell membrane lipid concentration, immune function, as
well as critical endpoints such as survival.
97-102
Based on these findings, the current
recommendations for fat intake focus not only on the percent of total calories coming
from fat, but also on the composition of the fat.
103,104
Thus, there has been a surge of
investigations in the area of alternative lipid sources such as -linolenic acid,
monounsaturated fatty acids, -3 polyunsaturated fatty acids (particularly fish oil),
medium-chain triglycerides, and structured lipids.
-6 Polyunsaturated Fatty Acids
In the past, naturally occuring vegetable oils consisting of long-chain triglycerides
(LCT) of the -6 family were the conventional fat source because they were readily
available and relatively inexpensive. In addition, these oils are a rich source of the
major essential fatty acid, linoleic acid. Since linoleic acid can not be synthesized by
the body, it must be provided by the diet. Adult requirements for essential fatty
acids are usually met by providing 3 to 4% of total calories as -6 fatty acids.
102
Thus, corn, safflower, soybean, and sunflower oil serve as important sources of li-
noleic acid in nutritional formulations. The amount of linoleic acid provided in the
formula will vary depending upon the type and amount of LCT used. As shown in
Table 2.1, safflower oil contains the highest percentage of linoleic acid and the lowest
percentage of saturated fatty acids when compared to the other -6 fatty acids typically
used in enteral formulas.
106,107
There are a number of commercially available enteral formulas which contain
-6 fatty acids as their sole source of lipids, and, as previously mentioned, all com-
mercially available intravenous lipid emulsions are comprised solely of -6 fatty
acids. Yet, controversy exists over whether -6 fatty acids should be the primary
source of lipids in critically ill patients because of their potentially detrimental effect
on immune function.
Clearly, provision of a small amount of linoleic acid in the diet is necessary for
normal immune function.
108
However, provision of larger amounts of linoleic acid
leads to an increased production of arachidonic acid and its metabolites, prostaglandin
E2 (PGE2) and leukotriene B4 (LTB4). These eicosanoids are known to enhance
vasocontriction, platelet aggregation, neutrophil migration, immunosuppression,
36
2
cytokine depression, and free radical formation, all of which may predispose patients
to secondary inflammation and sepsis.
109
Although most of the work in this area
has been done in animals,
110,111
at least one prospective clinical trial suggests that
reticulendothelial system (RES) function is impaired when lipid emulsions are in-
fused in the standard intermittent fashion (over 10 hours) for 3 consecutive days.
112
Seidner, et al
112
provided 18 patients receiving parenteral nutrition (amino acids
and dextrose) with a 20% soybean oil emulsion administered over ten hours as a
piggyback infusion. Patients received the intermittent infusion for either 1 or 3
days at a rate that provided 0.13 g lipid/kg/hr or approximately 85 g lipid/day.
Patients receiving the lipid emulsion over 10 hours for 1 day showed no impair-
ment in RES function based on the clearance rate of intravenous technetium-99
sulfur colloid (TSC). However, patients receiving 3 days of intermittent lipid infu-
sion exhibited a statistically significant reduction in TSC. These findings prompted
the researchers to then determine whether administering the same amount of lipids
continuously as a three-in one admixture would have the same effect upon RES
function. In contrast to the intermittent lipid infusion, the continuous administra-
tion did not impair TSC clearance by the RES.
113
Thus, provision of standard LCT
lipid emulsions in a continuous manner may be preferable in critically ill or septic
patients. In addition, these authors recommend a modest lipid intake of 30 to 60 g
daily in this already immunocompromised patient population. These findings,
coupled with current recommendations regarding the optimal dietary fat intake
(i.e., < 30% of total calories), have prompted a search for alternative lipid sources.
-Linolenic Acid
Interest in the potential metabolic benefits of dietary -linolenic acid (GLA), a
plant seed oil found in borage oil and evening primrose oil, has grown as of late.
Dietary supplementation of -linolenic acid, a metabolite of the omega-6 essential
fatty acid, linoleic acid, has been shown to suppress both acute and chronic inflam-
mation in animals, as well as lower plasma cholesterol and triglycerides, and inhibit
platelet aggregation in diabetics.
114,115
More recent studies have demonstrated that
the addition of -linolenic acid to an eicosapentaenoic acid (EPA)-enriched diet
provides additional benefits with regard to lung function during endotoxemia.
116,118
The conversion of linoleic acid to -linolenic acid requires the presence of the
enzyme, -6 desaturase. However, under normal conditions, this enzyme has a low
activity, therefore, only a small portion of the linoleic acid is actually converted to
-linolenic acid which is, in turn, further metabolized to dihomo--linolenic acid
(DGLA). Dihomo--linolenic acid is a precursor of the anti-inflammatory
eicosanoids, prostaglandin E1 (PGE1) and thromboxane A1 (TXA1), as well as a
precursor for arachidonic acid. The conversion of dihomo--linolenic acid to arachi-
donic acid requires the presence of -5 desaturase, an enzyme that is rate limiting
in some macrophages.
119
Thus, the desaturation of dihomo--linolenic acid to arachi-
donic acid is relatively slow, particularly in the presense of EPA, an inhibitor of -5
desaturase.
120
It has been shown in animals that the addition of -linolenic acid (5.0 mole %)
to a diet containing EPA modulates the fatty acid composition of alveolar mac-
rophage phospholipids, thereby promoting a shift toward formation of less inflam-
matory eicosanoids by stimulated macrophages without causing an impairment in
macrophage bactericidal functions.
121
These changes in immune function observed
in animals receiving a diet containing -linolenic acid and EPA are undoubtably
37
2
responsible for the improvements in clinical outcomes seen in patients with acute
respiratory distress syndrome (ARDS) who received a similar diet.
122
In a multicenter trial, 98 patients with ARDS caused by sepsis/pneumonia,
trauma, or aspiration were randomized to receive an enteral formula containing
both EPA and -linolenic acid, as well as antioxidants (vitamins E and C, and
beta-carotene) or an isonitrogenous, isocaloric standard diet. By study day 7, pa-
tients receiving the EPA and -linolenic acid-enriched formula exhibited significant
improvements in pulmonary neutrophil recruitment and inflammation, gas exchange,
requirement for mechanical ventilation, length of intensive care unit stay, and a
reduction in new organ failures.
122
-3 Polyunsaturated Fatty Acids
There is a plethora of research to suggest that -3 fatty acids may have beneficial
effects on plasma cholesterol and triglyceride levels.
123,125
More recently, research in
this area has centered around the ablility of -3 fatty acids to favorably effect im-
mune function through their ability to alter ecoisanoid formation and metabolism.
Eicosapentaenoic acid (EPA) has been shown to be the metabolically active -3
fatty acid because of its structural similarity to the -6 fatty acid that is the usual
ecoisanoid precursor, arachidonic acid. In contrast to the -6 fatty acids, the omega-3
fatty acids favor production of prostaglandins of the 3 series (PGE3) and
leukotrienes of the 5 series (LTB5), which have significantly different biological
activities than the eicosanoids produced by the omega-6 fatty acids.
108
Thromboxane A3, one of the prostanoids formed from EPA, is a moderate vaso-
constrictor yet it does not aggregate platelets. In comparison, thromboxane A2, syn-
thesized from arachidonic acid, is a very potent platelet aggregator and
vaso-constrictor. Leukotriene B5, also derived from EPA, is a much less chemotactic
and aggregatory agent than the leukotriene B4 that is formed from arachidonic acid.
However, both prostacyclin I3, derived from EPA, and prostacyclin I2, synthesized
from arachidonic acid, are potent vasodilators and platelet antiaggregators.
109
In addition to synthesizing different eicosanoids than -6 fatty acids, EPA com-
petes with arachidonic acid as a substrate for the enzymes cyclooxygenase and
5-lipoxygenase, further reducing the formation of proinflammatory ecosanoids.
Furthermore, EPA and docosahexaenoic acid (DHA) have been shown to displace
linoleic acid and arachidonic acid in cell membranes and to reduce arachidonic acid
production through inhibition of the enzyme -6 desaturase.
108
These alterations in
eicosanoid metabolism suggest that provision of lipids rich in EPA may be advanta-
geous in critically ill patients suffering from systemic inflammation and infection.
A number of animal studies appear to support the aforementioned hypothesis.
In one set of experiments, administration of both short-term parenteral (i.e., 3 days)
and long-term enteral (i.e., 6 weeks) diets enriched with -3 fatty acids improved
survival in animals receiving an endotoxin infusion.
126
A similar set of experiments
showed that animals receiving short-term parenteral nutrition (TPN) containing
soybean oil developed significant metabolic and lactic acidosis after being infused
with endotoxin compared to animals receiving TPN enriched with -3 fatty acids
from fish oil.
127
In addition to having improved lactate levels, the animals receiving
the -3 fatty acid containing TPN also demonstrated a significantly higher mixed
venous oxygen than the animals given the TPN containing soybean oil. Administra-
tion of -3 fatty acids found in fish oil appears to attenuate tissue hypoxia and
38
2
improve survival in animals during endotoxemia, presumably through alterations
in prostaglandin metabolism.
Another area of intense research is the ability of -3 fatty acids to alter cytokine
production. The synthesis of several cytokines, specifically tumor necrosis factor
(TNF) and interleukin-1 (IL-1), is related to the production of prostaglandin E2
(PGE2). The presence of stress or sepsis causes an increased production of PGE2
from monocytes and macrophages, which, in turn, results in an increased production
of cytokines. It has been suggested that prolonged cytokine exposure results in in-
creased muscle degradation,
128
increased hepatic lipogenesis,
129
and hypertrig-
lyceridemia.
130
These findings have prompted some investigators to suggest that
administration of fish oil may help to suppress the deleterious effects of excessive
cytokine production. However, because certain cytokines help to control the bodys
defense system, a substantial reduction in their production may result in impairment
of normal immune response. Thus, researchers continue to search for the optimal
dose of -3 fatty acids with respect to cytokine production.
Hardardottir, et al
131
fed mice diets containing varying amounts of -3 fatty
acids, ranging from 0.15% to 1.5% by weight, for five weeks and noted an increased
production of TNF from peritoneal macrophages in animals receiving the 1.5%
-3 fatty acid diet compared to those receiving lower amounts of -3 fatty acids.
Simlarly, other investivators have noted increased TNF
132,133
and IL-1
133
production
in animals receiving -3 fatty acids compared to those fed corm oil. While other
researchers have found contrasting results,
134
Drs. Meydani and Dinarello
135
at-
tribute these discrepancies to the amount of EPA and DHA in the diet and/or the
duration of feeding.
With respect to human trials, several studies have examined the effects of fish oil
supplementation on eicosanoid and cytokine production in healthy volunteers.
136,137
These studies have consistantly shown a decrease in the production of
proinflammatory cytokines in volunteers receiving the fish oil supplemented diets.
However, one study also noted an impairment of the bodys ability to mount an
immune response in healthy individuals who ate a low-fat (< 30% of total calories),
high-fish (1.23 g EPA plus DHA/day or 121-188 g fish/day) diet for 6 weeks.
138
These individuals demonstrated a significant reduction in percentage of helper T
cells, mitogenic response to T-cell mitogen, delayed-type hypersensitivity skin response,
as well as production of TNF, IL-1, and IL-6 compared to those people receving a
low-fat, low-fish (0.27 g EPA plus DHA/day or 33 g fish/day) diet. Several undesir-
able changes in immune function (i.e. increased IL-6 release and decreased CD4
cell counts) have also been observed in patients with HIV infection who consumed
five food bars daily that provided a total of 1.96 -fatty acids/day for 6 weeks.
139
Chlebowski, et al,
140
however, demonstrated a significant reduction in hospitalizations
in patients with HIV infection who drank 500 mL/day of a commercially available
oral supplement that provided a mere 1.1 g fish oil/day (475 mg EPA plus DHA)
for a 6-month period. These findings suggest that for long-term (i.e., > 6 weeks)
feeding of fish oil to be of benefit in immunocompromised individuals, it must be
provided in modest amounts. With respect to the short-term (i.e., 1-2 weeks) use of
enteral formulas containing fish oil, a number of studies have shown that feeding
fish oil in amounts that provide 1.2-5.0 g -3 fatty acids/1000 kcal in select
populations is safe with respect to immune function.
A number of prospective, randomized trials have demonstrated improved im-
mune function,
44-46,50
fewer infectious complications,
43,45-49,51
and decreased length
39
2
of stay
43,45,47,49
in patients receiving enteral formulas enriched with fish oil, in addition
to other immunostimulatory nutrients, compared to those receiving standard diets
rich in -6 fatty acids (Tables 2.4 and 2.5). Only two studies have compared the
effects of -3 fatty acids alone.
141,142
Taken together, these studies suggest that short
term administration of enteral formulas containing 7 to 11 g fish oil/L (~ 1.4 to 1.7
g EPA plus DHA/L) may be beneficial in certain hospitalized patient populations.
However, further studies are needed to examine the immunological and clinical
effects of feeding such diets for an extended period of time.
As a result of these findings, an ever growing number of enteral formula manu-
facturers have begun to incorporate -3 fatty acids in to their products either in the
form of -linolenic acid from vegetable oils (particularly canola or soybean oil) or
from the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil.
However, a great deal of controversy exists with regard to the difference between
vegetable and animal sources of -3 fatty acids. The main difference between these
two sources of -3 fatty acids is that fish oil contains the preformed EPA and DHA,
whereas, the -linolenic acid in the vegetable oil must be converted in the body to
EPA. This conversion process, however, yields a relatively low amount of EPA when
compared to the amount of EPA obtained from consuming fish oil.
143
Thus, plant
sources, although useful, may not be an adequate substitute for the preformed EPA
and DHA found in fish oil.
Medium Chain Triglycerides
In addition to the naturally occurring and processed -6 and -3 fatty acids
currently used in enteral formulas, medium chain triglycerides (MCT) are a novel
lipid alternative frequently found in many of todays enteral formulas. Although the
incorporation of MCT into intravenous fat emulsions has been studied extensively,
these products are not yet commercially available. Medium chain triglycerides are
principally prepared by hydrolyzing and re-esterifying coconut oil, however, they
can also be derived from palm kernal oil. These lipids are significantly different from
the conventional fats (i.e., LCT) used in enteral formulas and intravenous lipid
emulsions. LCT are absorbed via the lymphatic system and are carnitine-dependent
for chylomicron formation and transport. In contrast, MCT are directly absorbed
via the portal system, are not carnitine-dependent, and do not require chylomicron
formation.
144
Thus, MCT are absorbed and metabolized as rapidly as glucose. Se-
verely catabolic patients may therefore benefit from this rapidly available, high en-
ergy fuel because MCT are less likely to be deposited and more likely to be oxidized
in tissues.
145
Furthermore, animal studies suggest that MCT do not depress RES
function.
110
MCT, however, have their greatest clinical impact in patients with impaired fat
absorption due to pancreatic, biliary, or intestinal dysfunction. In principle, replacing
LCT in the diet with MCT in the setting of impaired fat absorption should help to
decrease stool frequency and volume while concommitantly improving nutrient
absorption.
One important point about MCT is that they are devoid of essential fatty acids.
Thus, the provision of some LCT is necessary in order to meet essential fatty acid
requirements.
144
Most MCT-containing enteral products consist of a physical mixture
of LCT and MCT. However, there is now a new generation of fats known as struc-
tured lipids which combine both MCT and LCT on the same glycerol backbone.
4
0
T
h
e

B
i
o
l
o
g
y

a
n
d

P
r
a
c
t
i
c
e

o
f

C
u
r
r
e
n
t

N
u
t
r
i
t
i
o
n
a
l

S
u
p
p
o
r
t
2
Table 2.4. Summary of studies assessing efficacy of immune-enhancing enteral formulas
Author Patients Diets* Results
Gottschlich, et al
43
50 burn patients Modular diet (containing Significant reduction in length of hospital stay (LOS)
supplemental arginine and fish and incidence of wound infections in modular group
oil) vs. Osmolite with Promix
vs.Traumacal
Cerra, et al
44
20 surgical ICU patients Impact vs Osmolite HN Significant improvement in T-lymphocyte proliferation
with sepsis syndrome in Impact group
Daly, et al
45
85 patients undergoing Impact vs. Osmolite HN Significant reduction in LOS and infectious/wound
surgery for upper GI complications in Impact group
malignancies
Moore, et al
46
98 trauma patients Immun-Aid vs. Vivonex TEN Significant increases in total lymphocytes, T lymphocytes
and T-helper lymphocytes; significantly fewer intra-
abdominal abscesses, and less multiple organ failure
in Immun-Aid group
Daly, et al
47
60 patients undergoing Impact vs. Traumacal Significant decrease in peripheral WBC PGE
2
surgery for upper GI production, LOS, and infectious/wound complications
malignancies in Impact group
Bower, et al
48
326 ICU patients with an Impact vs. Osmolite HN Significant reduction in LOS and frequency of
APACHE score 10 infectious complications in septic patients receiving
Impact
Kudsk, et al
49
35 trauma patients Immun-Aid vs. Promote Significantly fewer major infectious complications
with Casec and shorter LOS in Immun-Aid group
continued on next page
4
1
C
u
r
r
e
n
t

N
u
t
r
i
e
n
t

S
u
b
s
t
r
a
t
e
s
2
Table 2.4. Summary of studies assessing efficacy of immune-enhancing enteral formulas (continued)
Author Patients Diets* Results
Kenler, et al
141
50 patients undergoing Osmolite HN vs. isocaloric, Significant incorporation of EPA into plasma and
surgery for upper GI isonitrogenous fish oil erythrocyte phospholipids, and 50% decline in
malignancies structured lipid-based diet gastrointestinal complications and infections in
FOSL-HN group
Kemen, et al
50
42 patients undergoing Impact vs isocaloric, Significant increase in total T lymphocytes, helper T
surgery for GI malignancies isonitrogenous diet cells, activated T cells, B-lymphocyte indices,
immunoglobin M & G concentrations in Impact group
Swails, et al
142
20 patients undergoing Osmolite HN vs isocaloric, Significant reduction in PGE
2
and 6-keto prostaglandin
surgery for upper GI isonitrogenous fish oil PGF
1a
production from PBMC with endotoxin stimulation
malignancies structured lipid-based diet in FOSL-HN group
(FOSL-HN)
Galban, et al
51
176 septic ICU patients Impact vs. Precitene Hiperproteico Significant reduction in mortality rate, number of
with an APACHE II bacteremias, and number of patients with more than
score > 10 one nosocomial infection in Impact group
Gadek, et al
122
98 patients with ARDS High fat, low carbohydrate Significant improvements in pulmonary netrophil
formula vs. isocaloric, recruitment and inflammation, gas exchange,
isonitrogenous EPA + GLA
**
requirement for mechanical ventilation, length of
lipid-based diet unit stay, and a reduction in organ failures
*Manufacturers of diets and protein modules: Ross Laboratories: Osmolite, Osmolite HN. Novartis Nutrition: Impact, Vivonex T.E.N. B
Braun.: Immune-Aid. Mead Johnson Nutritionals: Traumacal, Casec. Clintec: Promote. Navaco Laboratories: Promix.
**EPA=eicosapentaenoic acid; GLA=-linolenic acid
42
2
Structured Lipids
Another alternative to LCT are structured triglycerides. These triglycerides are
the product of MCT and LCT that have been hydrolyzed and then re-esterified
after a random distribution of the MCT and LCT has occurred. Depending on the
proportions of oils used, the resulting structured lipid may consist of one MCT
and two LCT or two MCT and one LCT on the same glycerol backbone. This
MCT/LCT mixture provides both rapidly and slowly metabolized fuels, as well as
essential fatty acids.
144,145
Preliminary animal studies suggest that structured lipids result in significantly
better nitrogen balance and weight gain, and increased protein synthetic rates in
both the skeletal muscle and liver when compared to either LCT, MCT, or a physi-
cal mixture of MCT and LCT.
146,147
These results were particularly evident when
the structured lipid contained a mixture of either 60% MCT and 40% LCT or
75% MCT and 25% LCT. In contrast, a 50:50 MCT/LCT mixture yielded no
improvement in the protein-sparing effect. The 75% MCT/25% LCT structured
lipid emulsion was then intravenously infused over a 19-hour period in 9 hospital-
ized patients, and no significant impairment in RES function was observed.
101
Additional clinical trials have shown that provision of parenteral structural lipid
emulsions (40% MCT/60% LCT by weight) are well tolerated
148
and cause a sig-
nificantly higher whole body fat oxidation, without promotion of ketogenesis, in
postoperative patients when compared with the provision of standard parenteral
LCT emulsions.
149
More recently, a parenteral structured lipid emulsion (64% MCT/
36% LCT by weight) was compared to a parenteral MCT/LCT physical mixture
(50% MCT/50% LCT by weight) in forty patients undergoing abdominal surgery.
Liver function tests (ASAT and ALAT) and plasma triacylglycerol levels were sig-
Table 2.5. Commercially available immune-enhancing enteral formulas used
in studies shown in Table 2.4
Per 1000 kcal Impact Immun-Aid
Kcal/mL 1.0 1.0
Carbohydrate 132 (53%) 120 (48%)
(g/% total kcal)
Carbohydrate source Hydrolyzed cornstarch Maltodextrins
Protein (g/% total kcal) 56 (22%) 80 (32%)
Protein source Sodium and calcium Lactalbumin
caseinates L-arginine (14.0 g)
L-arginine (12.3 g) L-glutamine (9.0 g)
Yeast RNA (1.2 g) BCAA (20.0 g)
Yeast extract (1.0 g)
Fat (g/% total kcal) 28 (25%) 22 (20%)
Fat source Structured lipid from MCT; canola oil
palm kernal oil and
sunflower oil; refined
menhaden oil
-3 fatty acids (g) 1.68 1.10
43
2
nificantly increased in the patients receiving the parenteral MCT/LCT physical
mixture compared to those patients receiving the parenteral structured lipid.
150
Presently, in the United States, intravenous structured lipids are still in the ex-
perimental phase. They are, however, present in several commercially available
enteral formulas as a mixture of palm kernal oil (MCT) and sunflower oil or fish oil
(LCT). More recently, a prospective, randomized clinical trial was conducted in
patients undergoing surgery for upper gastrointestinal malignancies using an enteral
formula that incorporated -3 fatty acids from fish oil directly into the structured
lipid.
141,142
Patients receiving the experimental formula demonstrated significant
improvements in renal function, presumably due to changes in eicosanoid metabo-
lism, and liver function, as well as a decrease in the number of patients with multiple
infections compared to patients receiving a commercially available enteral formula
differing only with respect to its lipid composition.
There is good evidence that lipid mixtures designed for special medical purposes
play an important role in the nutritional support of a wide variety of patient popu-
lations. It is clear from both animal and human studies that modulation of the
composition of lipid emulsions can significantly affect the response to disease, in-
jury, and infection. Based on these studies, several recommendations regarding fat
administration in hospitalized patients can be made. First, lipid intake should ide-
ally be limited to providing no more than 30% of total calories. Second, the type of
lipid administered should be based upon the patients disease state. There is con-
vincing evidence that critically ill patients may benefit from the administration of a
lipid mixture that contains -3 fatty acids and MCT in addition to LCT. Patients
undergoing surgery for upper gastrointestinal cancers may also benefit from receiv-
ing such a lipid mixture in the early postoperative period. However, more research is
needed in this area to further define the optimal dose and mixture of lipids that is
best suited for each specific patient population.
Conclusion
Recent evidence suggets that specific nutrients may favorably affect certain as-
pects of organ and immune function independent of their general nutrition effects.
The administration of branched-chain amino acids may be advantageous in patients
with significant renal failure due to the fact that BCAA are preferentially used by the
body for protein synthesis thereby decreasing the rate of urea production. In addi-
tion, the provision of glutamine-enriched nutrition may be efficacious in specific
patient populations. Finally, the addition of such nutrients as arginine, glutamine,
nucleotides, -3 fatty acids from fish oil and -linolenic acid to enteral formulas
administered to critically ill, burn, and trauma patients, as well as those with ARDS
and those undergoing surgical resections for upper gastointestinal malignancies has
been shown to decrease infectious complications and length of hospital stay. De-
spite this exciting promise with respect to nutritional immune moduation and pa-
tient outcome, broad application of the enteral and parenteral products shown to be
effective in specific populations is premature. Additional randomized, prospective
trials are required to evaluate the efficacy of using these products in other patient
populations.
As we forge ahead in the field of bionutrition, we can look forward to the con-
tinual development and refinement of specialized functional formulas-parenteral
and enteral formulas that provide health benefits beyond basic nutrition. In addition,
we can expect to see further advances in the use of ligand-binding proteins, probiotics
and prebiotics, and other natural phytonutrients.
151
44
2
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130. Hirschberg Y, Pomposelli JJ, Blackburn GI et al. The effects of chronic fish oil
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131. Hardardottir I, Kinsella JE. Tumor necrosis factor production by murine resident
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supl):397-401.
CHAPTER 3
Biochemistry of Amino Acids:
Rifat Latifi, Khawaja Aizimuddin
Introduction
Amino acids, as organic compounds, containing both an amino group and a
carboxylic acid group, are the monomeric and basic constituents of all proteins.
Amino acids occurring in protein are known as alpha-amino acids and have one or
two empirical formulae RCH (NH
+
)COOH
-
or R-CH-(NH
3
)COO
-
. Beta-amino
acids and gamma-amino acids also occur in nature but are not components of pro-
teins, and their significance is not known. This chapter reviews the basic biochemis-
try and physiology of amino acids and their functions as fundamental units of proteins.
Their increasingly recognized and valued role in the metabolic and nutritional man-
agement of critically ill patients will be discussed through out this volume.
Structure of Amino Acid and Proteins
A protein molecule consists of amino acids held together by peptide bonds, which
form a long polypeptide chain. The exact sequence of amino acids in the chain,
referred to as the primary structure of the protein, is determined genetically and
defines how the chain is folded into more complex conformations or shapes.
A polypeptide, which is folded into a helical or pleated sheet configuration, is
referred to as a secondary structure. If the sequence of amino acids is then folded
into a three-dimensional configuration, a tertiary structure is created. Some pro-
teins have a higher level of molecular architecture known as the quaternary struc-
ture, in which several chains aggregate and function as a unit. The amino acid sequence
and protein structure determine the nature and function of protein molecules upon
which virtually every process of life depends. The folding of polypeptide chains into
alpha helix and beta pleated sheets has clinical implications. The alpha helix is a
rod-like structure and contains a tightly coiled polypeptide main chain. Two or
more such alpha helices can entwine to form a cable, which serves as a mechanical
support by forming stiff bundles of fibers. Such alpha-helical coils are found in the
keratin of a hair, myosin and tropomyosin in muscle, epidermis in skin and fibrin in
blood clots. In contrast to the coiled alpha helix, beta-pleated sheets are fully ex-
tended sheets of polypeptide chains. Another type of periodic structure is the col-
lagen helix. Collagen is triple-stranded helical rod which is tightly held together by
the amino acid glycine. By virtue of its very small size, glycine fits into the inner
aspect of the tightly packed helical cable and thereby allows the different polypep-
tide chains to come together. It is easy to see that mutation of a single glycine in
collagen can lead to weak collagen as occurs in osteogenesis imperfecta.
53
Biochemistry of Amino Acids: Clinical Implications
3
Although more than 100 different amino acids have been identified in nature,
only 20 amino acids are used to build the enormous number of biologically active
peptides and proteins that comprise most of the dry weight of the human body.
When one realizes that muscle, bone, blood, brain, genes, and other tissues are all
composed of amino acids, it is not difficult to understand the importance of acquir-
ing knowledge of amino acid biochemistry and metabolism, not only for biochem-
ists and basic scientists, but also for surgeons and other physicians.
Amino Acid and Protein Synthesis
Amino acids are building blocks for protein. All proteins are initially synthesized
from 20 amino acids known as common or primary amino acids. Primary amino
acids are defined as amino acids for which a specific codon exists in the DNA ge-
netic code. The genetic code is a directory that provides the correspondence be-
tween a sequence of nucleotide bases and a sequence of amino acids. The codons
represent genetic words in a code composed of three nucleotide bases which are
transcribed from DNA into the messenger RNA (mRNA), and their sequence is
always read from its 5-end (amino-terminal end) to its 3-end (carboxyl-terminal
end). Codons exist for all 20 of the amino acids in the human body. Genetic infor-
mation is transmitted from the DNA sequence by mRNA translation into the amino
acid sequence of a protein. The genetic code is thought to be specific, usually uni-
versal, redundant or degenerate, non-overlapping and commaless. Conventionally,
the code is read from a fixed starting point as a continuous sequence of bases, taken
three at a time.
Protein synthesis is a highly complex biochemical process that requires
1. an amino acid sequence information, as coded by mRNA,
2. activated amino acids assembled as aminoacyl transfer RNA (tRNA)
complex
3. energy in the form of guanosine triphosphate (GTP), and
4. various protein initiation or release factors.
Protein synthesis occurs on the surface of ribosome, or multiprotein, multi-RNA
complexes that provide the enzyme, peptidyl-transferase. This enzyme is one of many
proteins of the larger ribosomal subunit and is imbedded in the surface of the sub-
unit. It catalyzes peptide bond formation and covalent linkage of one amino acid
residue to another. The process of protein synthesis itself is called translation,
because the language of the nucleotide sequence on the mRNA is translated into
the language of an amino acid sequence. The mRNA is translated from its 5-end to
its 3-end producing a protein synthesized from its amino-terminal end to its
carboxyl-terminal end. The direction of translation is precisely defined, with the
amino terminal of the evolving protein being synthesized first and the carboxyl ter-
minal synthesized last. The polypeptide chains produced by translation may be
modified further after translation. Protein synthesis has three steps: initiation, elon-
gation, and termination.
Initiation
Initiation involves assembly of the components of the translational system be-
fore the peptide bonds are formed. Components of the translational system include
two ribosomal subunits, the mRNA to be translated, the specified aminoacyl tRNA
along with GTP and the initiation factors. Eukaryotic initiation, which requires
ribosomal subunits 40S and 60S, mRNA, GTP, initiation factors (IF-1, IF-2, and
54
3
IF-3) and ATP, first involves the formation of a complex outer 40S ribosomal sub-
unit, and secondly, the addition of the 60S ribosomal subunit to give an 80S
initiation complex.
Elongation
The second step in protein synthesis is elongation of the polypeptide chain. The
necessary components for this process are the 80S initiation complex,
aminoacyl-tRNA, GTP and eukaryotic elongation factors eEF-l alpha, eEF-1 beta
and eEF-2. During elongation, the ribosome moves from the 5-end to the 3-end of
the mRNA that is being translated. At one time, a single mRNA molecule may be
translated by many ribosomes, thereby markedly increasing the efficiency of the
utilization of the mRNA. The group of ribosomes bound to a mRNA molecule is
called a polyribosome. The concluding event of elongation is translocation. Translo-
cation is a process in which the ribosome advances three nucleotide segments to-
ward the 3-end of the mRNA following formation of the peptide bond. It causes the
release of the uncharged tRNA and movement of peptidyl tRNA into the P site.
Termination
The final step of protein synthesis, occurs in response to termination signals,
after the final amino acid residue is placed at the carboxyl terminal of the newly
synthesized protein. This process occurs when one of the three termination codons
(UAA, UAG and UGA) moves into the A site.
These codons are recognized by release factors (RF): RF-1, RF-2, and RF-3 and
cause the newly generated protein molecule to be released from the ribosomal com-
plex, and also effect the dissociation of ribosomes from the mRNA.
Post-Synthetic Modification
The basic set of 20 amino acids can be modified after synthesis of a polypeptide
chain to enhance their capabilities. For example, the amino acid terminals of many
proteins can be acetylated to make them more resistant to degradation. Similarly,
the proline residues in collagen may be hydroxylated to form hydroxyproline, which
stabilizes the collagen fiber. Carboxylation of glutamate is another important step in
the synthesis of coagulation factor.
Protein Function
Protein function may be classified into two categories: dynamic and structural
(static). Dynamic functions include enzymatic catalysis of biochemical reactions,
transport and storage, contraction, generation and transmission of nerve impulses
and immune protection. Structurally, proteins provide the matrix for bone and con-
nective tissue, which give structure and form to the body. Some of these important
functions are discussed in detail below.
Enzymatic Catalysis
Specific enzymes catalyze chemical reactions in living organisms. Several thou-
sand enzymes have been recognized and many of them are essential for the function
and survival of the organism. Nearly all enzymes in biological systems are proteins.
It is easy to see that a defect in the amino acid constitution of an enzyme may lead to
abnormal functioning of that enzyme system.
55
3
Transport and Storage
Many small molecules and ions are transported or stored by proteins. Oxygen is
transported in blood by hemoglobin and stored in muscles in combination with
myoglobin. Similarly iron is carried in plasma by transferrin and stored in liver as a
complex with ferritin. Thyroxine, cortisol, sex hormone, calcium and copper are
examples of some of the large array of hormones and ions transported by proteins.
Coordinated Motion
Proteins provide the contractile element for the cytoskeleton. Movement of chro-
mosomes during mitosis, movement of organelles within the cell and the propul-
sion of sperms by flagella is produced by coordinated actions of contractile assemblies
consisting of proteins. Most importantly, muscle contraction is accomplished by
sliding motion of two proteins, actin and myosin.
Mechanical Support
Proteins provide the framework for the living organism. Collagen, a fibrous pro-
tein, provides tensile strength to skin and bone.
Immune Protection
Antibodies consist of highly specific amino acid chains, which protect the body
from viruses, bacteria and other exogenous or endogenous antigens. Nutrient sub-
strate deficits may therefore lead to suppressed humoral and delayed type hypersen-
sitivity immune responses
Tissue Repair
Proteins not only play a pivotal role in the inflammatory response but also pro-
vide building blocks for the process of repair after tissue injury.
Generation and Transmission of Impulses
The synaptic receptors at nerve terminals consist of small proteins which are in
turn stimulated by other protein molecules such as acetyl choline. Furthermore,
most membrane functions such as transport of ions or molecules, intercellular com-
munications and energy transduction are mediated by specific proteins that traverse
the cell membrane.
Control of Growth and Differentiation
Many hormones such as growth hormone, insulin and thyroid stimulating hor-
mones are proteins. Further more many of the growth factors such as nerve growth
factor, platelet derived growth factor are also proteins.
Specialized Functions
Some amino acids have specialized functions. For example, glutamine serves as
energy source for lymphocytes and macrophages. It is also required for the
maintenance of the intestinal mucosa. Similarly arginine is important for cell
mediated immunity.
Classification of Amino Acids
Amino acids occurring in biologic proteins are known as alpha-amino acids and
have one of two empirical formulae: R-CH-(NH
2
)-COOH or R-CH-(NH
3
+
)-COO
-
.
Beta amino acids and gamma-amino acids also occur in nature but are not
56
3
components of proteins, and their significance is not known. The core of an -amino
acid is the -carbon atom next to the carboxylic acid (COOH) group. All -amino
acids, except glycine, are asymmetric, with four different groups bonded to the
a-carbon: a hydrogen atom, a carboxyl group, an amino group (NH2), and a dis-
tinctive R-group. The characteristic acid-base properties of each amino acid and the
variety of possible R-group configurations and interactions make peptides and pro-
teins versatile in structure and function.
Although the primary amino acids can be polymerized to form proteins, each of
the 20 primary amino acids is a unique compound with its own individual biologi-
cal and metabolic functions. Many amino acids of biological significance, such as
thyroxine, triiodothyronine and beta-alanine, are not numbered among the 20 pri-
mary amino acids. Other amino acids, such as ornithine and citrulline, are interme-
diates of the urea cycle and have major roles in the body economy. Some proteins,
such as collagen, elastin, and prothrombin, incorporate special amino acids. For
example, collagen contains 4-hydroxyproline and 5-hydroxylysine; elastin con-
tains desmosine; myosin has n-methyllysine; and prothrombin contains
-carboxyglutamic acid.
Primary amino acids are classified in several ways. Because the nature of the side
chains ultimately dictates the role of an amino acid in a protein, one useful classifi-
cation of amino acids is based on the polarity of the side chain. This classification
identifies and categorizes amino acids as nonpolar (hydrophobic), uncharged polar
(hydrophilic), negatively charged (acidic), and positively charged (basic) (Table 3.1).
Amino acids with non-polar side chains typically do not bind or release protons, or
participate in hydrogen or ionic bonding. Proline is unique in this group in that it
contains an amino group rather than an alpha-amino group.
Amino acids with uncharged polar side chains have zero net charge at neutral
pH, although the side chains (R-groups) of cysteine and tyrosine can lose a proton
in alkaline conditions. Amino acids with acidic side chains (aspartic acid and glutamic
acid) are negatively charged and are proton donors; amino acids with basic side
chains bind protons (arginine, lysine and histidine). The side chains of arginine and
lysine are fully ionized and positively charged at neutral pH. Histidine, on the other
hand, is a weak basic amino acid because as a free amino acid it is largely uncharged
at physiologic pH. As a component of proteins, however, the histidine side chain
can have a positive or neutral charge, depending on the ionic environment. In addi-
tion to basic and acidic amino acids, a large number of amino acids are classified as
neutral. The neutral amino acids are monoamino-monocarboxylic acids and are
characterized by their side chains. This group includes glycine, alanine, valine, leu-
cine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, and the
sulfur-containing amino acids (cysteine, methionine, and cystine).
Another useful classification is based on whether amino acids are glycogenic,
glucogenic and ketogenic, or only ketogenic. Amino acids are classified as ketogenic
or glucogenic according to their metabolic end products. Amino acids that yield
either acetoacetate or one of its precursors, acetyl CoA or acetoacetyl CoA, are keto-
genic. The only amino acids that are exclusively ketogenic are leucine and lysine
because they cannot function as carbon sources for the net synthesis of glucose. On
the other hand, amino acids whose catabolism yields pytuvate or one of the inter-
mediates of the citric acid cycle (such as oxaloacetate) are glucogenic amino acids
(Table 3.2). However, as depicted in Table 3.2, some amino acids have both ketoge-
nic and glucogenic functions.
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3
Amino acids may also be classified as essential or non-essential. Whether amino
acids are nutritionally essential (indispensable) or non-essential (dispensable) de-
pends on whether they can be synthesized endogenously and are not necessarily
required in the diet (non-essential), or those that cannot be synthesized endogenously
and, therefore, must be provided in the diet (essential) (Table 3.3). A new category
of amino acids termed conditionally essential is emerging and includes arginine,
taurine, and others. An amino acid falls into this class when its production is either
limited by immature synthetic mechanisms or its requirements are increased under
certain stressful conditions.
Table 3.1. Classification of the 20 amino acids found in proteins according to
the charge and polarity of the side chains (R-groups)
Nonpolar (Hydrophobic) Uncharged Polar (Hydrophilic)
Side Chains Side Chains
Alanine Asparagine
Glycine Glutamine
Leucine Cysteine
Valine Serine
Isoleucine Threonine
Phenylalanine Tyrosine
Tryptophan
Methionine
Proline
Acidic Side Chains Basic Side Chains
Aspartic acid Histidine
Glutamic acid Lysine
Arginine
Table 3.2. Classification of primary amino acids according to metabolic
end products
Glycogenic or Ketogenic Both
Glucogenic
Glycine Leucine Threonine
Serine Lysine Isoleucine
Valine Phenylalanine
Histidine Tyrosine
Arginine Tryptophan
Cysteine
Proline
Alanine
Glutamate
Glutamine
Aspartate
Asparagine
Methionine
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3
Amino Acids in Critical Illness and Injury
Arginine is a semi or conditionally essential amino acid, and its requirements are
increased during sepsis and tissue injury. Through its role in the urea cycle, arginine
takes part in the synthesis of other amino acids, urea and nitric oxide. Arginine is
important for cell mediated immunity. It is required for the growth and function of
T lymphocytes in cultures. In vivo, arginine retards thymic involution by encourag-
ing production of thymic hormones and thymocyte proliferation. Arginine also pro-
motes leukocyte-mediated cytotoxicity. Growth hormone receptors are widely
distributed in the immune system, and by releasing growth hormone, arginine may
increase the cytotoxic activity of macrophages, neutrophils, NK cells and cytotoxic
T cells. Furthermore, nitric oxide, a product of arginine metabolism, has important
tumoricidal, anti-microbial and inflammatory activities.
Glutamine is the most abundant amino acid in blood and in the bodys free
amino acid pool. Lymphocytes and macrophages use glutamine as a source of en-
ergy. After entering the cell, glutamine is converted to glutamate and ammonia by
the action of glutaminase in the inner mitochondrial membrane. Further processing
results in production of aspartate and oxidation of about 25% of glutamine to
carbondioxide. This glutaminolysis pathway works in conjunction with the glyco-
lytic pathway to allow the combined use of glucose and glutamine as an energy
source for macrophages and lymphocytes. Thus, a relative deficiency of glutamine
stores that occurs during critical illness, is likely to lead to poor immune responses.
Table 3.3. Classification of primary amino acids based on
dietary requirements
Essential (Indispensable)
Arginine*
Histidine
Methionine
Threonine
Valine
Isoleucine
Lysine
Phenylalanine
Tryptophan
Leucine
Nonessential (Dispensable)
Alanine
Aspargine
Aspartate
Cysteine
Glutamine*
Glutamate
Glycine*
Proline
Serine
Tyrosine*
* These amino acids plus cystine, proline and taurine are considered to be
conditionally indespensable.
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3
Glutamine also plays an important role in maintaining the integrity of the intestinal
mucosa. In animal studies it has been shown that addition of glutamine to parenteral
nutrition inhibits gut mucosa atrophy, reduces bacterial translocation across the gut
epithelium and increases the production of secretory IgA.
Glutamine and arginine are mobilized from the skeletal muscles during critical
illness to provide substrate for production of glucose by the liver, to provide energy
substrate for rapidly dividing cells and to take part in the acid base balance. The
concentration of skeletal muscle glutathione also falls during critical illness. Since
glutathione is a scavenger of free oxygen radicals, the reduced levels may predispose
skeletal muscles to free radical injury. The plasma levels of phenylalanine rise after
critical illness and the ratio of phenylalanine to tyrosine has been used as an indica-
tor of the severity of muscle protein catabolism. The excretion of carnitine and
3-methyl histidine in urine is increased in critically ill patients, indicating muscle
breakdown and catabolism of proteins. The rate of excretion of pyridinium cross-liked
breakdown products of collagen is also increased.
Amino Acids in Circulation
Serum levels of free amino acids are generally low. The normal concentration of
total amino acids in the blood is between 35 and 65 mg/dL. Although some amino
acids circulate in higher concentrations than others, serum concentration averages
about 2 mg/dL for each of the 20 amino acids. Although the distribution of amino
acids in the blood can depend on the type of dietary protein ingested, the concen-
trations of some amino acids are regulated by selective synthesis in different types of
cells. The concentration of free amino acids in the intracellular compartment is
considerably higher than the concentration in the extracellular compartment. The
total amount of free amino acids in the body is about 100 g, of which 50% consists
of glutamate plus glutamine, and 10% consists of essential amino acids. Further-
more, because immediately after entering a cell, amino acids form peptide bonds to
create proteins, storage of large quantities of amino acids as such does not occur in
most cells. However, the cells of some tissues such as the liver, kidney, and the intes-
tinal mucosa can store large quantities of amino acids. The plasma concentration of
each amino acid is relatively constant although various hormones secreted by the
endocrine glands affect the balance between tissue proteins and free amino acids.
Digestion of Amino Acids
During digestion, proteins are degraded into peptides and amino acids. Protein
digestion begins during the gastric phase and is influenced by both hormonal and
neural factors. Pepsinogen, which is secreted by gastric chief cells in response to
ingested foods and low gastric pH, is converted by hydrochloric acid to pepsin, the
major gastric protease. Pepsin is an endopeptidase that is specific for disruption of
peptide bonds involving aromatic primary amino acids. Although important for
breaking down dietary proteins, pepsin is not essential for normal protein digestion
and absorption unless pancreatic function is impaired. For example, patients who
have had a total gastrectomy and those with pernicious anemia absorb protein effi-
ciently and can maintain positive nitrogen balance if adequate amounts of protein
are ingested.
The hydrolysis of proteins to free amino acids and their absorption into the
circulation is a stepwise process. Gastric hydrolysis of protein yields peptides that,
when entering the intestine, stimulate intestinal endocrine cells to release cholecys-
tokinin and secretin which, in turn, stimulate the pancreas to secrete enzymes and
60
3
bicarbonate into the intestinal lumen. When the gastric contents mix with the alka-
line pancreatic juice in the duodenum, pepsin activity is terminated, and digestion
by pancreatic proteases is initiated.
The pancreatic endopetidases (trypsin, chymotrypsin, and elastase) cleave the
proteins at specific interior peptide bonds. These pancreatic proteases are secreted in
inactive forms and are converted to active enzymes by the combined action of enter-
okinase, a brush border mucosal cell enzyme, and trypsin. The end products of the
additive action of endopeptidases and exopeptidases are free amino acids and
oligopeptides. Subsequently, proteases in the brush border cells contribute to the
enzymatic digestion of the oligopeptides (a peptide chain several peptides long).
The brush border oligopeptidases generally cleave the N-terminus amino acids from
their substrate to yield smaller peptides.
Absorption of Amino Acids
The final products of protein digestion, amino acids and small peptides (dipep-
tides and tripeptides) are absorbed by distinct transport systems. Whereas, proteins
are absorbed mainly in the form of small peptides and amino acids, the final mea-
surable amino nitrogen in postprandial portal-vein blood is primarily in the form of
amino acids. Nevertheless, a few small peptides, usually dipeptides and tripeptides,
do appear in portal blood after protein ingestion. Several mechanisms have been
identified for amino acid transport from the gut lumen into the intestinal epithelial
cells, but some amino acids (such as the amino acidsglycine, proline, and hydrox-
yproline) may be transported by more than one mechanism.
Separate transport mechanisms exist for neutral amino acids (alanine, valine,
leucine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan); basic
amino acids (lysine, arginine, and histidine); acidic amino acids (aspartic acid and
glutamic acid); and for beta-amino acids (beta-alanine and taurine). The transport
of amino acids across the special membrane of enterocytes is carrier mediated,
sodium-dependent, and characteristically energy-dependent. The transport is asso-
ciated with the entry of sodium into the cell and is fueled by the energy derived
from the electrochemical sodium gradient. In other words, the downhill entry of
sodium can bring about the uphill concentration of amino acids in the brush
border cells. Once inside the liver cells, amino acids may be catabolized, with the
conversion of their nitrogen to ammonia and urea. Because this process occurs in
the mitochondria, transport mechanisms may exist in the mitochondrial membrane.
Although little is known concerning the intracellular transport of amino acids across
the mitochondrial membrane, the transcellular transport of amino acids in the kid-
neys appears to occur by a special mechanism in which amino acids are covalently
linked to gamma-glutamyl residues of the tripeptide glutathione.
During absorption, peptides and amino acids are taken up by the mucosal cells
by independent processes. While oligopeptides, apparently, can be absorbed by the
intestine without first being broken down into individual amino acids, dipeptides
and tripeptides are actively transported against a concentration gradient by a carrier
mechanism separate from that for amino acids. The propensity for a dipeptide to be
transported is influenced by the dipeptide structure including the specific amino
acid residues, the position relative to the carboxyl and amino terminals, the length
of the side chains, and stereoisomerism. The majority of oligopeptides that are ab-
sorbed undergo additional intracellular hydrolysis.
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3
The absorption of small peptides may represent a major mechanism for absorp-
tion of dietary protein and has important physiologic and clinical implications. For
example, consideration of oligopeptide absorption is essential in designing formulas
for optimal enteral nutrition.
Absorption of oligopeptides across the brush border occurs more rapidly than
the transport of free amino acids. Whereas free amino acids are absorbed more rap-
idly in the proximal intestine, the peptides appear to be absorbed well in both the
proximal and distal gut. Resection of long segments of the small bowel, or jejunoileal
bypass in patients undergoing treatment for morbid obesity may result in protein
calorie malnutrition. This malnutrition is related to a reduced rate of amino acid
absorption in the residual functioning jejunum. On the other hand, dipeptide ab-
sorption is not affected significantly by jejunoileal bypass.
Biochemical Transformation of Amino Acids
The process by which an amino group at least in different amino acids (alanine,
arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, isoleucine,
phenylalanine, tryptophan, tyrosine, and valine) is transferred from one carbon chain
to another to form a new amino or keto acid is called transamination. The en-
zymes that catalyze this process, the transaminases (aminotransferases), are widely
distributed and are responsible for an active redistribution of amino groups among
amino acids in vivo. Furthermore, the transfer of the amino group from one carbon
chain to another helps to maintain appropriate ratios of the various amino acids
while individual compounds are undergoing synthesis or degradation.
An essential cofactor for all transaminases, and for many other reactions involv-
ing amino acids, is pyridoxal phosphate. The most important transaminases are
aspartate aminotransferase (AST), also known as glutamine-oxaloacetic transami-
nase (GOT); alanine aminotransferase (ALT), also known as glutamic-pyruvic tran-
saminase (GPT); a-amino acid-a-ketoglutarate aminotransferase and amino
acid-pytuvate aminotransferase. Because transaminases are present in high concen-
trations in the heart muscle and liver, damage to either or both of these organs leads
to transaminase leakage into the plasma or serum. Transamination is of great impor-
tance in the metabolism of amino acids and is the process, which allows a-keto acids
to be used as substitutes for many amino acids in nutrition regimens, especially in
the management of renal failure or insufficiency.
Before oxidation of the carbon group of the amino acid molecule can take place,
the amino group must be detached. Detachment is accomplished by oxidative deami-
nation, a process that occurs mainly in the liver and which, in contrast to transami-
nation, produces free ammonia. The main mechanism for net use or production of
amino acids is a reaction catalyzed by glutamate dehydrogenase. This enzyme cata-
lyzes the following reaction:
Glutamate + NAD (or NADP
+
) + H
2
O -ketoglutarate + NADH
(or NADP
+
) + H
+
+ NH
4
+
.
The reaction direction depends on the relative concentrations of glutamate,
a-ketoglutarate, and ammonia and the ratio of oxidized to reduced cofactors. After
ingestion of a meal containing protein, glutamate levels in the liver are elevated, and
the reaction proceeds in the direction of amino acid degradation and ammonia for-
mation. Glutamate dehydrogenase is located in the mitochondrial matrix space, is
polymorphic, and in vitro uses either NAD or NADP.
62
3
Glutamate is the only amino acid that undergoes rapid oxidative deamination,
which results in the liberation of the a21mino group as free ammonia. The sequen-
tial action of transamination that results in production of glutamate and its subse-
quent oxidative deamination provides a route by which the amino groups of most
amino acids can be released as free ammonia. Glutamate dehydrogenase therefore
plays a major role in the transport of nitrogen from muscle to liver, although the
major transporters are glutamine and alanine. Glutamine is also the main mode of
transporting NH
3
from the brain. The removal of the a-amino group from an amino
acid is the first step in amino acid catabolism. Once released, the nitrogen molecule
can be incorporated into other compounds or excreted.
Urea is the major disposal form of amino groups derived from amino acids and
accounts for 80% to 90% of the nitrogen-containing components of urine. Urea
nitrogen is produced during the urea cycle. Liver is the exclusive site of urea synthe-
sis, although the enzymes for producing arginine, the precursor of urea, are present
in the brain, kidney, and skin. Urea nitrogen is derived from glutamate, which is
present in both the mitochondrial matrix and the cytosol. While in the cytosol,
aspartate is formed by transamination of glutamate with cytosolic oxaloacetate in
the mitochondrial matrix; nitrogen can arise from glutamate via glutamate dehy-
drogenase and from glutamine via mitochondrial glutaminase. Urea cycle enzyme
levels depend on nutritional patterns; with a high-protein diet or during starvation
(during which glucogenesis from amino acids is increased), the levels of urea-cycle
enzymes increase several-fold. Additionally, the provision of carbamoyl phosphate
to the urea cycle is regulated by acetylglutamate synthetase, an enzyme whose activ-
ity is markedly increased by amino acids, especially arginine. After removal of nitro-
gen, the carbon skeletons of amino acids can be oxidized, providing a source of
energy. Based on their use as an energy source, amino acids may be grouped into a
nonfat-like (histidine and all nonessential amino acids) category and a fat-like cat-
egory that consists of tyrosine and all the essential amino acids except histidine. All
of the amino acids of the nonfat-like group are glucogenic because they either form
pytuvate or enter the tricarboxylic acid cycle. On the other hand, the fat-like group
of amino acids consists of some amino acids that are glucogenic, glycogenic, or both.
Selected References
1. Devlin MT. Textbook of Biochemistry with Clinical Correlations. Fourth edition.
New York: John Wiley & Sons, 1997.
2. Halberston IDK. Biochemistry. Second edition. New York: John Wiley & Sons,
1988.
3. Champe PC, Harvey RA. Biochemistry. Lippincotts Illustrated Reviews. Second
edition. Philadelphia: J.B. Lippincott Company, 1994.
4. Guyton AC, Hall JE. Textbook of Physiology. Ninth edition. Philadelphia: Harcourt
Brace & Company, 1994.
5. Latifi R. Amino Acids in Critical Care and Cancer. Austin: R.L. Landes Company,
1994.
6. Stryer L. Biochemistry. Fourth Edition. W H Freeman and Company, 1995.
7. Shils, ME, Olson JA, Shike M et al. Modern nutrition in health and disease. Ninth
edition. Baltimore: Williams and Wilkins 1997.
CHAPTER 1
CHAPTER 4
Acute Phase Proteins
Khawaja Azimuddin, Rifat Latifi and Rao R. Ivatury
Tissue injury initiates a complex series of rapid homeostatic events.
1-3
. The host
to prevent ongoing tissue damage and to activate the repair process initiates these
events. Classically, inflammation has been recognized as the hallmark of this re-
sponse. More recently, attention has been focused on defining these events at the
cellular, metabolic and molecular level. The physiologic changes that develop after a
traumatic insult occur irrespective of the type of injurious agent and result in a
predictable increase in the level of cortisol, catecholamines, insulin, glucagon, vaso-
pressin and growth factor.
An early non-specific component of this response to systemic tissue injury takes
place in the liver and is termed the Acute Phase Response (APR). It is characterized
by reprioritization of protein synthesis in the liver. While the production of some
proteins is exponentially increased (positive acute phase proteins), the production of
others (negative acute phase protein) is cut down (negative acute phase proteins).
The magnitude of the response is varied and depends upon the severity of the injury.
Role of the Acute Phase Response
The shift in the hepatic production of proteins from constitutive proteins to
acute phase reactants, after major injury or trauma, is aimed at fulfilling the needs of
the immune, coagulation and wound healing process. The most important part of
this protective response is to serve as a check on the injury-induced inflammatory
reaction and to limit further tissue damage by inhibition of serine proteases and
transport of proteins with antioxidant activity. Elimination of microbes, cleanup of
tissue debris and the initiation of the reparative process are other important aspects
of this rapid response system. These functions are further discussed under the indi-
vidual proteins.
The decrease in negative acute phase reactants may serve to reprioritize the body
to conserve nitrogen loss by shifting protein synthesis to those proteins that are
absolutely necessary for survival. Furthermore, the negative acute phase proteins
(albumin, prealbumin and transferrin) can be used to evaluate and monitor the
nutritional status of critically ill patients.
Physiology
Tissue injury or infection leads to a local inflammatory response. Cytokines re-
leased at the site of inflammation gain access to the circulation and are carried to the
liver where they act upon the hepatocytes. Quantitatively, liver is the major pool for
cytokines that circulate in the blood stream because it has the largest number of cells
64
4
with cytokine receptors and a high density of receptors per cell. The liver responds
to the cytokine signal by a burst of acute phase protein synthesis. These proteins
reach a maximum concentration within few days after the onset of tissue damage
and return to their normal concentrations within a week. Initially it was thought
that cytokines released from locally occurring mononuclear cells (Kupffer cells) in
liver initiate the APR but it is now agreed that circulating cytokines can ini-
tiate this reaction.
4
A variety of cytokines have been implicated in the production of acute phase
proteins from the liver, including interleukin (IL-1, IL-6) and Tumor necrosis
factor-alpha (TNF). IL-6 is the most potent of these stimuli and has been termed
the hepatocytes-stimulating factor. It is thought to be responsible for the induction
of a variety of APP in vivo and in vitro.
4
Although IL-6 may act on the hepatocytes
after being produced locally by the Kuppfer cells, it mainly acts as a long-distance
alarm signal that alerts the hepatocytes to the presence of tissue damage in periph-
eral tissues. It is secreted by monocytes, fibroblasts and several other cells at the site
of inflammation.
The serum levels of IL-6 increase dramatically after injury. The pattern of ap-
pearance of various cytokines has been studied in animals. TNF level peaks at about
90 minutes, while IL-1 peaks around three hours. IL-6 levels continue to rise up to
eight hours after injury.
It has been suggested that IL-6 act by binding with a specific receptor on the
surface of hepatocytes.
4
This interaction leads to a series of events, which result in
the re-orchestration of the pattern of gene expression for secretory proteins in the
hepatocytes.
5
This results in an increase in the expression of mRNA of various APP.
6
It has been shown that IL-6 transcriptional regulation of the acute phase response is
mediated through activation of transacting transcription factors of the C/EBP fam-
ily which bind to IL-6 response elements identified in the promoter regions of acute
phase response genes.
7,8
IL-6 can also downregulate one isoform of the C/EBP fam-
ily, C/EBP alpha, which binds to the albumin gene promoter.
9
This can explain the
mechanism of how cytokines induce a positive and negative acute phase response.
8
Other metabolic changes associated with injury may also be involved in regulat-
ing the acute phase response. Glucocorticoids have a permissive role, enhancing
IL-6 stimulation of acute phase protein synthesis.
7,8
However the presence of
glucorticoids is not an absolute requirement for induction of acute phase protein
synthesis by IL-6 in human hepatocytes.
4
In vitro, insulin is a nonspecific inhibitor
of the cytokine stimulation of acute phase protein secretion.
10
Insulin inhibition of
acute phase protein gene expression appears independent of C/EBP-mediated
transactivation, although other upstream promoter elements may be involved. Un-
like insulin, glucagon, catecholamines, growth hormone and triiodothyronine have
no effect.
Both IL-1 and TNF secreted by monocytes and macrophages at the site of in-
flammation are also responsible for the induction of acute phase response. However
these cytokines tend to produce a limited spectrum of acute phase proteins only.
Unlike IL-6, these cytokines, once produced by Kupffer cells in the liver, act in a
local or paracrine fashion only. In addition to its direct effects on the APR, TNF
may also indirectly increase the levels of IL-1 and IL-6.
4,11
65
Acute Phase Proteins in Critically Ill Patients
4
Sequence of Events During Acute Phase Response
Immediately after tissue injury or sepsis, there is a predictable pattern in the
alteration of the acute phase proteins. First, there is a decrease in the serum concen-
tration of most of the acute phase proteins, both for positive and negative reactants.
Redistribution of the body protein pool from intravascular to extravascular space
occurs immediately following injury as a result of increased microvascular perme-
ability and vascular stasis and accounts for part of the initial decline in acute phase
proteins. Later there is a decrease in the hepatic synthesis of negative acute phase
proteins and the concentration of serum albumin remains depressed for days to
weeks after injury. Albumin reaches a nadir by the fifth post-injury day. Whether
nutritional support in the immediate post-injury phase can alter this response has
not been adequately studied. In one study,
2
prealbumin concentrations increased
within the first week of injury, although lagging behind increased protein-calorie
intake and nitrogen balance, while serum albumin levels slowly declined over the
same time and were still decreased 18 days after injury. The positive acute phase
protein concentrations begin to rise after a lag period of six hours.
12
C-reactive pro-
tein (CRP) is the earliest acute phase reactant to respond and its serum concentra-
tion peaks at 48 hours.
The serum protein concentrations of the positive acute phase reactants in minor
injury returns to normal by the end of the first week. Failure of return indicates
ongoing tissue injury. It has been shown that in patients who survive thermal injury,
the APR quickly returns to normal.
13
Continued and prolonged production of acute
phase reactants in the critically ill patients may be an indicator of ongoing sepsis and
tissue damage and it has been shown that prolonged expression of alpha-1 acid
glycoprotein in burned animals is associated with higher mortality rates.
14
Measure-
ments of the acute phase response can therefore be used to detect the presence of
ongoing inflammation or sepsis following injury.
15
Modulation of the Acute Phase Response
The modulation of protease/antiprotease activity at the focus of injury is deli-
cately balanced to enhance efficient tissue repair without prolonged inflammation.
It has been suggested that the least intense APR and its timely recovery are most
beneficial in terms of survival after burn injury.
13
Pharmacological manipulation of certain aspects of the APR is possible and may
provide new modes of therapy in patients with major trauma. Adjuvant recombi-
nant human growth hormone (rhGH), which improves whole body protein synthe-
sis in severely injured trauma patients, can modulate the APR to the benefit of the
patient. It has been shown that rhGH therapy exerts an inhibitory effect on the
positive acute phase proteins and an additive effect on the constitutive proteins.
13,16,17
It has been shown that serum levels of most of the positive acute phase proteins,
except CRP, increase during the administration of total parenteral nutrition (TPN).
The entire negative APP also increase during administration of TPN.
18
The Acute Phase Proteins
As mentioned above, the acute phase response is bidirectional. The concentra-
tion of (CRP), Alpha-1 Acid Glycoprotien, alpha-l-antitrypsin, serum amyloid A,
fibrinogen, haptoglobulin, ceruloplasmin and complement factor C-3 is increased
during the response. The positive acute phase response seems to be a protective
response to tissue injury and appears to serve as a check on the injury-induced
66
4
inflammatory response. These reactants have diverse functions such as antioxidants,
proteolytic inhibitors, and mediators of coagulation, which may in part prevent
excessive tissue damage and hemorrhage from injury. The negative acute phase reac-
tants include the serum transport proteins: albumin, prealbumin (PA), retinol-binding
protein and transferrin. The serum concentrations of these proteins fall immedi-
ately and in proportion to the severity of the injury. These negative acute phase
proteins are used to monitor the nutritional status of acutely ill patients. Following
the trends in the serum concentration of these proteins may give valuable informa-
tion to the clinician about the improving or deteriorating nutritional status of
these patients.
Albumin
Albumin is a negative acute-phase reactant. Levels of albumin may drop up to
30-50% after severe injury. Inflammation reduces the hepatic mRNA level of albu-
min, which leads to decreased production of this protein. Also albumin is lost in the
interstitial space as a result of increased vascular permeability during periods of acute
stress and third spacing. Since albumin is a major transport protein, the reduced
levels seen during inflammation and infection may play a role in minimizing the
delivery of nutrients to microbes during infection.
Albumin is frequently used to assess and monitor nutritional status in the criti-
cally ill patients. However the use of albumin as a nutritional index has several draw-
backs. The half-life of albumin is approximately 21 days, and changes in the serum
concentration of albumin, in response to increased or decreased protein-calorie in-
take, takes weeks and not days to manifest. Therefore, albumin is a poor marker of
protein-calorie malnutrition. Even in severe malnutrition states like marasmus, the
serum albumin concentration may be normal. Albumin also has a large body pool,
with an extravascular-to-intravascular distribution ratio of 1:5.
3
Redistribution from
one space to the other can potentially mask a concurrent change in albumin synthe-
sis rate. The serum concentration of albumin can also be affected by non-nutritional
entities including liver disease, renal dysfunction and total body water composition.
Additionally, post-injury, critically ill patients may require albumin infusions, which
will alter its serum concentration irrespective of the nutritional status of the patient.
Despite these disadvantages albumin is widely used as a marker of nutrition status
perhaps because of the its widespread availability and low cost. Serum albumin lev-
els obtained at the time of admission re reasonably accurate markers of nutrition
status, and low levels have been shown to correlate with prolonged hospital
stay and mortality.
19,20
Serum hepatic secretory proteins with a shorter half-life are preferable indicators
of short-term changes in protein-calorie intake and correlate better with the nitro-
gen balance.
2,3
Several studies have evaluated the longitudinal response of short
half-life proteins to injury. However, few have evaluated their usefulness in monitor-
ing effects of nutritional support.
2,21
Boosalis et al
2
serially measured protein-calorie
intake, nitrogen balance, and serum albumin and prealbumin levels in trauma pa-
tients from the time of admission until 18 days post-injury. In the short-term,
prealbumin was a better indicator of nutritional intervention than albumin. Within
one week of increasing protein-calorie intake and improved nitrogen balance, the
prealbumin concentration increased while the serum albumin level continued to
decline during the first two weeks after injury.
2
67
4
Prealbumin
Prealbumin (transthyretin) is a serum transport protein for thyroid hormone
and the vitamin A-retinol binding protein complex.
12,22
It has a short half-life of
18-24 hours. Compared with albumin, prealbumin has a smaller body pool with a
greater intravascular-to-extravascular distribution. Numerous studies in non-trauma
patients have demonstrated a consistent correlation between the serum prealbumin
concentration and parallel increases or decreases in protein-calorie intake or nitro-
gen balance.
2,22,23
The response time is usually within the order of several days.
Non-nutritional factors including cirrhosis and hepatitis can lower prealbumin level
whereas increased levels of prealbumin occur with chronic renal failure.
Retinol-Binding Protein
Retinol-binding protein (RBP) has an even shorter half-life of 12 hours, though
clinically this does not improve its sensitivity as a nutritional marker over
prealbumin.
12
RBP transports vitamin A from the liver to peripheral tissues. Serum
RBP concentration is dependent on vitamin A stores which regulate hepatic release
of RBP. Aside from vitamin A deficiency, RBP concentration is decreased in chronic
liver diseases, cystic fibrosis, zinc deficiency and hyperthyroidism. Increased RBP
levels occur with chronic renal failure.
Both prealbumin and retinol-binding protein are accurate markers of nutrition,
and their serum concentrations are highly correlated.
24
However because prealbumin
can be easily monitored and its assay is subject to few interfaces, it is the preferred
biochemical index of follow the nutritional status of the critically ill patient.
Transferrin
Transferrin is also commonly used as a nutritional marker. Its mainly intravascu-
lar distribution and shorter half-life are advantageous. As the primary function of
transferrin is to transport iron, its serum concentration is dependent on the iron
stores of the individual. Another shortcoming of transferrin is its serum half-life of
7-10 days which, like albumin, significantly delays its response to changes in nutri-
tional repletion. An increasing concentration of transferrin is a good indicator of
positive nitrogen balance. However, a decreasing transferrin level is a poor indicator
of nitrogen loss.
3
Transferrin is also an unreliable index of nutritional status when
patients are receiving high doses of certain antibiotics.
25
Levels of serum transferrin
decrease 30-50% after injury. The decrease in circulating transferrin along with a
concomitant increase in intrahepatic transferrin helps to decrease the availability of
iron to peripheral sites of infection.
C-Reactive Protein
During the acute-phase response, there is almost a 1000-fold increase in the
circulating levels of CRP. Since the level of this pentameric protein is very low in the
non-stressed resting period, it has been suggested that the sharp rise in serum levels
indicates a central role for this protein during periods of stress. It has therefore been
suggested that CRP levels can be used for detecting and following septic complica-
tions and intra-abdominal infections.
26,27
CRP participates in complement activa-
tion and opsonization. It attaches to the phosphorylcholine containing membranes
of certain microorganisms including pneumococcus thereby activating the comple-
ment cascade. Digestion of CRP by neutrophil protease releases chemotactic pep-
tides including tuftsin and a component of the Fc segment of immunoglobulin (Ig)
68
4
heavy chains. In addition, the binding of CRP to necrotic host tissues may protect
against autoimmune responses by promoting the rapid removal of self-molecules
from circulation.
28
The serum levels of CRP are closely liked to changes in plasma levels of IL-6 and
it has therefore been suggested that this cytokine is the major mediator of CRP
production in liver during periods of stress.
Ceruloplasmin
Ceruloplasmin is a major copper binding protein. It also removes iron from the
sites of inflammation and may act as an oxygen radical scavenger.
Fibrinogen
Fibrinogen is the major protein involved in the coagulation process. It causes
bacterial clumping thereby preventing the dissemination of bacteria. It also creates a
fibrin scaffold, which helps the macrophages and neutrophil in the phagocytosis of
bacteria. In addition, by-products of fibrin formation (fibrinopeptides) can increase
vascular permeability and induce chemotaxis. The plasma level of fibrinogen in-
creases 2- to 2.5-fold after an inflammatory stimulus and the elevation persists for
several weeks.
Complement
During the acute phase response the levels of two important components of
complement, C3 and properdin are increased. Both are involved in bacterial
opsonization and their increase represents a state of readiness of the human body to
fight infection.
Amyloid
The level of serum amyloid increases drastically during the acute phase response.
Though the increase is almost as high as the 1000 fold increase in CRP level, the
exact role of amyloid in acute phase response is not well understood. A rising level of
serum amyloid A may be used as an indicator of transplant rejection. Amyloid, A
which binds to the extracellular matrix, is also a major component of the deposits
seen in secondary amyloidosis and thus may play a role in chronic inflammation.
Alpha 1 Acid Glycoprotein
The levels of alpha-1 acid glycoprotein (AAG) also increase 2-5 fold during the
acute phase response. It may play a role as inhibitor of platelet activation and as a
modulator of T-lymphocyte function. AAG has a short half-life of 12-18 hours and
is therefore a useful nutritional marker for the acutely ill patient.
Alpha-1 Protease Inhibitor
Proteinases released by dead or dying cells at the site of injury can further propa-
gate tissue destruction. Alpha-1 protease inhibitor is a major inhibitor of neutrophil
proteases, especially elastase. It is synthesized in liver as well as in the periphery by
monocytes and macrophages. The elastase released from neutrophil regulates the
synthesis of alpha-1 protease inhibitor, thereby providing an auto feedback mecha-
nism for preventing excessive tissue destruction at the sites of inflammation.
69
4
Monitoring Nutrition in the Critically Ill Patient
Following tissue injury a hypermetabolic, catabolic state exists. Energy require-
ments, depending on the nature of injury, can range from 1.5 to twice the basal
metabolic rate. Protein needs are also very high and increased amounts of protein
are required to yield a non-protein calorie to nitrogen ratio in the range of 150:1.
Once nutritional therapy is instituted the question is how to best monitor the re-
sponse to treatment. Over-feeding a patient can be as deleterious as under-nutrition.
An ideal monitor should respond quickly to changes in nutritional status, remain
uninfluenced by physiologic changes induced by trauma and pharmacological sup-
port of patients or sepsis and by pharmacological support of patients and should
provide easy and reproducible measurements.
The physical consequences of surgery can limit the use of traditional nutritional
parameters. Postoperatively, anthropometric measurements can be difficult to ascer-
tain and may be unreliable as nutritional indices. Fluid resuscitation or the applica-
tion of large dressings, casts, splints and so forth may alter body weight. Daily weights
are not always feasible in a critically ill patient. Skinfold thickness is often unattain-
able, for example in burn patients, and is not a reliable measurement in an edema-
tous patient. Skinfold thickness also responds to changes in nutritional intervention
in terms of weeks and not days. Arm muscle circumference or area has similar
limitations.
Biochemical indices such as nitrogen balance have their own restrictions, which
can be accentuated by the result of tissue injury.
21
The multiple trauma or burn
patient may have increased extraurinary nitrogen losses from fistulas, wounds, diar-
rhea or the burn surface area which, if unaccounted for, will lead to an overestima-
tion of nitrogen balance. Generally, nitrogen equilibrium is not attained until 2-12
days after a change in protein intake. Often nutritional support in critically ill pa-
tients needs to be intermittently interrupted to perform diagnostic tests or in prepa-
ration for surgery, making it difficult to sustain a consistent day-to-day protein-calorie
intake necessary to obtain nitrogen equilibrium for correct interpretation of nitro-
gen balance studies.
Other biochemical parameters, especially visceral serum proteins, have been uti-
lized as monitors of nutritional repletion in critically ill patients.
1,2
Ideally, to be a
clinically useful marker of nutritional repletion, a change in the concentration of a
serum protein should reflect only its synthetic rate, which in turn is dependent on
the provision of sufficient calories and proteins during the hypermetabolic state.
The serum protein should also have a short serum half-life, a small body pool, rapid
rate of synthesis and a constant catabolic rate.
3
A number of visceral proteins are
used to measure the nutritional status of the surgical patient. None of these meet all
of the above requirements and have one or more shortcomings. In practice there-
fore, a number of proteins are measured simultaneously in conjunction with weekly
anthropometric measurements. By serially measuring the serum concentrations of
several proteins with different half-lives together, we can better monitor the short
and long-term response to nutritional support. For example, in a patient with dete-
riorating weight, skinfold thickness and mid-arm muscle circumference, the benefit
of increasing the daily caloric intake should in several days be reflected by an in-
crease in AAG and pre-albumin, levels, later followed by an increase in transferrin.
Hopefully, albumin levels will rise and finally even later anthropometric measure-
ments will improve. Conversely, with nutritional depletion, AAG and prealbumin
70
4
levels will decrease first without a change in transferrin. Finally, albumin levels will
rise, and eventually anthropometric measurements will improve. Conversely, with
nutritional depletion, AAG and pre-albumin levels will decrease at first without a
change in transferrin, albumin or anthropometric measurements. Measuring several
proteins with similar half-lives eliminates some of the problems in misinterpreting
changes in their serum levels due to non-nutritional factors since each protein is
affected differently. These proteins are measured by nephelometry so results are avail-
able in less than 24 hours, and only 100 microliters of serum is required for the
entire panel.
Following tissue injury a hypermetabolic, catabolic response occurs which, left
unabated, will lead to depletion of somatic and visceral protein stores, delayed wound
healing and impaired immune response. Despite increased protein synthesis
post-injury, the magnitude of protein breakdown is so great that a state of negative
nitrogen balance exists. Adequate calorie (based on indirect calorimetric studies)
and protein supplementation during this time period will improve nitrogen reten-
tion but not sufficiently to achieve positive nitrogen balance.
29
Nutritional support
improves nitrogen retention by enhancing protein synthesis. However, it may not
effect whole body protein breakdown.
30
Post-injury there also appears to be less
efficient recycling of nitrogen.
11
Furthermore the mobilized protein may be
reprioritized from nitrogen recycling to provide carbon substrates for energy pro-
duction. Possibly, mediators of the inflammatory response dually regulate the en-
hanced post-injury protein catabolism and the negative acute phase response. In the
future nutritional support may involve selectively antagonizing the metabolic ef-
fects of cytokines and other mediators of the acute-phase response to preserve body
protein stores.
Selected References
1. Kudlackova M, Andel M, Hajkova H et al. Acute phase proteins and prognostic
inflammatory and nutritional index (PINI) in moderately burned children aged
up to three years. Burns 1990; 16:53-56.
2. Boosalis MG, Ott L, Levine AS et al. Relationship of visceral proteins to nutri-
tional status in chronic and acute stress. Crit Care Med 1989; 17:741-774.
3. Church JM, Hill GL. Assessing the efficacy of intravenous nutrition in general
surgical patients: Dynamic nutritional assessment with plasma proteins. JPEN 1987;
11:135-139.
4. Castell JV, Gomez-Lechon MJ, David M et al. Acute-phase response of human
hepatocytes: Regulation of acute-phase protein synthesis by interleukin-6.
Hepatology 1990; 12:1179-1186.
5. Fey GH, Gauldie J. The acute phase response to the liver in inflammation. Prog
Liver Dis 1990; 9:89-116.
6. Wu JZ, Ogle CK, Fischer JE et al. The m-RNA expression and in vitro production
of cytokines and other proteins by hepatocytes and Kuppfer cells following ther-
mal injury. Shock 1995; 3:268-273.
7. Baumann H, Morella KK, Campos SP et al. Role of CAAT-enhancer binding
protein isoform in the cyrokinc regulation of acute phase protein genes. J Biol
Chem 1992; 627:19744-19751.
8. Ramji DP, Vitelli A, Tranche F et al. The two C/EBP isoforms, IL-6DBP/NFIL6
and C/EBP8/NF-IL6p are mediated by IL-6 to promote acute phase gene tran-
scription via different mechanism. Nuc Acid Res 1993; 21:289-294.
9. Issihiki H, Akira S, Sugita T et al. Receprocal expression of NF-IL6 and C/EBP in
hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expres-
sion. New Biol 1991; 3(1):63-70.
71
4
10. Campos SP, Baumann H. Insulin is a prominent modulator of the cytokine stimu-
lated expression of acute phase plasma protein genes. Mol Cell Biol 1992;
12:1789-1792.
11. Bankey PE, Mazuski JE, Ortiz M et al. Hepatic acute phase protein synthesis is
indirectly regulated by tumor necrosis factor. J Trauma 1990; 30:1181-1187.
12. Fleck A, Colley CM, Myers MA. Liver export proteins and trauma. Brit Med Bull
1985; 41:265-273.
13. Jarrar D, Wolf SE, Jeschke MG et al. Growth hormone attenuates the acute-phase
response to thermal injury. Arch Surg 1997; 132:1171-1176.
14. Sevaljevic L, Glibetic M, Poznanovic M et al. Thermal injury-induced expression
of acute phase proteins in rat liver. Burns. 1988; 14:250-256.
15. Kudsk KA, Minard G, Wojtysiak SL et al. Visceral protein response to enteral
versus partenteral nutrition and sepsis in patients with trauma. Surgery 1994;
116:516-523
16. Jeschke MG, Wolf SE, DebRoy MA et al. The combination of growth hormone
with hepatocyte growth factor alters the acute phase response. Shock 1999;
12:181-187.
17. Jeschke MG, Wolf SE, DebRoy MA et al. Recombinant human growth factor
(rhGH) downregulates hepatocyte growth factor (HGF) in burns. J Sur Res 1998;
76:11-16.
18. Peterson SR, Jeevanandam M, Shahbazian LM et al. Reprioritization of liver pro-
tein synthesis resulting from recombinant human growth supplementation in
parenterally fed trauma patients: The effect of growth hormone on the acute-phase
response. J Trauma 1997; 42:987-996.
19. McEllistrum MC, Collins JC, Powers JS. Admission serum albumin level as a
predictor of outcome among geriatric patients. South Med J 1993; 86:1360-1.
20. DErasmo E, Pisani D, Ragno A et al. Serum albumin level at admission: mortality
and clinical outcome in geriatric patients. Am J Med Sci 1997; 314:17-20.
21. Mattox TW, Brown RO, Boucher BA et al. Use of fibronectin and somatomedinC
as markers of enteral nutrition support in traumatized patients using a modified
amino acid formula. JPEN 1988; 12:592-596.
22. Winkler MF, Gerrior SA, Pomp A et al. Use of retinol-binding protein and
prealbumin as indicators of the response to nutrition therapy. J Amer Diet Assoc
1989; 89:684-687.
23. Tuten MB, Wogt S, Dasse F et al. Utilization of prealbumin as a nutritional pa-
rameter. JPEN 1985; 9:709-711.
24. Sachs E, Bernstein LH. Protein markers of nutrition status as related to sex and
age. Clin Chem 1986; 32:339-41.
25. Spickerman AM. Proteins used in nutritional assessment. Clin Lab Med. 1993;
13:353-396.
26. Mustard RA, Bohnen JMA, Haseeb S et al. C-reactive protein levels predict post-
operative septic complications. Arch Surg 1987; 122:69-73.
27. McCartney AC, Grange GV, Pringle SD et al.. Serum C-reactive protein in infec-
tive endocarditis. J Clin Path 1988; 41:44-48.
28. Volanakis JE. Complement activation of C-reactive protein complexes. Ann NY
Acad Sci 1982; 389:235-242.
29. Jeevanadam M, Young DH, Schiller WR. Endogenous protein-synthesis efficiency
in trauma victims. Metabolism 1989; 38:967-973.
30. Shaw JHF, Wolfe RR. An integrated analysis of glucose, far, and protein metabo-
lism in severely traumatized patients. Ann Surg 1989; 209:63-72.
CHAPTER 5
Arginine Metabolism in Critical Care
and Sepsis
Rima I. Kandalaft, V. Bruce Grossie, Jr.
Arginine and ornithine are naturally occurring amino acids that exist in close
metabolic relationship in the urea cycle. These amino acids differ significantly, how-
ever, in their metabolism and their nutritional significance. Arginine is considered
to be an essential amino acid for growth, but the requirements of the adult man, rat,
and other species for arginine appear to be met by endogenous synthesis. Although
of considerable biological significance, ornithine is not considered a dietary essen-
tial amino acid and all of its cellular requirements are apparently supplied via the
urea cycle.
The concept of essential amino acids has changed over the past few years. The
classic definition used by Rogers et al
1
stated that an amino acid was essential if it
was required for growth. Recently
2,3
it has been suggested that certain amino acids
that are classified as nonessential under normal conditions may be essential under
certain disease conditions such as cancer, trauma, or sepsis. These are called condi-
tionally essential amino acids. The results of numerous studies in man and experi-
mental animals have shown that supplementation of arginine to otherwise balanced
diets
4,5
is beneficial during stress suggesting that arginine should be consid-
ered as a conditionally essential amino acid. This has not been a universal
conclusion, however.
6-8
Pathways of Arginine and Ornithine Metabolism
Urea Cycle
Arginine, a major component of the urea cycle (Fig. 5.1), is converted to orni-
thine and urea by arginase. Results from our laboratory
8
as well as others,
9,10
demon-
strate that ornithine can be substituted for arginine in its role of maintaining
appropriate ammonia levels but appears unable to replace arginine for cell growth.
As shown in Figure 5.1, ornithine is a precursor for several biologically active com-
pounds such as polyamines, proline and glutamate, that are significant cofactors for
cell growth.
11
Ornithine and it metabolites, therefore, may be the biological mecha-
nism that is responsible for the changes that occur when arginine is added to parenteral
and enteral regimens. In studies that evaluated amino acid concentrations, the con-
centration of ornithine in plasma
13,14
and liver
15,16
was altered in the same manner as
arginine, suggesting that a major part of the response seen when arginine is supple-
mented may be associated with an increase in ornithine concentrations. A mecha-
nism for this hypothesis, however, has not been critically evaluated. Our results
8,12
73
Arginine Metabolism in Critical Care and Sepsis
5
suggest that the tissue content of arginine is rate limiting to the TPN-associate en-
hanced growth of a Ward colon tumor. Tumor growth was enhanced during TPN
with arginine as part of the regimen but not when ornithine was substituted. The
polyamine content of the tumors was not changed when ornithine was substituted
while the arginine content was significantly decreased.
12
This may reflect a differing
requirement for arginine by normal and tumor cells.
Nitric Oxide Synthesis
A pathway of arginine metabolism that has become of major importance in the
past decade is that of nitric oxide synthesis. As is shown in Figure 5.2, arginine is
converted directly to citrulline with the release of nitric oxide. This conversion is
controlled by the enzyme nitric oxide synthase (NOS). The activity of NOS is tightly
regulated and exists as three isoforms which are structurally similar
17
but have differ-
ent cofactor requirements. Normal tissue requirements utilize a small amount of
nitric oxide at any one time. Epithelial and neuronal isoforms of NOS (eNOS and
nNOS, respectively) control these levels of nitric oxide and are normally present at
low activities in most tissues.
18
Another isoform is inducible (iNOS) by a number of
exogenous agents, such as those associated with sepsis, and can be induced to syn-
thesize a large amount of nitric oxide in a brief period of time.
One measure of nitric oxide synthesis by the host, used extensively to measure
acute changes in activity, is the plasma or urine concentration of nitrate/nitrites
(NO
x
). Nitric oxide is a stable gas that diffuses readily through cell membranes.
NO
x
are stable end products of nitric oxide that can be measured in biological fluids,
tissues, and cell culture media. Although not a stoichiometric reaction, an increase
in plasma NO
x
is correlated with an enhanced nitric oxide synthesis.
7
Fig. 5.1. Metabolism of arginine through the urea cycleornithine metabolites. ODC,
ornithine decarboxylase; OAT, ornithine amino transferase; OCT, ornithine carbamyl
transferase.
74
5
Arginine Availability for Nitric Oxide Synthesis
The cell has many mechanisms to insure that the arginine supply for NOS and
other essential metabolic pathways is maximal. Competition for arginine is mainly
through the urea cycle (arginine
arginase
>ornithine) (Fig. 5.1), which would in-turn
support the many diverse pathways of ornithine. The conversion of citrulline
ASS
>
ASL
> arginine (Fig. 5.1) has been reported to be the major urea cycle enzyme path-
way in kidneys, making host arginine synthesis possible. As will be reviewed later in
this chapter, this pathway may be induced during times of increased arginine re-
quirements. Thus, a change in the activity of arginase, ASS, or ASL will affect the
cellular supply of arginine.
The requirement for an exogenous source of arginine to support the synthesis of
nitric oxide has not been adequately defined but may be of importance to the deter-
mination of what may be expected from administration of exogenous arginine or
ornithine. Schott et al
19
demonstrated that the infusion of LPS at 10 mg/kg/hr for
50 min resulted in no change in the arginine content of plasma or aortic rings.
These authors concluded that circulating L-arginine was sufficient to maximally
activate the synthesis of nitric oxide in the aorta of endotoxemic rats. Pastor et al
20
demonstrated that for livers isolated from rats treated with LPS and perfused for 20
min with Krebs-Henseleit-bicarbonate buffer, the intracellular arginine was not suf-
ficient to support maximal nitric oxide synthesis. Although livers expressing iNOS
released high levels of NOx, this release could be enhanced by adding arginine to
the perfusate. Adding ornithine to the perfusate did not affect the NOx output. A
study to evaluate the requirements of specific organs under differing levels of stress
is needed to further define the arginine requirement of the host.
Absorption and Cellular Uptake of Arginine
The circulating levels of arginine can be significantly affected by trauma, sepsis
or injury. The absorption of arginine by the rat intestine using everted sacs in vitro
Fig. 5.2. Pathway of nitric oxide synthesis and its relationship with the urea cycle.
75
5
was decreased by experimental sepsis induced by cecal legation and puncture or
after administration of endotoxin,
21
presenting some potential problems with the
oral administration of arginine. A role for the gut in absorption/synthesis was also
suggested from observations of a patient with short bowel syndrome and renal fail-
ure .
22
The arginine, ornithine, and citrulline concentrations of the plasma from this
patient was significantly reduced which resulted in hyperammonemia. An I.V. supple-
ment of arginine normalized the arginine, ornithine, and citrulline levels and de-
creased plasma ammonia concentrations. It is of importance to this discussion that
during the arginine infusion (10.8 mg/kg/day) the patient developed hypotension
and fell into shock during hemodialysis. After this episode, the arginine supplemen-
tation was decreased to every other day and the patient survived for an additional 5
months. Although no data was presented, the possibility of an increased nitric oxide
synthesis during arginine infusion was suggested. Data to support this possibility
will be presented later in this chapter.
It has also been demonstrated that the plasma levels of arginine, ornithine and
citrulline were decreased in patients within 2-18 hours after gun shot injury.
14
The
results suggested that the changes in plasma concentrations of arginine, ornithine,
and citrulline were of systemic origin and not related to the type of injured tissues.
The results of other studies,
23-25
however, show that the uptake of arginine by
individual cells in vitro is enhanced by endotoxin. Our results (Fig. 5.3) show that
the plasma concentration of arginine in the rat is decreased as early as two hours
after a nonlethal dose of endotoxin (5 mg/kg, ip). The plasma concentration of
citrulline, but not ornithine, was increased at 5 hours after endotoxin. In addition,
the plasma concentration of NO
x
(Fig. 5.4) and liver iNOS protein content (Fig.
5.5) was increased at 5 hours but not at 2 hours. Subsequent results
26
demonstrate
that the plasma NO
x
begins to increase significantly between 120 and 180 minutes
after this dose of endotoxin. The early decline in plasma arginine concentration,
accompanied by a constant concentration of ornithine and citrulline (2 hours), sug-
gest an increase in arginine uptake by tissues. This would be significant since the
iNOS protein content of the liver (Fig. 5.5), intestine,
26
and spleen (data not shown)
does not differ from the control at 120 min.
Arginase
An increase in NOS activity would significantly increase the cellular require-
ment for arginine. Since ornithine is a direct metabolite of arginine (Fig. 5.1), argi-
nase activity would also be expected to have a significant effect. With arginine being
the only substrate for the synthesis of nitric oxide, a depletion of the available argi-
nine might serve to reduce the nitric oxide related effects. Hey et al
27
presented
results demonstrating that LPS shifted the available arginine away from the synthe-
sis of ornithine to nitric oxide synthesis for rat macrophages in vitro. Sonoki et al
28
reported that the mRNA for iNOS and arginase I in rat peritoneal macrophages
were induced in a dose-dependent manner. Bacterial LPS treatment of rats in vivo
resulted in a rapid increase of iNOS mRNA for lung and spleen reaching a peak at
2-6 hrs after LPS while the arginase I mRNA was increased rapidly but did not reach
a peak until 12 hours after LPS. Shearer et al
29
, however, demonstrated that when
nitric oxide synthesis was increased with Interferon (IFN- and LPS, the arginase
activity in mouse peritoneal exudate cells was decreased. These authors also demon-
strated that the products of nitric oxide synthasenitric oxide and citrullinein-
hibited arginase activity. Benninghoff et al
30
demonstrated that in mouse peritoneal
macrophages, combining IFN- with TNF or LPS treatment in vitro resulted in a
76
5
shift from increasing ornithine synthesis to increased citrulline synthesis. In these
studies, however, no further metabolism of ornithine to citrulline was evaluated.
Gotoh et al
31
reported that the mRNA for arginase II and NOS was coinduced by
LPS for RAW 264.7 cells. Since arginase I is located predominantly in the liver and
arginase II in extrahepatic tissues, any alteration in the activity of either of the isoforms
of arginase could have a significant impact on the arginine available for nitric oxide
synthesis in all tissues. Boucher et al,
32
Buga et al,
33
and Daghigh et al
34
reported that
an intermediate in the arginine to nitric oxide pathway, N

-hydroxy-L-arginine,
will inhibit arginase I activity of rat liver and murine macrophages. Nitric oxide has
been reported by Hrabak et al
35
to inhibit arginase. Although the enzyme arginase
may be have a role in down-regulating nitric oxide synthesis, direct impact of its
metabolic product, ornithine, has not been demonstrated. Recent results (Grossie
unpublished observations) show that adding ornithine to a parenteral regimen
containing arginine will not significantly alter the plasma NO
x
concentration 5
hours after an endotoxin challenge, suggesting that ornithine does not have an effect
on nitric oxide synthesis.
A treatment strategy may be to reduce the available arginine for nitric oxide
synthase. Bune et al
36
reported that reduction of arginine by arginase treatment
significantly decreased the synthesis of nitric oxide by the liver, kidney, lung, and
spleen and reduced the blood NO
x
concentration. Results from my laboratory show
that the endotoxin-induced increase in NO
x
from rats given a parenteral diet with
ornithine substituted for arginine was significantly decreased (Fig. 5.6) as compared
with that of isonitrogenous arginine. The plasma arginine concentration was also
significantly decreased (Fig. 5.7).
Fig. 5.3. Plasma arginine, ornithine, and citrulline concentration of endotoxemic rats.
Fischer 344 male rats (3-4/group) were given endotoxin (5 mg/kg, ip), anesthesized with
Ketamine/xylazine at 2 or 5 hours and blood and tissues removed. The controls received
0.85% NaCl ip. The data is presented as the mean sd. Means were compared using a
one-way ANOVA analysis using StatView
version 4.0 (Abacus Concepts, Inc., Berkley,

CA) with P<0.05 being considered significant. Significance is shown on the graph vs the
results of rats that receive saline*,P=0.0031; **, P=0.0004.
77
5
Arginine Synthesis from Citrulline
The enzymes, ASS and ASL, which catalyze the reactions responsible for this
conversion (Fig. 5.2) are normally at low activities and are present in different tis-
sues depending on their metabolic function. When endotoxin is administered, the
activities of ASS and ASL were reported to be significantly increased,
37-40
thus
Fig. 5.4. Plasma nitrate/nitrite (NO
x
) concentration of rats 2 and 5 hours after endotoxin
treatment. The treatment and data analysis is described in Figure 5.3.
Fig. 5.5. Inducible nitric oxide synthase (iNOS) content of the liver of endotoxemic rats.
The treatment and data analysis is described in Figure 5.3.
78
5
increasing the availability of substrate for the continued synthesis of nitric oxide.
Ellis and Conanan
41
reported that L-citrulline was both more potent and efficacious
than L-arginine in reversing an L-NNA nitric oxide synthesis inhibition in the guinea
pig trachea and human bronchus. Grossie
42
showed that a continuous IV infusion
of TPN with citrulline substituted for arginine on an isonitrogenous basis resulted
in a greater elevation in the plasma arginine than was observed after a TPN with
arginine. Xie and Gross
43
reported on studies using vascular smooth muscle cells
(VSMC) that were transfected with human ASS cDNA. The LPS/IFN- induced
nitric oxide production of these cells was 3-4 fold greater than untransfected VSMC.
For untransfected cells, a citrulline concentration 3-4 fold higher than arginine was
needed for comparative nitric oxide synthesis while in transfected cells citrulline
and arginine were equally efficient. The iNOS immunoreactivity from both cell
lines was equivalent, supporting an increased substrate as the mechanism for the
increased nitric oxide concentration.
Potential Effect of Glutamine
Glutamine is a nonessential amino acid that can be synthesized by virtually all
tissues in the body. It becomes conditionally essential during stress and critical ill-
ness, when endogenous supply fails to meet increased demands. Houdijk et al
44
showed that glutamine-enriched nasoduodenal feedings (30.5 g of glutamine per
100 g of protein) significantly reduced the number of infections in critically injured
patients. Plasma glutamine, as well as plasma arginine and citrulline, were increased,
suggesting that renal production of arginine was stimulated by glutamine supple-
mentation. Arginine increases the rate of wound healing and stimulates lymphocyte
immune responses. In rats, glutamine has been demonstrated to stimulate renal
production of arginine by raising plasma concentrations of the precursor citrulline.
45
Fig. 5.6. Effect of substituting ornithine (TPN-Orn) for arginine (TPN-Arg) on the plasma
nitrate/nitrite (NO
x
) concentration. The TPN solutions
7
were isocaloric and isonitrogenous
and were administered for 48 hours. At this time, endotoxin (5 mg/kg, ip) was adminis-
tered ip and the blood and tissues collect at 2 and 5 hours. Data analysis is described in
Figure 5.3.
79
5
The pathway from arginine to glutamine involves several steps including hy-
drolysis of arginine to ornithine by arginase. Yoshida et al
46
investigated the flux of
arginine to glutamine in tumor-bearing rats (TB) receiving a six-hour infusion of
U-
14
C-arginine (2.0 Ci/h). Glutamine production derived from the carbon skel-
eton of arginine via ornithine was significantly greater in TB rats than in control
rats. We have reported that the plasma glutamine concentration was increased when
ornithine was added to a complete regimen (unpublished data), and when ornithine
was substituted for arginine in TPN.
42
Fig. 5.7. Plasma arginine (Panel A), ornithine (Panel B), and citrulline (Panel C) concen-
trations of rats receiving a parenteral nutrition regimen with ornithine (TPN-Orn) substi-
tuted for arginine (TPN-Arg) for 48 hours followed by endotoxin (5 mg/kg, ip) or 0.85%
NaCl. Rats were anesthesized at 2 or 5 hours and blood and tissues collected. Data
analysis is described in Figure 5.3. Significance is shown on the graph is a comparison
with the results of TPN-Arg vs TPN-Orn*, P<0.0005; NS, not significant. The
LPS-associated reduction in plasma arginine concentration for TPN-Arg rats was signifi-
cant at 2 and 5 hours after LPS compared with the concentration at the previous time point.
80
5
Arginine is a precursor of nitric oxide (NO), which is known to mediate the
vascular effects of endotoxin and reduce bacterial growth.
47
Citrulline produced by
NO synthase can be recycled into arginine in endothelial cells (EC). Glutamine
inhibits the conversion of citrulline into arginine, and decreases NO synthesis from
arginine. Meininger and Wu
48
showed that NO synthesis in cultured bovine EC was
reduced by 22% to 44% by glutamine (0.5-2.0 mM) with or without the
receptor-mediated vasodilators bradykinin and substance P.
A decreased biosynthesis of nitric oxide was observed in rabbits receiving glutamine
at 205 nmols/hr (IV) for 24 hours prior to ischemic/reperfusion (I/R). I/R resulted
in an increase in serum nitric oxide concentration that was diminished when
glutamine was administered.
49
On the other hand, Murphy and Newsholme
50
dem-
onstrated the existence of a pathway for arginine synthesis from glutamine in mac-
rophages and monocytes. The addition of 10 mM of glutamine to Bacillus
Calmette-Guerin (BCG)-activated macrophages caused an approximate 6-fold el-
evation in nitrite production compared with incubation in standard tissue culture.
The authors suggest that glutamine can be converted to arginine, allowing NO
production in the absence of extracellular arginine. In contrast, glutamine has been
demonstrated to inhibit the conversion of citrulline to arginine
51-53
in cultured en-
dothelial cells. The protective effects of glutamine may be in part due to the en-
hanced conversion to arginine through citrulline, and consequently to increased
NO synthesis. This is of importance to determining the precise mechanism for im-
provements with glutamine-supplemented nutritional support regimens.
54,55
Fate of Exogenous Arginine
Several investigators have demonstrated that the amino acid pool in plasma and
tissues of rats
8,12
and man
16
can be significantly altered by relatively short term ad-
ministration of parenteral amino acid solutions. Beamier et al
15
found that the nitric
oxide synthesisas measured by plasma NO
3
, total daily output of NO
3
, and con-
version of [
15
N]-arginine to labeled NO
3
was not increased in normal man during
administration of an isonitrogenous diet supplemented to administer 561.3 mg argi-
nine/kg/d as compared with a diet formulated to administer 56.1 mg/kg/d. The
plasma free arginine and ornithine, but not citrulline concentration, was signifi-
cantly increased. This might be expected, however, since only the cNOS isoform
would be expected to be active in these normal volunteers. Nakabi et al
56
and
Hishikawa et al
57
demonstrated that an arginine infusion (500 mg/kg x 30 min)
57
resulted in a significant hypotension accompanied by a significant increase in the
plasma concentration of L-arginine, L-citrulline, and cGMP and the urine concen-
tration of nitrate. Castillo et al
58
measured urinary
15
N-NO
3
from [guanidino-
15
N-5,5-
2
H
3
] arginine and estimated that approximately 16% of dietary arginine is
converted to nitrate & nitrites during first pass in the splanchnic region of normal
adult males. Castillo et al
59
demonstrated that the arginine flux when tracer arginine
was given intragastrically was significantly higher than when the same tracer was
given intravenously. This suggests that there is a first pass disappearance of tracer
(and dietary) arginine in the splanchnic area after uptake from the gastrointestinal
tract. Kanno et al
60
reported that an iv infusion of L-arginine to adult healthy male
volunteers at 30 mg/30 min resulted in no change in plasma NOx or cGMP con-
centration. The urine output of nitrate and nitrites (mol/mg creatinine) and cGMP
(mmol/mg creatinine), however, was significantly increased. Adding arginine to
parenteral and enteral nutritional support regimens, may therefore, increase the basal
81
5
nitric oxide production by the host. Arginine is a major component of most com-
mercially available parenteral amino acid solutions and is present at various concen-
trations in all enteral diets given orally or by controlled administration. In addition,
arginine has been added to existing parenteral and enteral formulations alone or in
combination with other substrates.
Nitric Oxide in Critical Care
Endotoxin-Induced Sepsis
The activity of iNOS, and therefore the concentration of nitric oxide, may be
increased to damaging concentrations when sepsis is induced by factors such as
endotoxin.
18,61-64
An increase in the peripheral blood levels of NO
x
7
was correlated
with an increase in LPS-induced lethality to tumor bearing rats. Further results
from the authors laboratory demonstrates that an enhanced liver and spleen iNOS
86,87
protein content is associated with the increased toxicity and elevated plasma NO
x
concentration after an endotoxin challenge to tumor-bearing rats. This was inter-
preted as more evidence of the relationship of increased nitric oxide synthesis and
the toxicity of endotoxin.
The phrases double-edged sword and Jekell and Hyde, however, adequately
describe the many, diverse, biological roles of nitric oxide. Results from experiments
using non-specific nitric oxide inhibitors suggest that a complete inhibition of nitric
oxide synthesis increases the toxicity of endotoxin.
65,66
Tracy et al
67
presented results
using a specific inhibitor for iNOS, (dexamethasone) suggesting that the inhibition
of the endothelial and neuronal isoforms increased LPS toxicity to the rat and mouse.
When only iNOS was inhibited, the toxicity of LPS was not altered. Nava et al
68
suggested that the degree of NOS inhibition by N
G
-monomethyl-L-arginine
(L-NMMA) was dependent on the dose of the drug administered. The lethality to
rats given 4 mg/kg of endotoxin (7/19) was decreased when 10 mg/kg L-NMMA
was administered with endotoxin (0/5). The lethality was not affected, however,
when 300 mg/kg of L-NMMA was given (7/10). The differential in survival with
the higher dose of L-NMMA was accompanied by a drop in blood pressure and an
increase in blood levels of alanine aminotransferase (ALT) for these rats. The inhibi-
tion of iNOS by dexamethasone completely eliminated deaths from endotoxin,
normalized blood pressure, and blood ALT, suggesting that the critical factor deter-
mining the difference between a beneficial and an adverse effect of L-NMMA is the
degree of inhibition of nitric oxide synthesis. Park et al
69
reported that L-NNA
increased the mortality rates and damage to the lung, liver, and kidney of mice
treated with LPS. The LPS-induced increase in NOx of the major tissues examined,
however, was reduced to normal when L-NNA was administered with LPS.
Ischemia/Reperfusion Injury
Arginine, as a nitric oxide donor, has also been implicated in tissue damage after
ischemia/reperfusion (I/R). Reperfusion injury after ischemia of the intestine often
results in significant damage at sites such as liver and lung that are remote from the
original insult.
70,71
The role of nitric oxide in the process is becoming more evident.
Seekamp et al
72
reported that hind limb ischemia in rats resulted in limb and lung
damage that was ameliorated by systemic treatment (10 min prior to reperfusion)
with L-NNA and L-NAME. Belenky et al
73
showed that nitric oxide synthase in-
hibitors attenuate LPS-stimulated chemotaxis in vitro. Nitric oxide inhibitors were
shown by Seth et al
74
to inhibit free radical generation by rat PMN.
82
5
Many studies, however, suggest a protective role for arginine and/or nitric oxide.
Villarreal et al
75
reported that the nitric oxide donors (Spermine-NO and
3-morpholinosydonimine-N-ethyl-carbamide [SIN1]) attenuated the hyperthermic
ischemia-induced increase in mucosal permeability and the depressed net water ab-
sorption of the distal ileum of cats. The protective effects of nitric oxide on the
mucosal epithelium appeared to be unrelated to actions on the microvasculature.
Kanwar et al
76
demonstrated that L-arginine (2.5 mole/min x 4 hours) during
reperfusion of small intestine of cats attenuated the epithelial barrier dysfunction
for the first 120 min but not at 180 or 240 min. Epithelial permeability, quantitated
as blood-to-lumen clearance of the
51
Cr-EDTA from the intestine was increased
during reperfusion. Administration of a nitric oxide donor (CAS 754) at 60 min
after the start of reperfusion, however, attenuated the dysfunction throughout the
time and attenuated the intestinal dysfunction at 240 min. The constitutive NOS of
the small intestine was not affected by the 60 min of ischemia, but was significantly
lower at 180 and 240 min after reperfusion. The iNOS activity, however, was de-
tectable in the control, undetectable immediately after ischemia, but was increasing
by 240 min after ischemia. Niu et al
77
reported that prolonged inhibition of nitric
oxide synthesis by L-NAME of human umbilical vein epithelial cells (HUVEC)
caused an oxidant- and platelet activating factor (PAF)-associated rise in adhesion of
neutrophils in a dose dependent manner. This was prevented when L-arginine or
nitric oxide donors were added to the culture media but not when an analogue of
cGMP was added. An arginine infusion in man (17 mg/kg/min x 30 min) was
found to inhibit basal and FMLP-stimulated superoxide anion release from periph-
eral blood polymorphonuclear cells (PMN).
78
This inhibition was also seen when
PMN were pretreated with a 1mM arginine solution in vitro. Andrews et al
79
re-
ported that the mechanism for protection of the rat stomach by arginine from is-
chemia/reperfusion damage was a reduction in PMN infiltration to the mucosa.
Whittle et al
80
demonstrated that when coadministered with capsaicin (to deplete
sensory neuropeptides) or indomethacin (to inhibit prostaglandin synthesis),
L-NMMA resulted in a dose dependent-induction of acute gastric mucosal damage
in rats. The injury was inhibited by L-arginine. Shoskes et al
81
compared the effect
of ischemia followed by reperfusion in the rat kidney. They found that the total
NOS activity of the ischemic kidney increased during the first six hours of reperfusion
then decreased below the control from day 3 to day 14. The L-NAME sensitive
NOS activity was similar between groups and only the total NOS was reported.
The eNOS protein was consistently higher in the ischemic kidney at all times be-
tween 2 hours and 14 days of reperfusion. The ischemia-reperfusion related increase
in serum creatinine at 7 days was decreased when arginine was given at 1.25 g/L or
5 g/L in the drinking water 24 hours before ischemia and continued during the 14
days of reperfusion. Schleiffer and Raul
82
demonstrated that gavage pretreatment of
rats with L-arginine (0.8 g/kg) or molsidomine (a nitric oxide donor) at 19, 16, and
1.5 hours before a 90 min gut ischemia (superior mesenteric artery occlusion) in-
creased survival of rats, increased blood flow, and improved the barrier function of
the gut to
14
C-PEG. L-arginine, but not molsidomine, increased the cGMP content
of the intestinal mucosa.
Raul et al
83
demonstrated that pretreatment of rats with arginine or ornithine,
by gavage, 17 and 2 hours before ischemia accelerated the morphologic repair at the
intestine 4 hours after reperfusion. Arginine was significantly more effective than
orninthine. Intestinal sucrase and aminopeptidase were also improved. The polyamine
83
5
content of the mucosa was increased by arginine and ornithine to the same degree,
suggesting that this is not a likely mechanism. Formation of cGMP was increased by
arginine suggesting that nitric oxide was involved. The epithelial cell proliferation
(
3
H-tritium uptake) in this study was enhanced both in the arginine and ornithine
pretreatment groups. Kurose et al
84
demonstrated that the nitric oxide donors so-
dium nitroprusside, spermine NO, and SIN-1, 5 min before reperfusion after 20
min ischemia by SMA occlusion, significantly reduced the leukocyte adherence/
emigration and albumin leaks from the mesenteric venules. Plasma NOx concentra-
tion was significantly reduced 30 min after reperfusion suggesting a decrease in
endogenous nitric oxide synthesis. DiLorenzo et al
85
reported the efficacy of L-arginine
in a model of necrotizing entercolitis. They demonstrated that L-arginine, given by
peripheral IV infusion (600 mg/kg/hr x 3 hrs), attenuated the acidified casein-induced
damage to isolated intestinal loops in the terminal ileum and distal colon of the
neonatal pig. It is of importance that the arginine infusion was started after the
injection of the acidified casein.
The role of nitric oxide in critical care, therefore, and a potential challenge to
nutritional supplementation with arginine, is whether nitric oxide will be beneficial
or harmful in a specific circumstance.
Conclusion
The results reviewed in this chapter clearly show that nitric oxide is a biologically
active double-edged sword in the management of the critically ill and/or septic pa-
tient. The ability of nitric oxide synthase to respond to a change in the concentra-
tion of endotoxin or cytokines such as tumor necrosis factor is a great challenge to
the researchers and clinicians trying to improve the outcome of the critically ill
patient. The appropriate use of existing, and future, nutritional support regimens
can greatly improve the outcome for these patients if properly administered. Al-
though combining nutrients such as arginine, nucleotides, glutamine, and/or differ-
ent lipids has proven somewhat successful in the clinic for a subset of patients,
improving the outcome of all critically ill patients will depend on our knowledge of
the specific mechanism by which molecules such as nitric oxide function under
normal and pathological conditions.
Acknowledgments
The author wishes to thank Yerga Keflemariam for her assistance in preparing
this manuscript and Norman W. Weisbrodt, Ph.D. for his review and critique.
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CHAPTER 6
Wound Healing and the Role
David A. Lanning, Rifat Latifi
Basic Principles of Wound Healing
The details of the wound healing process vary depending upon the location and
type of wound. However, there are basic principles of the wound healing process
that are essentially common to all sites of healing wounds. Since more is known and
published in regards to cutaneous wound healing, the principles of wound healing
as they occur in the skin will be described below.
Normal wound healing occurs by a sequence of events in which cellular, soluble
factors, and matrix components act in concert to repair a wound. The healing re-
sponse can be described in four broad, overlapping phaseshemostasis, inflamma-
tion, proliferation, and remodeling.
1
The disruption in the integrity of the vascular
endothelium activates the coagulation cascade, which results in the formation of a
clot consisting of fibrin, platelets, and erythrocytes. The initial wound matrix of
fibrin acts as a scaffold upon which inflammatory cells enter the wound.
2
The injury
also stimulates the release of various mediators of cell-cell and cell-matrix interac-
tions, such as eicosanoids and cytokines. Eicosanoids are metabolites of cell mem-
brane essential fatty acids and function mainly as messengers in the wound and
initiate the signs and symptoms of inflammation, such as redness, swelling, and
pain. Included in this group are prostaglandins and thromboxanes, which are formed
via the cyclooxygenase pathway, and leukotrienes, which are formed via the
lipoxygenase pathway. Cytokines, such as platelet derived growth factor (PDGF)
and transforming growth factor- (TGF-), are polypeptides that mediate the early
inflammatory response but also modulate this and the immune response. Further-
more, cytokines are chemoattractants, mitogens and stimulators of extracellular matrix
(ECM) deposition for cells that enter the wound.
3-5
Initially, neutrophils are present
in increased numbers and are important in phagocytosis of foreign material and
bacteria. Shortly thereafter, monocytes migrate into the tissue, transform into mac-
rophages, and become the predominant inflammatory cell type. Similar to the neu-
trophils, macrophages continue to phagocytose foreign material and release various
cytokines.
6
Lymphocytes also appear in increased numbers in the wound at a de-
layed point and secret cytokines but are not able to phagocytose material. Studies
have demonstrated that only the macrophage is critical for normal healing. How-
ever, all of the cells contribute to the organized repair of a wound by cleaning the
wound site and releasing mediators of cell-cell and cell-matrix interactions, such as
eicosanoids and cytokines. In addition to that seen from the inflammatory cells,
platelet aggregation and degranulation result in the release of cytokines. The ECM
89
Wound Healing and the Role of Nutrient Substrates
6
contains various proteins, glycosaminoglycans (GAG), glycoproteins, and
proteoglycans. For example, the glycoprotein fibronectin, which is synthesized by
fibroblasts and epithelial cells, facilitates cellular attachment and migration.
7
The
GAG hyaluronan (HA) is also thought to be important in cell motility in the imme-
diate post-wounding period. Type II and III collagen are the predominant ECM
proteins deposited at the wound site resulting in a scar, which continues to be re-
modeled for years.
8
Approximately 10% to 20% of the collagen seen in the skin are
Type III, with increased levels seen prenatally and in the early wound. Studies have
suggested that it is deposited in a more organized pattern and can by remodeled
more easily. Fibroblasts interact with the ECM and other cells through heterodimeric,
transmembrane receptors called integrins. These cell-surface receptors are composed
of two subunits, one and one and are important in cell-cell and cell-ECM
interactions.
9
More specifically, the integrins 21 and 11 are thought to be the
receptors associated with wound contraction.
10,11
Despite extensive investigation, the mechanisms responsible for wound contrac-
tion remain unknown. There is continued controversy over this aspect of wound
healing, primarily amongst those investigators that believe that the myofibroblast
vs. the fibroblast is the effector cell in this process. The myofibroblast is character-
ized histologically by large cable-like actin-rich stress fibers.
12
Alpha-smooth muscle
(SM) actin is the actin isoform typical of contractile vascular SM cells and is also
expressed by practically all myofibroblastic populations in vivo.
12
Increased numbers
of this cell type are seen in contracting wounds and primarily at the wound edge,
which suggested that they contribute to closure of the wound. Furthermore, studies
have demonstrated that if the peripheral wound edge was excised, contraction wound
be prevented. However, additional studies by other investigators using in vitro and
in vivo models suggest that the fibroblast is in fact responsible for contraction.
The final phase of normal adult wound healing consists of continued remodel-
ing of the wound site with ongoing collagen deposition and resorption. The small
amount of collagen Type III, as well as Type II collagen are broken down and
replaced with Type II collagen. At approximately 21 days after wounding, the net
accumulation of collagen becomes stable.
13
The strength of the scar gradually in-
creases as it is remodeled up to its peak strength at 6 months after injury at which
point it remains about 80% of that seen in normal skin.
The complex mechanisms involved in wound healing on a molecular and cellu-
lar level remain poorly understood. In addition, the genes that regulate the mecha-
nisms seen in wound healing have not been determined. As a result, the implication
of malnutrition and the role of supplemental nutrition on wound healing are only
now beginning to be appreciated.
Malnutrition and Wound Healing
Even despite poor nutritional status and/or post injury starvation, the body is
able to heal most wounds. Reallocation of nutritional resources through the mobili-
zation of lean body mass occurs in order to provide substrates to the wound. The
bodys ability to mobilize substrates for healing is not unlimited as demonstrated in
studies of animals with multiple injuries. Those with femur fractures have reduced
tensile strength in incisional wounds compared to control animals without frac-
tures.
14
Also, wound implants placed in patients with concurrent major trauma were
found to contain lower hydroxyproline levels than in normal volunteers.
15
The causal
relationship between poor nutritional status and poor wound healing has been
90
6
suspected for many years yet the details of how nutrition affects the biology of the
healing wound continue to be investigated.
The healing of incisional wounds in mice that had restricted diets was performed
by Greenhalgh et al.
16
The authors demonstrated that the strength-to-disruption of
incisional cutaneous wounds in the group that underwent cecal ligation and punc-
ture (CLP) was less than that of wounds in sham-operated control animals up to 14
days after wounding. However, there was no difference in wound breaking strength
between the groups 3 to 5 weeks after wounding. In review of the groups, the ro-
dents in the CLP-wounded group lost weight and consumed 40% less food during
the first post-operative week than the control wounded group. A subsequent experi-
ment used pair feeding of animals with incisional skin wounds with and without
CLP and revealed a similar reduction in tensile strength of the incisional wounds in
those with CLP as those in the sham-operated group. These data supported the
conclusion that decreased food intake led to weaker wounds and not the concurrent
sepsis in the CLP group.
Another study looked at the effect of seven weeks of a protein-free diet on the
healing of colonic anastomoses in rats.
17
The investigators demonstrated that
colonic-bursting pressure and colonic-bursting wall tension was diminished in the
protein-starved group compared to the control group. Furthermore, there was a
34% weight loss in the protein-deprived group again implicating severe malnutri-
tion as a contributing factor to the altered anastomotic healing.
A number of studies have implicated the importance of nutrition in wound heal-
ing by demonstrating poor healing or high wound complication rates in patients
with hypoalbuminemia.
18
Other researchers have studied hydroxyproline levels in
subcutaneously-placed implants such as polytetrafluoroethylene (PTFE) tubing as a
wound-healing model.
19
One group utilized weight history, anthropometric mea-
surements, and recent dietary-recall history to determine nutritional status and found
decreased hydroxyproline levels in those that were malnourished by a weight loss
history of 10% 5% of original body weight.
20
One group using fasting guinea pigs investigated the cause of reduced hydrox-
yproline levels in subcutaneously-placed implants.
21
These authors found that the
level of collagen synthesis was significantly lower in the group starved for four days
than the control group. However, the level of collagen synthesis was restored within
four days of restarting feeds. Furthermore, there was no evidence of collagen degra-
dation and low levels of messenger RNA levels were confirmed in the fasting group.
Alterations in the level of various hormones were implicated in the reduced level of
collagen synthesis. A reduction of insulin and somatomedin levels but an increase in
glucocorticoids were some of the changes in fasting-induced hormones cited by the
authors. The importance of these hormones in wound healing were noted in that
somatomedin C, or insulin-like growth factor-1, is a competence growth factor and
promotes angiogenesis and collagen synthesis. In addition, glucocorticoids are known
to have anti-inflammatory and antihealing effects in wounds.
Many of these animal studies need to be reviewed in a critical manner in that
wounds in rodents heal differently than in humans and their response to protein-free
diets or complete starvation vary from the human. Furthermore, many of these
studies may show a reduced level of collagen in an implant or wound site but this is
at one time-point and the level of collagen does not necessarily correlate with the
quality of healing. Furthermore, the wounds in many of these studies were not evalu-
ated clinically using measurements such as tensile strength.
91
6
A number of human studies have been performed to address wound healing and
overall outcome after surgical intervention with and without associated malnutri-
tion. In a prospective study of female patients with femoral neck fractures that un-
derwent surgery, outcomes were determined in relation to nutritional status.
22
Those
that were greater than two standard deviations below the mean body weight had a
more prolonged period of rehabilitation and a higher overall mortality. Another
prospective study in over 200 non-cancer patients determined pre-operative nutri-
tional status as measured by percent ideal body weight, percent weight loss, serum
albumin levels, and arm muscle circumference and correlated these findings with
surgical outcome.
23
The group of patients that had one of the above indicators of
poor nutritional status were found to have a significant increase in overall complica-
tions, major complications, and in length of stay compared to the control group.
Nutritional Supplementation and Wound Healing
As a result of the numerous studies that have demonstrated that poor nutritional
status correlates with poor wound healing, much investigation has ensued in an
attempt to identify the ideal amount, timing, and content of nutritional supple-
mentation in patients undergoing surgery or after traumatic injury.
One study examined hydroxyproline content in subcutaneous PTFE grafts in
patients that received total parenteral nutrition (TPN).
24
Researchers found that
lower levels were found in patients that were considered to be malnourished when
compared to normal controls. However, levels were increased after patients had re-
ceived TPN for variable periods of time before wounding. Furthermore, patients
that received TPN pre- and postoperatively had greater hydroxyproline levels in
experimental wounds than those that received TPN only after surgery. Enteral feed-
ing has also been demonstrated to affect hydroxyproline levels in implants.
25
Pa-
tients that received four days of enteral nutrition post-operatively had elevated levels
in PTFE implants inserted at the time of surgery and harvested one week later.
A large study that addressed the relationship of perioperative TPN with surgical
outcome and wound healing was the Veterans Affairs Cooperative Study.
26
It en-
rolled 395 malnourished patients that had abdominal or thoracic surgical proce-
dures. Suprisingly, the TPN group had a higher rate of infectious complications
compared with the unfed control group. While the patients that were borderline or
mildly malnourished had no demonstrable benefit from TPN, those patients that
were severely malnourished had fewer wound complications such as anastomotic
leaks and bronchopleural fistulas.
The role of preoperative enteral hyperalimentation in malnourished surgical pa-
tients was assessed in a study by Shukla et al.
27
Patients that were randomized to
receive nasogastric feeds had significant improvement in body weight, serum pro-
tein levels, and multiple anthropometric measures compared with the patients in
the control group. These parameters have routinely been correlated with nutritional
status and the quality of wound healing and, in this study, the enteral
hyperalimentation group had significantly lower rates of mortality and wound in-
fection rates.
As previously mentioned, Bastow et al performed a randomized control trial to
determine the effect of nocturnal feeds in patients that were undergoing surgery for
femoral neck fractures.
22
Over 700 patients were grouped at the time of surgery
according to anthropometric measurements. Patients were either categorized as
well-nourished, thin (between 1 and 2 standard deviations below the mean), or very
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6
thin (greater than two standard deviations below the mean). Patients in the thin and
very thin groups were then randomized to receive noctural tube feeds in addition to
a standard diet or just standard diet alone. In both the thin and very thin groups, the
patients that received the nocturnal feeds in addition to the standard diet had sig-
nificant reductions in their rehabilitation times compared to their matched control
groups that had standard diets only.
Kiyama et al recently investigated the effect of enteral vs. parenteral nutrition on
gastrointestinal anastomotic healing.
28
Using 20 male Sprague-Dawley rats, a distal
colonic anastomosis was performed in an inverted, single-layer manner. Identical
nutrient infusates of amino acids, dextrose, and vitamins were either given via a
parenteral or enteral route. While there was no difference in nutritional parameters
at five days, colonic anastomotic bursting pressures were significantly higher in the
enterally fed group and the measured insoluble collagen and total protein content in
anastomotic tissue was enhanced. The authors conclude that the preservation of
colonic structural collagen in the enteral group may improve the ability of the gut to
hold sutures and thus improve anastomotic healing. In a similar study by another
group of investigators, rat colonic anastomotic bursting pressures were tested after
the intravenous infusion of n-butyrate.
29
Total collagen content was not altered but
the bursting pressures were significantly increased compared to control rats that
received TPN without additional n-butyrate. The role of enteral and parenteral supple-
mentation in improving the strength of anastomotic healing is yet to be determined.
A group of orthopedic surgeons from Sweden assessed whether supplemental
nutrition would improve healing and decrease mortality in patients that underwent
transtibial amputation for occlusive arterial disease.
30
In a prospective study, 28
malnourished patients were given pre and postoperative supplemental nutrition to
an average intake of 2098 kcal/day for a total of at least 16 days. A group of 32,
well-matched patients served as the controls and did not receive supplemental nu-
trition. Healing occurred in 26 of the nutrition group compared with 13 in the
control group, which was statistically significant. While mortality was not altered in
this study, supplemental nutrition did improve healing of transtibial amputation wounds.
Specific Nutrients, Vitamins, and Trace Elements
Arginine
Arginine is a nonessential amino acid that can become an essential dietary nutri-
ent with severe stress. It has multiple pharmacologic and biologic effects including
stimulation of various immune parameters, acting as a pituitary and pancreatic secre-
tagogue, and increasing angiogenesis in response to ischemic injury. In addition,
arginine may also serve as a local precursor for collagen-bound proline. More im-
portantly, the amino acid is the unique precursor of the highly reactive radical nitric
oxide (NO).
31
Various studies suggest that NO plays a critical role in wound heal-
ing. It is known to act as a messenger molecule for different physiological actions.
32
After injury, NO synthesis occurs for prolonged periods and macrophages appear to
be a major cellular source for it.
33
Schaffer et al investigated the role of NO in acutely malnourished rats that had
subcutaneously implanted polyvinyl alcohol (PVA) sponges.
33
The authors postu-
lated that wound NO production plays a regulatory role in wound collagen synthe-
sis in normal and impaired healing and that levels would be altered in the
malnourished group. The rats that had a 50% reduction of food intake lost 10% of
their weight while control animals gained 18% of their original body weight. Wound
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6
collagen accumulation and Types I and III collagen gene expression were measured
in the subcutaneously placed sponges. Nitric oxide synthesis was also determined in
wound fluid and from wound cell culture supernatants. Collagen content as mea-
sured by hydroxyproline levels in the sponges from the protein-calorie malnour-
ished animals was significantly less than compared to the control group. The gene
expression of Type III collagen, but not Type I collagen, was also reduced in the
malnourished group. The concentration of nitrite, nitrate, and citrulline, which are
stable end products of NO were also reduced in the wound fluid and wound cell
supernatants of the malnourished rats, indicating a net decrease in NO production.
The investigators concluded that impaired wound collagen accumulation caused by
protein-calorie malnutrition may be a reflection of reduced NO synthesis within
the wound.
To further investigate the mechanism by which NO affects wound healing, a
group of investigators utilized iNOS knockout (KO) mice to determine if arginine
acts through this enzyme in producing its vulnerary effects.
34
Twenty wild type and
20 iNOS knockout mice were randomized to receive either normal food and water
or food and water supplemented with 0.5% arginine. A 2.5-cm dorsal skin incision
was then made through which four PVA sponges were implanted into subcutaneous
pockets. The animals were sacrificed on post-operative day 14 and the dorsal wound
was tested for breaking strength and the sponges were assayed for hydroxyproline
content and total wound fluid nitrite and nitrate concentration. Wound breaking
strength and collagen deposition was increased in the wild type group but not in the
iNOS-KO group with dietary arginine supplementation. Also, wound fluid nitrite
and nitrate levels were higher in the wild type group compared to the iNOS-KO
group but were not significantly influenced by additional arginine. These data sup-
ported previous studies that demonstrated that supplemental dietary arginine en-
hances wound healing in normal mice. However, the loss of a functional iNOS gene
abrogates the beneficial effect of arginine in wound healing. The authors concluded
that the iNOS pathway is at least partially responsible for the enhancement of wound
healing by arginine and that exogenous arginine and its associated NO production via
iNOS most likely enhance wound healing through multiple physiologic mechanisms.
While arginine has been demonstrated to increase collagen deposition and break-
ing strength of cutaneous wounds, its role in altering the healing of intestinal anas-
tomoses is unclear. In an effort to determine if supplemental arginine improved
colonic anastomoses, a group of researchers fed 42 Sprague-Dawley rats either 0, 1,
or 3% arginine diets for three preoperative and three postoperative days prior to
transection and reanastomosis of the transverse colon.
35
Animals were harvested on
either postoperative day 6, 10, or 14 and the bursting pressure, histologic inflamma-
tion, and collagen content of the hand-sewn anastomoses were determined. Rats
that were fed a 0% arginine diet showed a significantly lower bursting anastomotic
pressure on postoperative day 6 than those fed 1 and 3% arginine diets, but no
bursting pressure differences by diets were noted by days 10 or 14. There were no
differences in the degree of inflammation in stained anastomotic tissue upon histo-
logic evaluation nor was there any difference in collagen content between the vari-
ous groups. Perioperative arginine deficiency resulted in reduced bursting pressures in
this model of rat colon anastomoses suggesting impaired healing. However, supranormal
levels of dietary arginine did not increase the bursting pressure of anastomoses above
the normal level of arginine. This study reinforces the importance of adequate nutri-
tion in the surgical patient, especially those with gastrointestinal anastomoses.
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6
In an attempt to further define the mechanisms responsible for collagen biosyn-
thesis and the role of NO, Shukla et al. studied the effect of topical arginine and the
NO releaser, sodium nitroprusside (SNP) in full thickness excisional wounds in
rats.
36
Interestingly, the SNP decreased the collagen content of the wounds at all
doses as demonstrated by reduced hydroxyproline levels and confirmed histologi-
cally, yet L-arginine decreased collagen content. Various doses of N-nitro-L-arginine
methyl ester (L-NAME), a competitive inhibitor of NOS, significantly increased
wound collagen when administered intraperitoneally and compared to untreated
and SNP treated animals. In addition, thick collagen bundles, proliferation of fibro-
blasts, and increased angiogenesis were seen on review of the wound histology from
the L-NAME treated group. An inactive isomer of the inhibitor, N-nitro-D-arginine
methyl ester did not affect wound collagen levels. Administering L-arginine to
L-NAME pretreated rats resulted in significantly elevated wound collagen content.
The authors postulate that NO could decrease collagen by inhibiting prolyl hy-
droxylase, which is an oxygenase type of enzyme. Also, they point out that the re-
duced collagen content may be as a result of the route of administration since arginine
given intraperitoneally resulted in a trend towards increased collagen content and
other studies have shown that systemically given arginine increases the level of wound
collagen. The authors conclude that NO plays a pivotal role in regulating the bio-
synthesis of collagen. Also, NOS inhibitors administered systemically may help to
lower NO concentration at the injury site as well as in whole body so as to enhance
collagen synthesis and to lower the inflammatory response for better healing.
Barbul et al investigated the effect of oral arginine supplementation on human
collagen synthesis and T-cell function in 36 healthy human volunteers.
37
After a 5
cm segment of PTFE tubing was inserted into a subcutaneous pocket in the deltoid
region, the volunteers where then randomly assigned to receive daily oral supple-
ments of either arginine hydrochloride (25 gm free arginine), arginine aspartate (17
gm free arginine), or a placebo for two weeks. Mitogenic responses of peripheral
blood lymphocytes to phytohemaglutinin and concanavalin A were determined at
0, 1, and 2 weeks after supplementation. The catheters were removed after two
weeks and the amount of hydroxyproline was determined. Both arginine-supple-
mented groups had increased amounts of hydroxyproline deposited in the grafts as
well as increased lymphocyte mitogenesis in response to phytohemaglutinin and
concanavalin A. These data suggested that arginine may be of clinical benefit in
improving wound healing and immune responses.
Another study by the same group of investigators addressed the affect of arginine
on wound healing and immune function in elderly patients.
38
In this double-blind,
randomized study, 15 patients received either arginine aspartate (17 gm free argin-
ine) while another 15 patients received a placebo syrup. PTFE catheters were placed
in a subcutaneous position in the deltoid region and a 2 x 2 cm split thickness
wound was created on the lateral aspect of the upper thigh. The catheters were
analyzed for -amino nitrogen to determine total protein accumulation, hydrox-
yproline content, and DNA accumulation. The mitogenic response of peripheral
blood lymphocytes to concanavalin A, phytohemaglutinin, pokeweed mitogen, and
allogeneic stimuli was determined at the beginning and end of the experiment. The
catheters were removed at two weeks and found to contain significantly more
hydroxyproline in the arginine supplemented group. There was no difference in
cellularity of the catheter as assessed by DNA content nor was there any difference
in time to complete epithelialization of the skin defect. However, the blastogenic
95
6
response of peripheral blood mononuclear cells to all the mitogens as well as to
allogeneic stimulation was significantly greater in the arginine supplemented group
compared to the control group. Furthermore, insulin-like growth factor-1 levels
were significantly elevated in the arginine group. These findings support previous
studies that demonstrated arginine supplementation increases protein and collagen
deposition and T-cell activity in experimental wounds.
Barbul and his colleagues have continued to study arginine and NO and, in a
series of papers over the last several years, they have provided additional convincing
evidence that inducible NO plays a critical role in the wound healing process. Using
Balb/C mice that had cutaneous incisional wounds and had PVA sponges implanted,
they demonstrated decreased wound breaking strength and wound collagen accu-
mulation when NO synthesis was inhibited by S-methyl isothiouronium, a com-
petitive inhibitor of NO synthase.
39
Furthermore, rat colon anastomoses were found
to have increased, localized expression of inducible NO synthase that, when blocked
with S-methyl isothiouronium, had lower bursting pressures than control anasto-
moses.
40
The investigators also demonstrated that impaired diabetic wound healing
was associated with decreased wound NO synthesis in Sprague-Dawley rats ren-
dered diabetic after streptozotocin administration.
41
Lastly, Barbul was able to successfully transfect male rats with plasmid DNA that
contained murine iNOS gene driven by a CMV promoter and demonstrated that
increased production of iNOS was associated with a localized increase in collagen
production.
42
These studies have strengthened the link between arginine, NO, and
wound healing but further investigation is necessary to understand the mechanisms
by which they participate in this process.
Glutamine
Glutamine is an amino acid that is considered to be a conditionally essential
amino acid during serious injury or illness but is nonessential in healthy adults.
43
It
is the most abundant amino acid in plasma and skeletal muscle, but levels in blood
and tissues fall acutely after injury, infection, or surgery.
44
This amino acid is a pre-
cursor for synthesis of nucleotides and may be a regulator of protein turnover.
45
More importantly, it has been recognized as a major oxidative substrate for enterocytes,
colonocytes, and cells for the immune system.
46,47
In the gastrointestinal tract,
glutamine has trophic actions that may decrease bacterial translocation and in ani-
mal studies it has been shown to improve growth and repair of small bowel and
colonic mucosa after injury.
48
However, limited studies have looked at its direct
effect on wound healing.
Demetriades et al examined the effect of early postoperative enteral administra-
tion of glutamine on the healing of gastrointestinal anastomoses in rats.
49
Four groups
of 15 rats were randomly assigned to receive 1 of 4 diets, one of which included
glutamine, after undergoing a colonic anastomosis. After seven days, the rats were
sacrificed and the anastomotic bursting pressure was determined for each animal as
well as histologic examination of each anastomosis. The rats fed with enteral diets
that contained glutamine had significantly higher bursting pressures and decreased
inflammation. The authors concluded that early postoperative enteral feeding with
glutamine improves healing of experimental colonic anastomoses in rats.
Vitamin C
L-ascorbic acid functions as a biologic cofactor in many diverse biochemical
reactions and as a nonspecific antioxidant.
50
Numerous studies have demonstrated
96
6
that Vitamin C facilitates collagen synthesis in the posttranslational hydroxylation
stage but also by influencing collagen messenger RNA levels.
51
Vitamin C defi-
ciency or scurvy results in scorbutic wounds that are characterized by decreased
accumulation of ECM, abnormal angiogenesis with hemorrhage, very little collagen
deposition, and markedly retarded gain in tensile strength.
52
In addition, there is an
increased susceptibility to wound and more severe infections secondary to reduced
production of neutrophil superoxide, complement components, and various gamma
globulins.
52
Interestingly, plasma concentration and urinary excretion of ascorbate
are markedly decreased in injured humans, and tissue saturation for ascorbate is
remarkably reduced in the early hours after injury.
53
Some postulate that this aspect
of ascorbate metabolism may contribute to the alterations in wound healing seen in
polytraumatized patients.
The effects of Vitamin C deficiency on wound healing are generally seen only
after a prolonged period of ascorbate deprivation. Crandon et al demonstrated that
clinical scurvy and impaired healing was present only after patients were deprived of
Vitamin C for 180 days.
54
Cutaneous wounds at 90 days healed without difficulty.
Another study showed that patients that were deprived of Vitamin C for seven months
had reduced tensile strength of cutaneous wounds compared to those on an
ascorbate-supplemented diet, but only for the first ten days after injury.
55
These
studies demonstrate that while Vitamin C is important in wound healing, this pro-
cess is fairly resilient to simple ascorbate deficiency in animals and humans.
Pharmacologic doses of Vitamin C have been proposed to improve wound heal-
ing in a handful of studies. However, many elderly patients, as well as smokers and
cancer patients, have low plasma and leukocyte ascorbate concentrations and levels
can be depressed in the acute injury setting. Therefore, improved wound healing is
most likely as a result of injury or surgery in patients that have marginal ascorbate
levels initially. As a result, dietary supplementation with Vitamin C may be beneficial.
Vitamin B
The B vitamins are coenzymes that function interdependently as coenzymes in a
wide variety of reactions involving carbohydrate, fat, and protein metabolism, as
well as being important in DNA synthesis.
56
Deficiencies of some of the B vitamins
can alter wound healing by impairing the relatively rapid turnover rate of cells that
is required for tissue repair and the immune response.
56
Vitamin B deficiency is
usually associated with poor food choices as a result of poverty, ignorance, illness, or
poor health habits such as alcohol abuse.
Vitamin A
The mechanisms responsible for the vulnerary effects of Vitamin A are not com-
pletely known. However, it is well known that Vitamin A counteracts the deleteri-
ous effects of glucocorticoids on wound healing in both animals and humans.
57
Supplementation with Vitamin A increases collagen content and breaking strength
of experimental cutaneous wounds and colonic anastomoses in normal rats.
58
In
addition, alterations in wound healing as a result of femoral fractures, whole body
irradiation, or streptozotocin-induced diabetes, were reversed with administration
of Vitamin A.
59-61
One of the theories for how Vitamin A exerts its effect is by
inducing fibroblast differentiation and collagen secretion.
62
In fact, topical applica-
tion of Vitamin A accelerated healing of cutaneous wounds that were healing poorly
secondary to steroids.
62
Alternatively, Vitamin A may exert its effects systemically by
97
6
upregulating overall immune responses as demonstrated by its prevention of thymic
involution after trauma.
63
It also increases cell-mediated reactivity as demonstrated
by skin graft rejection in animals consuming supplemental Vitamin A.
63
Despite
concerns about the increased incidence of intra-abdominal adhesions found in ani-
mals given Vitamin A, patients with severe injuries and those receiving steroids should
receive diets supplemented with standard doses of Vitamin A every day.
58
Vitamin E
Vitamin E is an antioxidant and free-radical scavenger that helps prevent the
oxidation of cell membrane polyunsaturated phospholipids.
64
Supplemental vita-
min E has been shown to increase the healing strength of wounds that are slow to
heal after radiotherapy.
65
However, excess dietary vitamin E has been found to delay
wound healing, slow allograft rejection, lessen postoperative adhesion formation,
and interfere with the beneficial effects of vitamin A.
58
Interestingly, serum concen-
trations of this vitamin are reduced in burn patients due to consumption by oxygen
radical release and subsequent systemic inflammation.
66
Vitamin D
Vitamin D is not only required for normal calcium metabolism and bone forma-
tion, but it also appears to be required for normal collagen production.
67
However,
deficiency states are uncommon in that Vitamin D can be synthesized by the
body with adequate exposure to sunlight. Supplementation may be necessary
in selected patients.
Vitamin K
While vitamin K is synthesized by intestinal bacteria, dietary sources are neces-
sary to meet the bodys total need. This vitamin is involved in the formation of at
least four protein-clotting factors and also a calcium-binding protein required
for bone metabolism.
68
A vitamin K deficiency can lead to impaired healing
and infection.
68
Copper
Copper is involved in the maturation of collagen by lysyl oxidase, a copper met-
alloenzyme that catalyzes the oxidation of lysyl residues on collagen.
69
Hydroxylysyl
groups add to the strength of the scar through cross-linking of extracellular collagen.
Copper deficiency results in anemia, neutropenia, leukopenia, and skeletal dem-
ineralization.
50,70
Zinc
Zinc is an essential component of multiple metalloenzymes, including RNA-
and DNA-polymerases.
71
The physiologic functions of zinc include tissue growth
by nucleic acid metabolism, protein synthesis, bone formation, skin integrity, and
the maintenance of host defense mechanisms.
50,58
Zinc deficiency in animals results
in alterations in the immune system including thymic atrophy, lymphopenia, T-cell
impairment, and decreased granulocyte function.
72
The role of zinc in wound heal-
ing was investigated in patients with pilonidal sinuses.
73
Oral administration of zinc
resulted in a more rapid rate of reepithelialization. Another study demonstrated that
zinc supplementation accelerated the healing of chronic venous leg ulcers but only
in those patients with a low pretreatment serum zinc level.
74
Since a significant
portion of hospitalized patients have been shown to have low serum zinc levels,
98
6
especially those that have poor food intake, diarrhea, a gastrointestinal fistula, or
malabsorption, supplementation of patients diets with zinc is recommended.
Other Trace Elements
Manganese, selenium, and silicon are a few of the additional trace elements that
participate in the wound healing process. Manganese is necessary for the function of
O-lysyl galactosyltransferase, the enzyme responsible for the glycosylation of
procollagen fibers.
75
This element is also involved in the production of HA, chon-
droitin sulfate, heparin, and other mucopolysaccharides that are important compo-
nents of the ground substance in healing wounds.
76
Selenium-dependent glutathione
peroxidase is an enzyme that protects the cell from oxidative damage by catalyzing
the reduction of hydrogen peroxide.
76
Altered macrophage and polymorphonuclear
cell function may result with selenium deficiency.
76
Lastly, silicon may stimulate the
production of collagen and mucopolysaccharides and deficiency of this trace ele-
ment has been linked to altered connective tissue matrix formation.
77
Fatty Acids
Several studies have shown that -3 fatty acids, which are abundant in fish oils,
have significant anti-inflammatory effects that appear to be mediated through the
inhibition of proinflammatory eicosanoid production.
78
Tumor necrosis factor-,
interleukin-1, and platelet-activating factor production are also decreased in pa-
tients with diets high in these compounds.
79,80
The anti-inflammatory effect pro-
duced has been shown to alter cutaneous wound healing in a study by Albina et al.
81
Animals that were fed diets rich in -3 fatty acids had weaker wounds when com-
pared to wounds in the control animals. These differences were attributed to altered
collagen spacing or cross-linking and not collagen production.
Conclusion
The quality and rate of the wound healing process is intricately dependent upon
the availability of a number of nutritional substrates. Reduced levels of one or more
of these substrates results in delayed or inadequate wound healing. Furthermore,
supplementation of various substrates to correct deficiencies or to produce
supranormal levels can increase the rate and/or quality of the healing process follow-
ing wounding and reduce the number of complications. Further research into the
mechanisms of wound healing and role of nutrient substrates will continue to reveal
new biological and chemical pathways that can be altered to reduce the morbidity
and mortality associated with injury, disease, and surgery in all patients.
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CHAPTER 1
CHAPTER 7
Protein Metabolism in Liver and Intestine
During Sepsis: Mediators, Molecular
Regulation, and Clinical Implications
Timothy A. Pritts, Eric Hungness and Per-Olof Hasselgren
Introduction
Sepsis is associated with pronounced metabolic alterations in various organs and
tissues. In particular, changes in protein metabolism are prominent in muscle, lungs,
liver and intestine.
1
Whereas the response to sepsis and severe injury, including burn
injury, is that of catabolism in muscle and lungs,
2-4
sepsis results in increased protein
synthesis in liver and intestine.
5,6
One of the consequences of protein breakdown in
peripheral tissues is net release of glutamine and other amino acids. A large portion
of these amino acids is taken up by the liver to serve as precursors for gluconeogen-
esis and acute phase protein synthesis, and by the small intestine where they serve as
an important energy source (Fig. 7.1). Glutamine is also taken up by cells in the
immune system and is important for maintained function of these cells.
7
Increased
production of acute phase proteins in the liver
5
and stimulated protein synthesis in
the mucosa of the small intestine
6
support the concept of an anabolic response to
sepsis in these tissues.
The metabolic response to sepsis in the liver and intestine is important from a
clinical standpoint for a number of reasons. Several of the acute phase proteins serve
as immunomodulators or participate in tissue repair. In previous studies, survival in
septic patients was dependent on a well-maintained protein synthesis in the liver.
Recent studies provided evidence that acute phase proteins are synthesized not only
by the hepatocyte but by the enterocyte as well,
8-10
and the intestine may be an
additional source of acute phase proteins during sepsis and other critical illness. Part
of the sepsis-induced increase in intestinal protein synthesis reflects increased pro-
duction in the enterocyte of gut peptides, including vasoactive intestinal peptide
(VIP) and peptide YY (PYY).
11
Some of the gut peptides may be involved in sepsis-
induced hemodynamic changes and in altered gastrointestinal motility.
In this Chapter, sepsis-induced changes in protein metabolism in liver and intes-
tine are reviewed together with mediators and molecular regulation. In addition,
clinical implications of the metabolic changes are discussed.
Liver
The Acute Phase Response
Acute phase proteins have been defined as plasma proteins whose concentrations
in blood are increased 25 % or more by various stimuli, including inflammation,
104
7
injury and sepsis. More recently, it has been suggested that the term should be limited
to proteins that are induced by cytokines derived from an inflammatory focus.
12
. In
contrast to these proteins, certain plasma proteins, most notably albumin, are re-
duced during sepsis and critical illness, and these proteins are usually referred to as
negative acute phase reactants. Thus, during sepsis and following severe injury, the
synthesis and release of certain proteins are reprioritized.
The acute phase proteins can be divided into different groups depending on the
degree of reactivity; some acute phase proteins show an increase of up to 1,000-fold,
whereas other proteins show a more moderate (2- to 10-fold) increase following
stimulus.
13
The acute phase response is species specific. In man, for example, C-reactive
protein (CRP) is a particularly strong reactant, showing increased levels even after mod-
erate trauma (Fig. 7.2),
14
whereas in rats,
2
-macroglobulin and
1
-acid glycoprotein
show pronounced increases in plasma concentrations during the acute phase response.
13
The biological functions of different acute phase proteins have been reviewed
elsewhere.
12
In general, the acute phase proteins serve a number of important func-
tions in the inflammatory response and in restoring homeostasis following injury
and sepsis. Considering the wide range of biological functions of the acute phase
proteins, it is not surprising that they are essential for the outcome in sepsis and
injury. Several authors have found evidence that survival in septic patients is depen-
dent on a well-maintained protein synthesis in the liver.
Fig. 7.1. Sepsis is associated with a catabolic response in skeletal muscle and lungs,
resulting in release of glutamine and other amino acids. The function of cells in the
immune system and in the gut and the synthesis of acute phase proteins in the liver are
supported by changes in protein turnover in muscle and lungs. Reprinted with permis-
sion from Hasselgren PO, Protein Metabolism in Sepsis, Austin: RG Landes, 1993.
105
Protein Metabolism in Liver and Intestine During Sepsis
7
Most clinical evidence for increased acute phase protein synthesis during sepsis
and other critical illness has been derived from elevated plasma levels of the pro-
teins. Direct evidence for stimulated protein synthesis in the liver during sepsis has
been reported in animal experiments using various experimental models and differ-
ent techniques to measure protein synthesis. Results from those experiments suggest
that sepsis stimulates the synthesis not only of secreted plasma proteins but of en-
dogenous (non-secreted) proteins as well, such as intracellular enzymes and struc-
tural proteins, and this is one of the reasons why liver weight and protein content
are typically increased during sepsis and inflammation.
5,15
Increased hepatic protein
Fig. 7.2. Changes in plasma levels of acute phase proteins following uncomplicated
open cholecystectomy. C-reactive protein (CRP) is a particularly strong acute phase re-
actant in man. Reprinted with permission from Aronson KF et al, Scand J Clin Lab Invest
1972; 29:127-136.
106
7
synthesis is not unique to sepsis, but occurs in a number of inflammatory condi-
tions, including endotoxemia, bacteremia, surgical trauma, and burn injury.
5,15
In addition to changes in the synthesis rates, plasma levels of the acute phase
proteins can also be influenced by changes in the secretion of the proteins. Plasma
proteins usually reach the cell surface of the hepatocyte within 20-25 min after their
synthesis. There is evidence that this time is shortened for some proteins during the
acute phase response. Thus, both synthesis and secretion of acute phase proteins
may be upregulated during sepsis. A more detailed discussion of mechanisms in-
volved in the production and secretion of secretary proteins is given below.
Cellular Mechanisms of the Acute Phase Response
The cellular mechanisms of the acute phase response are to a certain extent influ-
enced by the unique microanatomy of the liver. Sepsis and inflammation do not
affect all hepatocytes in a homogeneous fashion. Thus, at least during the early
phase of the acute phase response, protein synthesis is stimulated mainly in the
periportal hepatocytes. The inhibition of albumin synthesis also affects hepatocytes
in a heterogeneous fashion, with the most pronounced changes occurring in the
periportal hepatocytes.
16
This heterogeneous response in hepatocytes located in dif-
ferent regions of the liver lobule probably reflects gradients in oxygen, nutrients,
and inflammatory mediators with falling concentrations from the periportal area
towards the central vein. Although not all hepatocytes are recruited for the acute
phase response, at least not initially, each individual hepatocyte that participates in
the acute phase response is capable of exhibiting a complete response, i.e., simulta-
neously increasing the synthesis of multiple acute phase proteins and decreasing the
production of albumin.
The liver contains several different cell types (hepatocytes, endothelial cells,
Kupffer cells, Ito cells, pit cells and neutrophils), most of them arranged in well-
organized, repeating units. The anatomic and functional organization of the hepatic
architecture was reviewed recently by Clemens et al (Fig. 7.3).
17
Because the mi-
croanatomy of the liver is important for the understanding of the metabolic re-
sponse to sepsis and inflammation, it is briefly reviewed here with special emphasis
on the functional organization and the communication between different cell types.
The parenchymal cells of the liver, the hepatocytes, are arranged in cords with
sinusoids surrounding them. In addition to the heterogeneous function of the hepa-
tocytes caused by gradients in oxygen, nutrients and inflammatory mediators from
the terminal portal vein branches to the central vein, the hepatocytes exhibit differ-
ences in metabolic activity in different regions because of variations in enzymatic
activities. One example of this is the high activity of glutamine synthase in perivenous
hepatocytes by which NH
3
generated by upstream hepatocytes is cleared. This inter-
action between periportal and perivenous hepatocytes has led to the concept of a
perivenous scavenger system
18
in which substances left behind by periportal cells
are removed by perivenous hepatocytes.
The sinusoids are lined by endothelial cells which are characterized by large fenes-
trae, spaces between the cells, and lack of a well-developed basement membrane.
This arrangement allows for an easy exchange of large molecules, including acute
phase proteins secreted by the hepatocytes, between the sinusoidal and perisinusoidal
(Disses) spaces. Similar to other vascular beds, the endothelial cells in the liver are
metabolically active and may exhibit phagocytosis, in particular when the capacity
of the Kupffer cells has been saturated.
107
7
The Kupffer cells are located within the sinusoids (Fig. 7.3) and constitute the
majority of the fixed macrophages in the body. They are most numerous in the
periportal sinusoids and are also most active in this location. Following stimulation
with endotoxin, the Kupffer cells release a number of inflammatory mediators, in-
cluding cytokines, prostaglandins, oxygen radicals, and nitric oxide.
19,20
The inter-
action between Kupffer cells and the hepatocytes is of particular significance in the
regulation of the acute phase response (see below).
The Ito cells are specialized fat and vitamin A storing cells located in Disses
space where they encircle the sinusoids and also make contact with adjacent Ito cells
by long stellate processes; the Ito cells are also known as stellate cells.
21
In addition to
being a primary site of vitamin A storage in the body, activated Ito cells are contrac-
tile in response to mediators such as endothelin, prostaglandin F
2
(PGF
2
) or throm-
boxane A
2
and may act as postsinusoidal sphincters. The Ito cells may, therefore, be
important in mediating changes in the distribution of sinusoidal blood flow in vari-
ous pathophysiological conditions, such as sepsis and endotoxemia.
The pit cells are mononuclear cells located within the sinusoidal space and prob-
ably originate from infiltrating lymphocytes. They may be important for the host
defense response.
Neutrophils infiltrate the liver in large numbers during inflammatory states and
accumulate primarily in the sinusoids and hepatic venules.
22
Accumulation of neu-
trophils in the sinusoids may be particularly important since substances released
Fig. 7.3. Three-dimensional view of the microanatomy of the liver. The hepatocytes (H)
are arranged in cords surrounded by sinusoids. The sinusoids are lined by a discontinu-
ous endothelium, allowing for communication between the vascular and perisinusoidal
(Disses space) spaces. The Kupffer cells (K) are present in the sinusoidal lumen. The Ito
cells are located in Disses space where they wrap around the sinuoid. Reprinted with
permission from Clemens MG et al, Shock 1994; 2:1-9.
108
7
from the neutrophils in this position may influence the activity in other
nonparenchymal liver cells as well as in the hepatocytes. Recent studies suggest that
substances released from neutrophils are more important for reduced blood flow in the
postischemic liver than the mechanical blockade caused by accumulated neutrophils.
23
The morphological arrangement of the different types of liver cells is important
for the intercellular communication during sepsis, shock and inflammation. Com-
munication within the liver can be paracrine, juxtacrine, autocrine or gap junc-
tional. The acute phase response is probably influenced by all these mechanisms. In
this respect, the interaction between Kupffer cells and hepatocytes is the most im-
portant example of paracrine regulation of protein synthesis during sepsis and in-
flammation. The communication between Kupffer cells and hepatocytes is probably
bidirectional, with Kupffer cells talking to the hepatocytes and the hepatocytes talk-
ing back to the Kupffer cells.
Juxtacrine communication can take place when cells are in close apposition. For
example, activation of neutrophils by platelet-activating factor bound to the plasma
membrane of endothelial cells occurs through juxtacrine communication.
Autocrine regulation of protein synthesis and cytokine release occurs in both
Kupffer cells and hepatocytes. The production of nitric oxide (NO) and cytokines
in Kupffer cells is regulated by cytokines and prostaglandins produced in the same
Kupffer cells.
24
In addition to Kupffer cells, the hepatocytes release NO. Recent
studies suggest that acute phase proteins may down-regulate the production of
cytokines, possibly by an autocrine mechanism.
25
Gap junctions are large channels that connect the cytoplasms of adjacent cells.
26
The channels are formed by specific proteins (connexins) in each cell membrane
that align to form a pore between the cells. Connexins with different molecular
weights have been described; in the liver, connexins with a molecular weight of 26
and 32 kDa (Cx 26 and Cx 32) form gap junctions between hepatocytes; Cx 43
forms gap junctions between Ito cells.
26
Gap junctions allow for the passage of small molecular weight substances (less
than 1,000 daltons) such as cAMP, cGMP and inositol triphosphate, as well as ions
such as Ca
2+
, and electrical current. The nature of the substances that can pass through
the gap junctions supports the significance of this intercellular communication for
metabolic regulation. The speed of intercellular communication by gap junctions is
regulated by endotoxin. The function of the gap junctions is regulated at the mo-
lecular level. For example, the 26 and 32 connexin genes are differentially regulated
during inflammation.
Molecular Regulation of Acute Phase Proteins
Most acute phase protein genes have been cloned, making it possible to study
the acute phase response at the molecular level. Previous studies provided evidence
that the acute phase response is regulated at the transcriptional level, and this is
probably true for both positive and negative acute phase reactants. In rats, fibrino-
gen mRNA levels in liver tissue were increased and albumin mRNA levels were
reduced following induction of inflammation with turpentine injection.
27
Increased
mRNA levels for acute phase proteins were also noticed in isolated and cultured
hepatocytes following stimulus, further supporting the concept of upregulated gene
activity during the acute phase response. This increase in gene activity reflects the
activation of transcription factors which are cellular proteins that bind to responsive
elements in the gene promoter. By doing so, these proteins interact with the basal
109
7
transcription machinery and modulate mRNA production. Of the many transcrip-
tion factors involved in the inflammatory response, nuclear factor kappa B (NF-
B), activating protein-1 (AP-1), CCATT/enhancer-binding proteins (C/EBP), and
cAMP responsive element binding protein (CREB) are particularly important. It
should be noted that although transcriptional regulation is important for acute phase
protein synthesis, regulation probably occurs at the post-transcriptional level as well.
Because the acute phase proteins are secretory proteins, regulation of the intrac-
ellular sorting and processing of these proteins may be as important as the regula-
tion of the synthesis itself. The sorting and processing of secretory proteins and the
molecular regulation of these events were reviewed recently.
28
Secretory proteins are
synthesized in the rough endoplasmic reticulum from where they are transported to
the Golgi complex. Typically, proteins are secreted via a regulated or a constitutive
pathway, both of which involve transfer of vesicles or granules to the plasma mem-
brane followed by the secretary process itself, i.e., exocytic discharge of the vesicle or
granule contents. Most secretary proteins are synthesized as precursors carrying a
signal peptide. This peptide is cleared from the protein rapidly after the complex
enters the Golgi apparatus.
Recent evidence suggests that an alternative pathway exists in which proteins
may be secreted directly from the cytosol via membrane transporters or translocators
or as a result of localized evagination of the plasma membrane. Interestingly, this
novel pathway is involved in the secretion of certain cytokines, including interleukin-l.
The Golgi complex consists of the cis-Golgi network (CGN), the Golgi stacks
and the trans-Golgi network (TGN). It is in the TGN that proteins destined for the
regulated secretary pathway are sorted from those to be secreted via the constitutive
pathway (Fig. 7.4). In addition, proteins are diverted to lysosomes or to be retained
within the Golgi compartments. Regulation of secretion via the regulated pathway
occurs at the level of exocytosis itself, the most distal step in the pathway, and may
allow for the rapid release of large quantities of proteins stored in granules following
the appropriate stimulus. In contrast, exocytosis from the constitutive pathway is a
continuous process limited by the availability of product.
The molecular events involved in the intracellular sorting and processing of sec-
retary proteins are complex, and several important features involving both the sort-
ing mechanisms and the post-translational modification of proproteins to proteins
by conversion endoproteases remain unknown. The influence of sepsis and inflam-
mation on these cellular processes are also largely unknown and will be an impor-
tant field for future studies, in particular in liver and intestine, where inflammatory
stimuli have a significant impact on the synthesis of secretary proteins.
Mediators of the Acute Phase Response
The regulation of acute phase protein synthesis in the liver is complex, with a
number of substances influencing protein synthesis in the hepatocyte, either by act-
ing alone or as cofactors to other mediators. The three groups of substances that are
particularly important for regulation of the acute phase response are cytokines, glu-
cocorticoids, and nitric oxide (NO).
Cytokines
Among the cytokines, interleukin-6 (IL-6) is the most important regulator of
the acute phase response in the liver. The role of IL-6 in the acute phase response has
been reviewed in greater detail elsewhere.
13,29
110
7
There are several lines of evidence that support a role of IL-6 in the acute phase
response. Circulating levels of IL-6 are increased in patients with sepsis and follow-
ing infusion of endotoxin in healthy volunteers. In a group of patients with severe
sepsis, high IL-6 levels were associated with high serum concentrations of CRP,
30
consistent with the concept that IL-6 is a mediator of acute phase protein synthesis
in man. In other studies, correlations were found between IL-6 levels and severity
score and outcome, indicating that serum IL-6 levels may be useful as a marker of
severity of sepsis and as a predictor of survival.
31
When IL-6 was administered in vivo to rats, mRNA levels in liver tissue for
2
-
macroglobulin, -fibrinogen, cysteine protease inhibitor and
1
-acid glycoprotein
increased and albumin mRNA levels decreased, indicating that an almost complete
acute phase response can be induced by this cytokine. Also in mice, administration
of IL-6 resulted in an acute phase response. Evidence for a direct effect of IL-6 was
found in in vitro experiments in which acute phase protein synthesis was stimulated
in human hepatocytes, cultured in the presence of IL-6.
32
The predominant source of IL-6 during sepsis and inflammation is the Kupffer
cell, although other cell types, including the hepatocyte itself, have been found to
secrete IL-6. Recent studies in our laboratory suggest that the enterocyte may be an
Fig. 7.4. Sorting of secretory proteins in the Golgi complex. Proteins received from the
rough endoplasmic reticulum are transferred from the cis-Golgi network (CGN) to the
trans-Golgi network (TGN) via the Golgi stacks in non-clathrin-coated vesicles (NCV).
In the TGN, lysosomal proteins and regulated secretory proteins are actively sorted to
corresponding clathrin-coated regions. Delivery to the constitutive release takes place
by default. Reprinted with permission from Halban PA et al, Biochem J 1994; 299:1-18.
111
7
additional source of IL-6 during sepsis and endotoxemia.
33,35
Thus, it is possible that
acute phase protein synthesis in the hepatocyte is regulated by IL-6 both in an
autocrine (IL-6 produced in the hepatocyte), paracrine (IL-6 produced in Kupffer
cells) and endocrine fashion (IL-6 produced in the intestine and reaching the liver
through the portal vein).
The molecular regulation of IL-6-induced acute phase protein synthesis has been
extensively studied in recent years. When IL-6 binds to its receptor on the hepato-
cyte, a number of different transcription factors are activated to stimulate acute
phase protein genes. The induction of the acute phase protein expression is a fast
process with increased mRNA levels noticed already 1-2 h after stimulus.
In addition to IL-6, other cytokines as well are involved in the regulation of the
acute phase response, although these cytokines usually do not induce a complete
acute phase response. In experiments in our laboratory, administration of rIL-1_ to
rats during three days resulted in increased synthesis in perfused liver of total se-
creted proteins, complement component C3 and
1
-acid glycoprotein, whereas the
synthesis of albumin was unchanged and not reduced as expected.
36
There is evidence that TNF as well regulates the acute phase response. The liver
is an important source of TNF following injury and during sepsis and endotoxemia.
Treatment of cultured rat hepatoma cells with TNF in vitro stimulated the synthesis
of
1
-acid glycoprotein and inhibited the production of albumin, and these effects
of TNF were probably regulated at the transcriptional level since mRNA levels for
1
-acid glycoprotein were increased and those for albumin were decreased.
37
In the
same report, TNF had no effect on fibrinogen mRNA, consistent with a partial
acute phase response induced by TNF. Recent studies suggest that the effect of TNF
on hepatocyte protein synthesis is influenced by insulin and glucose substrate avail-
ability.
38
Thus, exposure of cultured rat hepatocytes to TNF did not affect albumin
synthesis in glycogen-depleted cells, whereas TNF inhibited albumin synthesis by
10-25% in cells exposed to insulin or in cells that were not glycogen-depleted. The
results are important because they imply that the acute phase response may be influ-
enced by an interaction between cytokines and nutritional and/or hormonal factors.
In addition to IL-6, IL-1 and TNF, other cytokines as well may be involved in
the regulation of acute phase protein synthesis. Those cytokines include interferon
(IFN)-, transforming growth factor , leukemia inhibiting factor, IL-11 and
oncostatin M. The large number of substances that regulate the acute phase re-
sponse illustrates the complexity of the system.
Glucocorticoids
Acute phase protein synthesis is under hormonal regulation and is influenced by
both catecholamines, glucocorticoids, and glucagon.
39
Most evidence suggests that
glucocorticoids act as an important or perhaps essential cofactor to IL-6 and other
cytokines in the induction of the acute phase response, and this interaction is regu-
lated at the molecular level.
40
The activated glucocorticoid receptor, i.e., the recep-
tor with bound hormone, may influence acute phase protein genes through a direct
activation of a glucocorticoid receptor element in the promoter or through a pro-
tein-protein interaction with other transcription factors or with nuclear coactivating
factors.
41
Treatment of isolated rat hepatocytes with cytokines induce an acute phase
response only in the presence of dexamethasone. In other studies, dexamethasone
potentiated several-fold the effects of IL-1 and IL-6 on the synthesis of plasma pro-
teins in cultured human hepatoma cells. In contrast, dexamethasone alone did not
112
7
influence the expression of plasma proteins. Evidence for a permissive role of gluco-
corticoids was found in vivo as well. Administration of IL-6 to rats stimulated the
acute phase protein expression in the liver, but glucocorticoids were needed to achieve
a maximal response to the cytokine.
An interaction between glucocorticoids and cytokines is important not only at
the cellular level for induction of the acute phase response, but also more proxi-
mally. Thus, a number of cytokines, including IL-1, IL-6 and TNF, stimulate the
hypothalamic-pituitary-adrenal axis to secrete ACTH and glucocorticoids. Gluco-
corticoids, in turn, inhibit the release of cytokines from macrophages in a negative
feedback manner.
The complexity of the regulation of acute phase proteins is further illustrated by
the fact that different classes of the proteins are individually regulated at the mo-
lecular level. The acute phase genes have been divided into two major classes: class I
genes (including the rat haptoglobin, C3,
1
-acid glycoprotein and the human CRP
gene) are regulated by IL-1, combinations of IL-1 and IL-6, and combinations of
these two cytokines with glucocorticoids;
42
class 2 genes (including the
1
-antitrypsin,
1
-antichymorrypsin, fibrinogen, and
2
- macroglobulin genes) are mainly regu-
lated by IL-6 and leukemia inhibitory factor and by combinations of these cytokines
with glucocorticoids. In studies using cultured human hepatoma cells, IL-6 activated
two different classes of acute phase genes and this activation, which was strongly poten-
tiated by glucocorticoids, was mediated by different transcription factors.
40
Nitric Oxide (NO)
NO is an important biological mediator released by a number of different cell
types, including endothelial cells, Kupffer cells and other macrophages, hepatocytes,
cerebellar neurons and neutrophils. The biological functions of NO as well as the
molecular regulation of NO production by constitutive and inducible NO synthase
have been extensively reviewed elsewhere.
43
The possible role of NO in the regulation of liver protein synthesis was initially
described in in vitro experiments in which rat Kupffer cells or peritoneal macroph-
ages were co-cultured with isolated hepatocytes. When this co-culture system was
treated with endotoxin, hepatocyte protein synthesis was inhibited. Subsequent stud-
ies provided evidence that the inhibition of protein synthesis was mediated by NO,
mainly released from the Kupffer cells and acting on the hepatocytes in a paracrine
fashion, but also released by the hepatocytes themselves and acting in an autocrine
fashion. The production of NO in the hepatocytes is probably regulated by cytokines
released from stimulated Kupffer cells. Thus, when supernatant from cultured Kupffer
cells that had been stimulated by endotoxin and IFN- was added to cultured hepa-
tocytes, the hepatocytes produced increased amounts of NO.
44
At the same time,
hepatocyte protein synthesis was reduced. The endotoxin-induced release from
Kupffer cells of substances that stimulated NO release from the hepatocytes was
regulated by cytokines and was maximal when a mixture of IL-1, TNF and IFN-
was added to the endotoxin-stimulated Kupffer cells.
45
Although most of the experiments described above were performed in hepato-
cytes from rats, other studies suggest that similar regulatory mechanisms are present
in humans as well. Plasma concentrations of nitrite/nitrate (NO
2
/NO
3
), the stable
end- products of NO, are increased in patients after trauma and during sepsis, and
NO production can be induced in human hepatocytes by a mixture of TNF, IL-1,
IFN- and endotoxin.
113
7
It should be noted that although in vitro experiments suggest that NO inhibits
hepatic protein synthesis, the role of NO for the regulation of hepatic protein syn-
thesis in vivo is not clearly understood. Several studies suggest that NO may be
protective in vivo and even increase hepatic protein synthesis. In studies in our labo-
ratory, treatment of endotoxemic rats with the NO synthase inhibitor N
G
-nitro-L-
arginine effectively blocked the increase in plasma levels of NO
2
/NO
3
and significantly
reduced the endotoxin-induced increase in in vivo hepatic protein synthesis.
46
The
results suggest that NO may participate in the stimulation of hepatic protein syn-
thesis in vivo during sepsis and endotoxemia. The mechanism of this effect of NO is
not known, but may be improved hemodynamics, perhaps at the microcirculatory
level, secondary to the vasodilatory effect of the substance or to prevention of plate-
let aggregation and adhesion.
Intestine
It is only relatively recently that the influence of sepsis and systemic inflamma-
tion on intestinal protein synthesis has been studied.
1,6
Changes in intestinal protein
synthesis are important from a clinical standpoint for several reasons. The intestine
has one of the highest protein turnover rates in the body, accounting for 10-15% of
total body protein production under normal conditions. Consequently, changes in
intestinal protein synthesis rates may have a significant impact on whole body pro-
tein economy. The intestine is the production site for a number of proteins with
important biological functions, such as digestive enzymes, gastrointestinal hormones,
mucin and immunoreactive protein. In addition, recent studies, including studies
in our laboratory, suggest that the intestine is an important source of cytokines
during sepsis, endotoxemia and shock.
33-35,47-49
The potential importance of the gut
during sepsis and endotoxemia is underscored by the fact that proteins (including
cytokines) synthesized in the intestinal mucosa can reach the liver directly via the
portal vein and may therefore be able to influence metabolic processes in the liver.
This concept is referred to as the gut-liver axis (Fig. 7.5) and is supported by a
recent report from our laboratory in which levels of several gut hormones were el-
evated in the portal, but not systemic, circulation following induction of sepsis.
50
Finally, changes in the production of IgA, mucin, and perhaps other proteins as
well, may be essential for bacterial translocation across the gut mucosa.
Sepsis Stimulates Intestinal Protein Synthesis
Initial studies concerning the potential role of the intestinal mucosa in the meta-
bolic response to sepsis examined the effect of sepsis on mucosal protein synthesis.
When sepsis was induced by cecal ligation and puncture (CLP) in rats, the protein
synthesis rate was increased by approximately 15% in jejunal mucosa after 8 h and
by 50-60% in jejunal and ileal mucosa after 16 h.
6
This increase was greatest in
jejunal mucosa, but also involved ileal mucosa and jejunal and ileal seromuscular
layers. Parenteral administration of the pro-inflammatory cytokines TNF- or IL-1
was also associated with increased mucosal protein synthesis, suggesting that the
response to sepsis may be mediated, at least in part, by these cytokines.
Interestingly, increases in mucosal protein synthesis rates during sepsis varied
among different regions of the gastrointestinal tract. Sepsis stimulated protein syn-
thesis in different regions of the small and large bowel, from the duodenum to the
anus.
51
In sharp contrast, protein synthesis in gastric mucosa was significantly re-
duced during sepsis (Table 7.1). The mechanism of this differential effect of sepsis
114
7
on protein synthesis in the stomach and the rest of the gastrointestinal tract is not
known, but may be differences in blood flow; gastric perfusion is reduced whereas
intestinal blood flow is unchanged or even increased during sepsis.
52
It may be specu-
lated that reduced protein synthesis in gastric mucosa during sepsis in part reflects
reduced production of mucin and other substances important for the protection of
the gastric mucosa. The finding, therefore, may be important for the understanding
of the pathogenesis of gastric stress ulcers, commonly observed in patients with
sepsis or other critical illness. Further studies are necessary to elucidate the implica-
tions of reduced protein synthesis in gastric mucosa during sepsis.
Studies in other laboratories confirmed our results of increased intestinal protein
synthesis during sepsis.
53
They found that protein synthesis in mucosa of small in-
testine was increased 20 h after the intravenous injection of live E. coli bacteria and
the increase in protein synthesis was more pronounced in the jejunum than in il-
eum, similar to our findings.
6
Interestingly, in those studies,
53
mucosal protein syn-
thesis was further stimulated in septic rats that were treated with glutamine-enriched
total parenteral nutrition.
In our previous experiments,
6
mucosal protein synthesis rates were measured by
using a flooding dose technique. Because that method measures total mucosal pro-
tein synthesis, it was not possible to delineate with cell type(s) were involved. In
addition to enterocytes, a number of other cell types are present in the intestinal
Fig. 7.5. The gut-liver axis. Substances synthesized by the gut may reach (and influ-
ence) the liver directly via the portal circulation. Reprinted with permission from
Hasselgren PO, in Cytokines and Abdominal Surgery, Schein M, Wise L, eds., Austin:
RG Landes, 1998:197-213.
115
7
mucosa, including endothelial cells, smooth muscle cells, lymphocytes, macroph-
ages and pericryptal myofibroblasts. To examine this issue, we measured protein
synthesis rates in enterocytes isolated from the jejunum of control and septic rats.
54
Results from those experiments suggest that sepsis stimulates protein synthesis in
enterocytes and that the effect of sepsis is particularly pronounced in crypt cell. In
other experiments in the same report, the subcutaneous injection of endotoxin in
rats gave rise to an almost identical metabolic response in jejunal enterocytes, indi-
cating that that findings in septic rats were not caused by the local effects of septic
peritonitis (induced by CLP), but that increased enterocyte protein synthesis is part
of the systemic response to sepsis.
Synthesis and Release of Secretory Proteins, Including Certain
Gut Peptides
When endogenous and secreted proteins were separately measured in enterocytes
isolated from the jejunum of control and septic rats, results showed that sepsis stimu-
lates the synthesis of both these classes of proteins (Fig. 7.6).
11
One important group
of proteins synthesized and released from the intestine are gastrointestinal hormones.
In previous studies, circulating levels of vasoactive intestinal peptide (VIP) were
increased during sepsis or endotoxemia. More recently, we found that plasma con-
centrations of VIP, peptide YY (PYY) and secretin were increased in septic rats.
Plasma levels of VIP and PYY were higher in portal than in peripheral blood, consis-
tent with a gut origin of these peptides.
To further elucidate the origin of gut peptides during sepsis, we measured the
release of PYY and VIP in isolated jejunal enterocytes .
11
The amount of VIP re-
leased into the incubation medium (determined by radioimmunoassay) was increased
10- to 15-fold in enterocytes from septic rats as compared with non-septic control
rats. Sepsis stimulated VIP release in enterocytes from different regions of the villi,
but the effect of sepsis was particularly pronounced in cells from the tips of the villi.
Table 7.1. Specific radioactivity of protein bound (S
B
) and tissue free (S
A
)
leucine and protein synthesis rate (K
S
) in mucosa of different parts
of the gastrointestinal tract of sham-operated and septic rats
Sham CLP
S
B
S
A
K
S
S
B
S
A
K
S
Stomach 0.430.03 986 655 0.220.03* 775 414*
Duodenum 0.560.03 873 944 0.760.04* 803 1395*
Jejunum 0.520.03 865 897 0.640.07* 814 1159*
Ileum 0.400.05 873 676 0.530.05* 876 917*
Ascending Colon 0.260.03 10314 405 0.560.07* 13913* 616*
Descending Colon 0.290.04 914 456 0.650.05* 13019* 748*
Rectum 0.410.04 9514 668 1.100.20* 13116* 12315*
S
B
and S
A
are given as dpm/nmol; K
S
is given as %/day
Protein synthesis rates in mucosa of different parts of the gastrointestinal tract were
determined following a flooding dose of
14
C-leucine. The studies were performed
16 h after sham-operation or CLP. Results are means SEM. The number of rats in
each group was eight. *p<0.05 vs sham. Reprinted with permission from
Higashiguchi T et al, Clin Sci 1994; 87:207-211.
116
7
Fig. 7.6. Effect of sepsis, induced by cecal ligation and puncture (CLP), on synthesis of
non-secreted (left panel) and secreted (right panel) proteins in jejunum of rats. Control
animals were sham-operated. *p<0.05 vs. corresponding sham-operated group. Based
on data in Higashiguchi T et al, Am J Surg 1994; 168:251-256.
117
7
The release of PYY from incubated enterocytes was also increased during sepsis, but
the changes were less pronounced than those for VIP. Studies using the protein
synthesis blocker cycloheximide suggested that the increased release of VIP and PYY
by enterocytes from septic rats reflected both stimulated de novo synthesis and re-
lease of preformed intracellular stores of the peptides. Thus, sepsis seems to stimu-
late both the synthesis and release of certain gut peptides.
Increased synthesis and release of gut peptides may have several important clini-
cal implications. Certain gut peptides may delay gastric emptying and impair intes-
tinal motility and may therefore play a role in the pathogenesis of abnormal
gastrointestinal motility during sepsis. VIP may stimulate glycogenolysis and lipoly-
sis during sepsis, and may also influence the hemodynamic changes induced by
sepsis through its vasodilatory and positive inotropic effects. In vitro experiments
have provided evidence that gut peptides may have a direct effect on enterocyte
metabolism. Other studies suggest that PYY may stimulate cellular proliferation in
the intestinal epithelium. Finally, because secreted gut peptides reach the liver at
high concentrations through the portal vein, it may be speculated that the peptides
influence hepatocellular functions. Thus, changes in intestinal protein synthesis
during sepsis may be important for the regulation of metabolic activity in the liver,
consistent with a functional gut-liver axis.
Sepsis and Mucosal Cytokine Production
Several lines of evidence suggest that the proteins secreted by the intestinal mu-
cosa during sepsis may include a wide variety of cytokines. In recent years, the gut
has been increasingly recognized as an important source of cytokines, during both
local and systemic inflammation.
33-35,47-49
There is evidence that enterocytes as well
as mononuclear cells in the lamina propria can produce cytokines.
34,35,49
In a previ-
ous report, endotoxemia in mice was associated with increased tissue levels of IL-1
in mucosa of small intestine and this increase in IL-1 production was regulated at
the transcriptional level.
47
Other studies have provided evidence that mucosal pro-
duction of TNF may also be increased during sepsis and endotoxemia.
Recent studies in our laboratory focused on the influence of sepsis and
endotoxemia on mucosal production of IL-6. Release of IL-6 from intestinal mu-
cosa may be of even greater significance than TNF and IL-1 considering the impor-
tant role of IL-6 in the regulation of acute phase protein synthesis, both in the liver
13
and locally in the intestinal mucosa.
8-10
Endotoxemia in mice resulted in increased
tissue levels of IL-6 in jejunal mucosa consistent with stimulated local production of
the cytokine (Fig 7.7, upper panel). Reverse transcriptase PCR analysis of RNA
extracted from jejunal mucosa demonstrated that the elevated mucosal IL-6 levels
were associated with increased IL-6 mRNA levels (Fig. 7.7, lower panel), consistent
with the concept that sepsis and endotoxemia may stimulate mucosal IL-6 produc-
tion at the transcriptional level.
33
The studies described above did not define in which cell type IL-6 production
was increased. In studies using cultured intestinal epithelial cells, we found evidence
that the enterocyte may be an important source of IL-6 during sepsis and
endotoxemia. Endotoxin treatment resulted in IL-6 protein and mRNA production
in IEC-6 cells (a rat intestinal epithelial cell line) in a time- and dose-dependent
fashion.
49
In Caco-2 cells, a human intestinal epithelial cell line, the pro-inflamma-
tory cytokine IL-1 stimulated IL-6 secretion into the culture medium (Fig. 7.8,
upper panel).
34
IL-6 mRNA levels were likewise increased, suggesting that
118
7
IL-1-induced IL-6 production is regulated at the transcriptional level (Fig. 7.8,
lower panel). In more recent studies utilizing examination of jejunal mucosa by
immunohistochemistry, we found that enterocytes, in addition to cells present in
the lamina propria, produced IL-6 in vivo during endotoxemia.
35
Thus, studies from our and other laboratories suggest that sepsis and endotoxemia
result in increased production in intestinal mucosa of TNF, IL-1, and IL-6 and that
the enterocyte may be an important source of cytokines in these conditions. Mu-
cosal production of cytokines is significant because they may influence enterocyte
metabolism locally in an autocrine or paracrine fashion. In addition, they may reach
the liver through the portal vein and may therefore influence the metabolic response
to sepsis in the liver.
Fig. 7.7 Effect of endotoxin (LPS) on IL-6 protein (upper panel) and mRNA levels (lower
panel) in jejunal mucosa as determined by ELISA and RT-PCR, respectively. *p<0.05 vs.
saline. -actin was used to control for equal mRNA loading. Reprinted with permission
from Meyer TA et al, Surgery 1995; 118:336-342.
119
7
Fig. 7.8. Effect of IL-1 on IL-6 protein (upper panel) and mRNA levels (lower panel) in
Caco-2 cells as determined by ELISA and RT-PCR, respectively. *p<0.05 vs. respective
control group. -actin was used to control for equal mRNA loading. Reprinted with
permission from Parikh AA et al, Shock 1997; 8:249-255.
120
7
Regulation of Cytokine Production in Intestinal Mucosa
Recent studies have examined the regulation of cytokine production in the
enterocyte and intestinal mucosa. Early experiments indicated that IL-6 production
in cultured intestinal epithelial cells was augmented by addition of other inflamma-
tory mediators to the culture medium. For example, prostaglandin E
2
interacted
synergistically with endotoxin to increase IL-6 production in IEC-6 cells
55
and in-
terferon- treatment augmented IL-1-induced IL-6 production in Caco-2 cells.
34
More recently, our and other laboratories have begun to explore the potential
role of transcription factors in cytokine and acute phase protein production in the
enterocyte and intestinal mucosa. Transcription factors are proteins that act to regu-
late gene transcription rates, leading to either increased or decreased transcription of
the target gene. A given transcription factor may influence the transcription of mul-
tiple genes, making these proteins attractive potential targets through which the
inflammatory response may be manipulated in a therapeutic fashion.
One transcription factor that my play an important role in the inflammatory
response of the intestinal mucosa to sepsis and endotoxemia is nuclear factor-kappa
B (NF-B). NF-B is a dimer consisting of various subunits, most commonly p50
and p65, and is normally sequestered in the cytoplasm in an inactive form by the
inhibitory protein IB (for review see ref. 56). Multiple proinflammatory media-
tors, including IL-1, LPS, and TNF-, can activate NF-B in different cell types.
Through various signaling pathways, these stimuli lead to phosphorylation of IB.
After phosphorylation, IB is ubiquitinated and degraded by the proteasome, free-
ing NF-B to translocate to the nucleus and bind to its target sequences. NF-B
activation is usually rapid, transient, and self-limited. In addition to other target
genes, NF-B also encourages transcription of the IB proteins, which then serve to
terminate NF-B activation and re-sequester NF-B in the cytoplasm. A simplified
diagram of the NF-B activation pathway is presented in Fig. 7.9.
Recent studies have examined NF-B activation in the enterocyte and intestinal
mucosa. Initial reports from this
57
and another
58
laboratory demonstrated that IB-
degradation and increased NF-B DNA binding activity occurred in cultured hu-
man intestinal epithelial cells after treatment with IL-1, concurrent with increased
expression of the NF-B-associated genes for IL-6 and IL-8. Subsequent studies
indicated that IB degradation and NF-B activation also occurred in cul-
tured intestinal epithelial cells in response to TNF-, LPS, bacterial adhesion,
and bacterial invasion.
Recent studies have begun to examine NF-B activation in the gastrointestinal
tract in vivo. In a report from our laboratory, the effect of endotoxin on IB-
protein levels and NF-B DNA binding activity was examined in jejunal mucosa.
59
We found that endotoxin injection resulted in rapid decrease in IB- levels, with a
concomitant increase in NF-B DNA binding activity, consistent with NF-B acti-
vation in this tissue (Fig. 7.10).
Additional experiments have indicated that NF-B activation varied in different
regions of the gastrointestinal mucosa during endotoxemia.
60
Interestingly, the je-
junum was the region most sensitive to endotoxemia, similar to our findings with
mucosal protein synthesis,
6
IL-6,
61
and complement C3 production.
62
In addition to NF-B, several other transcription factors likely play important
roles in regulating protein metabolism in intestinal mucosa during sepsis. We re-
cently found evidence that activating protein-1 (AP-1) and members of the C/EBP
transcription factor family, including CEBP- and CEBP-, are activated in cultured
121
7
intestinal epithelial cells in response to IL-1.
63,64
Further studies are needed to
determine the relative role of the different transcription factors in increased cytokine
and acute phase protein production in the enterocyte and intestinal mucosa during
acute inflammation.
The identification and characterization of the transcription factors activated in
the enterocyte and intestinal mucosa during sepsis may enable therapeutic modifi-
cation of the metabolic and inflammatory responses in gut mucosa. For example,
inhibition of NF-B activation by proteasome inhibitors resulted in decreased IL-8
production in cultured enterocytes. In other studies, treatment of cells with various
NF-B inhibitors decreased IL-1-induced IL-6 and complement component C3
Fig. 7.9. Schematic diagram showing the pathway leading to IB- degradation and
NF-B activation in response to pro-inflammatory stimuli. Reprinted with permission
from Perkins ND, Int J Biochem Cell Biol 1997; 29:1433-1448.
122
7
production.
65,66
The further modification of sepsis-induced changes in protein pro-
duction and metabolism will be an important goal for future work in this field.
Cytokines Induce a Sepsis-Like Response in Intestinal Mucosa
Several of the metabolic changes induced by sepsis and endotoxemia in intesti-
nal mucosa can be duplicated by cytokines. For example, administration of rIL-l
or rTNF- to rats resulted in increased protein synthesis in jejunal and ileal mucosa,
similar to the response seen during sepsis.
6
In other experiments, administration of
TNF in rats gave rise to increased portal plasma levels of PYY.
50
In contrast, no
changes in circulating gut peptide concentrations were noted following the admin-
istration of IL-1, suggesting a differential role of the two cytokines in the regulation
of gut peptide release.
For the interpretation of results seen following the administration of cytokines,
it is important to remember that cytokines interact with each other and with gluco-
corticoids. It is possible that metabolic changes observed following the administra-
tion of TNF are caused by IL-1, IL-6 and/or glucocorticoids since TNF induces the
release of other cytokines as well as glucocorticoids. Several of the in vitro studies
described above lend strong support to the concept that proinflammatory cytokines
are important mediators of metabolic changes in the enterocyte and that these changes
are caused by direct effects of the cytokines on the enterocyte.
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46. Frederick JA, Hasselgren PO, Davis S et al. Nitric oxide may upregulate in vivo
hepatic protein synthesis during endotoxemia. Arch Surg 1993; 128:152-157.
47. Mester M, Tompkins RG, Gelfand JA et al. Intestinal production of interleukin-
1 during endotoxemia in the mouse. J Surg Res 1993; 54:584-591.
48. Deitch EA, Xu D, Franko L et al. Evidence favoring the role of the gut as a cytokine-
generating organ in rats subjected to hemorrhagic shock. Shock 1994; 1:141-146.
49. Meyer TA, Noguchi Y, Ogle C et al. Endotoxin stimulates IL-6 production in
intestinal epithelial cells: A synergistic effect with PGE2. Arch Surg 1994;
129:1290-1295.
50. Zamir O, Hasselgren PO, Higashiguchi T et al. Effect of sepsis or cytokine admin-
istration on release of gut peptides. Am J Surg 1992; 163:181-185.
51. Higashiguchi T, Noguchi Y, OBrien W et al. Effect of sepsis on mucosal protein
synthesis in different parts of the gastrointestinal tract in rats. Clin Sci 1994;
87:207-211.
52. Lang CH, Bagby Gj, Ferguson JL et al. Cardiac output and redistribution of organ
blood flow in hypermetabolic sepsis. Am J Physiol 1984; 246:R331-R337.
53. Yoshida S, Leskiw MJ, Schluter MD et al. Effect of total parenteral nutrition,
systemic sepsis, and glutamine on gut mucosa in rats. Am J Physiol 1992;
263:E368-E373.
54. Higashiguchi T, Noguchi Y, Meyer T et al. Protein synthesis in isolated enterocytes
from septic or endotoxemic rats: regulation by glutamine. Clin Sci 1995;
89:316-319.
55. Meyer TA, Noguchi Y, Ogle C et al. Endotoxin stimulates IL-6 production in
intestinal epithelial cells: a synergistic effect with PGE
2
. Arch Surg 1994;
129:1290-1295.
56. Ghosh S, May MJ, Kopp EB. NF-B and Rel proteins: Evolutionarily conserved
mediators of immune response. Annu Rev Immunol 1998; 16:225-260.
57. Parikh A, Salzman A, Kane CD et al. IL-6 production in human intestinal epithe-
lial cells following stimulation with IL-1 is associated with activation of the tran-
scription factor NF-B. J Surg Res 1997; 69:139-144.
58. Jobin C, Haskill S. Mayer L et al. Evidence for altered regulation of IB degrada-
tion in human colonic epithelial cells. J Immunol 1997; 158:226-234.
59. Pritts TA, Moon MR, Fischer JE et al. Nuclear factor-B is activated in intestinal
mucosa during endotoxemia. Arch Surg 1998; 133:1311-1315.
60. Pritts TA, Moon MR, Wang Q et al. Activation of NF-B varies in different re-
gions of the gastrointestinal tract during endotoxemia. Shock 2000; 14:118-122.
61. Wang Q, Wang JJ, Boyce S et al. Endotoxemia and IL-1 stimulate mucosal IL-6
production in different parts of the gastrointestinal tract. J Surg Res 1998; 76:27-31.
62. Wang Q, Wang JJ, Fischer JE et al. Mucosal production of complement C3 and
serum amyloid A is differentially regulated in different parts of the gastrointestinal
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and IL-6 production is increased in IL-1-stimulated human enterocytes. Shock
2000; 14:386-391.
64. Hungness ES, Pritts TA, Luo G, Hasselgren PO. IL-1 activates C/EBP- and C/
EBP- in human enterocytes through a mitogen activated protein kinase (MAPK)
signaling pathway. Surg Forum 2000; 51:207-209.
65. Parikh, AA, Moon MR, Pritts TA et al. IL-1 induction of NF-B activation in
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66. Moon MR, Parikh AA, Pritts TA et al. Complement component C3 production in
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CHAPTER 8
Biochemical Assessment and Monitoring
of Nutritional Status
Robert S. DeChicco, Laura E. Matarese, Douglas Seidner and Ezra Steiger
The Incidence of Malnutrition
The prevalence of malnutrition in hospitalized patients ranges from 30 to 50%
(Table 8.1).
1-11
The incidence of malnutrition actually increases if patients are hospi-
talized for two or more weeks.
7
Although the criteria used to define malnutrition
and the types of patients and hospitals varies, the prevalence has remained relatively
constant throughout the years.
Malnutrition in the hospital setting has far-reaching implications. Malnutrition
has been associated with longer hospital stays,
7,13-17
delayed wound healing,
18-21
in-
creased morbidity and mortality,
1,7,11,13,17, 22-32
and ultimately, higher health care
costs.
15-17, 33-35
There is no clinical situation which benefits from malnutrition.
Methods of Nutrition Assessment
Changes in nutritional status, particularly in the critically ill patient, are often
subtle and influenced by many factors. It is important to have an objective assess-
ment tool to identify patients who are at nutritional risk and to document the effi-
cacy of therapy. Unfortunately, there is no single tool which can be used to identify
malnutrition. Thus, a variety of methods are used including patient history, physical
examination, anthropometric measurements, biochemical indices, and tests of im-
mune function.
History
The history comprises the basis of any assessment. For the purposes of determin-
ing nutritional status, the history can be divided into medical and nutrition. The
history should include an investigation of unexplained weight loss, abnormal or
inadequate nutrient intake, recent surgery or illness, chronic illness, and hypermeta-
bolic states (Table 8.2).
Malnutrition is classified as primary or secondary. Primary malnutrition results
from inadequate diet or excessive intake of certain nutrients (e.g., vitamins, calo-
ries). This type of malnutrition is generally a socioeconomic phenomenon but also
involves age, sex, and race. Secondary, or conditional malnutrition occurs when
nutrients are not absorbed or utilized appropriately, generally as a consequence of a
disease process. Causes of secondary malnutrition include the impaired ability to
ingest foods (e.g., esophageal cancer), the impaired ability to digest, absorb, or uti-
lize nutrients (e.g., Crohns disease, ulcerative colitis), and increased nutritional
127
Biochemical Assessment and Monitoring of Nutritional Status
8
requirements (e.g., sepsis, trauma). Nutritional deficiencies can also develop as a
result of drug-nutrient interactions.
The nutrition history should provide detailed information about the patients
general health, eating patterns, and nutrient intake. There are several methods avail-
able to assess nutrient intake including a 24-hour diet recall and a food frequency
questionnaire. The adequacy of the diet should be evaluated, usually by comparing
nutrient intake with estimated energy and protein requirements adjusted for disease
state, if necessary.
Physical Examination
Along with a medical and nutrition history, a physical examination is an essen-
tial component of a comprehensive nutrition assessment. A physical examination
consists of observing physical signs or symptoms that may be associated with nutri-
tional deficiencies (Tables 8.3 and 8.4). The appearance of symptoms of a nutri-
tional deficiency depends upon the specific nutrient in question. However, single
nutrient deficiencies are rare. An individual with symptoms of a single nutrient
deficiency is likely to have multiple deficiencies. Some fat soluble vitamins and min-
erals have body stores which require long periods, up to a year or longer, to become
depleted.
36
Conversely, some of the water soluble vitamins have more labile body
pools which result in physical manifestations of deficiencies after a much shorter
period, less than one month in some cases.
37
Recognizing signs of nutritional deficiencies requires experience and skill be-
cause the symptoms can vary in time of appearance and severity, and interpretation
of these symptoms can be affected by examiner and subject bias. Since most symp-
toms are non-specific and the criteria are not well-defined, there may be a lack of
consistency between observers.
Clinical Anthropometry and Body Composition Analysis
Anthropometry is the science in which the body is described by a series of mea-
surements of the external morphology. Anthropometry is used to assess nutritional
Table 8.1. The prevalence of malnutrition*
Investigator Date % Malnourished Patient Type Hospital Type
Bistrian et al
3
1974 50 General Surgical Urban Teaching
Bistrian et al
4
1976 44 or more General Medical Urban Teaching
Hill et al
5
1977 50 Surgical General Teaching
Mullen et al
6
1979 35 Elective Surgical Urban VA
Weisner et al
7
1979 48 on admission General Medical Teaching
69 after 2 weeks
Willard et al
8
1980 31.5 General Med/Surg Private
Community
Bastow et al
9
1983 53 Elderly Female University
Orthopedic
Sullivan et al
10
1989 39 Elderly General VA University
Medical/Surgical Affiliated
Coates et al
11
1993 38 on admission General Medical Teaching
48 after 2 weeks
* Adapted from: Mosner M and Bader S.
12
128
8
status and monitor the efficacy of therapy. Height, weight, skinfold and circumfer-
ence measurements are the most common anthropometric measurements used in
the clinical setting.
Height
Height (stature) can be obtained via recall from the patient of from the medical
archives but should be measured if possible because it is often misreported.
38
Accu-
rate assessment of stature is important because it is compared to weight to deter-
mine degree of adiposity and used in formulas to estimate energy and protein
requirements and to calculate creatinine height index and body mass index. There
are several methods available to measure height in nonambulatory patients.
39, 40
Frame Size
Frame size is useful in assessing body weight because it can affect weight inde-
pendent of stature and percent body fat. Frame size includes body width, muscular-
ity, bone thickness, and truncal length relative to weight.
41
There are several techniques
to estimate frame size including measurements of wrist circumference and elbow
breadth
42-44
although no consensus has been reached regarding the ideal method.
Weight
Weight can be used a gross estimate of muscle and adipose tissue stores. This
relationship is more meaningful when weight is corrected for height and frame size.
Serial measurements are also useful in monitoring the efficacy of nutrition therapy.
However, weight must be interpreted with caution since it may not accurately re-
flect an individuals body composition due to altered fluid status or tumor growth.
Weight is generally interpreted based on comparison with two parameters:
Table 8.2. Medical and nutrition history
Medical History
* Medication profile
* Diagnostic procedures
* Chronic illnesses
* Surgical procedures
* Weight history
Nutrition History
* Nausea/vomiting
* Anorexia
* Early satiety
* Dysgeusia
* Psychosocial history
* Previous dietary modifications and compliance
* Living conditions
* Ability to purchase and prepare food
* Food preferences
* Food allergies
* Use of vitamin/mineral supplements
* Alcohol intake
* Elimination habits
* Activity level
* Cultural/religious observances
129
8
1. The individuals usual or pre-morbid weight; and,
2. Ideal or desirable weight of a healthy population (Table 8.5).
The use of the term ideal or Adesirable in reference to weight is misleading
because there is no consensus regarding what set of values are truly ideal and these
values may change according to the population under study. In clinical practice,
ideal body weight is usually based on a set of established standards such as the Met-
ropolitan Life Insurance Company Height-Weight Tables
47
or calculated using the
following formula:
47
Males: allow 106 pounds for the first five feet of height and six pounds for
every additional inch
Females: allow 100 pounds for the first five feet of height and five pounds for
every additional inch
Ideal body weight should be adjusted for frame size by adding 10% for a large
frame and subtracting 10% for a small frame. Ideal body weight should also be
Table 8.3. Organ function alteration secondary to nutrient deficiencies
Cardiovascular Decreased RBC production
Decreased blood volume
Decreased cardiac output, stroke volume, and contractility
Decreased blood pressure
Decreased heart muscle mass
Decreased venous return
Bradycardia
Postural hypotension
Hemodilution
Anemia
Cutaneous Cheilosis, glossitis, ecchymosis, dermatosis, follicular
hyperkeratosis, petechiae
Gastrointestinal Decreased brush border enzymes
Maldigestion and malabsorption
Decreased mucosal cell integrity
Decreased bile production
Intestinal villus atrophy
Hepatic Decreased liver weight
Decreased visceral protein synthesis
Hepatic insufficiency
Fatty infiltration
Pulmonary Respiratory infections
Decreased functional, vital and maximum breathing capacities
Decreased response to hypoxia
Renal Decreased plasma flow
Reduced glomerular filtration rate
Decreased tubular function
Polyuria
Metabolic acidosis
Summarized from: Keys, A. Biology of Human Starvation and Torum B and Viteri
FE: Protein-calorie malnutrition. In: Shils M and Young V (eds). Modern Nutrition
in Health and Disease. Lea and Fibiger, 1988;746-773, and Baker JP, Detsky AS,
Wesson DE et al, N Engl J Med 1982;306(16):969.
130
8
adjusted for persons with amputations by subtracting the weight of the missing
body part as a percentage of the total weight.
48
Weight loss over time is another useful tool in assessing nutritional status be-
cause it reflects gross changes in energy and nitrogen balance and has a prognostic
Table 8.4. Physical signs of malnutrition
Body Part Symptoms/Signs Possible Deficiency
or System
Hair Lackluster, thinness, sparseness, Protein, protein-calorie, zinc,
dryness, dyspigmentation, easy copper, biotin
pluckability, texture change
Face Paleness, moon face (swollen), Riboflavin,niacin,pyridoxine,
greasy, scaling around nostrils iron
(nasolabial seborrhea)
Eyes Pale whites of eyes and eyelid lining Iron, vitamins A, C, and B12,
(pale conjuctivae), redness and riboflavin,pyridoxine, folate
fissuring of eyelid corners, dullness
and dryness (corneal or conjuctivae
(Bitots spots)
Mouth Angular redness, lesions or scars at Riboflavin,niacin,pyridoxine,
corners of mouth (stomatitis), iron
swelling and redness of lips and
mouth (cheilosis)
Tongue Smoothness, slickness (filiform Niacin, pyridoxine,riboflavin,
papillary atrophy), beefiness, vitamin B12, folate, iron
redness, pain (glossitis), swollen,
magenta color
Gums Swelling, sponginess, bleeding, Vitamin C
receding
Skin Dryness;scaling;lightening of skin Vitamins A, C, and K, zinc,
color often centrally on the face essential fatty acids, protein.
(diffuse pigmentation); rough,
goose-flesh skin (follicular hyper-
keratosis); small skin hemmorrhages
(petechiae); excessive bruising;
hyperpigmented patches that may
peel off, leaving superficial ulcers of
hypopigmented skin (flaky paint
dermatosis); edema, delayed
wound healing
Nails Spoon-shape (koilonychia), pale, Iron
brittle, ridged
Glands Enlarged thyroid or parotid Protein, iodine
Musculo- Bowlegs, knock knees, enlarged Protein-calorie, vitamins C
skeletal joints, hemorrhages, muscle and and D, calcium
fat wasting
Neurological Mental confusion, irritability, Thiamin, vitamin B12
psychomotor changes, motor
weakness, sensory loss
Nutrition Assessment. In: Manual of Clinical Dietetics, American Dietetic
Association, 1992:3-30.
131
8
value. An unintentional weight loss of 10% or greater within a period of six months
or less is considered severe.
49
Percent weight loss can be determined using the fol-
lowing formula:
Percent weight loss = usual body weightactual body weight x 100
usual body weight
Skinfold and Circumference Measurements
Skinfold and circumference measurements are indirect methods of estimating
body composition. These measurements are commonly used in the clinical setting
because they are simple, noninvasive, inexpensive, and require limited technical skill
from the observer or cooperation from the patient.
Skinfold measurements provide a gross estimate of body fat. The triceps skinfold
(TSF) is the most common site measured in the clinical setting. Circumference
measurements are used in estimating somatic protein stores. Results are compared
to sex and age standards, usually based on data from the National Health and Nutri-
tion Examination Survey. Results between the 15th and 85th percentiles are consid-
ered within the normal range. Patients with measurements below the 15th percentile
are at risk for nutritional depletion and above the 85th percentile are at risk for
obesity.
43
Alternatively, skinfolds can be compared with standards based on average
measurements for age and sex. A measurement 60-90% of the standard is consid-
ered a moderate nutritional deficit while less than 60% is considered severe.
45
An-
thropometry is specific but lacks sensitivity since skinfold and circumference
measurements change more slowly than other nutritional indices, making it diffi-
cult to detect short term changes.
Body Mass Index
Body mass index (BMI) is a method of evaluating body weight corrected for
height based on the assumption that it is correlated to degree of adiposity and corre-
sponding health risks associated with obesity
50, 51
(Table 8.6). The higher the BMI,
the greater the degree of body fat as a percentage of body weight.
53
BMI is not valid
in extremely muscular individuals or in cases in which weight is altered by fluid
status or pregnancy.
Table 8.5. Evaluation of weight
A. Percent usual body weight
Formula: Percent usual body weight = actual body weight x 100
usual body weight
Interpretation:
45
85-90% Mild nutritional depletion
75-84% Moderate nutritional depletion
< 75% Severe nutritional depletion
B. Percent ideal body weight
Formula: Percent ideal body weight = actual body weight x 100
ideal body weight
Interpretation:
45
200% Morbidly obese
130% Obese
110-120% Overweight
80-90% Mild malnutrition
70-79% Moderate malnutrition
69% Severe malnutrition
132
8
Direct Measurements of Body Composition
Body composition can be measured directly by a variety of methods such as
neutron activation and whole body conductivity but these tests usually require ex-
pensive equipment that is not widely available. These methods can be extremely
accurate compared with more traditional techniques of assessing body composition
in the clinical setting such as anthropometry. However, many of these methods have
been tested only in healthy individuals and their applicability to an ill population
remains in question. Radiographic techniques including ultrasound, computed to-
mography and magnetic resonance imaging have also been use to study body com-
position
54,55
and can provide cross-sectional images which clearly define muscle, fat,
and visceral organs. Since the images are cross-sections, these techniques are more
useful in determining regional fat distribution than overall body composition
Dual energy x-ray absorptiometry (DEXA) is emerging as an important technol-
ogy in the area of nutrition support and body composition analysis. It uses a
low-energy x-ray tube coupled to a filter that results in two energies of about 40 and
70 keV. DEXA provides independent assessments of bone mass, fat mass, and lean
body mass.
57
Creatinine Height Index (CHI)
Somatic protein stores can be estimated based on the amount of creatinine ex-
creted in the urine over a 24-hour period since creatinine is a byproduct of protein
metabolism and is excreted proportional to muscle mass. The actual amount of
creatinine excreted is compared to the amount of creatinine expected for sex and
height (Table 8.7). One method to determine expected creatinine is to use 23 mg/
kg for males and 18 mg/kg for females. There are several limitations of CHI which
prohibit its widespread use as a nutrition assessment tool. CHI requires an accurate
urine collection and can be affected by a number of non-nutritional factors such as
emotional stress, fever, and trauma.
Urinary 3-Methylhistidine
Measuring urinary 3-methylhistidine (3MH) is another biochemical method of
estimating somatic protein stores since 3MH is a nonrecyclable component of muscle
breakdown and excreted proportional to muscle mass. Similar to CHI, a valid test
requires adequate renal function and an accurate urine collection. Urinary 3MH is
not commonly used in clinical practice because it requires an amino acid analyzer
which is not widely available and no universally accepted standards exist for inter-
preting the results.
Table 8.6. Body mass index (BMI)
Formula: BMI = weight (kg)
height
2
(m)
Interpretation:
50,52
Males Females
Lean <18.5 <19.5
Normal 18.5 - 23.5 19.5 - 24.5
Excess weight >23.5 - 29.5 >24.5 - 29.5
Obese >29.5 > 29.5
133
8
Serum Proteins
Nutrition assessment parameters may be classified into somatic and visceral
compartments of the body. The somatic portion comprises primarily skeletal muscle
and adipose tissue; whereas, the visceral portion refers to the enzymatic and struc-
tural components of the remaining organ systems. Serum proteins such as albumin,
transferrin, prealbumin, and retinol binding protein, are commonly used to assess
the visceral protein compartment of the body, and recently other proteins such as
fibronectin and somatomedin-C have been studied in this capacity. Normal values
may vary slightly among laboratories but the results can help assess the degree of
malnutrition (Table 8.8).
Albumin
Serum albumin, produced by the liver, is the most abundant plasma protein,
representing approximately 60% of total body proteins. Albumin is necessary for
maintenance of oncotic pressure and functions as a carrier protein for zinc, magne-
sium, calcium, fatty acids and many drugs. Due to its large body pool and relatively
long half-life of 20 days, albumin is insensitive to acute changes in nutritional status
and is more reflective of chronic rather than acute protein depletion. Serum albu-
min concentration is commonly used as a screening indicator of nutritional status in
hospitalized patients since its measurement is routinely ordered, and it has been
shown to correlate with clinical outcome.
58,59
Caution should be exercised when evaluating albumin levels in stressed hospital-
ized patients because serum concentrations of albumin and other acute phase pro-
teins will decrease after trauma, surgery, or stress, primarily due to a redistribution
of albumin into extravascular compartments and through external losses of albumin
as in ascites, draining wounds, and burns. It is sometimes difficult to determine
whether a reduction in a patients serum albumin reflects protein-calorie malnutri-
tion or the metabolic response to trauma and stress. Plasma albumin levels will
generally not increase in stressed patients until the cause of the stress is removed.
Other non-nutritional causes of hypoalbuminemia include fluid overload, liver dis-
ease, infection, multiple myeloma, acute or chronic inflammation, hypervitamino-
sis A, and rheumatoid arthritis. Increased losses of albumin are seen in nephrotic
syndrome, protein-losing enteropathy, burns, and open wounds.
64
Exogenous albu-
min is sometimes used in critically ill patients to maintain fluid within the vascular
space. This results in a transient increase in the serum albumin level, thereby limit-
ing the use of serum albumin as a nutritional marker.
Transferrin
Transferrin is a beta globulin synthesized in the liver. Transferrin functions to
transport iron and prevents binding of gram negative bacteria with free iron. The
half-life of transferrin ranges from eight to ten days. Serum transferrin is thought to
Table 8.7. Creatinine height index (CHI)
Formula: % CHI = 24 hr urinary creatinine
ideal urinary creatinine
Interpretation:
49
90-100% Normal
60-80% Moderate malnutrition
< 60% Severe malnutrition
134
8
be a more sensitive indicator of acute changes in nutritional status compared with
albumin due to its shorter half-life and more rapid equilibration with the extravas-
cular compartment. Non-nutritional factors that can affect serum transferrin in-
clude pregnancy, iron deficiency anemia, blood transfusions, acute hepatitis, and
oral contraceptives.
42
Transferrin appears to be as effective as other visceral proteins
with shorter half-lives in assessing nutritional status. Levels of serum transferrin can
be obtained directly by radial immunodiffusion, or indirectly by measurement of
total iron-binding capacity as suggested by the following formula:
serum transferrin level = (0.8 x TIBC) - 43
Thyroxine-Binding Prealbumin
As a plasma transport protein, thyroxine-binding prealbumin (TBPA) carries
thyroxine and assists in the transport of retinol-binding protein (RBP). With a half-life
of 2.5 to 3.0 days, prealbumin responds rapidly to protein deprivation and rises
quickly with resumption of adequate intake. Since TBPA is synthesized in the liver
and degraded in the kidney, it is not valid in patients with severe hepatic or
renal insufficiency.
Retinol-Binding Protein (RBP)
Retinol-binding protein (RBP) is another plasma protein synthesized in the liver
and used as an indicator of visceral protein status. In addition to TBPA, RBP func-
tions to transport retinol, the alcohol form of vitamin A. With a half-life of 12
hours, RBP reflects acute changes in nutritional status. Plasma RBP is very sensitive
to calorie and protein restriction, however, measurement of RBP is reserved for
research purposes because it is difficult to obtain and is not practical for routine
clinical use.
Fibronectin (Fn)
Fibronectin (Fn) is a glycoprotein which functions in cell-to-cell adherence, cell
and tissue differentiation, wound healing, microvascular integrity, and the
opsonization of particulate. Endothelial cells, peritoneal macrophage, hepatocytes,
and fibroblasts are considered sites for synthesis of Fn. The half-life of Fn is 12
hours. Fn is considered a sensitive indicator of nutrition support and a potential
marker of visceral protein status because it increases regardless of the presence or
absence of inflammation. Fibronectin concentrations decline during starvation and
increase in response to refeeding in healthy subjects and hospitalized subjects receiv-
ing nutrition support.
61,62
Somatomedin-C
Somatomedin-C (SM-C), also called insulin-like growth factor-I (IGF-I), is a
peptide growth factor synthesized in the liver. SM-C is postulated to mediate the
growth promoting effects of growth hormone. Normal plasma concentrations of
Table 8.8. Standards for laboratory studies
57
Mildly Moderately Severely
Normal Depleted Depleted Depleted
Albumin (g/dL) 3.5-5.0 3.0-3.4 2.1-2.9 < 2.1
Transferrin (g/dL) 176-315 134-175 117-133 <117
Prealbumin (g/dL) 18-45 10-17 5-9 < 5
135
8
SM-C range from 1.0 to 1.7 U/mL. SM-C levels are low in chronically malnour-
ished as well as acutely starved patients and rapidly rise with refeeding.
63-65
Although
measurement of SM-C offers potential as a useful means of documenting the effi-
cacy of nutrition therapy, laboratory testing of this peptide is not routinely available.
Immunocompetence
Immunocompetence results from the interaction of three complex systems:
1. Cell-mediated immunity;
2. Humoral antibody response; and
3. Nonspecific immune response.
Protein-calorie malnutrition can compromise immune function and is the most
common cause of anergy in hospitalized patients.
66,67
Nutrition intervention has
been reported to reverse immunosuppression.
68,69
Total Lymphocyte Count (TLC)
The blood lymphocyte count has been recognized as one of the most simple and
reliable immunologic measurements of nutritional status. With protein malnutri-
tion, the TLC is reduced.
70
A reduced TLC has been associated with increased mor-
bidity and mortality in hospitalized patients.
28,70,71
Preoperative lymphocytopenia
has been identified as a risk factor in post-operative sepsis
72
and septic episodes in
thermally injured patients.
71
Factors other than malnutrition may cause or contrib-
ute to lymphocytopenia including pneumonia, sepsis, administration of
glucocorticosteroids and chemotherapeutic agents, as well as diseases of the immune
system.
60
TLC is obtained from a routine complete blood count with a differential
using the following formula:
TLC (mm
3
) = percent lymphocytes x white blood cell count
100
Delayed Cutaneous Hypersensitivity Skin Testing
Delayed cutaneous hypersensitivity skin testing (DHST) is an inexpensive, con-
venient, and widely available measure of cell-mediated immunity. Testing involves
an intradermal injection of an antigen to which the individual has been previously
exposed. Antigens generally utilized include: purified protein derivative (PPD), tri-
chophyton, candida albicans, and mumps. A positive reaction is considered an in-
duration of 5 mm or greater at 24 to 72 hours post-injection. Anergy is the absence
of a reaction to an antigen that normally would elicit a response. Immunocompe-
tence is generally classified as anergy, relative anergy, or normal.
Although higher rates of sepsis and mortality have been documented in anergic
patients compared with patients with a normal skin test response,
67,68
the utility of
skin testing in nutrition assessment remains unproven.
73
Many non-nutritional in-
fluences, such as administration technique, age of the patient, drugs, surgery, anes-
thesia, and presence of disease may affect DHST and must be considered when
evaluating an individuals response.
73
Prognostic Indices
Attempts to determine the value of various nutrition assessment parameters in
predicting clinical outcome has led to the development of prognostic indices. The
prognostic nutrition index (PNI) is a linear predictive model that relates the risk of
operative morbidity and mortality to nutrition status (Table 8.9).
23
The risk of compli-
cations and death increase with increasing PNI. The PNI model has been validated in
136
8
surgical patients; however, clinical usefulness in other patient groups is limited. The
Hospital Prognostic Index (HPI)
74
and Nutritional Risk Index (NRI)
75
are other
prognostic indices.
Assessment of Energy Requirements
Energy requirements are based on the age, sex, body build, activity level, and
disease state of an individual. Basal energy expenditure (BEE) is the energy required
to perform essential body functions such as respiration, cardiac function, and main-
tenance of body temperature. Resting energy expenditure (REE) is defined as the
energy expended at rest in a supine position and included physical and psychologi-
cal stress, and variations in ambient or body temperature. Measured REE is approxi-
mately 10% higher than BEE. Total energy expenditure (TEE) is comprised of REE,
diet-induced thermogenesis, shivering and non shivering thermogenesis, and physi-
cal activity. REE represents the major portion (i.e., 75-100%) of TEE in hospital-
ized patients. Energy needs may be assessed by direct and indirect calorimetry or
through use of predictive equations and nomograms.
Calorimetry
Direct calorimetry is the process of measuring heat production as the tempera-
ture change of a medium (e.g., water) and is reserved for research purposes because
it is expensive and time-consuming. Indirect calorimetry is the determination of
energy requirements by measuring oxygen consumption and carbon dioxide pro-
duction during respiratory gas exchange. Indirect calorimetry provides the clinician
with a measurement of energy expenditure and an assessment of substrate utiliza-
tion in the respiratory quotient (RQ). In hospitalized patients, REE is usually de-
rived from a 20 minute gas exchange measurement. Measurement of REE should be
done more than two hours post prandially in a thermoneutral environment. The
thermic effect of continuous enteral or parenteral nutrition is stable but should be
considered in interpreting the test. Measurements of O
2
consumption and CO
2
production are translated into REE by the Weir formula.
76
To account for other
activities during the day such as sitting in a chair, dressing changes, physical therapy,
and diurnal variations, REE is multiplied by 1.1 to 1.3 to determine TEE.
77
The RQ is the ratio of carbon dioxide produced to oxygen consumed (VCO
2
/
VO
2
). The physiologic range for RQ is 0.67 to 1.30 (Table 8.10).
78
Possible causes
for an RQ less than 0.71 include oxidation of ethanol or ketone bodies, lipolysis,
underfeeding, and hypoventilation. Reasons for an RQ greater than 1.0 include
hyperventilation, excess CO
2
production, hydrogen ion buffering by bicarbonate
generating carbon dioxide, lipogenesis, and overfeeding. If the RQ is equal to or
greater than 1.0, the total calories and/or carbohydrate should be decreased. If the
RQ is less than 0.8, total calories should be increased.
Predictive Equations
Over 190 equations to predict energy expenditure exist based on some combina-
tion of height, weight, age, and sex.
79
The Harris-Benedict equation
80
is frequently
used in clinical practice to estimate basal energy requirements (Table 8.11). The
Harris-Benedict is more reflective of REE than BEE and is usually multiplied by
activity and injury factors to determine TEE. The advantage of predictive equations
is that they are quick and easy to use without the need of expensive equipment.
However, they offer an estimate rather than a measurement of energy needs and can
be affected by the weight used in the calculation. Current or dry body weight should
137
8
be used unless the patient is considered obese (i.e., BMI 30 to 50). In obese patients,
an adjusted body weight (AdjBW) should be used in calculating energy expenditure
using the following formula:
82
AdjBW = [ (actual body weightideal body weight) 0.5] + ideal body weight
REE can also be estimated in patients with a pulmonary artery catheter by using
the Fick equation and the known caloric value of oxygen.
83
This requires the mea-
surement of cardiac output and arterial and mixed venous oxygen (Table 8.12). The
Fick equation has been correlated with indirect calorimetry
83
but requires an accu-
rate measurement of cardiac output and oxygen saturation and only provides a snap-
shot of energy expenditure at the moment the blood samples were drawn.
Assessment of Protein Requirements
Predictive Equations
There are several methods to estimate protein requirements. The requirement
for protein can be viewed as it relates to calorie needs. The nonprotein calorie to
nitrogen ratio (NPC:N) refers to the amount of nonprotein calories per gram of
nitrogen. In a typical oral diet, the NPC:N is 300:1. The greater the stress, the
higher the requirement for protein. Patients receiving parenteral nutrition may re-
quire 80 to 150 NPC/g N for tissue synthesis.
78
Protein may also be administered based on body weight and stress level (Table
8.13).
42
Adjustments in protein load should be made according to the patients clinical
response, and through monitoring laboratory and nitrogen balance techniques.
Nitrogen Balance
Nitrogen balance studies are utilized to assess protein requirements, stress level,
and efficacy of nutrition support therapy. Nitrogen lost in the urine measured from
Table 8.9. Prognostic nutritional index (PNI)
Formula: PNI % = 158 - 16.6 (ALB) - 0.78 (TSF) - 0.20 (TFN) - 5.8 (DH)
where ALB = serum albumin (g/dL)
TSF = triceps skinfold (mm)
TFN = serum transferrin (mg/dL)
DH = cutaneous delayed hypersensitivity reactivity to any of
the four recall antigens graded as 0 (nonreactive), 1
(< 5 mm induration), or 2 (> 5 mm induration).
Interpretation > 50 % = high risk
40 - 49 % = intermediate risk
<40% = low risk
Table 8.10. Respiratory quotient (RQ)
Substrate RQ
Alcohol 0.67
Fat 0.71
Protein 0.82
Mixed 0.85
Carbohydrate 1.00
138
8
a 24 hour urine urea nitrogen (UUN) is added to an estimate of nitrogen lost from
the skin, hair, nails, and GI tract and subtracted from nitrogen intake using the
following formula:
Nitrogen balance = Protein intake (g) (UUN + 2 to 4)
6.25
Additional nitrogen losses from draining wounds or burns must also be mea-
sured or estimated.
The goal of nitrogen balance is to be positive 2 to 4 g/d which is indicative of an
anabolic state and suggests accumulation of lean body mass (LBM). However, this
may be difficult to obtain in the critically ill patient. In these patients it may be
more realistic to strive for neutral balance or equilibrium which implies adequate
energy and protein support for preservation of LBM. A negative nitrogen balance
suggests a state of catabolism with progressive loss of LBM. Losses of 5 to 10 g/d
have been suggestive of mild catabolism, 10 to 15 g/d of moderate catabolism, and
more than 15 g/d of severe catabolism.
84
Determination of a valid nitrogen balance
is dependent primarily on an accurate urine collection and stable renal function.
Urea Kinetic Modeling
Urea kinetics is a pharmacokinetic model initially developed for use in hemodi-
alysis patients to assess protein balance and is based on the premise that the patients
protein catabolic rate is directly proportional to the rate of urea nitrogen genera-
tion.
85
Unlike the traditional nitrogen balance study in which urea measurements
become less accurate under conditions of renal insufficiency and changes in urea
pool, urea kinetic modeling accounts for the changing urea pool and allows for
changes in BUN and extrarenal losses or urea.
Urinary Nitrogen Appearance
Urinary nitrogen appearance (UNA) attempts to quantify changes in BUN and
is useful in clinical situations in which increased BUN levels and variations in weight
secondary to renal function exist.
86
This formula is applicable to measurements done
over one to three days and in dialysis patients during interdialytic interval. In stable
patients nitrogen balance may be estimated from the difference between nitrogen
Table 8.11. Estimating energy requirements
Basal Energy Expenditure (BEE)
Harris-Benedict Equation:
80
Men BEE (kcals/d) = 66.47 + (13.75 x W) + (5.0 x H) - (6.76 x A)
Women BEE (kcals/d) = 655.10 + (9.56 x W) + (1.75 x H) - (4.68 x A)
where W = weight in kg
H = height in cm
A = age in years
Activity and Injury Factors
81
Activity Factor: Confined to bed 1.2
Out of bed 1.3
Injury Factor: Minor surgery 1.2
Skeletal trauma 1.3
Major sepsis 1.6
Severe burns 2.1
139
8
intake and UNA. UNA is not an accurate reflection of total nitrogen output in
patients on peritoneal dialysis due to protein lost in the dialysate.
Determining an Endpoint of Nutrition Therapy
The purpose of the nutrition assessment is two-fold:
1. To determine the degree and type of malnutrition, and
2. To document the efficacy of therapy.
In resolving nutritional deficiencies, it is important to ensure that nutrients are
delivered safely and accurately in the amounts prescribed to meet the patients re-
quirements. This type of monitoring becomes integrated into the comprehensive
nutrition assessment. The amount of time required to improve nutritional status
will depend on the degree and type of malnutrition, surgical risk, medical treat-
ments and overall clinical course.
The follow-up assessment should occur at regular intervals (Fig. 8.3). The fre-
quency will depend on the depth of the assessment. For example, a daily assessment
of fluid and electrolyte status may be necessary for the patient receiving parenteral
nutrition; whereas an assessment of visceral protein status or lean muscle mass may
occur less frequently.
Monitoring the results of nutrition support requires the use of many nutrition
assessment parameters. The usefulness of each parameter will depend on the length
of time the patient is on nutrition support, the disease process and prior nutritional
status. Body weight is measured to monitor fluid status and effectiveness of nutri-
tion therapy. Although many patients gain weight during nutrition therapy, this
weight gain generally represents an increase in body water and adipose tissue rather
than lean body mass. Weight gain greater than a half pound per day probably repre-
sents fluid accumulation and not tissue synthesis. The composition of weight change
can be estimated if a nitrogen balance study is available using the following formula:
FFM = ( + g N balance x 6.25 g dry protein/g nitrogen) x 4.6 g FFM/g dry
protein
FM = ( + g body weight change) - ( + g FFM)
where FFM = fat free mass
FM = fat mass
+@ = gain or loss of that compartment
Table 8.12. Fick equation
CO = Hgb (SaO
2
- SvO
2
) x 95.18
where CO = cardiac output (L/min)
Hgb = hemoglobin
SaO
2
= arterial oxygen saturation
SvO
2
= mixed venous oxygen saturation
Table 8.13. Estimating protein requirements
No stress 0.7 to 0.8 g/kg/d
Mild stress 0.8 to 1.0 g/kg/d
Moderate stress 1.0 to 1.5 g/kg/d
Severe stress 1.5 to 2.0 g/kg/d
140
8
This is an estimate and will be influenced by fluid balance and accuracy of the
nitrogen balance study. Anthropometric measurements, although very specific, lack
the sensitivity to assess short-term changes in adipose tissue or lean body mass and
are more useful for monitoring long-term patients.
Energy and proteins requirements need to be reevaluated periodically to ensure
the patient is receiving adequate nutrition. The patients energy expenditure may
change during the course of nutrition therapy as clinical status changes. Protein
requirements can be assessed by performing a nitrogen balance study. For those
patients who do not have normal renal function, urea kinetics can be employed.
Changes in visceral proteins depend on their half-life, and total body pool. Se-
rum albumin, due to its relatively long half-life, may not return to normal levels
until well after nutrition support has been discontinued. Transferrin and
thyroxine-binding prealbumin are considered more sensitive nutritional markers
since each has a shorter half-life and smaller body pool than albumin. Total
Fig. 8.1. Reassessment of Nutritional Status. Adapted from Matarese LE. Reassessment
and determining an endpoint of therapy. Adapted from Dynamics of Nutrition Support.
Appleton-Century-Crofts, 1986.
141
8
lymphocyte count and delayed hypersensitivity skin testing has been corre-
lated with morbidity and mortality but both can be affected by a number of
non-nutritional factors.
Mineral and electrolyte imbalances can occur rapidly, especially in critical ill
patients receiving nonvolitional feeding. Clinical signs of vitamin and mineral defi-
ciencies as well as biochemical aberrations will reverse with therapeutic doses of the
limiting vitamin or mineral. However, the patients stores may take weeks to months
to replenish.
It is important to note that many patients will not return to normal or even
premorbid nutritional status until well after discharge. Because nutrition assessment
parameters are so nonspecific, one can not look for a single laboratory value or
parameter to determine the endpoint of therapy. While all of the parameters must
be evaluated within the context of the patients clinical condition, it is probably
more useful to look for trends in improving nutritional status.
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CHAPTER 1
CHAPTER 9
Optimizing Drug Therapy
Marcia L. Brackbill, Gretchen M. Brophy
Introduction
Recent clinical studies in surgical, trauma, and burn patients have demonstrated
the benefits of early initiation of enteral feedings over delayed enteral nutrition or
total parenteral nutrition (TPN).
1-7
Benefits include preservation of gut mucosa,
reduction of bacterial translocation, enhancement of immune function, improved
control of hypercatabolic state, reduction of septic complications, and improved
patient outcomes.
1-7
Surgical and endoscopic advancements allow health care prac-
titioners to place tubes for feeding access earlier in the hospital stay, with subsequent
initiation of enteral nutrition.
Although advantageous, enteral nutrition may be problematic. Critically ill pa-
tients receive numerous drugs that may directly effect the delivery of enteral formu-
las. Conversely, enteral formulas may alter the absorption of a drug, resulting in
clinically significant drug-nutrient interactions. Information regarding drug-enteral
nutrition interactions is sparse. Most of the literature consists of small pharmacoki-
netic studies and anecdotal case reports. A basic understanding of drug-nutrient
interactions and proper administration techniques will optimize drug therapy and
improve delivery of enteral feeds. This chapter will address clinically significant
drug-nutrient interactions in patients receiving enteral nutrition and provide sug-
gestions for avoiding these interactions. Specific guidelines for administering medi-
cations via feeding tubes are also provided.
Avoiding Tube Occlusions
Physical Incompatibilities
Physical incompatibilities between medications and enteral formulas may mani-
fest as a change in formula flow rate, texture, or viscosity; or cause separation or
precipitation of the formulation. One study evaluated the physical compatibility of
52 medications with Ensure
, Ensure Plus
, and Osmolite
.
8
Most suspensions,
elixirs, and emulsions were physically compatible with the enteral formulas. Medi-
cations known to be incompatible with enteral formulas are listed in Table 9.1.
Acidic syrups or those buffered to a pH below 4 were responsible for most physical
incompatibilities, which included gel formation and granulation of the enteral for-
mula. These incompatibilities resulted in consistent clogging of the feeding tube
146
9
and were not prevented by diluting the syrup with water or enteral formula. The use
of alternative dosage forms (i.e., tablets) is suggested in order to avoid problem
syrups.

To avoid physical incompatibilities, mixing of any medications with enteral
formulas is discouraged.
The investigators of one study evaluated the physical effects of a fiber-containing
formula (Enrich
), a nutrient-dense formula (TwoCal HN
), and an free amino

acid formula (Vivonex T.E.N.
) when mixed with 39 common pharmaceutical prepa-

rations.
9
Physical incompatibility was observed with 24 mixtures. All of the incom-
patibilities, except for one, resulted in clogged feeding tubes. Whole protein formulas
were incompatible with any preparation which contained iron, calcium, zinc or
phosphorus. Also, medications which lowered the pH of the enteral formula re-
sulted in protein precipitation, resulting in demulsification of the formula. Flushing
the tube with water before and after medication administration can be used to pre-
vent masses from forming in the tube.
High Viscosity Formulations
High viscosity formulations can cause tube occlusion if not properly diluted.
Medications reported to repeatedly clog tubes due to their high viscosity formula-
tions include psyllium, cholestyramine, co-trimoxazole suspension and clarithromycin
suspension.
10
Proper dilution and flushing allow for the administration of viscous
drugs via large bore feeding tubes, such as nasogastric or gastrostomy tubes. Avoid
administering these medications into small bore feeding tubes if other routes of
administration are available.
Enteral Formulas
Drugs are not always responsible for tube occlusions. One study determined the
in vitro clotting characteristics of frequently used enteral formulas.
11
Clotting was
primarily observed with intact protein formulas, resulting in tube occlusion within
36 hours. The investigators suggest that gastric acid-induced precipitation of pro-
teins in the enteral formulas may be an important factor in clotting. Intact protein
formulas are more likely to clot when acidified to a pH below 5; therefore, reflux of
gastric acid into the tube may cause formula precipitation. Flushing the feeding
tube before and after feeds will minimize the possibility of the enteral formula
Table 9.1. Medications physically incompatible with enteral formulas
8
Brompheniramine/phenylephrine elixir (Dimetane
)
Brompheniramine/phenylpropanolamine elixir (Dimetapp
)
Calcium glubionate syrup (Neo-Calglucon
)
Chlorpromazine concentrate (Thorazine
)
Ferrous sulfate elixir (Feosol
)
Guaifenesin elixir (Robitussin
)
Lithium citrate syrup (Cibalith-S
)
Medium chain triglyceride oil (MCT Oil
)
Methenamine suspension (Mandelamine Forte
)
Potassium chloride liquid 10% and 20%
Potassium chloride syrup (Klorvess
)
Pseudoephedrine syrup (Sudafed
)
Sodium bisphophate (Fleets Phospho-soda
)
Thioridazine oral solution (Mellarill
)
147
Optimizing Drug Therapy and Enteral Nutrition
9
occluding the tube. If the feeding tube frequently occludes and the patient is receiv-
ing an intact protein formula, consider moving the distal end of the feeding tube
into the small intestine.
11,12
Acid suppression therapy may be initiated to increase
the pH of the stomach and decrease the likelihood of further precipitation.
Non-Compatible Drug Formulations
Clogged feeding tubes are a major complication of physical incompatibilities. It
is common practice to crush tablets into fine particles and dissolve them with water
to ease administration through feeding tubes to avoid occlusion. Several solid dos-
age forms should never be crushed and administered via feeding tubes, these include
sublingual tablets, buccal preparations, encapsulated beads, extended-release and
controlled-release tablets, and wax matrix dosage forms. Physical alteration of any
medication before administration via a nasogastric tube will alter the drugs dissolu-
tion properties, ultimately affecting the bioavailability of the drug. Crushing
extended-release or controlled-release tablets for administration into an enteral tube
destroys the specialized matrix or enteric coating which convey the controlled-release
properties to the tablet or capsule. These medications are typically very difficult to
crush and result in rough, heterogeneous particles which may clog the feeding
tube. Another potential complication of administering extended-release or
controlled-release medications through a feeding tube is the possibility of toxic peak
concentrations and subtherapeutic trough concentrations later in the dosing inter-
val. Substitution of immediate-release products for controlled-release products will
prevent erratic serum concentrations and decrease the possibility of tube obstruc-
tion. Medications which should not be crushed are included in Table 9.2. A com-
prehensive list is published periodically in Hospital Pharmacy.
13
Methods of Restoring Tube Patency
Administration of an enzymatic solution into a clogged tube is an effective method
to restore tube patency.

In one study, a pancreatic enzyme solution was successful in
restoring tube patency in 96% of cases where the formula was believed to be the
cause of the occlusion.
14
The authors first injected 5 ml of warm water into the
feeding tube and capped it for 5 minutes. If the tube remained occluded, one tablet
of pancrelipase (Viokase
) and one tablet of sodium bicarbonate (324 mg) were

crushed and mixed in 5 ml of warm water. This enzyme solution was injected into
the tube and capped for 5 minutes. The enzymatic solution was gently flushed with
warm water using a 50 ml syringe. Administration of the enzyme solution at the site
of the occlusion may be necessary. Enzymatic disintegration appears to be most
effective when attempted within the first 24 hours of occlusion.
15
Other strategies that have been effective in unclogging enteral feeding tubes in-
clude administration of carbonated beverages, cranberry juice, or distilled water
into the clogged tube. A small amount of meat tenderizer diluted in water and
instilled into the nasogastric tube has also been used. None of these therapies appear
to be any more beneficial than administration of an enzymatic solution.
15
Recommendations to Avoid Occlusion
from Physical Incompatibilities
For medication administration through feeding tubes, it is important to dissolve
solid dosage forms and dilute the medication in approximately 30 ml of water, or
60-90 ml for viscous formulations. Flush the feeding tube with at least 15-30 ml of
148
9
warm tap water before and after medication administration. This procedure flushes
drug particles from the tube into the stomach or small intestine and minimizes the
number of drug particles exposed to the tubing. Water has been shown to be more
effective than cranberry juice as an irrigant to prevent clogged tubes and just as
effective as carbonated beverages.
15
When feasible, syrups, solutions, and elixirs should
replace solid tablets to decrease risk of tube occlusion.
Pharmacokinetic Interactions
A pharmacokinetic interaction occurs when enteral feeding alters the
bioavailability of medications. Decreased bioavailability may result in subtherapeutic
serum concentrations with inadequate clinical response. Medications with poten-
tially significant clinical interactions are phenytoin, carbamazepine and ciprofloxacin.
Table 9.2 Medications which should not be crushed or administered via
feeding tubes
13
Non-Crushable Medications (formulation)
Aspirin (EC)
Bisacodyl (EC)
Chlorpromazine (Spansule)
Diltiazem (CD, SR*)
Divalproex Sodium (Cap, EC)
Erythromycin (EC)
Felodipine (SR)
Glipizide (XL)
Guaifenesin (LA*)
Indomethacin (SR*)
Isosorbide Dinitrate (SR)
Lansoprazole*
(EC granules)
Lithium (CR, SR)
Methylphenidate (SR)
Metoprolol (XL)
Morphine (SR)
Nifedipine (XL)
Nitroglycerin (SL)
Omeprazole*
(EC granules)
Pancrelipase (EC)
Pentoxifylline (CR)
Potassium Chloride (XL)
Procainamide (SR)
Propranolol (LA)
Quinidine (Extentabs) Theophylline (ER)
Verapamil (SR)
EC = enteric coated SR = sustained-release XL = extended-release LA = long-acting
CR = controlled-release SL = sublingual
* Capsules may be opened and the contents may be administered via a nasogastric
tube without crushing
Special formulation for NG or J-tube administration

149
9
Phenytoin
Phenytoin is used in the critical care setting for seizure prophylaxis and treat-
ment. Oral dosage forms are preferred over intravenous dosage forms for maintenance
therapy because they are less likely to cause hypotension and thrombophlebitis. There
is a lack of data on the use of phenytoin capsules administered via enteral feeding
tubes. Phenytoin capsules are not recommended for tube administration, as crush-
ing the extended-release granules negates its sustained-release formulation and in-
creases the risk of tube occlusion due to poor dissolution of the medication. There is
evidence that continuous enteral feeding affects the phenytoin serum concentration
when using the suspension formulation. In one study, patients receiving simulta-
neous enteral feedings and phenytoin suspension displayed subtherapeutic pheny-
toin concentrations.
16
Discontinuation of enteral feedings resulted in therapeutic
phenytoin concentrations. In order to achieve higher phenytoin concentrations with-
out sacrificing the nutritional needs of the patients, the investigators held enteral
feeds 2 hours before and after phenytoin administration. This dosing technique
improved phenytoin concentrations; however, higher doses were also required. It
has been suggested that phenytoin binds to sodium caseinates, calcium caseinates
and calcium chloride found in enteral formulas.
17-19
Some researches have suggested
that the majority of phenytoin remains in its nonionized form under acidic condi-
tions in the stomach, allowing it to irreversibly bind to the nasogastric tubing.
20
Others support the phenytoin suspension-enteral formula interaction, but the exact
mechanism is still unknown.
21,22
Immediate-release phenytoin suspension should be used for enteral feeding tube
administration. One study evaluated the administration of phenytoin suspension
through a nasogastric tube using 10 different methods to simulate various patient
scenarios.
23
The suspension was administered undiluted and diluted with a variety
of irrigants, and phenytoin concentrations were subsequently measured. Lower se-
rum phenytoin concentrations were associated with the dosing methods that in-
volved no dilution or irrigation. The type of irrigation fluid did not appear to have
any influence on serum concentrations.
In order to optimize phenytoin and enteral nutrition administration, it is recom-
mended to administer the diluted suspension twice a day, holding enteral feeds for
one hour before and after each dose. The chapter authors assume that the
bioavailability of phenytoin suspension is 50-70% when administered via a feeding
tube and adjust doses accordingly. The rate of the enteral nutrition should be ad-
justed to ensure the patient is receiving adequate nutrition based on a 20 hour ver-
sus 24 hour period. This method is successful at maintaining therapeutic phenytoin
levels in critically ill patients. Phenytoin levels should be monitored closely when a
patient is receiving concomitant enteral feeds and phenytoin suspension, especially
when changes are made in phenytoin dose or enteral formula administration schedule.
Carbamazepine
Carbamazepine is an anticonvulsant used as a first-line agent for treating several
types of seizures. It is also used in pain syndromes, neurologic disorders, trigeminal
neuralgia, diabetes insipidus, bipolar disorder and schizophrenia. Carbamazepine
has a narrow therapeutic window, and requires serum level monitoring to guide
therapy. Controlled studies have shown that the bioavailability of carbamazepine is
compromised when administered through polyvinyl chloride (PVC) feeding tubes.
24,25
One study found a significant loss of carbamazepine during an in vitro study when
150
9
undiluted carbamazepine suspension was administered through PVC nasogastric
tubes.
25
No significant drug loss was reported with administration of diluted
carbamazepine suspension through the nasogastric tubes. The study investigators
postulate that carbamazepine binds to the PVC feeding tube and recommended
that carbamazepine suspension be mixed with an equal volume of diluent before
nasogastric tube administration.
Ciprofloxacin
Ciprofloxacin, a fluoroquinolone antimicrobial, is effective in the treatment of a
variety of gram-positive and gram-negative bacterial infections. It is available in
intravenous and oral dosage forms; however, oral ciprofloxacin has its drawbacks.
These formulations chelate a variety of multivalent cations, such as iron, magne-
sium, calcium, aluminum and zinc; markedly decreasing ciprofloxacin absorption.
26
One study showed a reduction in the bioavailability of ciprofloxacin from 67% to
27% in patients given enteral feedings orally, via gastrostomy and via jejunostomy
tubes.
27
Maximum serum ciprofloxacin concentrations were measured and corre-
sponding values for area under the concentration-time curve were calculated for
each of the treatment groups. The authors of this study suggest that the decreased
absorption caused by enteral feedings may be clinically important, especially when
enteral feedings and ciprofloxacin are co-administered by the oral or jejunostomy
routes. Another investigator examined the oral bioavailabilities of ciprofloxacin and
ofloxacin when they were co-administered with water or Ensure
formula.
28
Area
under the concentration-time curves, maximum serum concentrations and absorp-
tion were significantly reduced by Ensure
when compared to water. The Ensure
formula reduced the absorption of ciprofloxacin significantly more than the ofloxacin.
Subsequent studies evaluating the ciprofloxacin-enteral formula interaction have
not confirmed these findings. A study evaluated the bioavailability of ciprofloxacin
administered three ways: orally, through a nasogastric tube without enteral feeds,
and through a nasogastric tube while receiving enteral feeds.
29
No statistically sig-
nificant difference between treatment groups were found in terms of area under the
curve, maximum concentration in the serum, and time to peak concentration. An-
other study evaluated several pharmacokinetic properties in critically ill patients
receiving 750 mg of ciprofloxacin every 12 hours via nasogastric tube with enteral
feedings.
30
Although the absorption of ciprofloxacin was decreased, the serum con-
centrations of ciprofloxacin were well above the minimum inhibitory concentra-
tions for many pathogenic organisms.
Published studies suggest that the bioavailability of ciprofloxacin is variable in
patients receiving enteral nutrition. It is recommended to give ciprofloxacin 1 hour
before and 2 hours after bolus nasogastric feeds and separate the dose from any
cation administration. If a patient is on continuous feedings and not responding to
ciprofloxacin therapy, especially when treating a ciprofloxacin sensitive organism, it
may be reasonable to hold tube feeds for 1 hour before and after ciprofloxacin ad-
ministration or switch to an intravenous formulation. The enteral tube feeding rate
should be adjusted to meet the patients nutritional goals if tube feeds are held for
medication administration.
Pharmacodynamic Interactions
A pharmacodynamic interaction is one in which the effects of a drug are altered,
in this scenario because of enteral nutrition. There are many case reports of warfarin
151
9
resistance in patients who receive concomitant warfarin and enteral feedings.
31-34
Researchers have shown that patients receiving enteral feedings require higher doses
of warfarin to achieve therapeutic effects and a reduction in dose is necessary when
feeds are discontinued.
32
Investigators originally postulated that warfarin resistance
was due to inhibition of warfarin by excessive amounts of vitamin K in enteral
formulas. Manufacturers have reformulated most enteral formulas to contain only
small amounts of vitamin K; however, warfarin resistance remains a problem. Newer
evidence now suggests that warfarin is bound to several components of enteral for-
mulas, such as soy protein or proteinaceous caseinate salts.
35
Warfarin malabsorp-
tion has also been proposed as a possible mechanism of warfarin resistance.
36
When approaching this problem, clinicians should first consider the quantity of
vitamin K present in the enteral formula being administered. The vitamin K con-
tent/1000 ml of selected commercially available enteral formulas and are listed in
Table 9.3. Vitamin K can antagonize the pharmacologic effect of warfarin in doses
as low as 140 micrograms/day.
31,34
Therefore, vitamin K intake < 140 micrograms/
day will optimize effect in a warfarin resistant patient. Minimizing protein in the
enteral formula may also be prudent as warfarin is highly protein bound. Monitor-
ing INR is essential when titrating warfarin or changing the enteral feeding formu-
lation or regimen.
Influence of Tube Placement on Drug Efficacy
A small number of medications require a specific pH to be absorbed and an
understanding of these drug characteristics is crucial to prevent drug therapy failure.
Ketoconazole (Nizoral
), an imidazole antifungal agent, requires an acidic pH to be

absorbed. Administration into the small intestine or into a buffered gastric environ-
ment will render this drug ineffective. Ketoconazole should be administered on an
empty stomach to ensure an acidic environment for adequate absorption. For jejun-
ostomy tube administration, an acidic fluid may be mixed with Ketoconazole for
administration into the tube. Hydrochloric acid and acidic beverages, such as
Coca-Cola
, are suitable aqueous fluids and have been used successfully to improve
Ketoconazole absorption.
37,38
The absorption of itraconazole, a triazole antifungal,
is dependent upon the dosage form being used. Itraconazole capsule absorption
requires an acidic pH. The capsules should be opened and dissolved and given into
the stomach with enteral feedings to improve solubility and absorption. Clinically
significant differences in bioavailability occur if not given with food.
39,40
Itraconazole
oral solution absorption is not pH dependent, can be given via nasogastric or jejun-
ostomy tube and should be separated from enteral feedings. Fasting conditions are
not required, but such conditions will increase bioavailability.
40
Sucralfate is an oral anti-ulcer agent commonly used to prevent upper gastrointes-
tinal bleeding in ventilated patients in the ICU setting. It works by binding to pro-
teins in the stomach, forming a protective barrier over ulcers. Sucralfate can bind to
the protein components of enteral formulas and form insoluble complexes. It has
been implicated in causing bezoar formation in patients receiving enteral feeds
(Isocal
).
41,42
Not all patients receiving sucralfate appear to be at risk.
42,43
Sucralfate
should be administered directly into the stomach via a nasogastric tube or gastros-
tomy tube at least one hour before an enteral feeding, to facilitate drug binding to
the stomach. Sucralfate should not be administered into the small intestine as it will
fail to provide any clinical benefit.
152
9
Lansoprazole and omeprazole are proton pump inhibitors used for gastrointesti-
nal bleeding in ventilated patients and have special administration issues in patients
with feeding tubes. These drugs are available as capsules which contain acid labile
enteric-coated granules designed to dissolve in the alkaline environment of the small
intestine. When the enteric-coated granules are placed in water, the granules be-
come soft, sticky, and clump together; greatly increasing the possibility of tube ob-
struction. To avoid tube obstruction with lansoprazole, mix the uncrushed
enteric-coated granules with 40 ml of apple juice and administer into the nasogastric
tube.
44
Flush the tube with an additional 40 ml of apple juice to make sure the
granules enter the stomach. The apple juice is acidic and will not affect the enteric
coated granules; therefore, drug bioavailability is not compromised. Omeprazole
pellets have been successfully administered through a jejunostomy tube after the
omeprazole pellets were crushed and dissolved in a sodium bicarbonate solution (8
mmol/50 ml).
45
Another study evaluated nasogastric administration of omeprazole.
46
In this study, omeprazole pellets were dissolved in a syringe with 20 ml of 8.4%
sodium bicarbonate injection. The nasogastric tube was flushed with 20 ml of wa-
ter, the dose was administered, and the nasogastric tube was clamped for an hour.
Data demonstrate that both omeprazole and lansoprazole formulations can be ad-
ministered via the nasogastric and jejunostomy routes.
Optimizing Tolerance to Enteral Nutrition and Drug Therapy
Gastric Residuals
Increased gastric residuals are a possible manifestation of formula intolerance.
Under these circumstances, prokinetic agents, such as metoclopramide (Reglan
)
and erythromycin (E-mycin
) are used to increase gastric emptying. Although dis-

ease conditions, trauma, or surgical interventions may be the cause of decreased
gastric emptying, drug causes must also be ruled out. There are many drugs which
Table 9.3. Vitamin K content of selected commercially available
enteral formulas
Formula Vitamin K Content Formula Vitamin K Content
(g/1000 ml) (g/1000 ml)
Kindercal 32 Ensure Plus 83
Vivonex TEN 40 Pulmocare 85
Vivonex Plus 44 Nepro 85
Nutren 1.0 50 Boost with Fiber 97
Replete 50 Nutren 2.0 100
Glytrol 50 Isocal HN 106
Respalor 56 Magnacal Renal 118
Glucerna 57 Protain XL 12
Jevity 61 Boost 125
Boost Plus 68 TraumaCal 127
Ultracal 68 Criticare HN 131
Nutren 1.5 75 Isocal 132
Nutrivent 75 Comply 144
Probalance 80 Promote 180
Subdue 83 Deliver 250
Ensure 83
153
9
may decrease the rate of gastric smooth muscle contraction, including antihista-
mines, scopolamine, atropine, phenothiazines, propantheline, tricyclic antidepres-
sants, narcotic analgesics, alcohol, aluminum hydroxide, amino acids, glucagon, and
acidic solutions (i.e. fruit juices). There are also drugs which promote smooth muscle
relaxation and decrease gastrointestinal contractions, these include antihypertensive
agents (i.e. calcium channel blockers), antacids, hypnotics, anesthetic agents, and
antiparkinsonian drugs. Drug causes of decreased gastric motility should always be
considered or the nutritional needs of the patient may be unnecessarily compromised.
Gastrointestinal Adverse Effects
Although enteral feeding is beneficial, gastrointestinal adverse effects sometimes
present due to formula intolerance and include cramping, distension, vomiting and
diarrhea. Researchers report the incidence of diarrhea in critically ill tube fed pa-
tients as high as 68%.
47
However, there are many reasons a patient may develop
diarrhea other than feeding intolerance, these include increased gastric emptying
rate, clostridium difficile GI infections, low fiber or high osmolality formulas, and
drugs. It is important to look for each of these causes as enteral formulas may be
erroneously blamed for diarrhea and wrongfully stopped.
Diarrhea is a side of effect of many medications, such as magnesium containing
salts and antacids, electrolyte solutions (potassium chloride, sodium phosphate, po-
tassium phosphate), laxatives, colchicine, quinidine, cholinergic agents, and others.
However, the most common cause of diarrhea in the hospital setting may be sorbitol
containing medications. Sorbitol is commonly used in the pharmaceutical industry
as a sweetening agent with its primary drawback being an osmotic diarrhea. Sorbitol
may cause gastrointestinal distress in the form of cramping and diarrhea in amounts
of 10 to 20 g.
48
In one study, intake of sorbitol was attributed to at least 48% of the
causes of diarrhea in patients receiving tube feeding.
49
Diarrhea resolved in every
case when the sorbitol medications were discontinued.

The sorbitol content may be
highly variable depending on the manufacturer. Sorbitol is considered an inactive
ingredient so the amounts of sorbitol in various products are not always readily
available. Commonly used drugs with high concentrations of sorbitol include ac-
etaminophen elixir, Mylanta
suspension, codeine phosphate solution, theophyl-

line elixir, cimetidine solution, diazepam solution, digoxin elixir, lithium syrup,
metoclopramide syrup, sodium polystyrene sulfonate, carbamazepine, guaifenesin,
and aminophylline solution.
50
Administration of high osmolality medications into a feeding tube without ad-
equate dilution is another cause of diarrhea and cramping. Osmolality is the mea-
sure of the number and size of particles per kilogram of solution.
51
The osmolality of
a normal gastrointestinal tract ranges from 127-357 mOsm/kg and administration
of liquid medications with higher osmolalities through a feeding tube will typically
result in an osmotic diarrhea.
51,52
Hypertonic medications should be diluted with
60-90 ml of water before administration into the feeding tube to avoid this compli-
cation. Commonly used hypertonic medications are presented in Table 9.4.
Summary
Many potential interactions may occur between medications and enteral nutri-
tion making it difficult to optimize the management of the critically ill patient.
Physical incompatibilities, pharmacokinetic and pharmacodynamic interactions, tube
placement and tolerance issues need to be considered. The efficacy of the medications
154
9
administered, as well as the nutritional goals of the patient, may be compromised if
undetected. A basic understanding of potential interactions, proper administration
techniques and a multidisciplinary approach may improve drug and nutrition deliv-
ery. Critical care practitioners need to be aware of these drug-nutrient interactions
and take the necessary steps for prevention.
Summary Guidelines for Medication Administration
via Feeding Tubes:
1. Tube feeds should be stopped prior to administration of medications.
The tube should be flushed with 30 ml of tap water BEFORE and AF-
TER each medication is administered.
Table 9.4. Osmolalities of selected commercially available drugs
53
Product Average Osmolality
(mOsm/kg)
Acetaminophen elixir 5400
Acetaminophen with codeine 4700
Amoxicillin suspension 2250
Ampicillin suspension 2250
Cascara aromatic extract 1000
Cephalexin 1950
Cimetidine solution 5500
Co-trimoxazole suspension 2200
Dexamethasone solution 3100
Dextromethorphan syrup 5950
Digoxin elixir 1350
Diphenhydramine HCl elixir 850
Diphenoxylate/atropine susp. 8800
Docusate sodium syrup 3900
Erythromycin E.S. susp. 1750
Ferrous sulfate liquid 4700
Furosemide solution 2050
Haloperidol concentrate 500
Hydroxyzine syrup 4450
Kaolin-pectin suspension 900
Lactulose syrup 3600
Lithium citrate syrup 6850
Magnesium citrate solution 1000
Metoclopramide HCl syrup 8350
Milk of magnesia suspension 1250
Multivitamin liquid 5700
Nystatin suspension 3300
Paregoric tincture 1350
Phenytoin sodium suspension 1500
Potassium chloride liquid 3550
Potassium iodide sat sol (SSKI) 10950
Prochlorperazine syrup 3250
Promethazine HCl syrup 3500
Sodium phosphate liquid 7250
Theophylline solution 800
Thioridazine suspension 2050
155
9
2. Medications should be crushed, dissolved, and DILUTED with 30-60
ml tap water (with the exception of proton pump inhibitors which have
specific administration guidelines)
3. Liquid medications should be DILUTED with 30-60 ml of tap water
prior to administration. Hypertonic medications should be administered
with 60-90 ml of tap water.
4. Medications should be administered SEPARATELY. If multiple medica-
tions must be administered, the tube should be flushed with at least 15
ml of tap water between medications.
5. Medications should NOT be mixed with enteral feeds, especially syrups.
6. Specific drug considerations:
a. Hold tube feeding 1 hour before and after phenytoin dose and
adjust phenytoin for decreased bioavailability when given via feed-
ing tube (assume 50-70% bioavailability)
b. Never crush sustained or extended-release preparations
c. Sucralfate, omeprazole*, lansoprazole*, antacids, iron salts,
Ketoconazole, and itraconazole capsules should only be adminis-
tered into the gastric ports of feeding tubes
(*special formulations for NG or J tube administration)
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32. Howard PA, Hannaman KN. Warfarin resistance linked to enteral nutrition prod-
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33. Watson AJM, Pegg M, Green JRB. Enteral feeds may antagonize warfarin. BMJ
1984; 288:557.
34. Parr MD, Record KE, Griffith GL et al. Effect of enteral nutrition on warfarin
therapy (letter). Clin Pharm 1982; 1:274-276.
35. Kuhn TA, Garnett WR, Wells BK et al. Recovery of warfarin from an enteral
nutrient formula. Am J Hosp Pharm 1989; 46:1395-1399.
36. Martin JE, Lutomski DM. Warfarin resistance and enteral feedings. JPEN 1989;
13:206-208.
37. Chin TW et al. Effects of an acidic beverage (Coca Cola) on absorption of
Ketoconazole. Antimicrob Agents Chemother 1995; 39(8):1671-5.
38. Miyagawa CI. Hydrochloric acid given with Ketoconazole through a jejunostomy
tube. Clin Pharm 1984; 3(2):205-207.
39. Van Peer A, Woestenborghs R, Heykants J et al. The effects of food and soe on the
oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol
1989; 36:423-426.
40. Product Information. Sporanox, itraconazole. Titusville: Janssen Pharmaceutica
Inc., 1997.
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41. Algozzine GJ, Hill G, Scoggins WG et al. Sucralfate bezoar. N Engl J Med 1983;
309:1387.
42. Quigley MA, Flicker M, Caldwell EG. Sucralfate bezoar-theory or fact? (letter).
Am J Gastroenterol 1986; 81:724.
43. Reddy AN. Reply to Quigley et al (letter). Am J Gastroenterol 1986; 81:725.
44. Chun AHC, Shi HH, Achari R et al. Lansoprazole: Administration of the contents
of a capsule dosage formulation through a nasogastric tube. Clin Therapeutics
1996; 18(5):833-842.
45. Woods DJ, McClintock AD. Omeprazole administration (letter). Ann
Pharmacother 1993; 27:651.
46. Phillips JO, Metzler MH, Palmieri TL et al. A prospective study of simplified
omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit
Care Med 1996; 24(11):1793-1799.
47. Kelly TWJ, Patrick MR, Hillman KM. Study of diarrhea in critically ill patients.
Crit Care Med 1983; 11:7.
48. Hyams JS. Sorbitol intolerance: an unappreciated cause of functional gastrointes-
tinal complaints. Gastroenterology 1983; 84:30-33.
49. Edes TE, Walk BE, Austin JL. Diarrhea in tube-fed pateints: feeding formula not
necessarily the cause. Am J Med 1990; 88:91-93.
50. Lutmoski DM, Gore ML, Wright SM et al. Sorbitol content of selected oral liq-
uids. Ann Pharmacother 1993; 27:269-274.
51. Estoup M. Approaches and limitations of medication delivery in patients with
enteral feeding tubes. Crit Care Nurse 1994; 14:68-81.
52. Niemiec P, Vanderveen TW, Morrison JI et al. Gastrointestinal disorders caused by
medication and electrolyte solution osmolality during enteral nutrition. JPEN 1983;
7:387-389.
53. Dickerson RN, Melnick G. Osmolaltiy of oral drug solutions and suspension. Am
J Hosp Pharm 1988; 45:832-834.
CHAPTER 10
Techniques and Monitoring of Total
Parenteral Nutrition
Renee Piazza-Barnett, Laura E. Matarese, Douglas L. Seidner
and Ezra Steiger
Introduction
This chapter discusses the techniques of Total parenteral nutrition (TPN), which
include the provision of macro- and micro-nutrients and the various routes of access
used for TPN delivery. Also reviewed are the appropriate monitoring parameters for
minimizing TPN-associated complications. Finally, the short- and long-term compli-
cations of TPN are discussed and how these complications may be prevented
and managed.
Macronutrients
TPN formulas are composed of amino acids, carbohydrate, and fat in ratios
tailored to meet the needs of the individual patient.
1
The patients clinical status and
institutional factors determine the type of delivery system used. A two-in-one sys-
tem is a dextrose-amino acid combination with lipids infused separately. A
three-in-one or a total nutrient admixture (TNA) combines dextrose, amino acids,
and lipids in a single container. Lipid-based solutions are indicated in situations
where restricting the carbohydrate load is desirable, such as in patients with persis-
tent hyperglycemia or hypercapnia. Lipids are more expensive than dextrose and
admixing fat creates concerns regarding the stability of the emulsion and compat-
ibility with other additives.
2
The TPN prescription begins with calculation of protein, energy, and fluid
requirements.
Amino Acids
The primary function of protein in parenteral nutrition is to achieve nitrogen
equilibrium, thus preventing skeletal muscle from being degraded for gluconeogen-
esis.
1
Crystalline amino acids provide a balanced mixture of essential and nonessen-
tial amino acids. They are available in concentrations ranging from 3.5% to 15%,
with the dilute solutions most often used for peripheral administration and the
more concentrated solutions used for central administration. Modified amino acid
products have been developed for renal failure, hepatic failure, and metabolic stress.
Carbohydrate
Parenteral carbohydrates are provided as anhydrous dextrose monohydrate in
sterile water and are usually the primary calorie source in parenteral nutrition. The
159
Techniques and Monitoring of Total Parenteral Nutrition
10
concentration of parenteral dextrose solutions ranges from 5% to 70% and contain
3.4 calories per gram of dextrose.
The minimum amount of carbohydrate that has been found to be necessary to
suppress gluconeogenesis, and therefore protein catabolism, has been found to be
100 grams per day. The maximum oxidative rate for glucose is 5 mg/kg /minute
3
or
approximately 500 gm/day for a 70 kg patient. For critically ill patients it is sug-
gested that carbohydrate intake be reduced to a maximum 4 mg/kg/ minute
4
or
approximately 400 gm/day for a 70 kg patient.
Lipid
Intravenous lipid emulsions are composed principally of long-chain triglycer-
ides. They contain soybean or safflower oil as a source of polyunsaturated fatty ac-
ids, egg phospholipid as an emulsifier, and water. Glycerol is added to make the
emulsion isotonic. A 10% lipid emulsion provides 1.1 kcal/mL, a 20% lipid emul-
sion provides 2.0 kcal/mL, and a 30% lipid emulsion provides 3.0 kcal/mL.
Parenteral lipids provide a source of essential fatty acids and calories. They can
be substituted for dextrose calories for patients with glucose intolerance or used as a
concentrated calorie source for patients requiring volume restriction.
1
Intravenous
lipid emulsion is used as the primary source of calories in a parenteral nutrition
formula delivered by a peripheral vein (see Section on Peripheral Access).
Fluid
When patients are started on nutrition support and are converted to an anabolic
state, endogenous water production is decreased and daily requirements for exog-
enous fluids are increased.
5
The following factors need to be considered when deter-
mining a patients fluid requirements: provision of maintenance requirements,
correction of imbalances, replacement of ongoing losses, and extra fluid for anabo-
lism. See Table 10.1 for calculation of fluid requirements.
Micronutrients/Additives
Electrolytes
Electrolyte requirements will vary among individuals and will depend on the
patients current metabolic status as well as their underlying disease process.
2
See
Table 10.2 for daily electrolyte requirements for patients with adequate renal func-
tion receiving TPN. Appropriate electrolyte modifications will be discussed under
Micronutrient-Related Complications.
Vitamins
Adequate quantities of vitamins are required daily for the effective utilization of
nutrients (see Table 10.3). Patients receiving nutrition support may have increased
vitamin requirements because they are often highly stressed, catabolic, and are re-
ceiving high caloric and protein loads.
2
Trace Elements
Parenteral trace element injections are commercially available to provide mul-
tiple trace elements or individual nutrients. See Table 10.4 for trace element require-
ments in adults receiving TPN.
160
10
Zinc
Zinc is essential for more than 90 enzyme reactions involving energy, carbohy-
drate metabolism, protein synthesis and degradation, nucleic acid synthesis, heme
biosynthesis and carbon dioxide transport. The amount of parenteral zinc recom-
mended for a stable adult patient is 2.5 to 4.0 mg per day.
6
Patients with intestinal
losses will need 12 mg zinc/L of output from the small bowel and 17 mg zinc/L for
stool or ileostomy output.
7
Copper
Copper is associated with both intra and extracellular oxidation and plays an
essential role in the proper formation of red blood cells, and in connective tissue
Table 10.1. Calculation of fluid requirements
Method 1
Fluid (mL/kg)
Young, vigorous healthy adults 40
Other adults (18-55 years old) 35
Elderly adults 30
Method 2
For the first 10 kg of body weight, provide 100 mL/kg/d.
For the second 10 kg of body weight, add 50 mL/kg/d.
For weight above 20 kg of body weight, add 20 mL/kg/d if patient is 50 years of
age or less, or add 15 mL/kg/d if patient is more than 50 years.
Example:
Maintenance needs for 55 year old man, weighing 70 kg
1,000 mL (1st 10 kg)
+ 500 mL (2nd 10 kg)
+ 750 mL (15mL x 50 kg)
2,250 mL
Reprinted with permission from: Estimating macronutrient requirements. In;
Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland
Clinic Foundationn; 1997:33.
Table 10.2. Daily electrolyte requirements in patients with adequate renal
function receiving TPN
Electrolyte Usual Adult Daily IV Dose RDA Adult (oral)
Sodium 100-150 mEq 22 mEq*
Potassium 60-120 mEq 40-50 mEq*
Chloride 100-150 mEq 22 mEq*
Calcium 9-22 mEq 20-30 mEq
Magnesium 8-24 mEq 11.5-14.4 mEq
Phosphorous 15-30 mMol 26-39 mEq
*Minimum requirements of healthy persons
Reprinted with permission from: Parenteral nutrition. In: Matarese LE, ed. Nutrition
Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:52.
161
10
integrity.
2
Intravenous requirements of copper for a stable adult are estimated to be
between 0.5 to 1.5 mg/day.
8
Manganese
Manganese is a cofactor in a large number of enzyme systems and may have a
potential role in glucose utilization. Intravenous manganese administration of 0.15
to 0.8 mg/day is recommended for a stable adult.
9
Chromium
Chromium is essential in the prevention of glucose intolerance. Ten to 15 mcg
chromium/day appears to be adequate for a stable adult; 20 mcg chromium/day for
the adult with intestinal losses.
9
Table 10.3. Parenteral vitamin supplementation
Vitamin RDA Adult Range Intravenous
Multivitamin Formulation
A, international units 2,667-3,333 3300
D, international units 200 200
E, international units 11-14 10
Ascorbic acid, mg 60 100
Folic acid, mcg 180-200 400
Niacin, mg 13-20 40
Riboflavin, mg 1.2-1.8 3.6
Thiamin, mg 1.0-1.5 3.0
B6, mg 1.6-2.0 4.0
B12, mcg 2.0 5.0
Pantothenic acid, mg 4-7 15
Biotin, mcg 30-100 60
*RDA not established, estimated safe and adequate daily dietary intake
Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:55.
Table 10.4. Trace element requirements
Element Stable Adult Adult with 1 mL of Multiple
Intestinal Losses Trace Element
Chromium 10-15 mcg 20 mcg 10 mcg
Copper 0.5-1.5 mg ----- 1mg
Manganese 150-800 mcg ----- 500 mcg
Selenium 50-120 mcg up to 200 mcg -----
Zinc 2.5-4.0 mg 12 mg/ml small bowel fluid 5mg
+2 mg if lost; 17 ml/kg of stool or
catabolic ileostomy output
Support Handbook, Cleveland, OH: The Cleveland Clinic Foundation; 1997:57.
162
10
Selenium
Selenium is a component of glutathione peroxidase, an enzyme which protects
cell membranes from lipid peroxides and free radicals.
2
The usual intravenous dose
of selenium is between 50 and 120 mcg per day.
6
Iron
Iron is primarily involved in the production of hemoglobin and myoglobin. Iron
supplementation is generally not required during short-term TPN unless the pa-
tient is anemic. However, it is necessary to prevent anemia during long-term admin-
istration and in home TPN. Oral iron administration as either ferrous sulfate, ferrous
gluconate, or polysaccharide iron complex is the preferred route of administration.
2
If oral administration is not feasible, intravenous iron can be given as iron dextran.
However, iron dextran should not be added to lipid-based TPN solutions because
trivalent minerals could disrupt the lipid emulsion.
Parenteral supplementation of the remaining trace elements (cobalt, cadmium,
fluorine, iodine, nickel, silicon, molybdenum, and tin) is not currently recommended
since deficiency states while on TPN in humans have yet to be described.
2
Medications
Although TPN is primarily designed to deliver nutrients and fluid, there are
certain medications that can be added to the solution if consistent with institutional
policy. Heparin and, when necessary, insulin can be added to improve both efficacy
and safety of the TPN. Other medication, such as histamine H2 receptor antago-
nists, octreotide, and corticosteroids can be added to the solution to optimize the
management of the patients underlying disease.
Access/Delivery
Central or peripheral veins can be used to provide parenteral nutrition. The type
of access is selected according to how long it is expected to be needed, the limita-
tions presented by the patients condition, and the availability of equipment
and facilities.
1
Central
Central TPN is usually indicated in patients requiring long-term parenteral sup-
port who have increased nutritional requirements and/or a restriction on fluid in-
take.
2
Veins that can be used for gaining central access include the subclavian, internal
jugular, and femoral veins. Depending on institutional policy and overall patient
status, central TPN can be provided as a mixture of dextrose and amino acids with
fat emulsion given separately, or as a TNA with dextrose, amino acids, and fat emul-
sion combined into the same container.
Short-Term
Short-term access is provided via a central catheter inserted percutaneously at
the bedside under local anesthesia or under general anesthesia as part of a surgical
procedure. These are changed via a guidewire if infection is suspected or by chang-
ing sites if infection is proven.
Long-Term
Long-term venous access devices are usually required in patients leaving the hospi-
tal on home TPN. These include tunneled catheters, implanted ports, and
163
10
peripherally inserted central catheters (PICCs). Tunneled catheters and implanted
ports are available in single- or multiple-lumens and are placed by surgeons or radi-
ologists trained in this procedure. Peripherally inserted central catheters are either
placed in the operating room or at the bedside by specially trained nurses. These
catheters may be used for the delivery of central TPN as long as the tip of the
catheter is positioned in the superior vena cava or right atrium.
Peripheral
Peripheral parenteral nutrition (PPN) is usually reserved for patients requiring
short term parenteral nutrition who are not markedly hypermetabolic or fluid re-
stricted and have good peripheral access.
2
Peripheral veins in the hands are much
smaller than centrally located veins and are subject to phlebitis and thrombosis when
hyperosmolar products are infused.
10
Since the amount of dextrose and protein in
the PPN solution must be limited because they contribute to its osmolarity, PPN
solutions are lipid-based and may be unable to provide adequate calories and pro-
tein for hypermetabolic patients.
Monitoring Parameters
In order to maximize the efficacy of TPN and minimize its complications, it is
essential that nutritional, metabolic, and infectious protocols be established and
followed. General recommendations for TPN monitoring are summarized in
Table 10.5.
Nutritional
The amount of TPN infused is not always consistent with the amount prescribed.
Daily documentation of the actual TPN infused is the most desirable method to
assess the adequacy of the TPN delivered and minimize the risk of dehydration or
fluid overload.
11
For this reason, strict intake and output records, as well as weights,
must be recorded daily. The daily physical exam should include listening to the
lungs, and observing for tissue edema and other signs of excessive fluid retention.
Energy
Patients receiving TPN require periodic reassessment of energy needs to avoid
the complications of over- or under-feeding. Typically, the reassessment of energy
needs should be done every 7 days to 10 days. Energy requirements are usually
determined using formulas based on weight and height, such as the Harris-Benedict
equation.
12
Indirect calorimetry may be used in patients who are critically ill, se-
verely overweight or underweight, or in cases where there is suspected overfeeding.
Protein
The protein status of a patient receiving TPN may be followed by regular moni-
toring of visceral protein levels. Although serum albumin may be useful in a clini-
cally stable patient, during acute illness serum values are largely affected by
nonnutritional parameters such as altered vascular permeability, fluid imbalance,
and hypermetabolic states.
13
Other serum proteins with shorter half-lives that may
be monitored to determine visceral protein response to nutrition support therapy
include transferrin, prealbumin (transthyretin), and retinol-binding protein. Simi-
lar to albumin, these serum proteins are affected by non-nutritional factors that may
invalidate its use as a tool for nutrition assessment, but are more valuable than se-
rum albumin measurements in the acute care setting.
164
10
Metabolic
Serum electrolytes are monitored daily upon initiation of TPN until the levels
stabilize within normal ranges. Monitoring electrolytes every 2 to 3 days thereafter
in the hospital setting is usually sufficient. Serum phosphorous, magnesium, and
potassium levels may need to be assessed more frequently, especially when there is a
concern for the refeeding syndrome in a severely malnourished patient (See Table 10.6).
Upon initiation of TPN, blood sugars should be checked every six hours during
the initial two days to three days until the blood sugars remain at a consistent and
acceptable level. Baseline serum triglyceride levels should be checked if there is a
concern for preexisting hypertriglyceridemia in a patient receiving a lipid-based
TPN solution.
Table 10.5. General recommendations for TPN monitoring
Baseline Routine As Clinically Indicated
Weight, height, body Every 8 hours Fluid disorders
surface area Vital signs Urine sodium or fractional
Body composition (arm Temperature sodium excretion
fat and muscle areas, Urine fractionals Serum osmolality
bioelectrical imped- Daily Urine specific gravity
ance, subjective or Weight Protein status
functional measures) Fluid intake and Nitrogen balance, serum
Serum electrolytes, output prealbumin
glucose, creatinine, Serum electrolytes, Lipid disorders
blood urea nitrogen glucose, creatinine, Serum triglyceride or lipid
Serum magnesium, blood urea nitrogen clearance test
calcium, phosphorus until stable; then Respiratory quotient
Serum triglyceride and twice weekly Essential fatty acids (if fat-
cholesterol Weekly free TPN is necessary)
Liver function tests Serum magnesium, Hepatic encaphalopathy
Serum albumin or calcium, phosphorus, Plasma amino acids
prealbumin albumin Gastrointestinal losses
Complete blood count Liver function tests Serum trace elements
Energy (estimated or Complete blood count Stool electrolytes
measured), protein, Review of actual oral, Respiratory compromise
fluid, and micronutri- enteral, and TPN Paco
2
ent needs intake Indirect calorimatry,
respiratory quotient
Acid-base disorders
Blood pH
Anion gap
Long-term TPN
Body composition
measures
Serum trace elements,
vitamins
Reprinted with permission from: Management of Total parenteral nutrition. In:
Skipper A, ed. Dietitians Handbook of Enteral and Parenteral nutrition.
Gaithersburg, Maryland: Aspen Publishers, Inc; 1998:495.
165
10
Serum trace elements are usually not routinely assessed upon initiation of TPN
in the adult patient. Exceptions would be a severely malnourished patient, a patient
manifesting signs and symptoms of trace element deficiency, or a patient antici-
pated to be on long-term TPN.
14
Infectious
Daily monitoring of body temperature and of the vascular device site are impor-
tant due to the risk of catheter sepsis in patients receiving TPN. Catheter-related
complications will be discussed in the following section.
Complications of Parenteral Nutrition Therapy
Catheter-Related Complications
Placement
Central venous catheter complications occur in of 1-10% of patients.
15
Compli-
cations of subclavian vein catheterization include pneumothorax, subclavian artery
injury, air embolism, catheter embolization and catheter tip misplacement.
Pneumothorax
Pneumothorax is the most commonly reported complication of subclavian vein
access reported at 4 %.
16
It occurs when the needle tip penetrates or lacerates the
pleura near the apex of the lung. It is most likely to occur in thin, malnourished
patients due to the close proximity of the vein to the cupola of the lung with little
intervening fat. Entry of the needle into the lung is recognized by aspiration of air
instead of blood. If air is drawn into the syringe, or if a patient complains of pleu-
ritic chest pain, the needle should be withdrawn immediately to prevent laceration
of the lung. Other signs and symptoms may include tachycardia, dyspnea, persistent
cough, or diaphoresis. If the patient has no respiratory distress, the landmarks should
be reassessed and another attempt at cannulation made. If respiratory distress or
chest pain occurs, the cannulation should be aborted and a chest x-ray obtained
Table 10.6. Dosing and bolusing of minerals in TPN for adults
Mineral RDA Oral Usual Adult Techniques of
IV Dose TPN Bolus Replacement
Minimum Range
Calcium 800-1200 mg 9-22 mEq 7-14 mEq not to exceed
(20-30 mEq) 0.7-1.8 mEq / minute
Phosphorous 800-1200 mg 15-30* mM 0.08-0.2 mM / kg IV
(26-39 mM) over 6 hours ++
Magnesium 280-350 mg 8-24 mEq 24 mEq IV over 4-6
(11.5-14.4 mEq) hours
*22-44 mEq of potassium phosphate or 20-40 mEq of sodium phosphate;
++1 mEq of potassium phosphate = 0.68 mM phosphorous;
1 mEq of sodium phosphate = 0.75 mM phosphorous
Reprinted with permission from: Recognition and management of complications.
In: Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland
Clinic Foundation; 1997:77.
166
10
immediately. A small pneumothorax may resolve untreated. In some instances how-
ever, it may be necessary to place a chest tube. Occasionally a pneumothorax is not
seen on the initial post-insertion chest x-ray film but is seen in a subsequent x-ray
film, sometimes several days later.
17
The incidence of pneumothorax can be reduced
if the catheters are placed by or supervised by experienced personnel.
18
Subclavian Artery Injury
Subclavian artery injury can occur when the patient is dehydrated and the exter-
nal jugular veins cannot be distended by Trendelenburg position or Valsalva maneu-
ver. Penetration of the subclavian artery is recognized by the return of pulsatile bright
red blood into the syringe. The needle should be withdrawn immediately and local
pressure applied above and below the clavicle.
Venous Air Embolism
Venous air embolism occurs when the intrathoracic pressure becomes negative
compared with the atmospheric pressure at the open needle during subclavian cath-
eter insertion, while changing the intravenous tubing or accidental separation of the
tubing.
19
Patients who aspirate a small amount of air usually are asymptomatic. If
massive, however, the patient will become severely hypotensive and have a cardiac
murmur on auscultation. Cardiac arrest may result from blockage of blood flow
through the heart by the air embolus. The patient should be placed in Trendelenburg
position and rolled into a left lateral decubitus position in order to keep the air in
the apex of the right ventricle until it is reabsorbed.
20
The air may also be aspirated
through a central catheter that is inserted into the right atrium.
21
Catheter Embolization
With the use of the Seldinger technique for catheter insertion, intravascular cath-
eter embolization is no longer a problem during placement since the catheter is not
withdrawn through the insertion needle. However, it can occur if a portion of the
catheter inside the vein is inadvertently sheared off during dressing changes or there
is a breakage at a weakened or damaged area. The catheter tip can lodge any place
from the subclavian vein to the pulmonary arterial system. Catheter embolization
may cause cardiac arrhythmias. The embolized portion may be removed by
transfemoral intravenous snaring of the fragment under fluoroscopy.
22
When the
fragment is lodged in the distal pulmonary arterioles, a thoracotomy may be necessary.
Catheter Tip Dislocation
The tip of the catheter should be in the mid or distal portion of the superior vena
cava. However, the tip may enter the internal jugular vein, the opposite subclavian
vein, axillary vein, internal thoracic vein, azygos vein, hemizygous vein, or
pericardiophrenic vein.
23-25
Improper tip location can be a result of venous vascular
anomalies or improper placement by inexperienced personnel. Signs and symptoms
of improper tip location include phlebitis, cardiopulmonary distress and possible
thrombosis. The catheter should be removed over a guidewire and repositioned un-
der fluoroscopy.
Venous Thrombosis
Subclavian vein thrombosis has been observed in up to 50% of patients with
prolonged subclavian catheterization.
26,27
Catheter induced thrombosis occurs as a
result of irritation of the blood vessel wall. The thrombus is usually composed of
167
10
fibrin. Precipitation of medication within the catheter does occur, but less frequently.
Subclavian vein thrombosis should be suspected when collateral veins over the chest
and shoulder begin to appear. The patient may also demonstrate swelling of the
involved arm, neck and face. In some patients thrombosis is completely asymptom-
atic or symptoms are transient and are not noticed. The thrombosis may be identi-
fied when attempts at cannulating a vein is unsuccessful. Thrombosis is also a concern
from a septic standpoint. Sepsis from an unknown source may be due to bacterial or
fungal colonization of an unsuspected thrombus. Thrombosis can be confirmed
with a venogram or duplex ultrasound. Heparin and low dose Warfarin have been
used to help prevent subclavian vein thrombosis and to decrease thrombus forma-
tion at the catheter tip.
28-29
Catheter Occlusion
A catheter becomes occluded either by thrombus, drug precipitate, or lipid emul-
sion. If a fibrin thrombus has formed, a thrombolytic agent may be used to dissolve
the thrombus.
30,31
A precipitate from a medication may be treated with instillation
of hydrochloric acid if the drug has an alkaline base.
32
An occlusion caused by lipids
may be lysed with 70% ethyl alcohol.
33
Phlebitis
Peripheral administration of hypertonic solution may result in phlebitis exhib-
ited by redness, swelling, and pain at the peripheral site. The peripheral line site
should be changed. The incidence of phlebitis may be minimized by keeping the
osmolarity of the solution less than 900 mOsm/kg and by the addition of heparin to
the parenteral nutrition solution.
34
Catheter Sepsis
Central venous catheter infections are the most serious potential complications
of parenteral nutrition. These infections include catheter related sepsis, as well as
tunnel infections and exit site infections in long-term tunneled catheters. They can
be from poor technique during catheter insertion, contamination of the catheter
hub or infection of the skin due to inadequate catheter care, hematogenous seeding
from a distant source, and contamination of the nutrient solution. Diagnosing cath-
eter infections can be difficult. When there is a change in the patients usual tem-
perature or elevation in white blood cell count, a standard fever work-up including
a history, physical exam, chest x-ray, urinalysis, and blood cultures through a pe-
ripheral and central line should be done to rapidly determine the probable source of
the fever. The catheter should be changed over a guidewire and the tip cultured to
help determine if catheter sepsis is present.
35
If there is obvious pus coming out of
the catheter exit site, the exit site should be cultured, the catheter removed and a
new one placed at a different location. If the catheter tip replaced by guidewire is
positive for infection, the new catheter should be removed and another catheter
should be inserted in a new location. For suspected Hickman, Broviac or port infec-
tions, guidewire changes are not possible because of tissue growth into the dacron
cuff in the tunnel and quantitative blood cultures should be obtained through the
vascular access device along with peripheral venous blood cultures.
36
The perma-
nent vascular access device should not be used for TPN solutions until culture re-
sults are known. Quantitative blood cultures showing greater growth in the catheter
as opposed to a peripheral blood sample is diagnostic of a vascular access device
infection. If positive, the vascular access device should be treated with long-term
168
10
antibiotics. If blood stream sepsis is still not controlled, the device should be re-
moved. Intravenous Vancomycin
R
is the usual drug of choice for empiric treatment
since most of these infections are due to Staphylococcus aureus or coagulase-negative
staphylococci (Staphylococcus epidermidis) bacteria, and should be started immedi-
ately once the preliminary cultures have been obtained.
37,38
If the blood cultures are
positive for fungus, the catheter should be removed.
39
The best treatment for
catheter-related sepsis is prevention and adherence to strict protocols.
Hepatic
The cause of hepatic dysfunction in patients receiving TPN is usually multifac-
torial. Elevations of liver enzymes within the first three weeks of TPN infusion are
associated with hepatic steatosis.
40-43
The sequential laboratory abnormalities most
likely to be found in hepatic steatosis are elevations in serum aminotransferase val-
ues, alkaline phosphatase, and bilirubin.
42,44
The incidence of hepatic steatosis has
decreased with more moderate provision of calories and the substitution of some of
the dextrose calories with lipid.
Long-term TPN has been associated with cholelithiasis,
45
steatohepatitis, and
cholestasis.
46
The use of cyclic TPN, restriction of daily carbohydrate load to <5.0
mg/kg/min or <500 gm/day for a 70 kg patient, avoidance of overfeeding, and early
enteral stimulation may minimize the risk of cholestasis.
Gastrointestinal
Lack of luminal nutrients during TPN is associated with villous hypoplasia of
the small bowel, colonic mucosal atrophy, decreased gastric function, impaired gas-
trointestinal immunity, and gut bacterial translocation in experimental models.
47,48
It is important to initiate enteral feedings as soon as possible. If full nutritional
requirements are unable to be met by the enteral route, then small amounts of en-
teral nutrition may be delivered to the gastrointestinal tract while meeting the patients
full nutritional requirements by TPN.
Histamine H2 receptor antagonists are used to decrease gastric acid output, par-
ticularly in patients with massive small bowel resection, or to prevent stress ulcers.
49
These medications can be added directly to the TPN solution so that they are ti-
trated in over a 24-hour period.
50
The dose of H2 receptor antagonists should be
decreased in patients with decreased renal clearance.
51
Macronutrient-Related Complications
Calories
Overfeeding calories, especially in the form of dextrose, above requirements can
result in hyperglycemia, hepatic dysfunction from fatty infiltration, potential respi-
ratory acidosis from increased CO
2
production, and difficulty in weaning from ven-
tilators.
52-54
Underfeeding may result in depressed ventilatory drive, decreased
respiratory muscle function, impaired immune function, and increased infection.
55-57
Measurement of energy expenditure through indirect calorimetry may be desirable
in some patients, especially those with high fever, acute pancreatitis, malignancy,
critical illness, severe malnutrition, or obesity.
Hyperglycemia
Hyperglycemia is the most common complication associated with the adminis-
tration of TPN. It occurs secondary to diabetes mellitus, insulin resistance due to
169
10
ongoing stress, and infection. Depending on institutional policy, insulin may be
added to the TPN solution or provided subcutaneously. Severe hyperglycemia (se-
rum glucose >400) may necessitate an IV insulin infusion or discontinuation
of the TPN.
Hypoglycemia
Hypoglycemia can result from excess insulin administration. Treatment may in-
clude initiation of a 10% dextrose infusion with concurrent decrease of the
insulin-containing TPN solution, or administration of an ampule of 50% dextrose.
Serum glucose levels should be monitored closely until they rise to acceptable levels.
When TPN solutions are stopped abruptly for fluid and electrolyte management
when glycemic control is good, a rebound hypoglycemia may occur. If a TPN solu-
tion cannot be weaned of gradually, 10% dextrose should be infused for one hour to
two hours to avoid rebound hypoglycemia.
Refeeding Syndrome
The refeeding syndrome refers to the metabolic and physiologic shifts of electro-
lytes and mineral (e.g., potassium, phosphorous, and magnesium) which occur as a
result of aggressive nutrition. The delivery of calories, especially in the form of car-
bohydrate, may induce the refeeding syndrome in a patient who is severly malnour-
ished. For patients who are at risk for refeeding, calories should be initiated at 20
kcal/kg/day and advanced slowly over a period of three days to four days, while
monitoring potassium, magnesium, and phosphorous levels on a daily basis.
Protein
Protein provided in the form of crystalline amino acids in TPN solutions are
well tolerated by patients with adequate renal and hepatic function. Prerenal azotemia
may result from dehydration, excess protein, and/or inadequate non-protein calo-
ries. If the cause is thought to be excessive protein, these patients may benefit from
a reduction in the amount of amino acids.
Imbalances in plasma amino acids have been noted in a variety of clinical situa-
tions. Branched-chain enriched formulations that have reduced content of aromatic
amino acids and methionine may help reverse hepatic encephalopathy, but should
be reserved for patients who do not respond to conventional management.
Fat
Hyperlipidemia is associated with an individuals inability to clear lipid emul-
sions from the bloodstream. Critically ill patients with major organ dysfunction
may exhibit less efficient clearance and thus require frequent monitoring for el-
evated blood lipids.
58
Plasma triglycerides should be monitored routinely during
TPN anytime hyperlipidemia is suspected. Acceptable serum triglyceride levels are
less than 250 mg/dL four hours after lipid infusion for piggybacked lipids and less
than 400 mg/dL for continuous lipid infusion.
59
Reducing the dose for continuous
infusion or lengthening the delivery time for piggybacked lipids usually lowers se-
rum triglyceride levels.
Stressed patients receiving fat-free TPN demonstrate biochemical evidence of
essential fatty acid deficiency within a matter of weeks.
60
Clinical manifestations
occur as early as 6 weeks after the initiation of fat-free TPN.
61
Essential fatty acid
deficiency is prevented by providing 2-4% of total calories from linoleic acid. This
translates into approximately 500 mL of 10% lipid emulsion or 250 mL of 20%
170
10
lipid emulsion administered over 8 to 10 hours three times a week; or 500 mL of a
20% lipid emulsion once a week.
There is a concern regarding the detrimental effect of parenteral long-chain trig-
lycerides (LCTs) on immune function. To minimize the adverse effect of intrave-
nous lipid delivery, fat intake should be restricted to less than 30% of total calories
or 1g/kg/day for adults and provided slowly over 8 to 10 hours if administered as an
IV supplement.
Micronutrient-Related Complications
Once tolerance to the macronutrients has been established, the day-to-day man-
agement of TPN centers around fluid and electrolytes. Fluid and electrolyte shifts
between the intracellular and extracellular space or changes in total body water or
electrolyte content may require changes in the TPN composition and volume.
When evaluating the fluid and electrolyte status of a patient receiving TPN it is
important to evaluate the other intravenous fluids and medications that the patient
is receiving. Although some institutions use the TPN prescription as a vehicle for
fluid and electrolyte management, if a patient has excessive losses it may be neces-
sary to replace these fluids and electrolytes with separate intravenous fluids (IVFs)
outside of the TPN.
Fluid
Fluid deficits may be due to extravascular, intravascular, interstitial, or total body
water losses. Extracellular fluid deficits may result from abnormal losses from the
gastrointestinal tract, kidneys, skin, hemorrhage, and fever. Appropriate interven-
tion would be fluid replacement with fluid of similar composition to that lost (see
Table 10.7).
Intravascular to interstitial shifting of fluids is known as third spacing. Treat-
ment involves maintaining intravascular volume while minimizing the fluid and
sodium content of the TPN. Colloid therapy may be indicated in some instances.
Total body water deficits can occur from losses associated with fever, gastrointes-
tinal losses, diabetes insipidus, prolonged artificial ventilation, and inadequate wa-
ter intake. Treatment consists of free water replacement. The calculated water deficit
is computed as:
water deficit (L) = 0.6 (wt. in kg) x [Na/140 - 1] (see refs. 62,63)
Half of the deficit should be replaced over the first 24 hours and the remainder
over the next one to two days.
64
Extracellular fluid overload may result from renal dysfunction, nephrotoxic drugs,
decreased renal blood flow, congestive heart failure, and liver disease. Treatment
includes the administration of diuretics, sodium and fluid restriction, and the
use of concentrated TPN solutions.
Total body water overload occurs as a result of excessive free water intake or
syndrome of inappropriate antidiuretic hormone (SIADH). Intervention involves
decreasing the volume of the TPN solution and other IVFs.
Sodium
Sodium is the most prevalent of the extracellular electrolytes and has a primary
role in controlling the distribution of water throughout the body. The usual dose of
sodium in TPN is 100-150 mEq/day (see Table 10.2).
171
10
Hyponatremia (see Table 10.8)
Hyponatremia (sodium <130 mEq/L) represents a relative loss of sodium in
proportion to water or a gain of water in proportion to sodium. Hyponatremia in a
hypovolemic patient with a low serum osmolality should be treated with the admin-
istration of isotonic or hypertonic saline and by increasing the sodium in the TPN.
The sodium deficit may be calculated as:
Na deficit (mEq) =0.6 (Wt in kg) x (140 - Na) + (140) x (Volume Deficit in L)
One half of the deficit should be replaced over the first 24 hours, then the re-
mainder over the next one or two days.
Hypertonic hyponatremia may be due to hyperproteinemia or hyperlipidemia
since the volume of the aqueous component in which the sodium is dissolved is very
high.
64
Hyponatremia may also be seen with hyperglycemia. Each 100 mg/dL eleva-
tion of glucose above normal will decrease sodium by 1.6-2.0 mEq per liter. In each
of these cases, the sodium will return to normal once the underlying problem
is corrected.
Dilutional hyponatremia results from excess free water and not by sodium defi-
cit. When hyponatremia is associated with a low serum osmolality, and the
patient is euvolemic or hypervolemic, water should be restricted and the TPN
solution concentrated.
Hypernatremia
Hypernatremia (sodium >150 mEq/L) can result from dehydration, osmotic
diuresis, hypoglycemia, hypocalcemia, antidiuretic hormone deficiency, head trauma,
and pituitary tumors. Treatment includes fluid replacement if the patient is dehy-
drated (see section on Fluid) and/or decrease of the sodium in the TPN.
Potassium
Potassium is the most prevalent intracellular cation and functions primarily in
maintaining cell volume, hydrogen ion concentration (pH), enzyme function, pro-
tein synthesis, and cell growth. Therefore, potassium should be monitored frequently
when starting TPN. The normal dose of potassium in TPN is 60-120 mEq/day (see
Table 10.2)
Table 10.7. Approximate electrolyte composition of various body fluids
Electrolytes (mEq/L)
Source Volume (mL/d) Na K HCO3 CL
Gastric 2000-2500 pH<4 60 10 --- 90
pH>4 100 10 --- 100
Pancreatic 1000 140 5 90 75
Bile 1500 140 5 35 100
Small Bowel 3500 100 15 25 100
Diarrhea 1000-4000 60 30 45 45
Urine 1500 40 0 --- 20
Sweat 50 5 --- 55
Reprinted with permission from: Grant JP. Handbook of Total parenteral nutrition.
2nd ed. Philadelphia: W.B. Saunders Co; 1992:174.
172
10
Hypokalemia
Hypokalemia (K+ <3.5 mEq/L) results from a decrease in body potassium (more
often due to increased losses than to insufficient intake) or a shift of potassium from
the extracellular fluid (ECF) to the intracellular fluid (ICF).
64
Shifts of potassium
from the ECF to the ICF occur as a result of anabolism (e.g., part of the refeeding
syndrome), metabolic alkalosis, and increased levels of insulin. Hypokalemia should
be corrected prior to starting TPN since the resultant anabolism will worsen the
hypokalemia. Total body potassium deficit may be calculated (see Table 10.9) or an
estimate can be made based on serum values. In general, for serum potassium levels
of 3.0-3.5 mEq/L, the estimated deficit is 100-200 mEq; for levels of 2.5-3.0 mEq/
L, the estimated deficit is 150-250 mEq; and for levels of 2.0-2.5 mEq/L, the esti-
mated deficit is 200-300 mEq.
63
In addition to providing potassium in the TPN, intravenous replacements of
potassium should be given to patients for serum values less than 3.5 mEq/L who
have urine output of at least 30 mL per hour. Replace half of the deficit over the first
12 to 24 hours. Typically, a dose of 20 mEq of potassium in 100 mL of saline over
one hour can be expected to increase the serum potassium by 0.2 mEq/L. A repeat
serum potassium measurement should be done at least one hour after the IV re-
placement to assure potassium has been adequately repleted.
Hyperkalemia
Hyperkalemia (K+ >5.5 mEq/L) can result from an increase in exogenous or
endogenous potassium load, an extracellular potassium shift, or inadequate potas-
sium excretion. When a TPN patient develops hyperkalemia it may be necessary to
discontinue the TPN and infuse standard non-potassium-containing IVFs tempo-
rarily until the next TPN solution is hung.
Chloride
Chloride is an extracellular anion that is found primarily in the interstitial and
lymph fluid compartments. Sodium and chloride are usually added in a 1:1 ratio in
TPN to prevent metabolic alkalosis and hyperchloremic acidosis. Generally chlo-
ride losses and gains follow those of sodium. The usual dose of chloride in TPN is
100-150 mEq/day (see Table 10.2)
Table 10.8. Evaluation and treatment of hyponatremia in TPN patients
Level Osmolality Etiology Treatment
High (>285 mOsm) Hyperproteinemia Underlying condition
Normal (280-285 mOsm) Hyperlipidemia Hyperglycemia
Low (<280 mOsm) H2O intoxication Restrict H2O
Euvolemic or SIADH
Hypervolemic Renal failure
Cardiac failure, Cirrhosis
Hypovolemic GI losses Isotonic saline
Renal losses
Third-space losses
Reprinted with permission from: Recognition and management of complication.
173
10
Hypochloremia
Hypochloremia usually occurs in conjunction with metabolic alkalosis. Hypov-
olemia due to overdiuresis or unreplaced nasogastric suctioning can also lead to
contraction alkalosis. Treatment of hypochloremia due to metabolic alkalosis will be
discussed in the section on acid-base disorders.
Hyperchloremia
Hyperchloremic metabolic acidosis is usually a result of excessive saline adminis-
tration. Appropriate treatment includes reducing the chloride content of the TPN
solution or changing to an IVF with a lower chloride concentration. Treatment of
hyperchloremia due to metabolic acidosis will be discussed in section on
acid-base disorders.
Calcium
Calcium is an extracellular cation that regulates many neuromuscular functions
and enzymatic processes. The usual dose of calcium in TPN is 9-22 mEq/day (See
Table10.2).
Sixty percent of serum calcium is bound to protein, primarily albumin. There-
fore, patients with low albumin levels will have low serum calcium concentrations.
An ionized calcium level should be measured when calcium balance is a concern. In
states of hypoalbuminemia when only the total serum calcium is available, there is a
0.8 mg/dL decline in total serum calcium for each 1.0 mg/dL decrease in albumin
concentration below 4.0 g/dL.
11
Serum calcium concentration may be corrected for
hypoalbuminemia as follows:
corrected serum calcium = [(4.0 gm/dL-measured serum albumin) x 0.8] +
measured serum calcium
Table 10.9. Dosing and intravenous replacement of electrolytes in TPN
Electrolyte RDA* Usual Adult Calculation of Technique of
Oral IV Dose Deficit Intravenous Replacement
Sodium 500 mg 100-150 Na deficit(mEq)= Replace 1/2 deficit over
(Na) (21.7 mEq 0.6 wt(kg)x(140-Na)+ 24 hours and repeat
mEq) (140)x(Vol. def. in L) serum Na
Potassium 2,000 60-120 K deficit (mEq)= Replace 1/2 deficit in
(K) mg mEq 100-200 mEq if 12-24 hours with boluses
(51 serum K 3.0-3.5 of 20 mEq KCL in 100 mL
mEq) D5W over 1-2 hours.
Recheck K level 1 hour
after bolus. If K < 3.5,
repeat IV replacement. If
K > 3.5, add additional K
to next TPN bag.
Chloride 750 mg 100-150 Cl deficit (mEq)= Replace 1/2 deficit over
(Cl) (21 mEq 0.5 x wt (kg) x (103 - 24 hours.
mEq) measured Cl)
*Minimum requirement for health persons.
Reprinted with permission from: Recognition and management of complications.
174
10
Hypocalcemia
Hypocalcemia (total Ca
++
corrected <8.0 mg/dL; ionized Ca
++
<4.5 mg/dL) can
result from many disorders that decrease calcium absorption, increase its loss, or
alter its regulation. As long as the calcium-to phosphorous ratio is still acceptable,
calcium may be increased in the TPN solution to treat hypocalcemia. The combina-
tion of calcium and phosphorous in TPN formulas has the potential to form a
precipitate. If calcium in the TPN cannot be increased, or for acute, symptomatic
hypocalcemia, intravenous calcium is indicated (see Table 10.6). Calcium gluconate
can be administered, either as 10 to 20 mL of 10 percent calcium gluconate or as a
continuous drip of 100 mL 10 percent calcium gluconate in 1000 mL of 5 percent
dextrose in water, infused over at least four hours.
65
Hypercalcemia
Hypercalcemia (total Ca
++
corrected >11.0 mg/dL, ionized Ca
++
>5.5 mg/dL) can
occur with either a rise in total serum calcium level or an increase in the fraction of
ionized calcium. The reduction or deletion of calcium from the TPN solution is the
usual treatment of asymptomatic hypercalcemia. Symptomatic hypercalcemia is typi-
cally treated by the expansion of the ECF to increase urine output and administra-
tion of loop diuretics to increase calcium excretion.
66
Phosphorus
Phosphorus is the major intracellular anion and plays an important role in ATP
synthesis, cell membrane integrity, energy metabolism, acid-base balance, and
oxygen delivery to tissues. The usual dose of phosphorous in TPN is 15-30 milli-
moles (mmol) per day.
11
Hypophosphatemia
Hypophosphatemia can be divided into two categories: moderate (1.0-2.5 mg/
dL) and severe (<1.0 mg/dL). The number reflects a reduction in serum phosphorus
concentration rather than a decrease in cellular phosphate content.
67
Gradual deple-
tion of body phosphate stores occurs as a result of inadequate dietary phosphate
intake or impaired absorption. Hypophosphatemia that develops suddenly is more
common and can result from intracellular shifts, increased urine losses, or a sudden
increase in phosphorus utilization (e.g., refeeding syndrome, anabolism).
64,68,69
Moderate hypophosphatemia can be treated with oral sodium or potassium phos-
phate supplements if the patient has a functioning gastrointestinal (GI) tract. Intra-
venous phosphate replacement as sodium phosphate or potassium phosphate is
indicated for severe hypophosphatemia or when the GI tract is nonfunctional. The
recommended dose is 0.24 mmol/kg for severe symptomatic hypophosphatemia
and 0.16 mmol/kg for severe asymptomatic hypophosphatemia.
66
Intravenous phos-
phorus replacement should be done over a period of six hours to keep the serum
calcium level from falling concomitantly. If the patient is receiving TPN, the amount
of phosphorus in the solution should also be increased, providing that the calcium
to phosphorus ratio remains within acceptable ranges. Continue to monitor serum
levels until the phosphorus levels normalize and then periodically thereafter for fur-
ther decreases as the phosphorus moves into the intracellular compartment.
Hyperphosphatemia
Hyperphosphatemia (PO4 >than 5.0 mg/dL) is usually asymptomatic, but it
may induce hypocalcemia. If the calcium-phosphorus product in the blood exceeds
175
10
70 mg/dL, calcification of soft tissue may occur.
65
Phosphorus is reduced or elimi-
nated from the TPN solution in cases of hyperphosphatemia. Also, the use of 20
percent rather than 10 percent lipid emulsion is recommended because the phos-
phorus content per calorie delivered is less.
70
Magnesium
Magnesium is an important coenzyme in the metabolism of both carbohydrate
and protein. It is also involved in neuromuscular activity. The usual dose of magne-
sium in TPN is 8-24 mEq/day (see Table10.2).
Hypomagnesemia
Hypomagnesemia (Mg <1.5 mEq/L) can occur in patients with excessive GI
losses , during anabolism, or with renal losses. Magnesium may appear low in pa-
tients with hypoalbuminemia. A corrected magnesium level may be calculated as:
Corrected Mg
++
= Mg
++
+ 0.005(40 - serum albumin)
Patients with normal renal function can receive a replacement of 8-24 mEq IV
over four to six hours (see Table10.6). The magnesium content of the TPN solution
should also be increased. Serum magnesium levels should be monitored until the
patient is repleted and periodically thereafter to minimize the risk of
hypermagnesemia.
Hypermagnesemia
Hypermagnesemia (Mg
++
>2.5 mEq/L) occurs infrequently and is most often
seen with acute or chronic renal failure. Treatment of hypermagnesemia involves
eliminating any exogenous sources of magnesium (e.g., reduction or elimination
from the TPN solution) and correcting any volume deficits or acidosis.
Acid-Base Disorders
Acid-base disorders include metabolic acidosis and alkalosis and respiratory aci-
dosis and alkalosis. Acidosis or alkalosis may result from a variety of causes in the
TPN patient.
Metabolic Acidosis
Metabolic acidosis is characterized by an arterial pH <7.35 and serum bicarbon-
ate (HCO
3
-
) <25 mEq/L. Chloride concentrations are normal or increased, sodium
concentrations are normal, and potassium concentrations are increased. The in-
crease in serum potassium occurs as the potassium moves from the ICF to the ECF.
As the metabolic acidosis is corrected, the serum potassium level should return
to normal.
The causes of metabolic acidosis include increased generation/addition of acids
(e.g., diabetic ketoacidosis, lactic acidosis, rhabdomyolysis), retention of acids (e.g.,
renal insufficiency), or loss of base bicarbonate (severe diarrhea, small bowel fistulas,
pancreatic drainage, renal tubular acidosis). Treatment of metabolic acidosis is di-
rected at treating the underlying disorder.
Serum bicarbonate is not stable in TPN solutions because of the formation of
insoluble calcium or magnesium carbonate. Therefore, acetate, its precursor, is added
for regulation of acid-base balance. Acetate is rapidly metabolized to bicarbonate in
the liver. Serum CO
2
levels are used as a guide for administration of acetate addi-
tives. When the CO
2
level is low, sodium or potassium should be added in the form
of an acetate salt. When metabolic acidosis is caused by excessive saline administration,
176
10
the chloride content of the TPN solution can be reduced by replacing some of the
salts with acetate.
Metabolic Alkalosis
Metabolic alkalosis is characterized by a rise in arterial pH >7.45 and HCO
3
>25
mEq/L and a decline in the H+ in the serum. Volume contraction is often present.
Potassium concentrations are usually decreased in metabolic alkalosis secondary to
an intracellular shift. Metabolic alkalosis occurs via the addition of HCO
3
or its
precursors (e.g., administration of excessive amounts of NaHCO
3
or acetate), mas-
sive blood transfusions (citrate added as a buffer), loss of acid (e.g., via nasogastric
suctioning, vomiting, excessive use of antacids), or loss of fluid containing more
chloride than HCO
3
(e.g., thiazide diuretics, chronic diarrhea, hyperadrenocorticism).
Treatment of metabolic alkalosis is directed at correcting the underlying disor-
der. Normal volume needs to be restored in a hypovolemic patient and potassium
needs to be replaced in cases of hypokalemia. Chloride replacement is indicated in
cases where alkalosis is the result of diuretics or nasogastric losses. The chloride
deficit can be calculated as follows:
Cl
-
deficit (mEq) = 0.5 x wt (kg) x (103 - measured Cl
-
) (see ref. 62).
Chloride may be increased in the TPN solution or provided as a separate infu-
sion of potassium or sodium chloride.
Respiratory Acidosis
Respiratory acidosis is characterized by hypercapnia (pCO
2
>40 mm Hg) and a
pH <7.35. Hypercapnia can result from impaired alveolar ventilation or from exces-
sive CO
2
production, which can be caused by overfeeding, especially carbohydrate.
2
This is primarily seen in patients with compromised respiratory function. Acute
respiratory acidosis can result from sleep apnea, adult respiratory distress syndrome
(ARDS), aspiration of a foreign body, asthma, pneumothorax, or hemothorax.
Chronic respiratory acidosis can be secondary to chronic obstructive pulmonary
disease (COPD), morbid obesity, neuromuscular diseases, hypothyroidism, and star-
vation cachexia.
Treatment of respiratory acidosis is directed at treating the underlying cause. If
there is increased CO
2
production as a result of high dextrose concentrations, some
of the dextrose calories should be replaced with fat. It is important to avoid over-
feeding with any substrate.
Respiratory Alkalosis
Respiratory alkalosis is characterized by hypocapnia (PCO
2
<40 mm Hg) and a
pH >7.45. Primary respiratory alkalosis has not been reported to be a complication
of TPN therapy. It can occur with central stimulation (e.g., anxiety, pain, head in-
jury, cerebrovascular accident, tumors, salicylate overdose, and early gram negative
sepsis) or peripheral stimulation (e.g., pulmonary embolism, congestive heart fail-
ure, pneumonia, interstitial lung disease, and high altitudes). As with all acid-base
disorders, treatment should be directed at correcting the underlying disease.
Long-Term Complications
Metabolic bone disease is reported as a complication of long-term TPN infu-
sion.
71-73
The etiology is thought to be multi-factorial. Increased urinary losses of
calcium, phosphorous, and magnesium have been associated with cycled long-term
TPN. Continuous TPN appears to promote mineral homeostasis better than cycled
177
10
TPN.
59
Hypercalcuria in home TPN patients can be minimized by providing ad-
equate levels of vitamin D, calcium, and phosphorous; and avoidance of metabolic
acidosis and high protein loads.
Cycling Total Parenteral Nutrition
When a decision is made to send a patient home on TPN, cycling of the daily
infusion in a stepwise fashion should begin. Infusion of TPN for only part of the
day provides both metabolic and psychological benefits. Depending upon tolerance of
fluid volume and glucose load, the desired infusion time may range from 8 -16 hours.
Conclusion
Total parenteral nutrition enables feeding of patients who formerly would have
succumbed to starvation. Adherence to technique and monitoring standards help to
ensure the safety and efficacy of TPN. Periodic assessment of energy and protein
needs assure that patients are receiving the appropriate amount of substrates. Strict
catheter care and monitoring techniques help to minimize complications, while treat-
ing them as they occur. Finally, providing fluid and electrolyte requirements for
maintenance, as well as extra renal or GI losses, is important to minimize the risk of
metabolic complications
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115:238-240.
28. Brismar B, Hardstedt C, Jacoson S et al. Reduction of catheter-associated throm-
bosis in parenteral nutrition by intravenous heparin therapy. Arch Surg 1982;
1196-1199.
29. Bern MM, Bothe A Jr, Bistrian B, et al: Prophylaxis against central vein thrombo-
sis with low-dose warfarin. Surgery 1986; 99:216-220.
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central venous access devices. J Intravenous Nurs 1992; 15(1):36-41.
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LE, Gottschlich MM, eds. Contemporary Nutrition Support Practice. Philadel-
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53. Starker PM, LaSala PA, Forse A et al. Response to total parenteral nutrition in the
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cronutrients. Surg Clin North Am 1986; 66:1025-1047.
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Osteopenia without mineralization defect. Am J Clin Nutr 1986; 44:89-98.
71. Vargas JH, Klein GL, Ament ME et al. Metabolic bone disease of total parenteral
nutrition: Course after changing from casein to amino acids in parenteral solu-
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73. Koo WWK. Parenteral nutrition-related bone disease. JPEN 1992; 16:386-394.
CHAPTER 1
CHAPTER 11
Radiologic Assessment of Nutritional
and Metabolic Status
Diane R. Horowitz, Rifat Latifi
Introduction
Accurate metabolic measurements are essential for evaluating the nutri-tional
status of patients requiring nutritional support. Many of the currently used bio-
chemical and anthropometric methods for assessment of nutritional status, as discussed
in the previous chapter, have inherent limitations which may result in inaccurate esti-
mations of total body fat and protein status. These limitations have led to the search for
new methods to assess metabolic status using body composition measurements.
Typically, methods of determining body composition are based on the model
which divides the body into two chemically distinct compartments: fat and fat free.
The fat free compartment is further divided into three chemical groups: water, pro-
tein, and bone minerals. Additional methods for assessing body composition in-
clude: a) assessment of total body water using isotopes of hydrogen, deuterium and
tritium, b) estimation of lean body mass from total body potassium or urinary crea-
tinine excretion, and c) assessment of human body composition by densitometry
and anthropometry. More recent methods, however, include measuring the multi-
elemental composition of the human body via neutron activation analysis; deter-
mining total body skeletal muscle mass with total plasma creatinine and endog-
enous urinary 3-methylhistidine excretion; and determining fat free mass by electrical
conductance techniques. Although, more specific, some of these methods require
complex laboratory equipment and do not provide accurate estimates of body fat in
an individual.
1
Various radiologic examinations are now used to assess body compo-
sition, in the attempt to objectively determine the metabolic and nutritional status
in patients requiring nutritional support. These methods of estimating body com-
position will be the focus of this chapter.
Ultrasound Use in Assessing Body Composition
Ultrasound is used as a method for predicting body fat by measuring subcutane-
ous fat thickness.
2
Ultrasound overcomes the limitations of the caliper method of
measuring subcutaneous fat thickness such as variation in skinfold compressibility
and difficulty in obtaining interpretable measurements especially on obese subjects.
3
In addition to fat measurements, ultrasound is also useful for direct assessment of
muscle tissue, which is helpful since loss of body protein usually is of greater concern
than loss of body fat.
4
Ultrasound uses an instrument in which electrical energy is converted within a
probe to high frequency ultrasonic energy, which is then transmitted into the body
182
11
in short pulses. When the sound waves impinge perpendicularly upon interfaces of
tissues with different acoustical properties, part of the ultrasonic energy is reflected
back to the probe which contains a receiver. This is converted back to electrical
energy and is displayed on a screen. High frequency transducers are best suited for
characterizing the subcutaneous tissues. The ultrasound transducer is coupled to the
skin with transmission gel to avoid compressing the underlying tissues. Skin is rela-
tively echogenic and the subcutaneous fat is virtually anechoic.
3,4
Ultrasound is used to estimate body density in a fashion similar to calipers. Sub-
cutaneous fat thickness is measured at several sites using the electronic calipers di-
rectly on the screen. Regression equations are then used to predict body density and
body fat. Measurements taken at the triceps, waist and thigh are found to correlate
best with body density. While there is no correlation between triceps skinfold measure-
ment obtained with calipers and measurement of fat thickness by ultrasound, there
is a statistically significant correlation between the ultrasound measurements of mid-
arm fat area (MAFA) and the triceps skinfold measurement.
3
Sonographic measure-
ments of subcutaneous fat at the waist and thigh sites are the best predictors of body
density.
3
When ultrasound is used to measure mean arm muscle mass (MAMA), it
correlates with lean muscle mass which subsequently correlates with body protein stores.
3
Ultrasound has the advantage over anthropometry of being able to calculate bone
area and, hence, exclude it from measurements. Anthropometric MAMA does not
accurately reflect actual muscle composition because no correction is made for the
bone area.
The ultrasound method begins with a two dimensional image of the arm taken
at a point marked for anthropometric measurements. The subcutaneous fat thick-
ness and muscle thickness of the posterior upper arm are measured on this image.
The mid-arm muscle area and mid-arm fat area can be calculated using the ultra-
sound measurements and the mid-arm circumference. The formulas used assume
that the cross section of the arm is circular and the components are made up of
concentric rings.
4
(Fig. 11.1)
Although both anthropometry and ultrasound overestimate MAMA (22.8+/-
17% and 10+/-12% respectively, mean +/- SD) ultrasound measurements exclude
bone area and are, therefore, more accurate than those obtained by anthropometry.
In patients with advanced liver disease, measurement of MAFA by ultrasound, us-
ing triceps skinfold as the standard, was found to be an accurate index of fat stores.
4
Further, when MAMA was measured by ultrasound, it correlated well with lean
muscle mass, as estimated by using creatinine height index as the standard.
4
Since
ultrasonography accurately measures MAFA and MAMA and assesses fat and pro-
tein stores, it appears to provide more accurate measurements than anthropometric
methods in nutritional and metabolic assessment. In addition, ultrasonography is a
reproducible, noninvasive method that has been shown to be especially useful in
quantitation of muscle and fat in malnourished children,
5
where CT was used as a
reference standard.
Computerized Tomography
Computerized tomography (CT) can be used to analyze body fat, muscle, and
bone composition because it generates high contrast between adipose tissue, muscle
and bone tissue. CT scan may have several applications in assessment of nutritional
status because it can be performed quickly, the radiation dose is minimal (<1 Rad)
and it can be performed in healthy as well as ill patients.
6
183
Radiological Assessment of Nutritional and Metabolic Status
11
CT can be a useful tool for investigating whether abnormal body fat distribution
is associated with the pathogenesis of abnormal glucose tolerance.
7
When CT scan-
ning of the thigh was compared with anthropometric and urinary creatinine deter-
minations to assess nutrition in children with inflammatory bowel disease receiving
TPN, it was found that there is a correlation between the thigh muscle area, as
measured by CT scan, and muscle area calculated from urinary creatinine excretion
rate.
8
By CT studies it was found that total muscle thigh area is a better predictor of
muscle mass as compared to the mid-arm muscle area.
CT may be used to evaluate changes within the liver parenchyma following total
parenteral nutrition (TPN). Because of the inability of the liver to metabolize the
acute increase in protein load associated with TPN, protein accumulates in the liver
and may cause hepatomegaly. Protein accumulation and hepatomegaly are more
pronounced with severe malnutrition, however, the liver returns to normal size
and density on CT studies within approximately three to four days as nutri-
tional status and liver metabolism improves.
9
Fig. 11.1. Transverse ultrasound image of the arm taken at the point marked for triceps
skinfold thickness. The muscle thickness has been measured directly (26.3mm). The
subcutaneous fat thickness is the total soft tissue thickness minus the muscle thickness
(40.3-26.3=14.0 mm). Note that bone is excluded from measurement.
184
11
Another application of CT is the measurement of intrabdominal fat. Because of
its cross-sectional imaging capabilities and its high contrast resolution, CT is able to
quantify subcutaneous fat, total body fat, and internal fat, and it does not rely on
abdominal subcutaneous fat thickness to estimate total body fat as do ultrasound
and anthropometry.
7
(Figs. 11.2.A-F).
The CT method begins with a cross sectional image of the body part of interest.
The parameters of the structure of interest (i.e., total cross section of the image,
subcutaneous fat, muscle plus bone, intraperitoneal and visceral fat) can be outlined
using a cursor on the viewing console, and the cross-sectional areas can be deter-
mined for each image using a computerized planimetric method. Since the scan
thickness is known, volume occupied by that tissue can be calculated.
1
Subcutane-
ous fat may be calculated separately by first drawing lines around the area of inter-
est.
8
As the volume of each pixel is known, the volume of individual tissues can be
determined by adding the number of pixels within a specific Hounsfield unit (HU)
range for each slice and then adding the information from each slice.
2
In order to evaluate fat and lean body composition, forearm or limb or trunk
measurements are used. Techniques using a single CT slice and those using multiple
CT slices have been described. Shuman et al describe using three scans, one in the
thorax at the nipple level, one in the abdomen at the umbilicus and one in the thigh
midway between greater trochanter and patella.
7
Tokanuga et al.
1
used five levels of
measurements:
1. forearm at midpoint of elbow and wrist,
2. chest at fourth intercostal space;
3. abdomen at umbilical level;
4. thighs midway between crotch and popliteal fossa; and
5. calves at midpoint between popliteal and lateral malleolus.
Computerized tomography has several advantages over both anthropometric and
sonographic methods of estimating mid-arm adipose tissue. First, CT does not rely
on the assumption that the arm and its compartments are concentric circles. Fat and
muscle are distributed asymmetrically around the arm, and because CT provides a
cross-sectional view of the arm with precise delineation of fat, bone and muscle,
more accurate measurements of these individual compartments can be made.
10
Sec-
ond, since the CT scan does not include bone area in its assessment of mean arm
muscle area as does anthropometry, it offers a more accurate measurement of muscle
and muscle wasting in malnutrition. Third, as CT scan does not depend on the
differences in compressibility between firm and flabby fat, it is not affected by fat
which remains adherent to muscle when the triceps skinfold is gathered for mea-
surement. CT is also more helpful in measuring mid-arm adipose tissue in
obese people.
9
CT of the lower extremity has been studied and compared with anthropometric
measurements. As in the upper extremity, the formula used to assess muscle mass
and fat by anthropometry in the lower extremity assume that the cross-sectional
area of the various compartments is circular and concentric and may lead to an
overestimation of total area, total volume, muscle plus bone area, and muscle plus
bone volume and an underestimation of fat content.
11
CT scan is not subject to
these errors.
CT scan evaluation of tissue compartments in the trunk has been performed
using single scan and multiple scan techniques. Single scan techniques used to evaluate
fat content generally involve obtaining a single axial scan at the umbilical level. The
185
11
Fig. 11.2A. A small area of
known fat density has been
placed within a region of inter-
est on a cross sectional CT im-
age of the abdomen.
Fig. 11.2B. Graph of the region of
interest in Figure 11.2A shows the
range of Hounsfield units that will
correspond to fat density.
Fig. 11.2C. Cross sectional CT
image of the abdomen where the
area which will contain the sub-
cutaneous fat has been placed
within the region of interest us-
ing a cursor on the computer
console.
186
11
Fig. 11.2F. Graph depicting the
region of interest outlined in
Figure 11.2E. Using this graph, to-
tal fat area and volume may be
calculated. Visceral fat area and
volume are then obtained by sub-
tracting subcutaneous fat area (vol-
ume) from total fat area (volume).
Fig. 11.2E. Cross sectional CT
image of the abdomen with the
entire abdomen now included in
the region of interest.
Fig. 11.2D. Using the range of
Hounsfield units obtained from
the graph in Figure 11.2B, a sec-
ond graph has been formed plot-
ting these pixel values by fre-
quency. Subcutaneous fat area
and volume are easily calculated
using this graph.
187
11
umbilicus is used because it is an easy landmark to identify, and the maximum ratio
of fat to total tissue area is present at this level.
12
As is the case with any other technique for nutritional assessment and estimation
of body composition, the CT scan has its limitations. The primary limitation of
estimating fat content from a single scan results secondary to regional variations in
fat distribution which are not apparent when a single scan is used. Also, partial
volume averaging effects cause inaccurate identification of pixels with attenuation
values of fat. In addition, single scan analysis may not be accurate because of fat
distribution differences between men and women.
11
The ratio of body fat distribu-
tion at each level for a given sex is relatively constant regardless of whether the
patient is obese or lean. However, the distribution of body fat between males and
females changes at different levels and is most pronounced at the L1 level.
6
Al-
though total body fat does not differ between males and females, males store more
fat within the abdominal cavity and women store more fat in the subcutaneous
tissues. Therefore, abdominal CT scan may be more accurate in males.
13
In summary, although CT scan as a method of assessing nutritional status and
body composition has its limitations, (expensive, availability), it is of great value in
energy-balance experiments in which high reproducibility is required,
14
and it is the
most appropriate technique in studies of adipose tissue distribution.
Magnetic Resonance Imaging (MRI)
The possibility of utilizing MRI to evaluate changes in body fat, fatty involve-
ment of the liver and fatty bone marrow changes has been recently studied. The
most obvious advantage of utilizing MRI over CT scan is that MRI provides
good tissue contrast without exposing the patient to ionizing radiation and con-
trast. MRI is based on the fact that atomic nuclei, made up principally of neu-
trons and protons, can behave like magnets. Furthermore, MRI depends on the
density of hydrogen nuclei and the physical state of the tissue as reflected in the
magnetic relaxation times. Tissue contrast between fat and muscle is high and can
be enhanced by changing the magnetic relaxation time variable of the magnetic
resonance instrument.
2
Hydrogen protons in fat are primarily held in aliphatic
chain hydrocarbons and have nuclear magnetic properties distinct from protons
in water or protein chains.
15
Adipose tissue has a short longitudinal relaxation time
(T1) compared with other tissues.
Multiple scan techniques have been described which maximize the contrast be-
tween fat and muscle. In standard MR imaging, signal from protons of water and fat
cannot be differentiated. Therefore, pixel intensity is the summed contribution from
water and fat. A modified spin-echo technique exploits the differences between pro-
tons in water molecules and protons in fatty acid molecules. This proton spectro-
scopic imaging technique increases contrast between fat-containing tissues and other
tissues and may help to detect smaller masses of fat containing tissue.
13
This method
also helps to identify tissue based on measured parameters rather than by image
appearance, thereby allowing the individual contributions of fat and water to total
signal intensity to be assessed.
Whichever method is chosen, quantitation of fat volume in one image or in
multiple images is accomplished by morphometric computer analysis similar to those
methods described in the computerized tomography section (Figs 11.3.A-E).
Subcutaneous fat area is measured by outlining the body surface in a slice and
outlining the inner contour of the subcutaneous fat. The difference between these
188
11
Fig. 11.3C. Graph depicting
the region of interest in
Figure 11.3B. Pixels having
values chosen to represent
fat are plotted by frequency.
Subcutaneous fat area and
volume are easily calcu-
lated from this graph.
Fig. 11.3B. T1 weighted MR
image where the subcuta-
neous fat area has been out-
lined using a computer con-
sole cursor.
Fig. 11.3A. As with CT im-
ages, an area of known fat
signal is measured to deter-
mine the range of values for
fat containing tissues.
189
11
two area measurements is the subcutaneous fat area.
15
Measurement of visceral fat is
accomplished in a manner similar to that described in the CT section. However,
MRI does not use Hounsfield units or attenuation values. Instead, signal intensity
of pixels is scaled in arbitrary units with zero as no signal (black) and +4095 as
maximal signal (white).
16
Tissue volume is calculated by multiplication of the area
and the effective slice thickness (actual slice thickness + interslice gap thickness).
17,18
Several problems inherent to MRI affect fat measurements obtained with this
method. First, MRI is sensitive to respiratory motion and bowel peristalsis. These
movements cause changes in relative area of fat in a slice. Using multiple slices with
averaging of signals or using rapid scanning techniques decreases the effects of mo-
tion. Secondly, inhomogeneities in the magnetic field lead to slight intensity varia-
tions across an image plane. This can be minimized by proper gradient and RF
tuning. Finally, bowel contents may have the same signal intensity as visceral fat.
This problem can be minimized by emptying the bowel prior to imaging.
15-19
Fig. 11.3E. Graph of the
region of interest in Fig-
ure 11.3D. The range of fat
values has been calculated
previously (Fig. 11.3A). Total
fat containing tissue area is
calculated from this graph.
Fig. 11.3D. T1 weighted
MR image with the entire
abdomen included in the
area of interest. Using the
graph in Figure 11.3E, vis-
ceral fat area and volume
may be tabulated by sub-
tracting subcutaneous fat
area (volume) from total fat
area (volume).
190
11
Although MRI can reliably measure fat areas with no radiation risk to the pa-
tient, it is not a very accurate method for determining the absolute amounts of visceral
adipose tissue.
16
Furthermore, this method is still very expensive and takes longer than
ultrasound or CT scan to be performed.
In the future, quantitative MRI may be able to predict trabecular bone density
in the spine because trabecular bone varies inversely with fat deposition in the bone
marrow. As hematopoietic marrow is replaced by fatty marrow, T1 and T2 relax-
ation times for lumbar vertebrae progressively decrease. The inverse relationship of
hematopoietic to fatty bone marrow and the T1 and T2 relaxation times may be
used to indirectly measure bone density.
Conclusion
Accurate assessment of nutritional status and body composition is of great im-
portance in patients requiring nutritional support. In addition to careful patient
history, physical examination, and anthropometric and biochemical measurements,
radiographic methods may prove to be helpful in assessing body composition of
these patients. Current experience with radiographic methods used in assessing nu-
tritional status, however, does not allow for the use of these methods as the only
means of determining the level of malnutrition and the therapeutic interventions for
correction of nutritional status.
Selected References
1. Tokunaga K, Matsuzawa Y, Ishikawa K et al. A novel technique for the determina-
tion of body fat by computed tomography. Internat J OB 1993; 7:437-445.
2. Lukaski HC. Methods for the assessment of human body composition: traditional
and new. Am J Clin Nutr 1987; 46:537-556.
3. Fanelli MT, Kuxzmarski RH. Ultrasound as an approach to assessing body com-
position. Am J Clin Nut 1984; 39:703-709.
4. Cuba T, Lat DA, Bowen A et al. Ultrasonography as a method of nutritional as-
sessment. JPEN 1989; 13:529-534.
5. Koskelo EK, Kivisaari LM, Saarinen UM et al. Quantitation of muscles and fat by
ultrasonography: a useful method in the assessment of malnutrition in children.
Acta Pediatr Scand 1991; 80:682-687.
6. Grauer WO, Moss AA, Can CE et al. Quantification of body fat distribution in
the abdomen using computed tomography. Am J Clin Nutr 1984; 39:631-637.
7. Shuman WP, Morris LLN, Leonetti DL et al. Abdominal fat distribution detected
by computed tomography in diabetic men. Invest Radiol 1986; 21:483-487.
8. Lerner A, Feld LG, Riddlesberger MM et al. Computed axial tomographic scan-
ning of the thigh: an alternative method of nutritional assessment in pediatrics.
Pediatrics 1986; 77(5):732-737.
9. Riddleberger MM Jr. Radiographic observations in patients receiving total parenteral
nutrition. In: Lebenthal E, ed. Total parenteral nutrition: Indications, utilization,
complications, and pathophysiological considerations. New York: Raven Press,
1986:207-218.
10. Heymsfield SB, Olafson RP, Kutner MH et al. A radiographic method of quanti-
fying protein- calorie undernutrition. Am J Clin Nutr 1979; 32:693-702.
11. Mayo-Smith W, Hayes CW, Biller BMK et al. Body distribution measured with CT:
correlation in healthy subjects, patients with anorexia nervosa, and patients with
Cushing Syndrome. Radiology 1989; 170:515-518.
12. Borkan GA, Gerzof SG, Robbins AH et al. Assessment of abdominal fat content by
computerized tomography. Am J Clin Nutr 1982; 36:172-177.
13. Dixon AK. Abdominal fat assessed by computed tomography: sex differences in
distribution. Clin Rad 1983; 34:189-191.
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14. Kvist H, Sjrstrm L, Tylen U. Adipose tissue volume determinations in women
by computed tomography: technical considerations. Inter J Ob 1986; 10:53-67.
15. Staten MA, Totty WG, Kohrt WM. Measurement of fat distribution by magnetic
resonance imaging. Invest Radiol 1989; 24:345-349.
16. Seidell JC, Bakker CJG, van der Kooy K. Imaging techniques for measuring adipose-
tissue distribution - a comparison between computed tomography and 1.5-T mag-
netic resonance. Am J Clin Nutr 1990; 51:953-957.
17. Gerald EL, Ferry JA, Amrein PC et al. Compositional changes in vertebral bone
marrow treatment for acute leukemia: assessment with quantitative chemical shift
imaging. Radiology 1992; 183:39-46.
18. Lancaster JL, Ghiatas AA, Alyassin A et al. Measurement of abdominal fat with
T1- weighted MR images. JMRI 1991; 1:363-369.
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tion in young women: quantification with MR imaging. AJR 1991; 157:99-104.
CHAPTER 12
Enteral Nutrition: Indications, Monitoring
and Complications
Gayle Minard
Introduction
The use of supplemental enteral nutrition in surgical patients has increased as
more evidence of its benefit compared with parenteral nutrition (PN) has been dem-
onstrated. Enteral feeding has been shown to decrease significant infections and
length of hospital stay following trauma, speed the recovery of head-injured pa-
tients, and decrease complications in patients with pancreatitis although these ben-
efits cannot necessarily be applied to all surgical patients. Enteral nutrition has also
been shown to be less expensive than PN in all patient groups studied. Many clini-
cians also consider enteral supplementation easier than PN because formulas are
prepackaged and manipulation of ingredients is generally unnecessary. However,
neither enteral nor parenteral feeding can be safely administered without concomi-
tant monitoring which is best done by a nutrition support team; however, if a team
is not available, the surgeon must closely follow the patients for tolerance and com-
plications. Despite this drawback, it is extremely worthwhile from a cost and patient
care perspective to use enteral rather than parenteral feeding whenever possible.
Indications
In many cases, the decision about whether or not to enterally supplement a
patient is straightforward. For instance, awake, alert patients with no impediments
to eating (i.e., a healthy young person who has just had an elective inguinal hernia
repair) should be allowed to take an oral diet as soon as his or her anesthesia wears
off. Conversely, no clinician would start enteral nutrition immediately after admis-
sion on a patient with a small bowel obstruction. The decisions become more com-
plicated when the situations are between the above scenarios. Should a severely
malnourished patient admitted for an elective procedure receive preoperative nutri-
tional support? How long is it safe to withhold nutrition from a well-nourished
patient following trauma or surgery? Is this time frame the same for all patients
regardless of diagnosis? What other factors affect timing and route of feeding?
There are three general categories of surgical patients who need enteral nutritional
supplementation:
1. Patients who are malnourished
2. Those who are at high risk for becoming malnourished, and
3. Those in whom early enteral nutrition has been shown to provide ben-
efits other than just prevention of malnutrition.
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Enteral Nutrition: Indications, Monitoring, and Complications
12
Malnourished Patients
Assessment of patients nutritional status can be done a number of ways. Cer-
tainly, patients who have a recent weight loss greater than 10% of their usual body
weight are considered malnourished. Patients with cancer, active AIDS, and those
with an acute exacerbation of inflammatory bowel disease may also fit into these
categories. Overweight patients can be malnourished as can patients following un-
usual diets despite lack of weight loss. Each patient needs an individual assessment
which can be as simple as performing a global assessment, or as complex as using a
DXA scan to measure lean body mass.
High-Risk Patients
Well-nourished patients entering the hospital for trauma, burns, or surgical pro-
cedures can quickly become malnourished during their hospitalization. In an un-
stressed state, healthy individuals can survive 4-6 weeks without eating before
irreversible muscle depletion occurs. Major surgery and trauma add a large physi-
ologic stress increasing catabolism, shortening this time period tremendously. Fol-
lowing major surgical procedures, well-nourished patients will need to be nutritionally
supplemented if they are not able to take adequate oral nutrition within 5-7 days. In
addition, nutrition support should be initiated in well-nourished surgical patients if
they have an abnormal level of consciousness or other physical limitations such that
oral feedings are precluded. Examples of this are patients with moderate head inju-
ries, those undergoing major oropharyngeal resections for cancer, or those who will
require prolonged ventilator support for poor pulmonary function. Since these pa-
tients will require nutrition support during their hospitalization, there is no reason
to delay feeding if their gastrointestinal tract is functional. Many clinicians will place
a feeding tube while performing a laparotomy for a major abdominal procedure
(pancreatic resection, transplant) in order to start early postoperative nutrition sup-
port although there is not yet data to prove its benefit. When in doubt, it is better to
initiate feedings than wait for malnutrition to develop.
Patient Populations with Improved Outcome
from Enteral Nutrition
Several patient populations have been shown to benefit from early enteral nutri-
tion as compared with parenteral or delayed enteral nutrition. Severely injured trauma
patients (i.e., those with an Abdominal Trauma Index 25 and/or an Injury Severity
Score 20) have been shown to have a decreased incidence of infectious complica-
tions when compared with those fed parenterally. Although the data is conflicting,
early enteral feeding has been associated with faster recovery and decreased infec-
tions in head-injured patients. Burn patients also benefit from early enteral nutri-
tion; most burn specialists begin nutrition within hours of admission. Patients with
pancreatitis have also been shown to have fewer infections from jejunal feeding com-
pared with PN. Several studies have also shown decreased complications in patients
with inflammatory bowel disease in whom early enteral nutrition was provided. In
general, the more physiologically stressed the patient, the earlier they should be
started on nutrition, and the adage When the gut works, use it should be fol-
lowed. Any patient with a fully functional GI tract should be fed enterally; there is
no place for PN in these patients.
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Contraindications
Certain conditions preclude enteral feedings; however, common sense should
easily identify most of them. Patients who are hemodynamically unstable or not
fully volume resuscitated can have very serious complications if fed enterally. These
patients shunt blood from their GI tracts so that feeding them, especially via the
small bowel, can have disastrous consequences. Lack of enteral access also precludes
feeding; however, this situation should be rare with modern endoscopic, surgical,
and radiologic techniques. Enteral feeding should not be delivered proximal to a
bowel obstruction or a high output fistula, and peritonitis should be resolved prior
to feeding. However, a bowel anastamosis is not a contraindication to small bowel
feeding nor is a low output distal fistula. Patients with mesh closure of their abdo-
mens can also be fed, and patients with pancreatitis can be fed cautiously as long as
jejunal access is obtained. Obviously, these types of patients need to be moni-
tored closely.
Monitoring
Monitoring patients receiving enteral feeding is a multidisciplinary task. For
example, the nursing staff checks the gastric residuals periodically during enteral
feeding and records events such as vomiting and diarrhea. The dietitian tracks the
patients caloric intake and adjusts the nutrition prescription accordingly. The phy-
sician should question the patient about bowel habits and abdominal pain as well as
assess the patient for abnormal physical signs such as abdominal distention and
tenderness. The specifics of monitoring depend to some extent on the location of
the access tube; however, some issues are common to all patients.
Tube Specific Monitoring
Gastric Tubes
Any patient with a gastric tube (whether it is a nasogastric tube or a gastrostomy)
should have gastric residuals checked prior to each bolus feeding or every 4-6 hours
if feeds are continuous. The cutoff for a high residual is controversial and probably
depends on the rate of feeding but is generally accepted to be 100-200 ccs in adults.
If the gastric residual exceeds this amount, feeds are held for 4 hours or until the
next bolus feeding. This is done to prevent gastric distention, vomiting, and aspira-
tion. The measurement of gastric residuals is not always accurate; aspirating from a
gastrostomy tube will only reveal fluid that is adjacent to the anterior gastric wall,
and small bore nasogastric tubes frequently collapse when trying to aspirate residu-
als through them. Therefore, a high residual should be taken seriously, but a low
residual does not eliminate the risk of aspiration. Aspirating for gastric contents also
helps confirm correct placement of the tube.
Nasal Tubes
Patients with nasal tubes, whether nasogastric or nasoenteric, are at higher risk
for sinusitis than patients without them. Excessive or purulent nasal drainage should
be investigated by obtaining sinus radiographs (usually CT). The diagnosis of si-
nusitis should be entertained in patients who have a fever of unknown origin and a
nasal feeding tube. Nasal tubes can be easily displaced so the amount of tube exiting
the nose should be noted, and the location of the tip of the tube should be sought on
any radiograph that is taken. Some institutions recommend daily radiographs to
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monitor tube location; however, this is prohibitively expensive. At the very least,
confirmation of tube placement should be done by insufflating with air while aus-
cultating the abdomen.
Jejunal Tubes
Because the jejunum is a narrow, relatively high flow area, checking residuals
while feeding is not helpful. Patients with these tubes must be watched very closely
for abdominal pain and distention because the small bowel can become ischemic if
tube feeds are continued in the face of intolerance.
General Monitoring
All patients receiving enteral nutrition should be monitored for certain compli-
cations, regardless of access site. The chart should be reviewed, and the patient should
be questioned about nausea, vomiting, abdominal pain, and bloating. Patients should
also be asked about diarrhea; adjustment of medications or the feeding formula or
even stopping the feeding may be required if it is severe and recalcitrant to other
maneuvers. The abdomen should be inspected for distention, auscultated for bowel
sounds, and palpated for tenderness. Percussion to differentiate ascites from intralu-
minal air may be helpful. The tube insertion site should be inspected for necrosis,
infection, and excessive bleeding.
The patients airway should be observed, and any report of tube feedings in the
airway should be quickly evaluated. Some institutions put blue food coloring in the
tube feedings to help detect aspiration. Aspiration is frequently subclinical, so it
should be suspected if the patient has a history of recurrent pneumonia or episodes
of choking, wheezing, or tachypnea associated with feeds.
Metabolic Monitoring
Patients receiving enteral feedings should be assessed for adequacy of caloric,
protein, and micronutrient intake along with metabolic complications. Two com-
mon methods of monitoring adequacy of intake are the use of metabolic carts and
measuring nitrogen balance. Volume status should also be estimated by following
inputs and outputs, weights, skin turgor, or more sophisticated methods if available
(i.e., pulmonary artery catheters).
Feeding malnourished patients may initiate the refeeding syndrome. There-
fore, potassium, magnesium and phosphate levels should be watched, along with
standard electrolytes and liver functions tests. In addition, many stressed patients
become hyperglycemic, so serum glucose levels should be followed closely until the
patient is stable on feedings.
Complications
Although the use of enteral nutrition is very safe, feeding via the enteral route is
not without complications. Fortunately, many of these problems can be minimized
or avoided with proper techniques and monitoring. Complications can be catego-
rized into tube related, formula related, or metabolic complications.
Tube Related Complications
Many complications of feeding tubes can be avoided with proper insertion and
maintenance techniques. Complications that are common to all tubes include dis-
placement, occlusion and rupture; however, some are related to the particular type
of tube.
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Nasoenteric Tubes
Like other tubes that traverse the nasal cavity, nasoenteric tubes can be associated
with sinusitis, crico-pharyngeal ulceration, and nasal necrosis. The smallest bore
tube available that can accommodate the patient and the formula should be used to
help minimize these complications, and the insertion site should be watched for
pressure sores. Nasoenteric tubes cross the gastroesophageal junction which many
believe predisposes patients to esophageal reflux and aspiration. Again, a smaller
tube will help minimize this. Keeping the head of the bed elevated at least 30 may
also decrease the risk of aspiration.
Gastrostomy Tubes
Insertion of a gastrostomy tube, whether done surgically, endoscopically, or ra-
diologically, carries a risk of infection, bleeding, and bowel obstruction. Placing a
gastrostomy surgically also carries the risk of anesthesia and dehiscence of the surgi-
cal wound. Perforation of other organs, such as the colon or liver, has been reported
when inserting gastrostomy tubes non-surgically. In addition, their internal bolsters
can erode through the stomach and migrate into the abdominal wall. Gastrostomy
tubes should not be put on tension, and the external bolster can be loosened once a
well-defined tract is formed.
Jejunostomy Tubes
Similar to gastrostomy tubes, insertion of jejunostomy tubes can lead to infec-
tion, bleeding, and bowel obstruction. Instilling feeding into the small bowel when
it is stressed (for example, when the patient is under-resuscitated) can lead to bowel
ischemia, pneumatosis intestinalis, and ultimately bowel infarction. The clinician
must be very diligent when monitoring patients receiving small bowel feedings and
be acutely aware of new abdominal pain, acute distention, or any signs of sepsis.
Formula Related Complications
Instillation of tube feeding into the gut can lead to a number of complications,
most of them minor and easily treatable.
Abdominal Distention
Many patients develop mild abdominal distention while receiving tube feedings.
In studies comparing patients receiving enteral feedings with those receiving parenteral
feedings, an equivalent number of patients fed intravenously have this problem.
Patients with distention should be closely monitored, however, and consideration
should be given to slowing or holding feedings, particularly if the patient complains
of bloating or pain.
Diarrhea
Diarrhea is a common symptom in patients receiving enteral feeding. Although
many clinicians will be quick to blame the tube feedings, frequently other factors are
at fault. Many medications are associated with diarrhea including liquid formula-
tions made with sorbitol, motility agents such as metoclopramide, H2 blockers,
antibiotics, antacids and guafenison. Patients with impactions or pelvic abscesses
can present with diarrhea, so these should be investigated. Patients receiving antibi-
otics may develop overgrowth of resistant bacteria such as Clostridium difficile. Loss
of normal flora may be associated with diarrhea so the addition of Lactobacillus
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granules may be of benefit. In endemic areas, the stool should be tested for parasites
such as Giardia. In the past, hyperosmolar feedings were a frequent cause of diar-
rhea; however, the osmolarity of modern formulas is much lower which has reduced
this problem. Sometimes adding or even removing fiber from the formula may alle-
viate tube feeding related diarrhea. When all else fails, the formula can be diluted or
slowed. Some patients, particularly those with gut atrophy, may benefit from chang-
ing to a low residue or elemental formula. Antimotility agents, such as loperamide,
can be used but only after infectious causes have been rules out.
Aspiration
Patients receiving tube feedings are at risk for aspiration, particularly if their
mental status is poor. Although it is intuitive that patients who are at risk for aspira-
tion would benefit from jejunal rather than gastric feedings, studies comparing this
have been mixed. It seems that some patients will aspirate regardless of the site
where nutrition is delivered. Checking gastric residuals and holding feeds if they are
high may help decrease the incidence of aspiration. A higher caloric formula will
allow a slower infusion rate and less volume to be delivered which may help gastric
emptying. Keeping the head of the bed at least 30 degrees during gastric feeding
may also help reduce the risk of aspiration. Obviously, the use of motility agents
may decrease formula transit time in the stomach, reducing the risk of aspiration.
Metabolic Complications
Metabolic complications related to feeding occur whether it is delivered enter-
ally or parenterally. This is one area in which a nutritional support team can be
invaluable in preventing and treating these problems.
Hyperglycemia
Patients who are stressed secrete excess amounts of cortisol, glucagon, ACTH,
catecholamines, and growth hormone that stimulate glycogen breakdown and glu-
cose release, and they also have a relative insulin resistance all of which leads to
hyperglycemia. In addition, many of these patients are infected which only worsens
the situation. Provision of nutrition, particularly as carbohydrates, may exacerbate
hyperglycemia; changing to a higher fat and lower carbohydrate formula may be
helpful. Hyperglycemia can also be minimized by advancing feedings slowly and
monitoring high-risk patients closely. Some patients will require sliding scale insulin
or an insulin drip to control their sugars despite these maneuvers.
Refeeding Syndrome
Patients who are malnourished (i.e., alcoholics) will quickly utilize nutrients,
such as potassium, phosphorous and magnesium, leading to relative deficiencies.
Therefore, these electrolytes should be followed closely in patients at risk. They may
require substantial supplementation during the early phases of feeding.
Mineral Deficiencies
Most enteral formulas are nutritionally complete; however, some of the specialty
formulas are missing certain nutrients. For example, renal formulas may lack iodine,
and some hepatic formulas lack vitamins. A dietitian can be very helpful in trying to
keep track of these issues. As soon as patients metabolic problems are stable, they
should be switched to a more complete formula.
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Elevated Liver Function Tests
Some patients may develop elevated liver function tests during nutrition sup-
port. This is thought to be due to overfeeding and deposition of fat in the liver. This
can be alleviated by reducing patients caloric intake. Obviously, other causes should
be sought such as hepatitis, acalculous cholecystitis, and drug toxicity among others.
Conclusion
Although somewhat labor intensive, the use of enteral nutrition is associated
with decreased length of stay and infectious complications in many surgical patient
populations. If the GI tract is intact, it is preferred over parenteral nutrition if for no
other reason than it costs less. Although patients must be monitored, administering
enteral nutrition rather than parenteral is the preferred nutritional support method
in most patients.
Selected References
1. Grahm TW, Zadrozny DB, Harrington T. The benefits of early jejunal
hyperalimentation in the head-injured patient. Neurosurgery 1989; 25:729-735.
2. Greenberg GR, Fleming CR, Jeejeebhoy KN et al. Controlled trial of bowel rest
and nutritional support in the management of Crohns disease. Gut 1988;
29:1309-1315.
3. Ibez J, Peafiel A, Raurich JM et al. Gastroesophageal reflux in intubated pa-
tients receiving enteral nutrition: Effect of supine and semirecumbent positions.
JPEN 1992; 16(5):419-422.
4. Kalfarentzos F, Kehagias J, Mead N et al. Enteral nutrition is superior to parenteral
nutrition in severe acute pancreatitis: Results of a randomized prospective trial. Br
J Surg 1997; 84:1665-1669.
5. Kudsk KA, Croce MA, Fabian TC et al. Enteral versus parenteral feeding. 1992;
215:503-513.
6. Lazarus BA, Murphy JB, Culpepper L. Aspiration associated with long-term gas-
tric versus jejunal feeding: A critical analysis of the literature. Arch Phys Med Rehabil
1990; 71:46-53.
7. McClave SA, Greene LM, Snider HL et al. Comparison of the safety of early en-
teral vs parenteral nutrition in mild acute pancreatitis. JPEN 1997; 21:14-20.
8. Metheny N. Minimizing respiratory complications of nasoenteric tube feedings:
State of the science. Heart Lung 1993; 22:213-223.
9. Minard G, Kudsk KA. Is early feeding beneficial? How early is early? New Hori-
zons 1994; 2(2):156-163.
10. Moore FA, Feliciano DV, Andrassy RJ et al. Early enteral feeding, compared with
parenteral, reduces postoperative septic complicationsthe results of a meta analysis.
Ann Surg 1992; 216:172-183.
11. Moore FA, Moore EE, Jones TN et al. TEN versus TPN following major abdomi-
nal traumareduced septic morbidity. J Trauma 1989; 29:916-923.
12. Rai J, Flint LM, Ferrara JJ. Small bowel necrosis in association with jejunostomy
tube feedings. Am Surg 1996; 62:1050-1054.
13. Rapp RP, Young B, Twyman D et al. The favorable effect of early parenteral feed-
ing on survival in head-injured patients. J Neurosurg 1983; 58:906-911.
14. The A.S.P.E.N. Nutrition Support Practice Manual. American Society for Parenteral
and enteral nutrition. Silver Spring: 1998.
15. Wood RH, Caldwell FT, Bowser-Wallace BH. The effect of early feeding on
postburn hypermetabolism. J Trauma 1988; 28(2):177-183
16. Young B, Ott L, Twyman D et al. The effect of nutritional support on outcome
from severe head injury. J Neurosurg 1987; 67:668-676.
CHAPTER 1
CHAPTER 13
Enteral Access: Open, Endoscopic
& Laparoscopic Techniques
Keith Zuccala, John M. Porter
When the decision to provide long-term nutritional support to the patient has
finally been made the surgeon has several options regarding specific technique. The
debate of enteral vs. parenteral has been discussed elsewhere. Now that the decision
has been made to provide enteral feedings, the choice of what type of enteral access
comes to the forefront. Essentially two sites exist for enteral access; the stomach and
the small bowel, more specifically the jejunum. Gastric devices are generally pre-
ferred because they offer the most flexibility in feeding schedules. Patients may be
fed using either a continuous drip or with bolus feedings, which allow a more regu-
lar lifestyle. However, gastric feeding is only appropriate in those patients who have
intact gag and cough reflexes, and adequate gastric emptying. The combination of
poor gastric emptying, reflux with possible aspiration, and the inability to protect
the airway can be deadly! Small bowel devices are indicated for those patients who
may be at risk for aspiration due to any compromise in glottic closure, cough reflex,
or gastric emptying. The choice of location of enteral feeding sites will also be af-
fected by the type of surgery and/or pathology that the patient has. For instance, s/
p esophageal resection for adenocarcinoma, the patient would probably be better
served by a jejunostomy than a gastrostomy access procedure. Once the decision has
been made regarding where to place the enteral access, gastric vs. jejunal), the next
decision is how to access the GI tract. In these next few sections we will assess the
different surgical access procedures. (Fluoroscopically placed devices and procedures
will not be discussed here.)
Gastrostomy
Gastrostomies may be placed using essentially three main techniques that are
within the scope of the general surgeon;
1. Open technique,
2. Endoscopic technique, and
3. Laparoscopic technique.
Each has its own inherent advantages and disadvantages. The traditional ap-
proach, before the advent of laparoscopy and endoscopy involved surgical or open
placement of the enteral access device. Although the first planned surgical gastros-
tomy is credited to Sedillot in 1846, Stamm was responsible at the turn of the cen-
tury for the refinements involved in the procedure used today.
1
Since that time the
technique has been refined slightly but essentially remains the same. Although this
procedure was the gold standard for close to 100 years, it has now been almost
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completely replaced by percutaneous endoscopic gastrostomy (PEG), except in the
case where the surgeon is in the abdomen for other reasons and when PEG place-
ment is contra-indicated or has already been attempted without success.
Though the open technique has withstood the test of time, it still has its fair
share of complications, some of which are common to almost all enteral access de-
vices and some of which are related to gastric tube placement alone. Table 13.1 lists
those complications generic to all enteral access. Those complications specific to
enteral access in the stomach include esophageal reflux, gastric outlet obstruction
from the catheter, and gastric ulceration.
The most feared complication of enteral feeding is aspiration. This was reviewed
by Minard
2
and again by Lazarus et al
3
who reviewed the literature for comparison
of aspiration rates between patients receiving gastric versus jejunal feedings. The
literature showed aspiration rates ranging from 0-40 percent in patients receiving
gastric feedings and from 0-13 percent in those receiving jejunal feeding. Interest-
ingly, more studies showed an aspiration of zero in gastric feeding than jejunal feed-
ing. Thus the aspiration rate with jejunal feeding is not zero, as is commonly thought.
Specifically, no aspiration with gastric feeding in 18 studies compared to no aspira-
tion with jejunal feeding in only four studies. Most of the articles reviewed had one
or more methodological problems and therefore, there is no conclusive evidence
that aspiration is decreased with jejunal feedings compared to gastric feedings. The
current standard of care is that patients who appear to be at high risk for reflux/
aspiration should be treated with a jejunostomy but this has not been conclusively
proven in the medical literature.
Techniques
Open
All of the open techniques can be performed through either a left upper quad-
rant or upper midline incision. Although not proven, these patients should prob-
ably receive perioperative prophylactic antibiotics. Ancef is a reasonable choice.
Stamm
This is the classic temporary gastrostomy, although it can be used long-term.
Once the feeding tube is removed; the site will close spontaneously over a relatively
short period. The feeding tube is placed through the anterior abdominal wall via a
separate stab incision. The feeding tube has an internal bolster or balloon, which
once placed within the stomach holds the device in place after the two purse-string
sutures are tied down. Tacking sutures are then used to attach the stomach to the
anterior abdominal wall. These tubes can become displaced frequently and will close
in a rapid fashion if the tracts patency is not maintained by timely replacement.
Dislodgment within the first two weeks post-operatively or any difficult reinsertion
should have placement confirmed by a gastrograffin study. This can be accomplished
at the bedside by placing 100 cc of gastrograffin into the tube and taking a plain film
of the abdomen. Equivocal studies can be confirmed by a formal fluoroscopic study.
Even tubes that have been in place for long periods can have their tracks close rather
rapidly. Every effort should be made to reinsert a feeding tube or maintain tract
patency with a Foley catheter within the first 4-6 hours after dislodgment.
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Enteral Access: Open, Endoscopic & Laparoscopic Techniques
13
Dragstedt
The same technique as the Stamm is used with the addition of an omental wrap
around the tube, between the stomach and the anterior abdominal wall. This extra
step is added to help reinforce the junction. This is to prevent any intraperitoneal
leak, although there is no definite evidence of a lower leak rate.
Janeway
This technique involves the actual construction of a gastric ostomy. This is a
permanent opening used for long term feeding. Using a stapling device, a tube of
stomach is fashioned and brought out as the stoma. The tube must be long enough,
usually 8-10cm, to prevent continual reflux of gastric contents onto the anterior
abdominal wall. Its base should be large enough, usually 5-6cm, to prevent possible
stricture or torsion. Again, this is a permanent stoma located in the left upper quad-
rant. Since this stoma is permanent, feeding tubes/devices can be inserted and re-
moved as needed to conform to the patients feeding schedule. The patient is not
encumbered by a tube permanently exiting from their anterior abdominal wall and all
the attendant hazards and complications that go with an externalized feeding device.
Witzel
The Witzel technique entails tunneling of the feeding catheter through the stom-
ach wall before exiting to pass out through the anterior abdominal wall. This tech-
nique is also used to form a jejunostomy and is more fully explained under that
section of the chapter. The purpose is to decrease the intraperitoneal leak rate.
Endoscopic
Percutaneous Endoscopic Gastrostomy (PEG)
This has now become the gold standard for obtaining either permanent or
temporary gastric access. It is contraindicated in patients with esophageal tumors or
strictures, altered anatomy (e.g., prior gastric surgery) that might interfere with the
endoscopic portion of the technique, ascites, morbid obesity and esophageal/gastric
varices.
4
Previous upper abdominal incision is only a relative contraindication. This
technique was initially described by Gauderer et al in 1980.
5
There have been sev-
eral modifications but overall the technique used by most endoscopists is similar.
First, a standard esophagogastroduodenoscopy (EGD) is performed to exclude any
pathology that may interfere with gastric feeding, such as gastric outlet obstruction,
Table 13.1. Complications of enteral access
Abdominal wound infection, including necrotizing fasciitis
Post-operative bleeding
Dislodgment of the access device post-op
Tube/device obstruction
Intra-abdominal leakage at the enteral access site, +/- peritonitis
Intraoperative iatrogenic injury to intraabdominal structures, including insertion
into the wrong hollow viscus
Tube site infection
Persistent sinus/site leak
Aspiration
Failure to tolerate feedings (discussed elsewhere)
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tumor or ulcer. The right upper quadrant of the abdomen is prepped and draped
aseptically and the brightest transillumination point is palpated. If the light cannot
be visualized the PEG should not be performed. This point cannot be overempha-
sized. Local anesthetic is used as needed and an incision is made in the skin approxi-
mately 1-1/2 times the diameter of the feeding tube to be used. A large bore needle
and sheath are placed through the incision into the stomach and grasped by a snare
passed through the endoscope. The needle is removed and a guide-wire is inserted
through the sheath. The snare secures the guidewire and the endoscope, guidewire
and snare are all removed out through the patients mouth.
At this point there are now two different techniques that may be used to insert
the feeding tube. The first is the pull method. In the pull method the feeding tube is
attached to the guidewire and pulled back through the mouth, esophagus, stomach
and out the anterior abdominal wall. Of note, once the feeding tube starts to emerge
from the abdominal wall, the endoscope should be reinserted to directly visualize
placement. This avoids over-exuberant pulling which may dislodge the tube from
the stomach, as well as avoiding excessive tension of the internal bolster against the
stomach wall. Excessive tension can lead to pressure necrosis and perforation of the
stomach with subsequent leakage and peritonitis. Bleeding is also assessed at this
time. It is of vital importance to visualize the stomach and the PEG after insertion.
This needs to be documented in the chart.
The second technique is the push method whereby the feeding tube is pushed
over the guidewire, much like a central venous catheter is inserted using a Seldinger
technique. Again, the endoscope should be reinserted to visualize the stomach and
the PEG.
Laparoscopic
Many standard operative techniques have been modified and incorporated into
the armamentarium of the minimally invasive surgeon. One of the major advan-
tages of using laparoscopy is that the peritoneal cavity can be examined for pathol-
ogy grossly and iatrogenic injury to adjacent organs can be avoided, though this is
somewhat counterbalanced by the risk of initial trocar insertion. Several different
techniques have been described. Haggie
6
described a technique which was in effect
a laparoscopic Janeway gastrostomy, using a stapler to fashion the stomach tube and
creating a stoma in the left upper quadrant. Edelman et al
7
employed a technique
that involved bringing the stomach up to the anterior abdominal wall with a grasper
and then placing several Cope anchor sutures to fix the stomach to the anterior
abdominal wall. These Cope sutures have an appearance similar to plastic price tag
holders used in the clothing industry. Next, a large bore needle is passed percutane-
ously into the stomach at the site transfixed by the Cope sutures. A guidewire is then
passed through the needle, the needle is removed and progressively largT) dilators
are passed over the guidewire. The gastrostomy site is dilated up until a 17 French
peel-away sheath can be inserted. A gastrostomy tube with balloon is then inserted
through the sheath and the balloon is inflated. Once the balloon is inflated, the
peel-away sheath is removed and the G-tube is pulled up against the anterior ab-
dominal wall. Edelman et al report on twenty patients one of whom died secondary
to complications from the surgery, specifically gastric necrosis. Although the
laparoscopic techniques have advantages over the traditional open techniques, PEG
still remains the gold standard.
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13
Devices
There are different types of devices that may be used as gastrostomy tubes. There
are several different products on the market from varying manufacturers but they
share similar characteristics. Almost all are made of polyurethane today. Hunter first
reported the delivery of feedings directly into the stomach in 1793 by way of a
leather tube.
8
Recently the use of buttons has become popular. These devices are
low contour and avoid dangling tubes which may become entangled and lead to
damage or injury to the feeding device. Buttons are primarily advocated for use in
children and cognitively impaired adults. They require slightly more dexterity to
access and may be difficult to engage for patients who have poor eyesight or who are
obese. Also there are a variety of tubes that can be placed through the gastricostomy
and fed through the pylorus into the duodenum or jejunum.
Jejunostomy
Jejunostomies may be placed using three main techniques that are within the
scope of the general surgeon: open, laparoscopic and endoscopic techniques. Each
has its own inherent advantages and disadvantages. Bush performed the first open
jejunostomy for nutritional purposes
9
in 1858 in a patient with non-operable gas-
tric cancer. In 1891, Witzel described his classic technique, which has undergone
many modifications but is still utilized today. In 1973, Delany et al
10
described the
needle catheter technique. As previously mentioned Gauderer et al described the
PEG in 1980, and it was not long after that, people were modifying this approach
into a combined PEG/PEJ procedure. In the 1990s as minimally invasive surgery has
become more widespread, laparoscopically placed jejunostomies have been performed.
Table 13.2 lists the indications for placing a jejunostomy. They can be summa-
rized as whenever enteral nutrition is desired and cannot be accomplished via the
oral or gastric route. The main advantage of jejunostomies is the decreased risk of
aspiration. However, as stated earlier, this rate is not zero, nor has it been conclu-
sively shown to be less than that with gastrostomies. The contraindications for je-
junostomy placement are listed in Table 13.3. As early post traumatic enteral feeding
has become more popular, feeding too early when the small bowel is still relatively
ischemic can lead to frank small bowel ischemia and necrosis. Table 13.1 listed the
complications that are generic to both gastrostomy and jejunostomy. Complica-
tions specific to jejunostomies include small bowel obstruction from either the tube
itself or volvulus and pneumotosis intestinale.
Technique
Open
This can be performed in conjunction with other procedures or as the primary
procedure. Access to the abdomen is usually via midline incision, although other
incisions, such as the left subcostal or paramedian can be used. Common to all
techniques is the selection of the appropriate location for the jejunostomy. Specifi-
cally, it must be distal enough from the ligament of Treitz so to decrease the risk of
aspiration. However, if it is too distal, there will not be enough absorptive surface
for the enteral feedings to be effective. Also the loop of jejunum must be of suffi-
cient length to reach up to the anterior abdominal wall without tension. The proper
distance is 20-25 centimeters from the ligament of Treitz. Selection of the proper
location cannot be overemphasized.
204
13
Witzel
This is the classical technique for an open jejunostomy. The appropriate site of
proximal jejunum is selected. Usually a red rubber catheter, 12-16 french, is used. It
is passed through the anterior abdominal wall in an open fashion. A pursestring is
placed in the small bowel and the jejunum is opened. The catheter is fed 10-15
centimeters distally and palpated to insure that it is not kinked. The pursestring is
tied. From the pursestring site to 5-10 centimeters proximally, a serosal tunnel is
created to bury the catheter. At the proximal end of this tunnel, the jejunum is
secured to the anterior abdominal wall. The tunnel is created to decrease the inci-
dence of leakage from the catheter. Tubes originally designed for other purposes
have been adapted and used for feeding jejunostomies.
11
The classic tube, as men-
tioned, is a red rubber catheter which is usually used in combination with a Witzel
tunnel. Catheters with polyester-fiber cuffs such as the Hickman or the Tenchkhoff
have also been used with some success.
Needle Catheter Jejunostomy
First described by Delany,
12
the needle-catheter jejunostomy is another open
technique. The site on the anterior abdominal wall is selected, as previously de-
scribed. A 5-7 french catheter is inserted through the abdominal wall either via large
bore needleor in an open fashion. A 7 french tube is required for feeding of
casein-based protein supplements in order to prevent clogging. Administration of
non-liquid medications through these tubes is not recommended. A purse string
suture is placed on the anterior aspect of the jejunum and a large bore needle is
passed into the bowel lumen through the purse-string suture. A subserosal tunnel
prior to insertion into the lumen makes for a better seal and a less likely chance of
leak when the tube is finally removed. The 5-7 french catheter is inserted through
the needle, the needle is removed, and then the purse-string suture is tied around
the catheter. A Witzel tunnel is an option. If desired, it is fashioned as described
above. If not, then the jejunum is tacked up to the anterior abdominal wall at the
site of the pursestring.
Table 13.2. Indications for jejunostomy
1. enteral nutrition favored.
2. Oral route inaccessible or inadequate
3. Length of feeding > 6 weeks
4. GI surgery with postoperative complications of;
a. anastomotic dysfunction
b. postop pancreatitis
c. residual sepsis
d. enterocutaneous fistula
e. hypercatabolic patients (e.g. malignant neoplasia)
f. moderate to severe malnourishment
g. intraabdominal organ transplant recipients
h. immunocompromised pts.
i. prolonged fast
j. gastric atony
5. Polytrauma
205
13
Permanent
The aforementioned techniques and catheters are for the most part pertinent to
jejunostomies that are not meant to be permanent. For a more permanent jejunos-
tomy, Maydl developed a technique in which a Roux-en-Y limb is brought out as a
stoma. This is tunneled subcutaneously for several centimeters to prevent leakage of
sucus onto the abdominal skin. The stoma is cannulated with a balloon-tipped cath-
eter at each time of access. DeCou et al
11
described a modification whereby a
mushroom-tipped catheter is sewn into the end of the Roux-en-Y limb and brought
out through a separate incision. The catheter is sewn in using two purse string su-
tures. This method seems to have the advantage of a lower leak rate compared with
Maydls technique.
Other
The jejunal tube can also be placed via an open gastrostomy incision with an
apparatus placed that serves a dual purpose of not only allowing gastric suction and
decompression but also simultaneous feeding via a jejunostomy tube which passes
trans-pyloric. Theoretically, the risk of obstruction and volvulus should be lower
than with other open jejunostomies because the stomach, not the intestine, is fixed
to the abdominal wall.
12
Laparoscopic
Several different techniques may be used to access the jejunum laparoscopically.
One of the earliest successful techniques was described by Morris et al
13
and in-
volved bringing a piece of jejunum, as with open techniques 20-25 centimeters
from the ligament of Treitz, out through the 10 mm, supraumbilical port. 3-0 silk
seromuscular sutures are then used to secure the jejunum to the fascia. A red rubber
catheter feeding tube is held in the jejunum by two concentrically placed purse-string
sutures. The fascia is closed around the red rubber catheter, which is then tunneled
for several centimeters subcutaneously before being brought out through a lateral
trocar site. In fact, a purist might argue that this is a laparoscopically guided tech-
nique as a portion of the procedure is done open however, it started a wave of
more completely laparoscopic techniques.
Several different surgeons reported purely laparoscopic techniques that varied
only slightly in how the jejunum is secured to the anterior abdominal wall. Duh and
Way
14
used T-fasteners to secure the small bowel; Sangster & Swanstrom describe a
similar procedure using 3-0 silk on a Keith needle. Both similarly describe the
Table 13.3. Contraindications for jejunostomy
1. Intestinal obstruction
2. Predisposing factors for enterocutaneous formation
a. intestinal wall edema
b. postradiation enteritis
c. IBD affecting small intestine
3. Coagulopathies
4. Ascites
5. Serious immunodeficiency problems (increased risk of intraabdominal Infection or
necrotizing fasciitis)
6. Ischemic bowel
206
13
obtainment of enteral access using a venous access kit with peel-away sheaths and
dilators to create an opening large enough to insert the feeding tube, after the stay
sutures/fasteners were in place. In circumstances where stay sutures are used they
can be either tied over a fascial bridge or over a bolster externally
16
or sutured en-
tirely within the abdominal cavity.
Rosser et al
17
described a simplified technique which actually uses a similar
technique as previously described but includes the use of advanced technology with
special instruments specifically designed for laparoscopic jejunostomies, Endoclose
and Endostitch [United States Surgical Corporation, Norwalk, Conn.] and the
FLEXIFLO LAP J laparoscopic jejunostomy kit [Ross Laboratories, Columbus, Ohio].
Endoscopic
Percutaneous endoscopic jejunostomy (PEJ) is a term applied to several different
techniques whose only similarity is that the feeding tube ideally delivers nutrients
into the second portion of the small bowel. As Clevenger and Rodriguez
18
point out
currently three jejunal tube placement techniques have been given the name PEJ.s
The first and most common is simply placement of a jejunal feeding tube through a
traditional PEG tube. The jejunal portion is passed trans-pyloric and down the
jejunum either directly by via the endoscope or over a guidewire, which is placed
initially by the endoscope. Sometimes a dual lumen tube is used with the shorter
end opening into the stomach and used for gastric decompression, and the longer
end being passed into the jejunum for feeding purposes.
The second technique, which carries the label PEJ, involves endoscopic assis-
tance in an open technique of jejunostomy tube placement.
19
The purported advan-
tage being that by using the endoscope to identify and deliver the jejunum that a
smaller incision can be made.
The third technique is a true PEJ. As described by Shike et al
20
a 160-cm endo-
scope is required to place the tube directly into the jejunum. There have been no
prospective studies to demonstrate one methods clear-cut advantage over another.
Conclusion
The benefits of providing nutrition in ill patients are myriad and well known.
Once the decision has been made to provide this nutrition enterally, the surgeon is
still faced with several options concerning the appropriate access. Both gastric and
jejunal access have their complications and advantages. Each patient must be indi-
vidually scrutinized and the specific circumstances examined. If long-term access is
deemed appropriate then either gastrostomy or jejunostomy are appropriate. Cer-
tain patients are amenable to gastrostomy placement while others have certain rela-
tive contraindicationskeeping in mind that it is truly by convention, and not
necessarily documentation in the medical literature, that jejunostomy is considered
less likely to put the patient at risk of aspiration. Next, the astute surgeon must
decide which particular procedure is most appropriate for their patientopen,
laparoscopic or endoscopic. Finally, once the particular technique is decided upon,
the specific variant must be selected. Enteral access may seem a rather cut-and-dry
topic surgically, but the multiple decisions involved, requiring thoughtful insight
and astute clinical judgement, make this facet of surgery as much an art as it is
a science.
207
13
Selected References
1. Clevenger FW, Rodriguez RD. Decision-making for enteral feeding administra-
tion: The way behind where we are now. Nutr Clin Prac 1995; 10:104-113.
2. Minard G. Enteral access. Nutr Clin Prac 1994; 9:172-182.
3. Lazarus BA et al. Aspiration associated with long-term gastric versus jejunal feed-
ing: A critical analysis of the literature. Arch Phys Med Rehab 1990; 70:46-53.
4. Meguid MM et al. The delivery of nutritional supporta potpourri of new de-
vices and methods. Cancer 1985; 55(suppl):279-289.
5. Gauderer MWL et al. Gastrostomy without laparotomy: A percutaneous endo-
scopic technique. J Ped Surg 1980; 15:872-875.
6. Haggie JA. Laparoscopic tube gastrostomy. Ann Rev Coll Surg Engl 1992;
74:258-259.
7. Edelman DS et al. Laparoscopic gastrostomy or percutaneous endoscopic gastros-
tomy. Contemp Surg 1994; 44:269-272.
8. Hunter J. A case of paralysis of the muscles of deglutition cured by an artificial
mode of conveying food and medicines into the stomach. Trans Soc Improve Med
Chir Know 1973; 1:182-188.
9. Tapia J et al. Jejunostomy: Techniques, indications and complications. W J Surg
1999; 23:596-602.
10. Delaney HM et al. Jejunostomy by needle catheter technique. Surgery 1973; 73:786.
11. DeCou JM et al. Feeding Roux-en-Y jejunostomy in the management of severely
neurologically impaired children. J Ped Surg 1993; 28:1276-1280.
12. Minard G. Enteral access. Nutr Clin Prac 1004; 9:172-182.
13. Morris JB et al. Laparoscopic-guided jejunostomy. Surgery 1992; 112:96-99.
14. Duh QY, Way LW. Laparoscopic jejunostomy using T-fastener as retractors and
anchors. Arch Surg 1993; 128:105-108.
15. Sangster W, Swanstrom L. Laparoscopic-guided feeding jejunostomy. Surg Endosc
1993; 7:308-310.
16. Shatz DV et al. Laparoscopic suturing technique for enteral access procedures.
Surg Endosc 1994; 8:717-718.
17. Rosser JC et al. A simplified technique for laparoscopic jejunostomy and gastros-
tomy tube placement. Am J Surg 1999; 177:61-65.
18. Clevenger FW, Rodriguez RD. Decision-making for enteral feeding administra-
tion: The why behind where and how. Nutr Clin Prac 1995; 10:104-113.
19. Adams DB. Feeding jejunostomy with endoscopic guidance. Surg Gyn Obstet
1991; 10:104-113.
20. Shike M et al. Direct percutaneous endoscopic jejunostomies. Gastrointest Endosc
1991; 37:62-65.
CHAPTER 14
Total Parenteral Nutrition:
Current Concepts and Indications
The decision to initiate and to maintain adequate nutrition via
TPN should be based upon the achievement of a specific, definable,
and realistic goal for each patient and each condition. It should
always be borne in mind that the ultimate aim of the technique is
to prolong meaningful life and not merely to prolong an active
process of inevitable death.
Introduction
The majority of hospitalized patients with a normally functioning gastrointesti-
nal tract usually do not require special nutritional support. However, significant
malnutrition, as defined by anthropometric, biochemical measurements and weight
loss, may be documented in up to 50% of surgical patients.
1
This percentage may be
even higher among indigents and patients in intensive care units. Although most
patients are malnourished at the time of admission or diagnosis as a consequence of
disease-induced poor food intake, a significant number of other patients become
malnourished iatrogenically during hospitalization.
2
Many factors are responsible
for the development of malnutrition in the hospitalized patient, among which are
the hypercatabolic states associated with trauma, sepsis, cancer, surgical interven-
tions and many other interacting biologic and social factors. For patients who mani-
fest signs and symptoms, of malnutrition including, 1) a history of unintentional or
unexplained weight loss of 10 pounds or 10% of body weight during the previous
two months; 2) a serum albumin concentration of less than 3.4g/dL; 3) impaired
immunocompetence as determined by a standard battery of skin tests; and 4) a total
lymphocyte count of less than 1200/mm
3
, prior to hospitalization, or who are likely
to develop them during hospitalization as a result of stressful periods of diagnostic
and therapeutic interventions, efforts should be directed toward maintenance or
restitution of nutritional status. If a patients gastrointestinal (GI) tract cannot, or
should not be used for oral or direct enteral feeding, or if a patient is unable to
receive adequate amounts of nutrition via the oral or enteral route, then total
parenteral nutrition (TPN) should be considered as the primary technique of pro-
viding all nutrient substrates and caloric needs until the GI tract can be used safely
and effectively.
209
Total Parenteral Nutrition: Current Concepts and Indications
14
Because it is not possible for a single parenteral nutritional formulation to be
standardized for optimal use in all patients with a wide variety of disorders, nor for
all age groups, nor for the same patient during all aspects of a specific pathologic
process, specific parenteral nutrient regimens should be individually designed and
tailored for each patient. As a result, a wide variety of maintenance and therapeutic
parenteral nutritional formulas for pediatric and adult patients has evolved through-
out the years, and many commercial products are now available for clinical use.
Efforts are under way in many centers to understand and define the individually
specific nutrient requirements for patients sustaining major trauma, single or mul-
tiple organ system failure syndromes, extensive full-thickness burns, sepsis, cancer,
immunologically related diseases, primary gastrointestinal disorders and severe ath-
erosclerotic cardiovascular disease. Current special substrate mixtures represent sig-
nificant progress in clinical nutrition and are the seminal precursors of the antici-
pated specifically formulated and highly sophisticated parenteral nutrition regimens
of the future. Total parenteral nutrition has not simply enabled us to establish an
alternate feeding route for our patients, but has had a profound effect on the
multimodal management of patients with inflammatory disease and has created an
innovative tool that has allowed the rapid progression of a complex and diverse
aspect of nutritional support.
3-4
Current indications for use of TPN demand clear
demonstration of therapeutic effects. In many conditions the use of TPN has been
shown to be beneficial, and at times it is the only acceptable mode of providing all
nutrients. In many others, the efficacy, cost effectiveness and outcome data have not
clearly supported the hypothesis that TPN should be initiated in all malnourished
or undernourished patients who cannot use their GI tracts optimally or at all during
relatively short periods (5-7 days) of starvation induced by their pathophysiologic
processes and therapies. However, most experienced clinicians agree that, ideally,
patients should be fed optimally at all times, and that no pathological process can be
treated better when the patient is starved than when the patient is well nourished.
This chapter will briefly review some of the general principles of TPN therapy and
the current indications for use of this modality which has provided a great stimulus
for development of surgical nutrition and metabolic practice.
General Indications for Use of TPN
The original goals of nutritional support
3
were to provide adequate nutrients to
meet the normal or increased metabolic requirements for:
1. growth and development,
2. restoration of body weight,
3. restoration of optimal bodily function,
4. achievement of homeostasis,
5. improvement of nitrogen balance,
6. improvement of protein status,
7. improvement of response to therapy,
8. restoration of immunocompetence, and
9. reduction of morbidity and mortality.
5
The general indications for the use of TPN are:
1. provision of adequate nutrition for as long as necessary intravenously when
use of the gastrointestinal tract is impractical, inadequate, ill-advised, or
impossible;
2. reduction of mechanical and secretory activity of the alimentary tract to
basal levels in order to achieve a state of bowel rest;
210
14
3. provision of specially tailored formulas to improve nutritional status in
patients with kidney or liver failure; and
4. reduction of the urgency for surgical intervention in patients who might
eventually require operation, but in whom prolonged, progressive mal-
nutrition will greatly increase the risk of operation and postoperative com-
plications.
3
Specific Indications for Total Parenteral Nutrition
TPN efficacy has been demonstrated clearly in many pathophysiologic condi-
tions including short-gut syndrome, fistulas, severe burns, renal failure, hepatic fail-
ure, inflammatory bowel disease, acute pancreatitis, chemotherapy and radiation
induced enteritis, transplant patients and severely malnourished cancer patients in
their perioperative management, when provision of nutrition enterally is not pos-
sible. Other conditions in which TPN is indicated but in which its efficacy has not
been clearly demonstrated in the literature include acute exacerbations of chronic
pancreatitis, anorexia nervosa, cardiac cachexia, hyperemesis gravidarum, prolonged
respiratory support, chronic protein losses and cancer patients with mild malnutri-
tion. In general, when GI tract cannot be used for more than five days in patients in
a catabolic state with or without evidence of malnutrition, or when patients cannot
be fed for 3 days after major surgery, parenteral nutrition should be started. Areas of
intense clinical investigation in which TPN may eventually be shown to be of great
value are cancer patients in general, sepsis and trauma, and general perioperative sup-
port to prevent or correct malnutrition.
Short Bowel Syndrome
Short bowel syndrome is a complex entity characterized clinically by intractable
diarrhea, steatorrhea, weight loss, dehydration, maldigestion and malabsorption,
and eventually malnutrition. The intestinal adaptation and regeneration, together
with the nutritional and pharmacologic aspects of management of short bowel syn-
drome, discussed comprehensively in Chapters 15, 16, and 18. The predominant
manifestations of short-bowel syndrome depend on several factors, among which
are: the extent and site of resection, associated diseases, age of onset of short bowel
syndrome, the length and location of the intestinal tract, the residual function of the
remaining GI tract (stomach, pancreas, biliary system and colon), the adaptive ca-
pacity of remaining intestinal segment, and finally the nature of the primary disease
and the residual activity of the disease.
Metabolically, this syndrome is manifested by anemia, bile salt depletion,
cholelithiasis, lactic acidosis, hypokalemia, hypocalcemia, osteoporosis, renal stones,
liver dysfunction, trace element and vitamin deficiency, and essential fatty acid defi-
ciency (EFAD).
Development of safe and efficacious TPN has revolutionized the treatment of
patients with short-bowel syndrome by allowing maintenance of adequate nutrition
until the remaining intestine can adapt optimally to oral feeding. TPN should be
started on the second post-operative day and continued for as long as needed, through
the immediate post-operative period, the bowel adaptation period, and the long-
term management period. The patient with short bowel syndrome represents one of
the greatest challenges to clinicians, and maintaining optimal nutritional and meta-
bolic support until bowel adaptation can occur is the top priority in the manage-
ment of these patients.
211
14
Enterocutaneous Fistula
The most frequent causes of enterocutaneous fistula are direct operative injury
to the small bowel, disruption of an anastomosis, or a perianastomotic leak and
abscess. Other causes include sharp or blunt trauma that results in fistula formation
by direct penetration, compression, ischemia, or necrosis of the bowel; benign and
malignant neoplasms of the bowel; inflammatory bowel diseases (Crohns disease);
the presence of a foreign body, radiation injury, or open abdomen with exposure of
bowel to mesh or dressings.
7
Malnutrition is very common in patients with enterocutaneous fistulas and is
often associated with electrolyte imbalance and sepsis. High-output fistulas that
originate in the upper small bowel initially may drain as much as 3,000 ml or more
of fluid daily. The difficulties presented by such massive losses of water, electrolytes,
and nutrients are formidable. A significant but lesser degree of malnutrition is asso-
ciated with moderate-output fistulas, which drain between 200 and 500 ml per day.
Low-output fistulas with fluid losses of less than 200 ml daily have a much lower
incidence of associated malnutrition. They usually take origin from the lower small
bowel or colon.
A major objective in nonoperative fistula management is to minimize its output.
Absolutely nothing should be allowed by mouth, not even ice chips, if this goal is to
be achieved. Gastric acid secretion and intestinal and pancreatic secretions are ini-
tially inhibited maximally by intravenous H
2
receptor blockers, and parenteral so-
matostatin. TPN is initiated when fistula is recognized. This should be done after
stabilizing the patients with an enterocutaneous fistula and correcting the blood
volume and electrolyte and clotting deficits. Infusion of the nutrient solution is
begun at levels to provide water (35 to 45 ml per kilogram body weight per day) and
protein (1.5 to 2.0 g per kilogram body weight per day) requirements. Although the
final caloric intake is calculated at 25-30 kcal per kilogram body weight per day,
usually only one-third to one-half of the caloric ration is given as dextrose on the
first day. After tolerance and utilization of the dextrose are established, the concen-
tration and dosage are gradually increased over the next few days to meet full caloric
requirements. Fat emulsion of 20 percent concentrations may be infused in 250 ml
doses two to three times a week primarily to prevent essential fatty acid deficiency,
although this is still a controversial issue. In patients with diabetes mellitus, conges-
tive heart failure, or severe obstructive pulmonary disease, it is sometimes infused
daily in 500 ml doses to provide high-density fat calories, thus reducing the dextrose
and water in the ration and reducing the carbon dioxide produced subsequently by
oxidation of the dextrose.
Serum electrolyte, glucase, urea nitrogen, creatinine, calcium, phosphorus, and
magnesium levels are determined daily during the first 5 to 7 days to facilitate prompt
repletion of deficits and metabolic stabilization. Thereafter, serum electrolyte, glucase,
urea nitrogen, and creatinine concentrations are determined two or three times a
week, and calcium, phosphorus, magnesium, zinc, copper, and albumin levels, liver
function tests, prothrombin time, activated partial thromboplastin time, com-
plete blood count, differential count, and platelets are determined weekly. Adjust-
ments in the formulation and volume of the infusate are made as indicated.
Although it is often difficult or impossible to provide adequate enteral nutrition
in the presence of an enterocutaneous fistula because of sepsis, ileus, and/or inad-
equate absorptive capacity, spontaneous fistula closure during enteral nutrition can
be accomplished in a reasonable number of selected patients. If at least 4 feet of
212
14
functioning small bowel exist between the ligament of Treitz and the fistula, oral
feeding nasogastric or nasoduodenal tube feedings of highly absorbable, low-residue
nutrients can be administered with reasonable results. Sometimes a small, soft tube
can be passed into the bowel below a high fistula for continuous feeding by pump.
The volume and concentration of tube feedings initially must be low, and subse-
quently increased incrementally to full volume and strength or to tolerance. This
process ordinarily takes 3-5 days for achievement of caloric and nitrogen balance,
during which time the patient should be supplemented with TPN. A combination
of both of these techniques may be necessary to provide optimal nutrition in some
patients.
The use of TPN in managing enterocutaneous fistulas is usually associated with
a prompt decrease in the ongoing protein losses from fistulas, and even when TPN
does not induce definitive closure of the fistula, patients having received a course of
TPN will be prepared better for operative interventions designed to close the fistulas.
Inflammatory Bowel Disease
The etiology and specific treatment of Crohns disease and ulcerative colitis are
not fully understood. Consequently, the treatment strategy for these patients is es-
sentially symptomatic and supportive. Malnutrition that frequently accompanies
inflammatory bowel disease (IBD) should be corrected with TPN, elemental enteral
diets or both. TPN should be used in conjunction with multimodal medical man-
agement or as an adjunct to an operative procedure. Evidence exists that TPN is of
value in IBD, and judicious nutritional therapy remains a cornerstone in the overall
adjunctive management of these patients.
8
For more details of nutrition support in
patients with IBD (see Chapter 19).
Liver Failure
Although nutritional support in chronic liver failure will be discussed in Chap-
ter 22, we will briefly present some aspects of metabolic changes, and nutritional
and metabolic support, of patients with liver failure.
The complex metabolic derangements which accompany liver failure reflect the
magnitude of the problems associated with insufficiency or decompensation of the
liver as a master metabolic organ.
9,10
Correction of these alterations, by manipu-
lating nutrients and other biochemical substrates, forms the basis for maintaining
adequate nutritional status, and represents one of the most important therapeutic
strategies in the management of patients with severe liver disease.
11
The primary abnormality of carbohydrate metabolism in chronic liver failure
(CLF) is glucase intolerance. Decreased insulin activity, on the other hand, may be
a consequence of a depletion of insulin receptors on target cells.
12
As a result of
decreased insulin activity, increased amounts of free fatty acids (FFA) are released
into the circulation. Impaired degradation, portal systemic shunting, and in-
creased plasma concentrations of ammonia and aromatic amino acids (AAA) are all
responsible in part for elevated plasma levels of glucagon. The insulin:glucagon
effective ratio and lipoprotein lipase activity are also decreased in chronic liver
failure. The clearance capacity of exogenous triglycerides is reduced, and the pa-
tient may be intolerant of large amounts of fat. Impaired glucase and fat utilization
are responsible for the increased catabolism of protein and are the limiting factors
in providing the caloric needs of patients with advanced liver disease.
One of the most important metabolic changes in CLF, however, is alteration of
plasma amino acid patterns. Insufficiency of liver function and accentuated muscle
213
14
breakdown induce an elevation in AAA and a reduction in branched chain amino
acid (BCAA) levels. This rather consistent presentation of plasma amino acid profile
in patients with CLF strongly suggests a role in the pathogenesis of hepatic encepha-
lopathy and serves as an explanation for the attendant protein intolerance. Decreased
clearance of AAA by the liver is a major cause of increased plasma and brain AAA
concentrations. Decreased plasma BCAA concentrations contribute to the accumu-
lation of AAA in the brain as well. The AAA together with methionine, glutamine,
asparagine, and histidine undergo 80-100% first pass clearance by the liver. Sponta-
neous portal systemic shunting with significant partial bypass of the liver mainly
affects the metabolism of these amino acids. The characteristic profile of amino acid
disturbances observed in liver failure formed the basis for the initial formulation of
an intravenous solution enriched in BCAA as a potentially effective nutritional mo-
dality for the treatment of CLF and hepatic encephalopathy. Experience since then
has shown BCAA to ameliorate hepatic encephalopathy temporarily, but not to
affect the ultimate outcomes of patients with CLF, either with or without accompa-
nying encephalopathy. More work in this vital area is obviously urgently indicated.
Protein malnutrition is a well known feature of advanced liver disease, and is
characterized by decreased creatinine-height index, low plasma albumin and trans-
ferrin levels, reduced triceps skinfold thickness and total lymphocyte count. The
most important nutritional indicator, however, is hypoalbuminemia, which is a con-
sequence of decreased albumin synthesis, increased albumin degradation, malnutri-
tion secondary to malabsorption and poor oral intake, and third space losses of
albumin in ascitic fluid and in the extravascular compartment. Decreased plasma
albumin concentration is one of the prominent biochemical indices in Childs clas-
sification of cirrhotic patients and is a good indicator of hepatic functional reserve.
Hypoalbuminemia causes decreased capillary colloid oncotic pressure which is a
major contributing factor in the accumulation of ascites and edema, which in turn
are persistent characteristics of patients with decompensated liver function. Daily
nutritional monitoring of these patients is recommended, together with complete
biochemical and metabolic studies. Plasma levels of vitamins, trace elements, and
apolipoprotein A-IV have been reported to reflect intestinal absorption of nutri-
ents,
13
and may be useful in a comprehensive nutritional assessment. Measurement
of other plasma proteins produced by the liver, such as fibrinogen, transferrin and
prealbumin with their shorter half-lives, can be used to monitor acute changes in
hepatic protein synthetic function.
The hepatic mitochondrial redox potential represents the ratio of acetoacetate
to B-hydroxybutyrate and can be expressed as the arterial blood ketone body
ratio (AKBR).
14
This reflects metabolic derangements of the whole body, charac-
terized by hepatic mitochondrial accumulation of NADH, which consequently
inhibits proton transport through the respiratory transport chain, and markedly
depresses TCA cycle enzymes and other metabolic pathways. The arterial blood
ketone body ratio is not a specific measurement of liver insufficiency, but it allows
grading of the severity of liver damage. Different biological phenomena are associ-
ated with a decrease in the AKBR, most prominent being enhanced catabolism,
impaired oxygen utilization, and deterioration of the immune response.
Cirrhotic patients eventually manifest protein malnutrition with consequent
functional alterations and histologic liver abnormalities. Protein deprivation
profoundly depletes liver protein stores and adversely affects the breakdown and
conversion of polysomes to free ribosomes.
15
On the other hand, in chronic liver
214
14
disease, alterations in visceral protein synthesis, cellular immunity and total lym-
phocyte count may be present independently of protein malnutrition.
16
Plasma pro-
tein levels in general correlate inversely with the degree of liver damage. Other markers
of lean body mass and fat stores are not true indicators of structural liver damage.
Measurement of nitrogen balance in liver disease also has its limitations,
17
because
the hypercatabolic state makes it difficult to differentiate impaired hepatic protein
synthesis from accelerated circulating protein breakdown.
The main objective of nutritional support in liver failure is to provide adequate
calories and protein needs without inducing or aggravating hepatic encephalopa-
thy,
18
thereby ensuring the availability of critical energy substrates for optimal func-
tion of the hepatic mitochondria. Nutritional support, even though controversial,
should be initiated and actively maintained during the phase in which the AKBR is
decreased.
14
Adequate measures should be taken to increase the AKBR or at least to
prevent a further decline, because AKBR ratios under 0.4 have ultimately been asso-
ciated with markedly increased mortality.
For patients unable to tolerate oral or enteral feeding, total parenteral nutrition
is the only feasible means of providing nutrition support. Significant hypoalbumin-
emia and hypoproteinemia are almost always present in liver failure, and since di-
etary protein intolerance is the rule rather than the exception in liver insufficiency,
serious consideration must be given to restoring plasma albumin and total protein
levels to normal by infusing salt-poor human albumin intravenously. Adequate calories
should be given in order to provide calculated requirements while maintaining blood
glucase levels below 200 mg/dL. Fat emulsions can be given cautiously
19
in dosages
sufficient to prevent EFAD requirements (usually 250 ml 20% emulsion every other
day). Vitamin K and folic acid may require supplementation above usual TPN dos-
ages in patients with liver failure.
In formulating the nutrient solution, the amino acid composition is of primary
concern. Since it is apparent that plasma amino acid concentrations are frequently
abnormal in hepatic failure, it seems logical that manipulation of the levels of the
plasma amino acids, as well as brain amino acids, with correction of the observed
abnormalities, should be an important task of physicians involved in the care of
these complex patients.
To date, however, the results of specialized nutritional support of liver failure
have rather consistently shown that although parenteral and/or enteral BCAA en-
riched nutrient regimens may relieve the symptoms of hepatic encephalopathy and
may improve the protein nutritional status of the patient with liver failure, the ben-
eficial effects in both situations are usually transitory, and outcome remains the
samedismal.
Acute Pancreatitis
Most episodes of acute pancreatitis are short-lived and self-limited, and extraor-
dinary nutritional support in these patients is rarely indicated (20, 21). However, in
those patients with severe pancreatitis who manifest any three of the adverse prog-
nostic factors
22
at admission or develop them subsequently within the first 48 hours
of hospitalization, nutritional support with TPN should be undertaken as soon as
possible. Aggressive nutritional support is essential to insure optimal provision of
nutrient substrates, while maintaining the gastrointestinal tract and the pancreas at
rest. Several reports have confirmed that administration of all nutrients parenter-
ally has reduced morbidity and mortality substantially.
21,23
Recently, use of TPN was
215
14
evaluated in 29 patients with moderate to severe pancreatitis.
24
Patients receiving
TPN had a mortality rate of 7% compared with 45% in patients receiving conven-
tional intensive therapy without TPN.
TPN in pancreatitis should be administered continuously over 24 hours, with
appropriate adjustments to infusion rate and to nutrient concentration and compo-
sition as indicated.
20
Conscientious and meticulous biochemical and hematologic
monitoring of these patients is necessary to identify and promptly treat any renal
failure, hepatic decompensation, or fluid and electrolyte imbalances which might
accompany unrelenting or capricious disease. Plasma total protein and albumin con-
centrations should be maintained at about 6.5 g/dL and 3.5g/dL, respectively, in
order to minimize edema, ileus and plasma colloid osmotic pressure derangements.
Positive nitrogen balance has been shown to have a striking beneficial influence on
survival of the patient with severe pancreatitis, while failure to achieve positive ni-
trogen balance has been associated with an increase in the mortality rate. Patients
with severe necrotizing or hemorrhagic pancreatitis may require rather large amounts
of insulin to maintain normal blood glucase levels, especially in the presence of
uncontrolled infection, occult abscesses or frank sepsis, and/or diabetic ketoacido-
sis. In addition, these patients have a high incidence of malnutrition and require
aggressive nutritional support. Local and systemic complications, abdominal sepsis
and repeated surgical interventions further complicate the course of the disease.
The indications for the use of TPN in patients with severe acute pancreatitis are
multiple. Not only may the nutritional status of these patients deteriorate very rap-
idly, but prolonged ileus, respiratory and renal failure, severe metabolic aberrations,
and multiple major surgical interventions may interfere with provision of adequate
oral or enteral feeding, further complicating or aggravating existing malnutrition.
In other clinical conditions that may result from complications of pancreatitis, such
as pancreatic fistulas, pseudocyst, and ascites, nutritional support with TPN has
been shown to be a more effective therapy than enteral feeding.
TPN bypasses cephalic, gastric and intestinal phases or pancreatic secretion; re-
duces the pancreatic acinar nuclear volume, cell volume, and synthetic activity; and
significantly reduces the basal pancreatic proteolytic and bicarbonate secretions. None-
theless, TPN is not indicated routinely in all forms of acute pancreatitis, but is
recommended in patients with APACHE II scores >9 and in those having more
than two of Ransons criteria.
Cancer and TPN: To Feed or Not to Feed?
One of the areas of major debate over the past decade has been the adjunctive
use of TPN in the treatment of patients with cancer. Thus far, a vast amount of data
and experience has been acquired in understanding the interactions of neoplastic
disease and nutrient regimens while treating and studying cancer patients. Because
of the debilitating nature of most oncologic processes on the body cell mass, the
proportion of patients with malignant disease experiencing a significant degree of
malnutrition is larger than the number of hospitalized patients without malignant
diseases.
25
Cancer related malnutrition has a very poor prognosis, but may be treated
or prevented to some extent with TPN or enteral nutrition. For this reason, it is
especially important that the treatment of cancer patients be accompanied by ad-
junctive nutritional support in order to achieve the best possible therapeutic results
with the lowest morbidity and mortality and, to prevent death from starvation rather
than from the neoplastic process itself.
216
14
Some cancer patients, especially those with a malignancy of the oral cavity, phar-
ynx or cervical esophagus, may present with painful deglutition and progressive
difficulty with ingesting and swallowing solid food. Moreover, patients with cancer
of the head and neck often have a history of heavy smoking, excessive alcohol in-
take, and/or dietary indiscretions which render them protein-calorie malnourished
prior to developing malignancies. Since most oncologic therapy impairs optimal
oral nutritional repletion to some degree for a considerable period of time, such
patients may enter a vicious cycle of compounded malnutrition. Surgical treatment
of a patient with head and neck cancer also often results in diminished oral intake.
Preoperative, postoperative, or primary radiation therapy induces severe stomatitis,
mucositis and diminished salivary secretions. These adverse symptoms further ag-
gravate the already decreased oral intake and accelerated weight loss of such patients.
Patients with malignancies present the quintessential challenge to restoration or
improvement of nutritional status while receiving primary oncologic therapy. De-
termining the best method for nourishing the cancer patient depends on three ma-
jor factors:
1. the patients nutritional status;
2. the level and degree of residual gastrointestinal function; and
3. the type and magnitude of antineoplastic therapy. Ideally, adequate vol-
untary ingestion of food orally is the ultimate goal for all patients.
However, most antineoplastic treatment modalities diminish optimal oral in-
take. If a patient is unable to obtain daily nutritional requirements voluntarily by
oral ingestion of ordinary normal nutrients, oral supplementation together with
aggressive dietary counseling should be initiated and maintained. Patients should
also be encouraged and allowed to make dietary selections of their food preferences
whenever feasible. Alert, well-motivated patients can often be urged to increase their
daily calorie and protein intake through the ingestion of hospital-prepared or com-
mercially formulated supplements. If, on the other hand, patients are unable to be
fed by mouth, but have an intact and functioning alimentary tract, then tube feedings
should be introduced. Although a functioning alimentary tract provides the best
means of assuring normal digestion, absorption, and assimilation of foodstuffs, use
of the enteral route is contraindicated in the presence of severe gastrointestinal dys-
function, such as intestinal obstruction, prolonged ileus, upper gastrointestinal bleed-
ing, and/or intractable vomiting or diarrhea. If the alimentary tract is not available
for use, or if rapid nutritional repletion is deemed essential, parenteral nutrition
should be instituted.
TPN should be used in cachectic cancer patients as a means of nutritional reha-
bilitation. Currently, studies suggest that TPN is of benefit in only malnourished
cancer patients in whom treatment toxicity will preclude oral or enteral intake for
longer than one week.
26
Regardless of postulated or demonstrated tumor-induced
abnormalities in the intermediary metabolism of the host, the predominant factor
in the development of cancer cachexia is an imbalance between nutrient intake and
host nutrient requirements, which can be treated beneficially in severely malnour-
ished patients by enteral or parenteral nutrition, or both.
Optimal results from surgical procedures, pharmacologic therapy, chemotherapy,
radiotherapy, immunotherapy, respiratory therapy, physical therapy and other forms
of care can only be obtained when the patient is maintained in optimal nutritional
condition. Yet, a fear of potential stimulation of tumor growth with nutritional
support (enteral or parenteral) has stimulated much controversy regarding nutritional
217
14
support in cancer patients. Animal studies have clearly demonstrated that spontane-
ous tumor development and growth of established tumor can be stimulated or re-
duced by manipulating exogenous nutrient substrates.
27
No data have been reported
unequivocally documenting accelerated tumor growth in cancer patients receiving
TPN.
Increased caloric and fat intake has been associated with increased incidence of
spontaneous tumorigenesis in animal models. Increased fat and caloric intake is also
associated with breast carcinoma, ovarian carcinoma and colorectal cancer in hu-
mans. Acceleration of tumor growth in animal models has been demonstrated by
increasing tumor volume, tumor mitotic activity, H
3
-thymidine labeling, tumor pro-
tein synthesis, increased S-phase and aneuploid tumor cells. Furthermore, cell-cycle
kinetics are also altered during exogenous nutrient administration. Such induced
tumorigenesis in animal models has not yet been demonstrated clinically in human
studies, although few studies have attempted to address this important problem.
Although, potentially the tumor mass growth may be accelerated, the metastatic
effect of tumor can be enhanced, and the tumor cell cycle kinetics can be altered by
vigorously feeding cancer patients, further clinical studies are needed to clarify all of
these hypotheses. Until then, the ultimate goal in the nutritional management of
patients with cancer is the same as with all other patients: provision of optimal
nutrition to all patients under all conditions at all times, as long as there is a reason-
able chance for curing or improving the quality of life of that patient. On the other
hand, TPN should not be used in cancer patients who are completely unresponsive
to therapy and in whom extraordinary measures to provide nutrients can serve only
to prolong unrelieved suffering and inevitable death.
Selected References
1. Bistrian BR, Blackburn GL, Vitale J et al. Prevalence of malnutriton in general
medical patients. J Am Med Assoc 1976; 235:1576-1570.
2. Butterworth CE Jr. The skeleton in the hospital closet. Nutrition Today 4:1974.
3. Dudrick SJ. Parenteral nutrition. In: Dudrick SJ, Baue AE, Eiseman B et al, eds.
Manual of Preoperative and Postoperative Care. Philadelphia: WB Saunders Co,
1983:86-105.
4. Dudrick SJ, Latifi R. Total parenteral nutrition: current status. Contemp Surg
1992; 41:41-48.
5. Dudrick SJ, Wilmore DW, Vars HM et al. Long-term total parenteral nutrition
with growth, development and positive nitrogen balance. Surgery 1968; 64:134-142.
6. Dudrick SJ, Latifi R, Fosnocht D. Management of short bowel syndrome. Surg
Clin North Am 1992; 71:625-643.
7. Dudrick SJ, Mock TC. Enterocutaneous fistula. In: Cameron J, ed. Current Surgi-
cal Therapy, 3rd ed. Philadelphia: BC Decker, Inc., 1988:35-61.
8. Dudrick SJ, Latifi R, Schrager R. Nutritional management of inflammatory bowel
disease. Surg Clin North Am 1991; 71:609-623.
9. Latifi R, Killam R, Dudrick SJ. Nutritional support in liver failure. Surg Clin
North Am 1991; 3:567-578.
10. Latifi R, Dudrick SJ. Hepatic encephalopathy: metabolic and nutritional implica-
tions of amino acids. In: Latifi R. Amino Acids in Criticial Care and Cancer. Aus-
tin: R.G. Landes, 1994:125-136.
11. Hiyama DT, Fischer JE. Nutritional support in hepatic failure. Nutr Clin Prac
1988; 3:96-105.
12. Rossi-Fanelli F. Nturitional support in liver failure. In: Tanaka T and Okada A,
eds. Nutritional Support in Organ Failure. Amsterdam: Elsevier Science Publish-
ers, 1990:261-265.
218
14
13. Muto Y, Yoshida T, Yamatoh M. Nutritional treatment of liver cirrhosis with
branched chain amino acids (BCAA). In: Tanaka T, Okada A, eds. Nutritional
Support In Organ Failure. Amsterdam: Elsevier Science Publishers, 1990:267-276.
14. Shimahara Y, Kiuchi T, Yamamoto Y et al. Hepatic mitochondrial redox potential
and nutritional support in liver insufficiency. In: Tanaka T, Okada A, eds. Nutri-
tional Support in Organ Failure. Amsterdam: Elsevier Science Publishers,
1990:295-308.
15. Sidransky H. Regulatory effect of amino acids on polyribosomes and protein syn-
thesis of liver. In: Popper H, Schaffner F, eds. Progress in liver disease, Vol. IV. New
York: Grune and Stratton, 1972:31-43.
16. Schenkin A. Assessment of nutritional status: The biochemical approach and its
problems in liver disease. J Hum Nutr 1972; 33:341-349.
17. McCullough AJ, Mullen KD, Smanik EJ et al. Nutritional therapy and liver dis-
ease. Gastroenterol Clin of North Am 1989; 18:619-643.
18. Fischer JE. Hepatic Failure. In: Wilmore DW, Brennan MF, Harken AH et al,
eds. Care of the Surgical Patient. A publication of The American College of Sur-
geons Committee on Pre and Postoperative Care. Scientific American Medicine.
1990:1-13.
19. Nagayama M, Takai T, Okuno M et al. Fat emulsion in surgical patients with liver
disorders. J Surg Res 1989; 47:59-64.
20. Latifi R, McIntosh JK, Dudrick, SJ. Nutritional management of acute and chronic
pancratitis. Surg Clin North Am 1991; 73:579-578.
21. Pisters PWT, Ranson JHC. Nutritional support for acute pancratitis. Surg Gynecol
Obstet 1992; 175:275-284.
22. Ranson JHC. Etiological and prognostic factors in human acute pancreatitis: A
review. Am J Gastroenterol 1983; 77:663-668.
23. Blackburn GL, Williams LF, Bistrian B et al. New approaches to the management
of severe acute pancreatitis. Am J Surg 1976; 131:114-124.
24. Robin AP, Campbell R, Palani CK et al. Total parenteral nutrition during acute
pancreatitis: Clinical experience with 156 patients. World J Surg 1990; 14:572-579.
25. Copeland EM, Dudrick SJ. Nutritional aspects of cancer. Curr Probl Cancer 1976;
1:3-51.
26. Pillar B, Perry S. Symposium proceedingsPart III. Evaluating total parenteral
nutrition. Core statements of the technology assessment and practice guidelines
forum. Nutrition 1990; 6:474-489.
27. Torosian MH. Stimulation of tumor growth by nutrition support. JPEN 1992;
16(S):72-75.
CHAPTER 1
CHAPTER 15
Intestinal Adaptation: New Insights
Jon S. Thompson
Introduction
Normal intestinal structure and function is maintained by a complex interaction
between luminal, humoral, local and neural factors. The intestine will adapt to changes
in these regulatory mechanisms and in response to other stimuli, such as partial
resection and injury. Alterations of intestinal structure and function may result in
the intestine failing to meet one or more of its important roles. While malabsorp-
tion is perhaps the most common and easily recognized manifestation of intestinal
failure, disordered motility, impaired barrier function, and immune dysfunction
can also occur. Patients undergoing extensive resection of the small intestine clearly
are at risk for intestinal failure. Although intestinal adaptation following intestinal
resection is a widely recognized and well studied phenomenon, this process is still
incompletely understood.
The adaptive potential of the small intestine following resection was first noted
more than 100 years ago.
1
A historical perspective of the evolution of current con-
cepts of intestinal adaptation has been published previously.
2
However, during the
past few years, there have been many advances in our understanding of the adaptive
response of the intestine and its regulation. Apoptosis, or programmed cell death,
has emerged as an important regulatory factor in mucosal adaptation. The func-
tional changes, which occur in enterocytes, have been more clearly defined. While
intestinal muscle adaptation had been recognized for some time, its role in func-
tional adaptation has only recently been appreciated. The understanding of the motor
changes, which occur, has also expanded. The role of specific nutrients continues to
be investigated. The number of involved regulatory humoral factors has increased
markedly. The relationship between the colon and the intestinal remnant has also
recently attracted attention. Our concepts of the basic mechanisms of intestinal
adaptation have evolved because of a better understanding of the molecular mecha-
nisms involved. The intent of this chapter is to review the current understanding of
intestinal adaptation and present new insights into this process.
Structural Changes
Compensatory structural changes occur in all layers of the intestinal wall after
resection. However, changes in the mucosa are predominant and have gained most
attention. Adaptive structural changes are greater after proximal resection compared
to distal resection and are also related to the extent of resection.
3-10
Adaptation be-
gins almost immediately following resection and continues for weeks to months.
While adaptive structural changes have been clearly demonstrated in a variety of
animal species, there has been some debate as to whether they occur as consistently
in man.
3-14
220
15
Measurements of DNA, RNA and protein in intestinal mucosa increase within
24 to 48 hours after resection.
4-9
These changes are associated with an increase of
crypt cell production rate.
15,16
Both the total number of cells and proportion of
proliferating cells are increased in the crypt. Kinetic studies have indicated a short-
ening of the cell cycle.
15
Cells migrate at a faster rate along the villus.
A more recent observation is that rates of apoptosis increase during intestinal
adaptation.
17-20
This may represent a counter regulatory process in response to in-
creased crypt production of cells. This increase in programmed cell death occurs in
both crypt and villus cells. Similar to crypt cell production, apoptosis is rapidly
induced but then diminishes as a new set point in enterocyte balance is reached.
Endonuclease activity, which produces DNA cleavage in this process, and levels of
pro-apoptotic gene products, e.g., Bax, increase transiently after resection and
pro-survival products, e.g., Bcl, diminish.
19,20
The increased number of cells results in an increase in villus height and crypt
depth.
3-11,14-16
Correspondingly mucosal weight increases. Villus lengthening occurs
by cellular hyperplasia as indicated by an unchanged number of cells per unit length
of villus, the overall increased number of cells, and an unaltered RNA/DNA ratio.
21
While there do not appear to be consistent ultrastructural changes in the enterocytes,
microvilli have recently been shown to lengthen.
22,23
Ileal villi change their shape to
that of the jejunum as they elongate.
4
There is disagreement as to whether the num-
ber of villi increases in relation to crypts.
4,24
However, crypt fission, or bifurcation,
occurs at a greater rate resulting in an increased number of crypts.
25
The thickness and length of the muscle layers also increase after resection and
results primarily from hyperplasia rather than hypertrophy of the muscle cell.
4,5,26,27
These changes are most marked in the longitudinal layer. Muscular hypertrophy
occurs transiently proximal to the anastomosis.
6
Muscle adaptation occurs at the
later time and only after more extensive resection than does mucosal adaptation,
4,5,26,27
These changes in the components of the intestinal wall result in marked thicken-
ing of the intestinal wall, up to 150% of normal thickness. The intestinal circumfer-
ence and length also increase to 130% of initial values.
11,14
These increases probably
reflect primarily changes in circular and longitudinal muscle length. Thus, there is
an overall increase in mucosal surface area due to both villus hypertrophy and the
increases in length and circumference of the remnant.
14
Functional Adaptation
Intestinal Absorption
In vivo studies confirm increased intestinal uptake of fluid, electrolytes and nu-
trients after resection.
14,27-31
This improved function occurs primarily due to in-
creased mucosal surface area.
19,28
While formerly individual cells were not thought
to increase their function, more recent in vitro studies have demonstrated both in-
creased nutrient transport and enzyme activity.
9,14,32-37
Increased nutrient absorption clearly occurs. The enterocyte response to intesti-
nal resection involves a transcriptional increase of Na
+
/glucose transporter within
hours of resection.
33,34
This adaptive response is quite specific. For example, glucose
dependent electrogenic Na
+
absorption is increased but electroneutral NaC1 ab-
sorption is unchanged.
35
Increased expression of the cotransporter gene correlates
with increased glucose transport across the bowel wall.
38
Increased transport of
glutamine, alanine, and leucine has been demonstrated in a site specific fashion after
221
15
enterectomy.
37
Acid-base transporters may be down regulated after resection.
40
Ma-
jor changes in carrier mediated nutrient absorption are most likely to be achieved,
from a kinetic perspective, by alterations in the Vmax.
39
This appears to occur by
both modulating the number of transporting vs. nontransporting enterocytes popu-
lating the villus, as well as increased transport capability of individual cells.
Increased activity of digestive enzymes by the enterocyte also occurs after resec-
tion.
41
As with transport properties, this is a specific response e.g., -glucosidase but
not neutral aminopeptidase increases. However, there is still no evidence to suggest
that enterocytes can adopt specialized transport function not characteristic of that site.
42
Intestinal Motility
While less attention has been given to motor adaptation, it has an important role
in improved nutrient absorption.
28,43-49
Studies of gastric emptying and intestinal
transit in the rat following various types of resection have demonstrated an adaptive
response with slowed intestinal transit and delayed gastric emptying primarily fol-
lowing proximal resection.
43,50
There is prolongation of the migrating motor com-
plex (MMC), a reduction in MMC Phase I duration, an increase in MMC Phase II
duration and a prolonged post-prandial inhibition of the MMC in the intestinal
remnant.
44-45
Thus, the remaining jejunum and proximal ileum developed motor
characteristics typical of the intact distal ileum. Distal resection resulted in little
change in motor parameters in the remnant. These findings are consistent with the
presence in the terminal ileum of a mechanism which can sense unabsorbed fat
within the ileal lumen and lead to delayed gastric emptying and slowed small intes-
tinal transit-the so called ileal brake.
46
Loss of even small segments of distal ileum
could thereby influence transit along the entire gut.
The response of the canine small intestine to varying degrees of resection has also
been described.
47
Fifty percent and 75% distal resections were associated with the
development of clinical features of the short bowel syndrome, and though there was
some improvement in this malabsorption during the 3-month study period, the
75% group, in particular, continued to demonstrate marked steatorrhea. In terms of
motility changes, a biphasic motor response was identified. Initially, in the distal
segment of the intestinal remnant in each of the resection groups and in the entire
remaining small intestine in the 75% group, motility recordings were dominated by
recurring bursts of clustered contractions. In the 75% group, these clusters were
often prolonged and associated with a baseline tonic change. In this group, also, the
incidence of jejunal MMCs was markedly reduced, and Phase II duration was sig-
nificantly prolonged. Later, in the 25% and 50% groups, evidence of motor adapta-
tion was noted with the development of a progressive slowing of intestinal transit
and a return of MMC cycling. Furthermore, the propagation velocity of Phase III of
the MMC progressively slowed to a rate seen in the ileum of intact control animals.
Such adaptation did not, however, occur in the 75% group; prominent cluster activ-
ity continuing to be the dominant motor pattern.
Long-term studies in humans demonstrate that the intestinal remnant develops
a shorter duration of the MMC-cycle and fed pattern.
48,50
These changes only occur
after extensive resection (jejunal remnant 60-100 cm). Evidence of a biphasic re-
sponse to resection such as that observed in canines comes from case reports.
50,51
Small intestinal motility was studied 2 to 12 months after resection in an infant.
Cluster activity dominated the early study while clusters diminished and the MMC
period shortened in the later study. In an adult patient, Phase III of the MMC was
222
15
absent during the first month after resection but returned thereafter.
51
Thus, a con-
sistent pattern of motor adaptation in the intestinal remnant has been identified.
In vitro studies demonstrate a reduction in contractibility of intestinal muscle
after resection.
52
This may be due to muscarinic receptor activation. This response is
specific to the intestinal remnant location and muscle type.
53
Overall, however, these
appear to be transient, modest effects.
26
Intestinal Barrier and Immune Function
There is little information about changes in barrier or immune function after
intestinal resection. The number of horizontally oriented strands, which is a strong
morphologic predictor of transepithelial permeability, is unchanged after resection.
35
However, tight junction depth is slightly increased. In the suckling rat, there are
decreases in the T and B-lymphocyte populations in gut-associated lymphoid tissue
after massive bowel resection.
54
There is also reduction in certain intraepithelial lym-
phocyte subpopulations after resection.
55
Such changes might be associated with a
risk of infectious complication in infants with the short bowel syndrome.
Mechanisms of Adaptation
Although a number of factors have been identified which influence intestinal
adaptation (Table 15.1), this complex process is still not completely understood.
From the mechanistic perspective, there are a number of aspects which need to be
explained. These include the greater adaptive response after proximal resection and
after more extensive resection, the rapid onset and prolonged duration of adapta-
tion, and the termination of this response with maintenance of a new steady state
for gut proliferation and function. Different components of the intestinal wall e.g.,
mucosa and muscle appear to have different mechanisms of adaptation. There is
also apparent disassociation between the morphological and functional changes seen
following resection.
Loss of intestinal mass is obviously the important inciting event for postresection
adaptation. In fact, synchronous autotransplantation of resected ileum will blunt
the adaptive response.
56
Adaptive changes which occur within a few hours imply
that there are alterations in enterocytes already upon the villus. Modifications oc-
curring within several days suggest that the mechanism for these changes relates to
altered crypt cell production rate or cell turnover. Moreover, adaptive responses which
persist for many weeks after removal of the inciting stimulus, suggest that perma-
nent changes are occurring in the crypt cells.
Functional adaptation is probably influenced by the same signals that control
structural adaptation, i.e. systemic peptides, the ingestion of food, and neural influ-
ences. Food intake is most likely to have the greatest effect on nutrient transport.
The role of dietary lipid has some interest since this might influence the physico-
chemical properties of cell membranes. However, it is apparent that luminal con-
tents and regulatory peptides influence all aspects of adaptation. Each of the potential
factors influencing adaptation will be considered.
Luminal Contents
Luminal Nutrients
An important role for luminal nutrition in postresectional adaptation has been
recognized for some time. This is particularly true following proximal resection,
223
15
since the ileum is usually not exposed to high luminal concentrations of nutrients.
This concept has been supported by the observations that transposition of the ileum
and jejunum results in ileal hyperplasia and intestinal bypass results in atrophy.
57-59
Luminal nutrients have both direct and indirect effects on the intestinal mucosa by
virtue of local nutrition, gastrointestinal secretion and peptide release, stimulated
motility and blood flow, and other effects. The adaptive response is blunted if nutri-
tion is maintained intravenously rather than orally after resection.
60,61
Bulk and other
non-nutrition intake does not stimulate adaptation.
62,63
The effect of fasting on ad-
aptation is reversible with refeeding, however, suggesting that luminal nutrients are
a permissive factor.
64
Malnutrition due to inadequate enteral nutrition will also im-
pair the adaptive response.
65
The role of nutrient type, e.g., fat, protein or carbohydrate, and form e.g. amino
acids versus peptides is less clear. Glucose stimulates proximal mucosa whereas fat
stimulates the mid intestine.
66
Disaccharides appear to stimulate mucosal adapta-
tion to a greater extent than monosaccharides.
67
Furthermore, carbohydrates stimu-
late intestinal growth via a variety of mechanisms suggesting that direct mucosal
contact, absorption, osmolality and humoral factors may be involved.
68
Casein and
casein hydrolysates have similar effects on postresection mucosal adaptation.
69
Lip-
ids also influence the adaptive response.
70
Long chain triglycerides stimulate intesti-
nal adaptation to a greater extent than medium chain triglycerides.
71
Whereas long
chain triglycerides have their greatest effect on the mid-small intestine, medium
chain triglycerides have a greater effect proximally.
72
Polyunsaturated fatty acids are
more effective at inducing adaptation in a dose dependent manner.
70,73
Dietary pec-
tin supplementation improved adaptation.
74
Pectin also enhances while cellulose
impairs fat absorption after resection.
75
The importance of specific nutrients has been appreciated more recently.
Glutamine, in particular, has an important role in adaptation which is related to its
role as a major enterocyte fuel as well as stimulating release of various gut trophic
factors.
76,77
High glutamine diets may impair adaptation, however.
76
Even provision
of the enterocyte fuels glutamine and short chain fatty acids parenterally will stimu-
late intestinal adaptation.
78-80
While arginine becomes an essential amino acid after
massive resection, arginine supplementation does not enhance adaptation.
81,82
Defi-
ciency of nutrients can also influence adaptation. Zinc deficiency and essential fatty
acid deficiency impair mucosal hyperplasia.
83-85
Vitamin A deficiency impairs adap-
tation and provision of retinoic acid enhances adaptation.
86,87
Table 15.1. Factors promoting intestinal adaptation
Luminal Contents
Luminal Nutrients
Luminal Secretions
Gastrointestinal Regulatory Peptides
Systemic Factors
Growth Factors
Hormones
Cytokines
Neural Influences
Changes in Blood Flow
Mesenchymal Factors
224
15
Luminal Secretions
A variety of experimental models have supported an important role for upper
gastrointestinal and pancreaticobiliary secretions in the adaptive response.
88-90
Trans-
planting the ampulla distally to the proximal ileum results in ileal hyperplasia.
88-90
Both biliary and pancreatic secretions appear to be important.
91
However,
pancreaticobiliary secretions are not essential for adaptation in animals fed enter-
ally.
90
Furthermore, pancreaticobiliary secretions are not as strong a stimulus to
mucosal growth as resection itself.
7
Which components of the luminal secretions are the important growth promot-
ers remains unclear. EGF from saliva and the duodenal Brunners glands may have a
significant role.
92
Increased salivary secretion promotes mucosal hyperplasia, while
excision of submandibular glands abolishes this response.
92
EGF recirculates in the
bile and, thus, may play a role in the stimulatory effects of bile. There may be other
growth promoting factors in the upper gastrointestinal secretions, as well.
89
Gastrointestinal Peptides
An important role for regulatory peptides in the adaptive response of the intes-
tine to resection has long been appreciated and are related in large part to ingestion
of nutrients.
93,94
While initial studies focused on gastrointestinal hormones, more
recently other regulatory peptides have been considered candidates for mediators of
intestinal adaptation.
95
It appears that intestinal adaptation is a complex process
which involves multiple regulatory mediators functioning both locally and systemi-
cally. Furthermore, different mechanisms may be important depending on the ex-
tent and site of resection and interval since resection. As seen in Table 15.2, a
regulatory peptide may influence one or more aspects of adaptation. Peptides cur-
rently under investigation for a potential role in intestinal adaptation are described
below (Table 15.3).
Calcitonin Gene-Related Peptide
The neuropeptide calcitonin gene-related polypeptide (CGRP) is found in the
peripheral end of sensory neurons in the stomach and small intestine.
96,97
It is re-
leased in response to various noxious stimuli. CGRP has several effects, including
inhibition of gastric acid and pancreatic exocrine secretion, inhibition of gas-
trointestinal motility, stimulation of mesenteric blood flow, and release of soma-
tostatin. Its precise role in the regulation of digestive function remains unclear.
The intestinal effects suggest a possible role of CGRP in intestinal adaptation.
CGRP content is increased two fold in jejunal and ileal mucosa after resection and
seven fold in the muscle layers.
98
While it may play a role in preventing gastric
ulceration, it is not clearly trophic or cytoprotective for the small intestine.
99
Since it
may play a role on the intestinointestinal inhibitory reflex, CGRP might influence
the motor response to intestinal resection.
97
Cholecystokinin
Cholecystokinin (CCK) is found both in the brain and the intestine, where it is
localized to the mucosa of the duodenum and proximal jejunum. CCK is released
by luminal digestion products of fat and protein appears to play a major role in the
gastrointestinal response to feeding, including satiety. CCK has both direct and
neurally mediated indirect effects on the small intestine.
100
It also influences the
release of other hormones.
101
CCK might influence intestinal absorption both directly
225
15
and via its effect on gastrointestinal secretion.
102
CCK stimulates contractile activity.
The fat induced enterogastric reflex, inhibiting gastric acid secretion, may be medi-
ated in part by CCK.
103
Basal and postprandial levels of CCK increase transiently after 75% distal intes-
tinal resection in dogs, returning to normal within 3 months.
104
Meal stimulated
but not basal plasma CCK activity is diminished in adapted short bowel syndrome
patients.
105
Tissue CCK mRNA levels also increase.
106
CCK administration increases
DNA synthesis and intestinal weight.
107
This trophic effect occurred in incontinuity
but not bypassed intestinal segments, so this is probably an indirect effect mediated
via stimulation of pancreaticobiliary secretion. CCK administration increases post
resection mucosal adaptation in animals maintained on TPN but does not stimulate
adaptation to the same extent as oral feeding.
108
CCK might also influence motor
and absorptive adaptation based on the effects observed in intact intestine. CCK
mRNA and peptic levels are markedly increased during recovery from cytotoxic intes-
tinal injury, suggesting that CCK may play a role in maintaining barrier function.
109
Proglucagon-Derived Peptides
The proglucagon gene is expressed in pancreatic A cells and the L cells of the
distal intestine. Posttranslational processing gives rise to a variety of different pep-
tides.
110
Glucagon is the primary pancreatic peptide whereas the L cells produce
several structurally related peptides, including glucagon-like peptide-1 (GLP-1), glu-
cagon like peptide-2 (GLP-2), glicentin and oxyntomodulin. The two latter pep-
tides contain glucagon in their sequence. Little is known about the biologic activities
of glicentin and oxyntomodulin. GLP-1 regulates gastric emptying, stimulation of
glucose-dependent insulin secretion and inhibition of glucagon secretion, appetite
and food intake. Glucagon-like activity is stimulated by luminal nutrients,
especially fat,
46
and inhibits intestinal motility and secretion. The physiologic
Table 15.2. Regulatory peptides and their potential role in adaptation
Trophic Barrier/Immune
Peptide Effect Absorption Motility Function
CGRP ? ?
CCK + + + +
Enteroglucagon ? 0 0 ?
GLP-2 + + ? +
GIP 0 ?
Gastrin ? + ? ?
Motilin 0 + ?
neuropeptide Y 0 + ?
Neurotensin + 0 + +
PP ? ? + ?
PYY ? + + ?
Somatostatin +
VIP ? ?
+ = increased or stimulated
0 = no change
= decreased or inhibited
? = response unclear
226
15
actions of these multiple peptides has formerly been attributed to the hormone
enteroglucagon.
Enteroglucagon was given early consideration as a humoral agent involved in
intestinal adaptation due to a report of an enteroglucagon producing renal tumor in
a patient who also demonstrated intestinal hypertrophy.
111
Subsequently, it was dem-
onstrated that serum enteroglucagon levels were elevated during the early adaptive
phase after intestinal resection.
104,112-116
These elevated levels appeared to correlate
both temporally and quantitatively with increased mucosal proliferative activ-
ity.
112,113,116
Enteroglucagon mRNA is elevated significantly in both jejunum and
ileum after resection
116
and this is related, in part, to increased cellular content.
117,118
Tissue content of enteroglucagon decreases with time after resection.
117
Despite all of these suggestive findings, the role of enteroglucagon in the
postresection adaptive response remains unclear. Although enteroglucagon appeared
to be mitogenic in vitro, administration of enteroglucagon in vivo failed to increase
crypt cell production rate or stimulate mucosal growth.
108,119,120
Gregor et al
121
found
that infusion of a monoclonal antibody against enteroglucagon did not alter the
postresection adaptive response. Thus, there is no direct evidence that elevated
enteroglucagon levels are responsible for intestinal adaptation after resection. El-
evated enteroglucagon levels do not correlate with changes in small bowel transit
time.
114
Whether or not enteroglucagon enhances absorptive function also re-
mains unclear.
122
Glucagon-like peptide-2 has emerged as an important regulator of the adaptive
response.
123-129
GLP-2 administration rapidly induces intestinal mucosal growth in
a dose dependent manner via a variety of routes.
123
This augmented growth subsides
when GLP-2 is withdrawn. GLP-2 stimulates crypt cell proliferation and inhibits
apoptosis. Administration of GLP-2 augments the adaptive response to massive in-
testinal resection.
124
GLP-2 also enhances nutrient digestion and absorption.
125
Table 15.3. Changes in regulatory peptides during adaptation
Serum Tissue
Peptide Level Content mRNA Receptors
CGRP 0 + ? ?
CCK + + ?
Enteroglucagon + + + ?
GLP-2 + 0 ? ?
GIP + ? ?
Gastrin + + ? ?
Motilin + 0 ? ?
neuropeptide Y ? 0 ? ?
Neurotensin 0 0 + ?
PP + ? ? ?
PYY + + ?
Somatostatin 0 + ?
VIP 0 ? ?
0 = no change
227
15
Plasma, but not tissue, GLP-2 levels increase after resection.
126
Meal stimulated GLP-2
release is impaired in patients with the short bowel syndrome.
127
GLP-2 administra-
tion in short bowel patients improves intestinal absorption.
128
GLP-2 also enhances
intestinal barrier function.
129
GLP-2 is metabolized by dipeptidyl peptidase IV and
mRNA levels of this enzyme diminish during intestinal adaptation which may en-
hance GLP-2 activity.
130
Gastric Inhibitory Polypeptide
Gastric inhibitory polypeptide (GIP) is a potent hormone localized to K cells in
the upper small intestine and released in response to ingested nutrients.
131
GIP in-
hibits gastric secretion and motility and stimulates insulin secretion. It inhibits fluid
and electrolyte absorption in the small intestine. GIP also increase mesenteric
blood flow.
132
Basal and postprandial levels of GIP are elevated after distal intestinal resection
and remain so for several months.
104
However, these elevations were not found long
term after ileal resection in humans.
114
Basal GIP levels are not influenced by proxi-
mal resection but meal stimulated levels are reduced for as long as 6 months.
131
GIP
levels correlate with length of resection and diminished GIP activity is seen in hu-
mans where less than 150 cm jejunum remains.
133
However, GIP activity and glu-
cose metabolism begin to correct at 6 weeks. Since the response of the pancreas to
GIP does not appear to be altered, these changes in GIP after resection appear to be
due to the initial loss and then adaptation of GIP containing cells.
134
Postresective
increases in GIP levels may play a role in motor adaptation. These elevations might
be related to change in gastric secretion and gastrin levels, as well.
Gastrin
Gastrin, found primarily in antral G cells, is released by peptides, amino acids,
and calcium in the gastric lumen, by neural reflexes and by circulating factors. Its
release is inhibited by low luminal pH, prostaglandins, and several peptides, includ-
ing somatostatin. While its major effects are stimulation of gastric secretion, motil-
ity and mucosal growth, it does influence the lower intestinal tract as well.
Gastrin was one of the initial hormones considered for an important role in the
regulation of intestinal adaptation. Gastric hypersecretion and hypergastrinemia have
been demonstrated to occur, at least transiently, in man and various animal species
after resection.
135-138
Both increased fasting and postprandial serum gastrin levels are
affected and these changes occur within the first few days after resection. However,
while gastrin is generally agreed to have a trophic effect on the stomach and large
intestine, its effect on the small intestine is less clear.
139-142
Results have been con-
flicting and supraphysiologic doses may be required. performing antrectomy to abolish
gastrin secretion after resection did not prevent postresection hyperplasia.
140,143
In a
long-term canine study, we found that serum gastrin levels did not correlate with
changes in parameters of intestinal adaptation.
144
Neither mean gastrin levels or
duration of hypergastrinemia correlated with remnant length or villus hypertrophy.
Evidence does exist to suggest that gastrin influences intestinal absorption. Lu-
minal perfusion but not subcutaneous administration of gastrin increases carbohy-
drate and protein absorption in the rat.
145,146
Thus, gastrin may play a role in altered
intestinal absorption postresection. However, the associated gastric hypersecretion
may actually impair absorption.
145
Gastrin does not appear to have a significant
effect on intestinal motor activity.
147
228
15
Motilin
Motilin, found in highest concentration in the mucosa of the proximal small
intestine, appears to be the physiologic mediator of interdigestive motility.
148
It is
released during fasting but also by vagal stimulation and duodenal nutrients. Motilins
primary biologic effect is contraction of gastrointestinal smooth muscle. Motilin is
thought to influence jejunal motor activity via indirect rather than direct means.
149
Depending on the composition of luminal contents, motilin either decreases ab-
sorption or enhances secretion of electrolytes.
150
Whereas serum motilin levels were not increased up to 6 months after resection
in dogs, humans with ileal resection had a four fold increase in both basal and post-
prandial levels.
104-114
This discrepancy might be explained by the heterogenous re-
sections performed in humans and their underlying disease. While it has not been
clearly demonstrated, motilin may have a role in postresective motor adaptation.
Neuropeptide Y
neuropeptide Y (NPY) is found in peripheral sympathetic nerves and enteric
nerves of the gut and neuroendocrine cells of the mucosa.
151
NPY is released post-
prandially. It appears to have primarily an inhibitory effect on motility.
152
This effect
occurs by interrupting excitatory pathways rather than affecting muscle directly.
NPY has a proabsorptive effect on the intestine which is mediated by the
2
-adrenergic
receptor system.
152
NPY may counteract the stimulatory effects of VIP on gut secre-
tion.
153
Tissue NPY levels are preserved after intestinal resection.
98
It remains un-
clear whether or not NPY plays a role in adaptation of motor and absorptive function
after resection.
Neurotensin
Neurotensin, which is found primarily in N cells of the ileum, has several effects
on the gut, including mesenteric vasodilation, stimulation of pancreaticobiliary se-
cretions, inhibition of gastric secretion and inhibition of intestinal motility.
155-157
Neurotensin changes intestinal motility from a fasting to fed pattern and prolongs
intestinal transit time.
156,157
Neurotensin is released from the ileum in response to fat
in the proximal gut and this response is abolished after ileal resection.
158
Neurotensin has trophic effects on the rat small intestine.
159
The effect is most
pronounced on the jejunum while the effect on the ileum was transient. Disaccha-
ridase activity is also increased.
160
Serum neurotensin levels are normal after distal intestinal resection.
104,114,115
Neurotensin mRNA levels increase within hours.
161
Presumably a posttranslational
mechanism is involved.
162
Neurotensin exerts a systemic effect independent of lumi-
nal factors on the proliferation of proximal gut mucosa in addition to an indirect
effect produced by stimulation of endogenous luminal secretions.
163
An indirect
mechanism appears to predominant in its effect in distal gut mucosa.
164
However,
given its effect on motility, one could speculate that following distal resection, a
diminished effect of neurotensin leads to increased acid secretion and disruption of
the normal fed motor response.
Pancreatic Polypeptide
Pancreatic polypeptide (PP) is secreted from the pancreas and, to a lesser extent,
the distal small intestine in response to a meal, mediated via vagal cholinergic stimu-
lation and hormones, especially CCK, bombesin and neurotensin.
165,166
PP inhibits
229
15
pancreatic secretion. Plasma PP levels correlate with changes in migratory motor
complexes, similar to motilin, suggesting a causal relationship.
167
It may increase
gastric and intestinal transit. PP does not appear to affect intestinal absorption and
secretion. PP may also reduce food intake.
Fasting PP levels are increased after resection.
104,114
Any trophic effect of PP might
be related to stimulated pancreaticobiliary secretion. Whether it has a primary mo-
tility effect after resection remains unclear.
Peptide YY
PYY is produced by L cells of the ileum and colon and has several physiological
effects in the gastrointestinal tract, including inhibited pancreatic exocrine secre-
tion, reduced gastric acid secretion, delayed gastric emptying, and increased small
intestinal transit.
168,169
PYY also appears to have proabsorptive effects on the small
intestine and may regulate postprandial absorption.
170
PYY is released by stimula-
tory signals arising from the proximal jejunum and bile acids and fatty acids in the
colon and thus, may contribute to the ileal brake.
171
Peptide YY levels, both basal and postprandial, increase after intestinal resec-
tion.
104,172,173
These changes occur within hours after experimental studies and are
associated with increased PYY mRNA levels.
173
Tissue content falls.
173
These el-
evated serum levels may be transient in dogs but long lasting in humans.
104,172
Un-
like enteroglucagon, fasting and postprandial PYY levels were not increased after
limited (250 cm) resection of normal ileum in humans, suggesting that levels change
only with extensive resection and intestinal disease.
174
In fact, despite colocalization
of PYY and enteroglucagon to the same cell type, there appears to be a gene specific
response to resection.
175
While PYY may be responsible for the changes in absorp-
tion and motility seen after intestinal resection, it remains unclear whether or not it
has trophic effects. Immunoneutralization of PYY failed to prevent intestinal adap-
tation after resection in rats.
176
Interestingly, central PYY administration causes hy-
perphagia which may play a role in intestinal adaptation.
177
Somatostatin
Somatostatin is found in the nervous system, pancreas and gastrointestinal mu-
cosa. It is primarily released in response to meals. Somatostatin has many biological
effects, which are produced by paracrine, endocrine and neurocrine mechanisms. It
inhibits the release of growth hormone, thyroxine, insulin, glucagon, gastrin, secre-
tin, VIP, motilin and other polypeptides.
178
Somatostatin also has direct effects on
the intestinal tract, inhibiting secretion, decreasing absorption and altering motil-
ity.
179
There is evidence that somatostatin inhibits proliferative activity of intestinal
cells in vitro and intact intestine in vivo.
180-183
Somatostatin suppresses the release of
EGF from the salivary glands and Brunners glands.
181,184
Somatostatin has been
shown to inhibit the growth promoting effects of both exogenous and endog-
enous gastrin.
181
Sucrase and maltase activity were diminished in jejunal cells
by somatostatin.
181
Somatostatin inhibits intestinal adaptation after intestinal resection.
185,186
Pre-
sumably the effect is mediated in part by inhibiting epithelial cell migration and
proliferation and via indirect effects on other hormones. The somatostatin analogue
octreotide also predisposes enterocytes to apoptosis.
187
Plasma somatostatin levels
are not increased after resection.
104
Tissue somatostatin concentration is increased
and binding sites decreased in the intestine several weeks after intestinal resection
230
15
when resection stimulated proliferation begins to subside.
188-189
However, levels are
normal later.
98,189
This further suggests that somatostatin might have a regulatory
role in the adaptive response to intestinal resection. The binding capacity for soma-
tostatin is greater in the jejunum than the ileum which might explain the greater
adaptive potential of the ileum.
190
Vasoactive Intestinal Polypeptide
Vasoactive intestinal polypeptide (VIP) is thought to be the major inhibitory
transmitter of the gut and is distributed throughout the submucous and mesenteric
plexuses of the intestinal wal.
191,192
Its release is stimulated by a variety of neural,
hormonal and mechanical stimuli, including bile.
192,193
VIP stimulates intestinal and
pancreatic secretion. It relaxes intestinal smooth muscle.
Circulating VIP levels have been reported to be unchanged or increased after
intestinal resection, but since circulatory VIP arises primarily from outside the gut,
this is not unexpected.
115,194
We found that tissue content of VIP decreases markedly
after 75% resection in dogs.
98
With its major effects on blood flow and secretion,
VIP might alter intestinal adaptation. One can speculate about a possible trophic
effect for VIP since VIP stimulates secretion of EGF from Brunners glands.
183
Given
its major motor effects, VIP may have a role in adaptive changes in motility
after resection.
Summary
At the present time, GLP-2 and neurotensin are the most likely trophic hor-
mones during intestinal adaptation. In fact, neurotensin augments the enterotropic
effects of GLP-2.
195
While PYY stimulates absorption it does not clearly have a
trophic effect. CCK, gastrin, and neuropeptide Y also have proabsorptive effects
and questionable trophic effects during adaptation. Several hormones have impor-
tant motility effects and thus might participate in motor adaptation(Table 15.2).
PYY, neurotensin and enteroglucagon are potential mediators of the ileal brake
reflex which may influence motor adaptation after proximal resection. Given the
small amount of data available, the importance of hormones in barrier and immune
function is only speculative.
Systemic Factors
Systemic factors may also play a role in intestinal adaptation, including growth
factors, systemic hormones, and other intermediary agents e.g. cytokines (Table 15.4).
Their effects may be primary or they may function as mediators of the effects of
other regulatory factors. These factors appear to have their greatest effect on the
trophic changes in the adaptive intestine.
Local Growth Factors
Epidermal Growth Factor
Epidermal growth factor (EGF) is secreted by the salivary glands and Brunners
glands in the duodenum and plays an important role in maintenance of normal
intestine and structure.
196
EGF receptors are present throughout the gastrointestinal
tract. EGF has trophic and proabsorptive effects on the intestine.
197,198
EGF stimu-
lates both epithelial cell proliferation and migration in a dose dependent fashion
whether given systemically or luminally.
199
Gastrointestinal hormones influence EGF
secretion, including VIP and somatostatin.
184
231
15
The role of EGF in intestinal adaptation has recently been reviewed.
200
Endog-
enous EGF is increased in saliva and diminished in urine after intestinal resection.
This suggests increased tissue utilization of endogenous EGF during adaptation.
201
Intestinal EGF receptor activity is increased after resection.
202
Intestinal adaptation
is impaired in animals with defective EGF receptors.
203
Thus, EGF receptor activity
is important during adaptation. The results of experimental studies suggest that
EGF administered at the time of resection enhances intestinal adaptive function.
200
Both structural and functional adaptation are augmented. The route, dose and tim-
ing of EGF administrations are important factors.
201
EGF has additive effects with
glutamine and growth hormone.
205,206
Current information suggests that to stimu-
late adaptations EGF should be given early after resection. Even transient adminis-
tration, whether enteral or parenteral, is effective. Luminal nutrients are not essential
to an EGF mediated effect.
Insulin Like Growth Factor
Insulin like growth factors I (IGF-I), and II (IGF-II), structurally similar to in-
sulin, are synthesized and secreted in the liver via a growth hormone-dependent
process. IGF-I has major endocrine, autocrine and paracrine effects.
207-209
IGF-I is a
potent mitogen which stimulates glucose and amino acid transport.
208
Its effects are
modulated by membrane receptors and soluble binding proteins. IGF-I receptors
are present in intestinal epithelium, with the highest concentration in crypt cells.
209
They are even more abundant in the muscularis. The highest density occurs in the
ileum. IGF-II receptors have a higher density in the mucosa whereas IGF-I is more
predominant in the lamina propria. IGF influences paracellular permeability.
207
Intestinal resection is associated with increased IGF-I mRNA.
210
The number
of cells expressing IGF-I receptors increases transiently several fold within the first 2
days. This occurs even with IGF administration.
211
IGF-II receptor binding is in-
creased in the intestine within the first 2 days and prior to increased cell mass.
212
IGF-I administration enhances mucosal adaptation after jejunoileal resection.
210-21
Table 15.4. Systemic factors and adaptation
Trophic Barrier/Immune
Growth Factors Effect Absorption Motility Function
EGF + + 0 +
IGF-1 + + 0 +
System Factors
Growth hormone + ? 0 ?
Insulin + + 0 ?
Prostaglandins + 0 + +
Thyroxine + 0 0 0
Cytokines
TNF ?
IL-1 ? ? ?
IL-11 + ? ? ?
0 = no change
232
15
IGF has a greater trophic effect on the ileum.
210
This effect is modulated, in part, by
altered IGF binding protein levels. IGFBP-4 mRNA increases but IGFBP-3 mRNA
decreases in ileum after resection.
210
IGF binding protein levels diminish within
hours which may permit IGF to regulate adaptation.
215,216
Glutamine and IGF-I
have additive trophic effects.
217
Thus, there is convincing evidence that IGF I plays
a role in intestinal adaptation.
Systemic Hormones
Growth Hormone
Growth hormone (GH) is a pituitary peptide that binds to a specific cell recep-
tor but also binds to GH-binding protein. GH receptors are distributed throughout
the gastrointestinal tract with highest activity in distinct epithelial cell populations.
218
GH stimulates IGF production locally and in the liver.
218
Chronic growth hormone
excess results in growth of intestinal mucosa.
219
This may be secondary to an effect
on cell life span rather than increased proliferation. GH excess increases IGF-I mRNA
in the gut. Growth hormone releasing and inhibitory factors may also regulate
this response.
220
Growth hormone appears to have an important role in intestinal adaptation.
Hypophysectomy impairs the normal adaptive response and this effect is not due
entirely to hypophagia.
221
Growth hormone increases amino acid uptake by the in-
testine.
222
Exogenous GH administration stimulates mucosal but not muscle hyper-
plasia after intestinal resection.
222-225
This effect may be region specific since a
GH-analog augmented the adaptive response in the proximal but not distal intesti-
nal remnant.
225
Growth hormone does enhance amino acid absorption after resec-
tion.
226
This occurred despite normal IGF-1 levels suggesting that GH probably
works via direct and indirect mechanisms. Disaccharidase activity was not increased.
Thus, GH may be an important mediator of the trophic response after resection.
Insulin
The pancreatic hormone insulin appears to have several effects in the small intes-
tine. These include regulation of brush border enzymes, absorption of nutrients,
and cell proliferation and differentiation.
227,228
Specific receptors for insulin in the gas-
trointestinal tract have been identified which are distinct from other growth factors.
229
Plasma insulin levels are not altered by small bowel resection.
227
Affinity but not
binding capacity of intestinal insulin receptors decreases after resection.
227
This loss
of binding correlates with accelerated proliferation. Interestingly, the enteroinsular
axis is disrupted by intestinal resection.
230
Oral glucose administration results in
lower insulin levels which might influence overall metabolism. Thus, insulin may
have a variety of effects during intestinal adaptation.
Prostaglandins
The eicosanoids, particularly, prostaglandins of the E series, appear to play an
important role in the gastrointestinal tract. They participate in motility, secretion,
blood flow, pancreatic biliary secretion and maintenance of barrier function.
231-235
Both endogenous and exogenous eicosanoids have a cytoprotective function which
is related to effects on the mucosal microcirculation, motor activity, glycoprotein
production, bicarbonate secretion, mucus production, tight junctions, lysosomal
membrane stabilization, hydrophobility, and epithelial restitution.
231
PGE analogues
restore MMCs after feeding.
234
Given these diverse actions, particularly the mitogenic
233
15
and motility effects, prostaglandins may play a role in intestinal adaptation. An
increased trophic response after resection has been demonstrated with prostaglan-
dins E2.
236
The effects of the prostaglandins do not appear to be mediated via other
peptides.
233,237
It is more likely that prostaglandins are mediators of the response of
hormones. Cytokines also increase prostaglandin production.
238
Thyroxine
Thyroxine is a known mitogen of intestinal crypt cells and hypothyroidism is
associated with mucosal hypoplasia.
239
Mucosal hyperplasia follows the induction of
hyperthyroidism experimentally.
240
Changes in food intake may be an important
factor. The growth promoting properties of thyroxine may also be mediated in part
via local changes in EGF activity.
241
Structural changes are more prominent than
functional ones. Thus, the extent of the role of thyroid hormone in adaptation is
poorly defined.
Cytokines
Cytokines have been demonstrated to have a number of potential effects on the
small intestine. Intestinal epithelial cell populations have been found to express and/
or respond to several cytokines, including IL-1, IL-2, IL-6, TNF and interferon-.
242
Tumor necrosis factor (TNF) reduces intestinal blood flow and limits fuel glutamine
availability to the intestine.
242
It reduces mucosal cellularity and may impair barrier
function. TNF down regulates collagen synthesis during wound healing and thus,
may influence intestinal adaptation at the subepithelial level.
244
Interleukin-1 (IL-1)
inhibits gastric acid secretion and suppresses postprandial motility in the duode-
num and j ej unum.
245
These effects appear to be medi ated both vi a
corticotropin-releasing factor and prostaglandins. Interleukin 11 promotes cell pro-
liferation and differentiation and enhances postresection adaptation.
246
It has an
additive effect with EGF. The marked interactions between cytokines and both local
growth factors and gastrointestinal peptides suggests that there may be an important
integration between the epithelium and the mucosal immune system which can
influence the adaptive response.
247,248
Neural Influences
Intestinal structure and function are under the influence of both the intrinsic
and extrinsic enteric nervous systems.
249-250
Interruption of innervation at various
levels results in marked changes in cell proliferation, intestinal motor responses, and
enteric peptide release.
251-254
Following intestinal transplantation the capacity for
adaptation remains, suggesting that neurohormonal regulation is re-established.
255
Thus,
neural influences are important in the regulation of the intestinal adaptive response.
Changes in Blood Flow
Mucosal blood flow increases transiently after intestinal resection.
256
These changes
are most marked distal to the resection. While it has been speculated that this in-
creased blood flow might contribute to trophic changes, there is not a correlation
between blood flow and hyperplasia.
257
The transient nature of blood flow changes
also argues against a significant role. These findings suggest that hormonal rather
than metabolic factors are responsible for the mucosal hyperemia that occurs. Va-
sodilators such as glucagon, gastrin and cholecystokinin may be responsible for in-
creased splanchnic blood flow.
258
It is not clear that ischemia diminishes the
adaptive response.
234
15
Mesenchymal Factors
Intestinal structure and function may be profoundly influenced by tissues adja-
cent to the epithelium, including the basement membrane and other subepithelial
constituents and lymphoid tissue. Basement membrane components influence epi-
thelial cell migration, proliferation and differentiation.
259,260
While there are interac-
tions between matrix proteins and growth factors, they appear to have independent
effects on epithelial cell proliferation and migration,
261-263
There is evidence that the
composition of such components, e.g., laminin, may be altered after resection.
264
There are numerous lymphoepithelial interactions.
265
Lymphoid tissues are an
important source of cytokines and growth factors.
266
Both epithelium and lymphoid
tissue are influenced by gastrointestinal hormones.
267,268
Given the importance of
neuroimmune regulation of intestinal transport of water and electrolytes, one might
speculate about a role for the immune system in functional adaptation.
269
Cellular Mechanisms
It is now recognized that intestinal resection results in changes in molecular events
in the intestinal epithelial cells within hours.
270,271
There is immediate increase in
genes which encode transcription factors. These include not only genes influencing
cell proliferation, but also those augmenting nutrient trafficking and heat shock
genes which maintain normal cellular function.
272
Many of these are novel genes,
not normally present in intestinal epithelium.
272,273
These responses are spatially and
temporally regulated.
273
Regulation of enzyme synthesis can be either pre- or post-
translational.
271
The specific triggers for these events are not clear and there are
obviously many candidates. It is also likely that this molecular response will be al-
tered by nutrients and other factors.
275
Further evidence for the importance of specific regulatory gene products in the
adaptive response comes from studies in knockout mice. P21 is a nuclear protein
whose production is influenced by P53. In P21 null mice apoptosis but not pro-
liferation increases after intestinal resection.
276
Bax is a pro-apoptotic gene.
Bax-null mice have the normal proliferative response but do not increase
apoptosis after resection.
277
Intracellular polyamine content appears to have an important role in cell prolif-
eration. The polyamines bind nucleic acids, influence RNA polymerase activity and
may be the final signal for initiation of protein synthesis and cell division.
278-280
Their effect occurs by virtue of their ability to regulate proto-oncogene expression.
281
The enzymes responsible for synthesizing (ornithine decarboxylase) and degrading
(diamine oxidase) polyamines change rapidly during the intestinal adaptive re-
sponse.
278-284
Inhibition of ornithine decarboxylase and diamine oxidase activity by
specific inhibitors reduces and increases intestinal adaptation, respectively.
285,286
Polyamine synthesis is a common mediator of the trophic effect of many of the
important stimuli during intestinal adaptation.
287-292.
There are multiple regulatory
pathways and epithelial cells can also alter their ability to take up polyamines.
291,292
The ubiquitous nature of the polyamine synthetic pathway and its tight regulatory
mechanism suggest that it has an important role in the initiation of cell proliferation
and perhaps its termination during intestinal adaptation.
The molecular mechanisms of hormone production are receiving increasing at-
tention. Levels of mRNA for CCK, enteroglucagon, neurotensin and PYY increase
within hours after resection. This provides evidence that these peptides play an im-
portant role in the early phases of intestinal adaptation.
235
15
The importance of membrane glycoproteins in the regulation of cell prolifera-
tion and function has recently been appreciated.
293,294
Tyrosine kinase receptors play
a prominent role.
295
As has been reported earlier, receptor activity for various pep-
tides is modulated after intestinal resection. These alterations may be more impor-
tant than changes in circulating concentrations of these regulatory peptides in
determining their effect on adaptation. This may provide a mechanism for termi-
nating the response to various regulatory factors.
293
Role of the Colon
Evidence is increasing that the colon plays an important role in adaptation of the
small intestine. Bypass or resection of the colon depresses epithelial cell production
in the small intestine.
297-298
This effect may be mediated by short chain fatty acids
(SCFA), which are products of bacterial fermentation of fiber in the colon.
297
SCFA
infused into the colon cause jejunal mucosal hyperplasia.
299-300
Butyrate alone does
not have a comparable effect.
299
This enhanced proliferation is related to increased
tissue content of gastrin but not increased plasma levels.
300-301
Plasma enteroglucagon
levels do correlate with crypt cell production rate during administration of ferment-
able fiber into the colon.
301
Thus, the colon appears to have a role in intestinal
adaptation if it is in continuity and processing nutrients.
Understanding the mechanism of intestinal adaptation is important for plan-
ning strategies for clinical management. An obvious goal is to maximize the normal
adaptive response. This might be achieved by providing the optimal dietary con-
stituents, augmenting critical growth factors and regulators, and suppressing stimuli
which inhibit this process (Table 15.5). The complexity of this response with its
numerous interrelationships will make manipulating the regulatory factors difficult.
Restoration of intestinal continuity, including to the colon remnant, may also in-
crease the small intestinal adaptive response. Another important aspect of clinical
management is to use our understanding of postresection gut structure and func-
tion to implement the diet most likely to be absorbed effectively.
Table 15.5. Strategies for maximizing intestinal adaptation
Provide optimal dietary constituents
Type of nutrients
Form of nutrients
Specific nutrients
Glutamine
Augment growth factors and regulatory peptides
EGF
IGF-1
GLP-2
Growth hormone
Suppress inhibitory factors
Restore intestinal continuity
Small intestine
Large intestine
236
15
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ornithine decarboxylase in intestinal epithelial cells. Am J Physiol 1990;
258:G454-G460.
292. Bardocz S, Grant G, Brown DS et al. Effect of fasting and refeeding on basolateral
polyamine uptake and metabolism by the rat small bowel. Digestion 1991; 50:28-35.
293. Tauber R, Reutter W, Gerok W. Role of membrane glycoproteins in mediating
trophic responses. Gut 1987; 28:S1:71-77.
294. Gorelick FS. Second messenger systems and adaptation. Gut 1987; 28:S1:79-84.
295. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase
activity. Cell 1990; 61:203-212.
296. Thompson JS, Saxena SK, Sharp JG. Effect of the duration of infusion of urogas-
trone on intestinal regeneration. Cell Tissue Kinetics 1989; 22:303-309.
297. Sakata T. Depression of intestinal epithelial cell production rate by midgut bypass
in rats. Scand J Gastroent 1988; 23:1200-1202.
298. Buchholtz TW, Malamud D, Ross JS et al. Onset of cell proliferation in the short-
ened gut: Growth after subtotal colectomy. Surgery 1976; 80:601-607.
299. Kripke SA, Fox AD, Berman JM et al. Stimulation of intestinal mucosal growth
with intracolonic infusion of short-chain fatty acids. JPEN 1989; 13:109-116.
300. Reilly KJ, Frankel WL, Klurfeld DM et al. Gastrin mediates trophic effects of
colonic short chain fatty acids on rat jejunum. Gastroent 1994; 106:A629.
301. Goodlad RA, Lenton W, Ghatei MA et al. Effects of an elemental diet, inert bulk
and different types of dietary fibers on the response of the intestinal epithelium to
refeeding in the rat and relationship to plasma gastrin, enteroglucagon and PYY
concentrations. Gut 1987; 28:171-180.
CHAPTER 16
Intestinal Regeneration and Nutrition
Jon S. Thompson, Shailendra K. Saxena and John G. Sharp
Introduction
The response of the intestine to a variety of insults or injury depends on the
depth of injury to the intestinal wall. Intestinal restitution is the repair of damaged
epithelium above the lamina propria due to a process primarily involving epithelial
cell migration or spreading along the surviving intact layer. Injury to the lamina
propria and into the deeper areas will cause a more generalized response with the
regenerating cells being derived from all the surviving components of the intestine.
This intestinal regenerative process is more complicated. It involves not only epithe-
lial cell migration, but epithelial cell proliferation, alterations in cell function and
adaptation of the subepithelial tissues. Furthermore, contraction of an injured area
will occur if the defect is a deep partial thickness or full thickness wound. Thus, the
regenerative response is associated with adaptive changes in the adjacent intestine.
Regulation of these processes involves communications and interactions of multiple
cell types by mechanisms that are still incompletely understood.
The intestinal regenerative response has important clinical implications. Both
local ulcerative lesions and more diffuse intestinal injuries that occur in response to
ischemia, irradiation and other inflammatory insults, heal by variants of this regen-
erative process. Furthermore, nutrients appear to be important regulatory factors of
regeneration, acting both directly and indirectly e.g., via stimulation of gastrointes-
tinal peptide secretion. Thus, nutrients have a potential therapeutic role in the treat-
ment of various intestinal injuries.
Mechanism
A detailed description of regeneration for discrete, full thickness intestinal de-
fects has been published, and only an updated summary will be presented.
1
One of
the earliest events is migration of epithelial cells onto the defect surface. Epithelial
cell migration involves a change in epithelial cell shape (columnar to squamous),
movement of cells onto the injured defect and provision of migratory cells from the
surrounding mucosa. This phenomena is enhanced in vivo by luminal contents and
a variety of systemic and local factors, including associated intestinal resection, loca-
tion within the intestinal tract, basement membrane components, and immune cells.
2-
12
Clearly endogenous peptides, chemotaxis, stimulated proliferation and cell adhesive
factors are important in this migratory response. Recent in vitro studies of cell mi-
gration in restitution suggest that migration is regulated by both epidermal growth
factor receptor (EGFR) ligands (EGF and TGF) and EGFR independent factors
(bFGF, IGF-1, IL-IB, and trefoil peptides.
13
A number of inhibitory factors have
251
16
also been identified in vivo, including the inhibitory polypeptide somatostatin, cor-
ticosteroids, and thiphenamil.
10,11,14,15
The response to these factors may be pharma-
cologic or a toxic effect, rather than physiologic.
Another important component of the intestinal regeneration response is stimu-
lated epithelial cell proliferation, as this will supply the cells for migration and pro-
mote crypt and villus development in the regenerating mucosa. Proliferation is
transiently increased in the crypts adjacent to the injured area with elongation and
bifurcation of the crypts (crypt fission). Thus, proliferation is increased both by
increasing the rate of cell production per crypt and increasing the number of crypts.
The adjacent villi become reduced in height, suggesting that proliferating cells are
directed to repair the injury. This priority is maintained until cell density is in-
creased and cell to cell contact re-established.
Stimulated proliferation continues until normal villus architecture is achieved.
In the regenerating mucosa, crypts form by invagination of the intestinal cells into
the underlying connective tissue and cell proliferation is stimulated for a longer
period of time until normal structure is reestablished. Eventually there is nearly
complete restitution of crypts and villi. These processes are stimulated by growth
factors, luminal contents, and associated intestinal resection and are also influenced
by the crypt density around the injured area.
2-11
EGF, in particular is an important
mitogenic factor. Intracellular processes, such as polyamine metabolism, are also
important stimuli for this process. A decrease in polyamine levels by inhibition of
ODC activity will transiently decrease mucosal proliferative activity and reduce crypt
fission.
10,16,17
Increasing polyamine levels by stimulating ODC activity or by de-
creasing polyamine degradation via diamine oxidase activity increases the intestinal
regenerative response.
2,9,18
Recently, many other potential regulatory factors have
been identified.
19
Mucosal development, i.e., mucosal structure and function, is enhanced by the
same factors that promote increased proliferation, indicating the predominant in-
fluence of proliferation on mucosal development. The mucosal response to injury
involves a specific alteration in enterocyte phenotype and the response of enterocytes
to regulatory factors.
20,21
Differentiation is initially delayed to permit migra-
tion and proliferation.
Recent evidence suggests that regulation of apoptosis may also play an impor-
tant role in the regenerative response.
22-26
Apoptosis of epithelial cells in the intes-
tine adjacent to the full thickness defect is reduced during the proliferative
response.
23,24
Apoptosis is reduced in the presence of mitogenic agents such as EGF
and GLP-2.
24,25
Counter-regulatory factors, such as somatostatin and TGF, in-
duce apoptosis.
23,26
Extracellular matrix components enhance regeneration, in part,
by reducing the apoptosis induced by disruption of cellular connections to the ex-
tracellular matrix.
27
Interestingly, the short chain fatty acid butyrate induces apoptosis.
20
Regeneration of subepithelial tissue also occurs, but more slowly.
28
Presumably
basement membrane components are produced by the advancing epithelium and
mesenchymal elements. The inflammatory response and angiogenesis stimulate con-
nective tissue development which becomes important in villus and crypt develop-
ment. Muscle regeneration occurs later. Muscularis mucosa repairs only after
epithelialization is nearly complete. It is not clear if muscularis propria regenerates
of if scarring persists in this layer.
8
Contraction of deep partial thickness and full thickness intestinal defects is another
important aspect of regeneration and appears to be independent of epithelialization.
28,29
252
16
This reduces the effective size of the injured area. This is initially related to smooth
muscle-like contractibility which begins within hours.
14,29
However, contraction is
related temporally to increased collagen content within a few days. Contraction is
regulated by both local and systemic factors. This process is influenced by the tissue
in the depth of the wound, and can be prevented mechanically by splinting the
injured defect. Corticosteroids and smooth muscle antagonists, e.g., thiphenamil,
inhibit contraction.
14,15
However, the transient effects of smooth muscle antagonists
suggest that the contractile properties of the subepithelial tissues do not heavily
influence this response. Increased collagen content may be important. Furthermore,
epidermal growth factor at high doses inhibits contraction by an as yet unknown
effect on subepithelial tissues.
10
Regenerating intestine re-establishes normal functional activity. Nutrient up-
take, mucosal enzyme activity and protein content progressively return to normal
levels.
5,28
Specific transport capabilities of the adjacent mucosa are maintained in
regenerative mucosa.
5
Whether or not regenerating intestine is able to participate in
integrated gut function, e.g., motility and immune function remains unclear.
Intestinal regeneration has high biologic priority and will occur eventually de-
spite inhibition of the various steps involved. Inhibition of increased proliferation
will delay but not prevent epithelialization and mucosal development.
10,16
If con-
traction is inhibited, epithelialization will occur over the larger injured defect.
12
The initial signal for initiation of regeneration is unclear. The inciting factor
may be tissue injury, loss of integrity of the intestinal wall, intraluminal exposure of
the deeper tissue layers or other undefined determinants. Different factors may be
important during different phases of the regenerative response. For example, loss of
cell to cell contact or a denuded basement membrane may be important early regu-
lators. There has been recent progress in identifying possible molecular mechanisms,
but these remained largely undefined.
19
Furthermore, it remains unclear if the mecha-
nisms important in maintaining normal intestinal structure and function are the
same as those involved in the regenerative response.
Regeneration of more diffuse intestinal injury has several distinct differences
from that occurring in discrete, full thickness injury. Inflammation and ischemia are
perhaps more significant in this setting. The injury is more heterogeneous, with
more superficial injury, leaving various tissue layers intact. These lesions are poten-
tially more extensive with resultant changes in the intraluminal environment such
as altered absorption and secretion and dysmotility. Thus, the mechanism and regula-
tion of a more diffuse regenerative response may not be the same as for discrete lesions.
We are just beginning to understand the importance of nutrients in this regen-
erative process (Table 16.1). Nutrients are important in gene expression, including
transcriptional responses, translation, and post translational modification.
30
Nutri-
ents also affect the production, release, and activity of a variety of peptides which
may play a role in regeneration. Both nutrient composition, e.g. fat, protein or
glucose, and specific nutrients, e.g. glutamine and arginine may influence regenera-
tion.
31,32
The response to nutrients may be region specific. For example, in the distal
intestinal tract short chain fatty acids may similarly be important.
20
Most research in
the area of intestinal injury has focused on prevention of the injury rather than the
regenerative response. However, a better understanding of this response may pro-
vide new therapeutic strategies for the management of inflammatory conditions of
the small intestine (Table 16.2).
253
16
Repair of Intestinal Injury
Intestinal Ulceration
Whereas gastroduodenal ulceration is a common, well studied phenomena, local
ulcerative lesions in the small intestine are more unusual. Small intestinal ulceration
in the clinical setting is commonly related to steroid and other immunosuppressant
therapy, inflammatory bowel disease, radiation therapy and intestinal ischemia.
33,34
Often the etiology is not clear and the ulcers are termed nonspecific. Recently, non-
steroidal anti-inflammatory drugs in particular have been implicated in this condi-
tion.
34,35
The gastrointestinal lesions caused by these anti-inflammatory agents are
due to reduction of mucosal prostaglandin levels, reduction of mucosal blood flow,
stimulation of neutrophil activation and increased apoptosis.
36
These agents have
also been shown to inhibit the normal increase in cell proliferation observed in the
adjacent mucosa during the regenerative response to duodenal ulcer.
37
Thus, in-
flammation caused by nonsteroidal inflammatory agents may results in abnormal
healing with stricture formation.
35
Many discrete, nonspecific ulcers will heal spontaneously. while others may re-
quire operation for complications. General medical therapy for this problem has
included nonspecific anti-inflammatory treatments such as corticosteroids and
sulfasalazine for ulcerations in Crohns disease. The prostaglandin E analog,
Misoprostol, has been shown to be efficacious in the management of anti-inflam-
matory drug induced gastroduodenal ulceration.
38
Misoprostol inhibits injury by
increasing mucosal blood flow. It also enhances intestinal regeneration by protect-
ing proliferative cells from injury, preventing the drug induced reduction in epithe-
lial cell proliferation and stimulating cell proliferation. However, misoprostol is less
effective at reducing small intestinal injury compared to gastric injury.
39
Little is known about the effects of either systemic or luminal nutrients on heal-
ing of discrete ulcers. Nutrients may enhance intestinal regeneration by stimulating
the release and/or activity of gastrointestinal peptides. Several peptide growth fac-
tors appear to have a role in healing of gastrointestinal ulcers. EGF, which has sig-
nificant effects on epithelial migration and proliferation, not only stimulates intestinal
regeneration, but has cytoprotective properties, which are mediated in part by pros-
taglandins.
40
EGF and its receptor are overexpressed in the mucosa at the ulcer mar-
gin.
41
In fact, ulceration may induce a novel EGF-secreting cell lineage in the
surrounding tissue.
42
Exogenous EGF has a beneficial effect on gastric ulcer heal-
ing.
43
Another EGF receptor ligand, TFG, is increased in injured gastric mucosa,
and thus may also play an important role in repair.
44
Platelet derived growth factor
Table 16.1. Potential mechanisms of nutrient effects on intestinal regeneration
Nutrient stimulation of production and release of gastrointestinal peptides and other
potentially beneficial molecules
Nutrient enhanced peptide function via improved absorption or inhibited
inactivation
Nutrient modulation of transcription/translation in target cells
Nutrient specific effects on enterocyte structure and function
Nutrient modulation of local immune responses
254
16
(PDGF) significantly accelerates the healing of cysteamine induced duodenal ulcers
and indomethacin induced gastric ulcers.
45,46
Fibroblast growth factor (FGF) accel-
erates the healing of acetic acid induced gastric ulcers and alcohol and aspirin in-
duced gastric mucosal lesions.
47
Thus, a variety of local growth factors that may be
effective in the presence of or which interact with nutrients may be involved in
regeneration of discrete ulcers.
The role of specific nutrients in treating discrete ulcers has been studied to a
limited extent in experimental models. Polyamines, for which arginine is a precur-
sor, are important in the regulation of intestinal regeneration. Polyamine levels are
increased during healing of mucosal injury and inhibition of polyamine synthesis
inhibits mucosal repair.
48,49
Luminal polyamines can substitute for endogenous
polyamines in the regenerative response to stress ulcers in the duodenum and in-
crease the normal healing rate by stimulating proliferation.
50
Inhibiting diamine
oxidase activity, the primary degradative enzyme of the polyamines, with
aminoguanidine also increases the healing of stress induced gastric lesions in rats.
51
Clearly more investigation is necessary in this area.
Diffuse Intestinal Injury
More diffuse inflammation and injury in the small intestine occurs in response
to ischemia, stress, radiation, and various toxins such as alcohol.
52-54
Depending on
the chronicity and extent of injury a variety of chronic intestinal lesions develop. A
common injury is acute mucosal necrosis which results from a variety of stressful
stimuli.
52
These injuries may or may not be associated with a significant inflamma-
tory response. Intestinal ischemia, when reversible, results in intestinal lesions sec-
ondary to both ischemia and reperfusion. Radiation induces both an acute mucosal
injury and a chronic ischemic condition secondary to vasculitis.
53
Alcohol causes an
acute mucosal injury which is usually superficial and heals by restitution alone.
54
While there has been considerable research into protecting the gut mucosa from
the damaging effects of radiation and other insults, less investigation has occurred
into enhancing the regenerative response. Elemental diets may be beneficial during
both acute and chronic radiation enteritis.
55
Acutely elemental diets may protect the
Table 16.2. Interactions of tissue injury and nutrition
Type of Effect on Role of
Tissue Injury Nutrition Nutrition Potential Solutions
Localized Minimal Luminal nutrition, Peptide stimulation of
epithelial polyamines restitution
damage
Diffuse Significant, Short chain fatty Dietary protection, growth
intestinal damage debilitating acids elemental factors, e.g. KGF
(radiation, diets, glutamine
chemotherapy,
inflammation)
Full thickness Significant, Enhanced Reduction of contracture
loss (necrosis, loss of absorption in stimulation of regenera-
resection) mucosal surviving bowel tion, cell transplantation
absorption and tissue engineering
255
16
mucosa by inhibiting release of pancreatico biliary secretions and generation of free
radicals. Elemental diets may be absorbed more effectively from intestine with chronic
radiation injury.
Nutrient enhanced peptides have been studied in diffuse injury. In contrast to
many discrete full thickness ulcers, diffuse injuries such as radiation often leave
progenitor cells at the base of the crypts.
56
One therapeutic possibility would be
stimulation of gastrointestinal progenitor cells using cell growth regulators, an ap-
proach which has proven beneficial in stimulating recovery in the stem cell com-
partment of bone marrow of irradiated patients.
57
FGF expression is induced after
radiation injury and enhances intestinal stem cell survival.
58
Keratinocyte growth
factor (KGF) also has significant gastrointestinal radioprotective effects. There are
other potential benefits of growth factors on the healing of diffuse intestinal injury.
TGF not only accelerates healing of radiation induced injury, but partially reverses
steroid impairment of intestinal wound strength which may be related to fibroplasia
and increased collagen content of the intestine.
59,60
Recombinant growth hormone
also improved anastomotic healing in irradiated bowel in one study.
61
Nutrient enhanced peptides have been evaluated in a variety of inflammatory
conditions as well. EGF improved healing of intestinal lesions caused by lipids and
methotrexate.
62
EGF has been used clinically to treat necrotizing enterocolitis in
one infant.
63
Specific nutrients have also been evaluated in intestinal repair of diffuse injury.
Dietary arginine accelerates mucosal regeneration following radiation enteritis in
rats.
64
Glutamine has been studied in both animals and humans. Oral, but not in-
travenous glutamine accelerates the healing of intestinal injury in rats caused by
whole abdominal irradiation.
30,65
Glutamine enriched feedings also promote heal-
ing of the intestinal injury caused by fluorouracil.
66
While glutamine has been dem-
onstrated to maintain gut integrity during TPN in humans, studies in repair of
intestinal injury are less common.
67
Both glutamine and butyrate suppositories have
had benefit in the resolution of pouchitis following restorative proctocolectomy.
68
The beneficial effects of short chain fatty acids are related both to their role as
enterocyte fuel as well as influencing the molecular response to injury.
69
Other nu-
trients, such as trace elements e.g., zinc, and vitamins e.g., vitamins A deserve clini-
cal evaluation based on their effects on intestinal adaptation.
70,71
Intestinal Regeneration for Increasing Absorption
There has been interest in using the regenerative powers of the intestine to ex-
pand the intestinal surface area as a therapeutic modality in patients with the short
bowel syndrome. Several strategies have been employed to achieve this.
72
Full thick-
ness intestinal defects can be created and patched with a variety of different surfaces,
including serosal surfaces and various prosthetic materials.
73-77
Lateral ingrowth of
the intestinal layers from the surrounding mucosa results in regenerated intestine,
which is functionally similar to the normal adjacent intestinal mucosa. It remains
unclear, however, whether sufficient intestinal surface area can be produced by in-
testinal patching to significantly increase intestinal absorption.
74,76,77
While several
studies suggested that this, in fact, might occur, our own experience was less favor-
able.
78
Serosal patching after extensive intestinal resection in dogs, in fact had a
deleterious effect on intestinal absorption and nutritional status compared to resec-
tion alone. Malnutrition and malabsorption occurred despite prolongation of intes-
tinal transit time by intestinal patching. Furthermore, marked contraction of the
256
16
patched defects limited the increase in surface area which could be achieved. The
deleterious effect of serosal patching on intestinal function may be related to several
factors, including impairing the normal postresection adaptive response, amplifying
the gastric hypersecretion which occurs after intestinal resection, and altering intes-
tinal motility.
78-80
Thus, while this approach may prove useful in the clinical setting
to preserve intestinal length by treating stricture and perforation, it does not appear
to be efficacious for expanding intestinal surface area.
Other surgical approaches to expanding the surface area via regeneration have
been investigated. There have been attempts to grow new intestine into tubular
structures rather than via the lateral enterotomies.
81,82
Replacement of colon mucosa
with small intestinal mucosa has also been evaluated.
83,84
More recently, efforts have
been directed at tissue engineering.
85
Intestinal epithelial organoid units transplanted
on porous biodegradable polymer tubes can successfully vascularize, survive and
regenerate into complex tissue resembling small intestine. This tissue engineered
intestine has been successfully anastomosed to native small intestine.
86
Intestinal
stem cell transplantation and other innovative techniques such as transfection to
transfer genetic information are also being studied.
87
Obviously, the ideal solution
might be to advance our understanding of the mechanisms of the intestinal regen-
erative response such that the normal intestine could be induced to undergo
supranormal growth to increase surface area.
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CHAPTER 1
CHAPTER 17
Nutritional and Metabolic Management
of Short Bowel Syndrome
Stanley J. Dudrick, Frizan Abdullah and Rifat Latifi
Introduction
The short bowel syndrome is a clinical entity characterized primarily by intrac-
table diarrhea, steatorrhea, dehydration, malnutrition, weight loss, and malabsorp-
tion of fats, vitamins and other nutrients, and not defined anatomically by a specific
length of remaining functioning small intestine. Subsequent adverse consequences
of short bowel syndrome include hypovolemia, hypoalbuminemia, hypokalemia,
hypocalcemia, hypomagnesemia, hypozincemia, hypocupticemia, fatty acid and vi-
tamin deficiencies, anemias, hyperoxaluria and metabolic acidosis. The actual clini-
cal presentation of the patient with short bowel syndrome depends on several factors,
including:
1. the extent of the bowel resection;
2. the site(s) of the resection;
3. the presence or absence of the ileocecal valve;
4. the residual function of the remaining small bowel, stomach, pancreas,
biliary tree and colon;
5. the adaptation capacity or the intestinal remnant;
6. the primary disease of disorder that precipitated the loss of the small bowel;
7. the amount and activity of the residual disease in the intestinal remnant;
8. the general condition of the organ systems of the patient.
1-5
The minimum length of small bowel sufficient for adequate absorption is con-
troversial. Standardization of the adaptive potential is difficult because of the vari-
able residual absorptive capacity of the remaining remnant, the wide variation in the
length of the normal small intestine, and the difficulty in obtaining reproducible
measurements of the length of the remaining bowel following massive resection.
Depending upon the state of contraction or relaxation of the intestinal musculature,
intraoperative estimates of the length of the normal intact small intestine in the
adult vary from 260 to 800 cm (approximately 8-26 feet). On the other hand, the
mean length of normal small intestine measured during life is 350 cm (11-12 feet)
and post-mortem is 600 cm (20 feet). Because of this large variability, it is virtually
impossible to determine the exact length of the remaining small bowel, and it is very
difficult to estimate the percentage of the total length of small bowel represented by
the segment remaining following massive intestinal resection. Moreover, many sur-
geons not only measure the length of the resected small bowel, rather than measur-
ing the length of the remaining intestinal segment, but then fail to describe accurately
262
17
the nature, condition and extent of the remaining small bowel in the patients medi-
cal record for future reference. Furthermore, since inflamed intestine generally short-
ens after operation, the absorptive functions following massive small bowel resection
often do not correlate well with the intraoperative estimated length of the
remaining intestine.
6
Because of the rather ample functional reserve capacity of the small bowel, seg-
mental resections of the small intestine usually do not result in significant problems
with digestion and absorption.
7-8
Indeed, resection of as much as 40% of the small
intestine is usually well tolerated, provided that the duodenum, the distal half of the
ileum, and the ileocecal valve are spared.
9
On the other hand, resection of 50% or
more of the small intestine usually results in significant malabsorption initially, but
can be tolerated eventually without extraordinary parenteral or enteral nutritional
support. However, resection of 75% or more of the small intestine usually leaves the
patient with 70 to 100 cm (2-3 feet) of remaining intestine, resulting in a short
bowel syndrome which can significantly impair the ability of the patient to main-
tain normal nutrition and metabolism. Such patients will likely require special nu-
tritional care on a long-term or permanent basis, especially with the loss of the
terminal ileum and the ileocecal valve, if normal body cell mass and function are to
be preserved.
The severity of symptoms following massive small bowel resection is related both
to the extent of the resection and the specific anatomic site(s) of the resected small
bowel.
10
However, the minimal residual small intestinal absorptive surface required
to sustain life without permanent parenteral nutritional support appears to vary
somewhat with each patient.
11,12
Development of effective total parenteral nutrition
has revolutionized the treatment of the short bowel syndrome by allowing mainte-
nance of adequate nutrition indefinitely or until the remaining bowel can adapt
maximally to oral feeding, thus reducing the morbidity and mortality significantly.
13-
18
Prolonged survival has now been achieved in a number of patients having only an
intact duodenum and 15 cm (6 inches) of residual jejunum, with or without the
colon.
2,8,19
If approximately 60 cm (2 feet) of jejunum or ileum remain functional, in
addition to the entire duodenum, survival has been the rule rather than the exception.
Preservation of the ileocecal valve is of paramount importance during massive
small bowel resection, and by significantly increasing the intestinal transit time,
allows a longer exposure time of the intestinal chyme to the residual absorptive
mucosa. Salvage of the ileocecal valve, whenever possible, has the clearly beneficial
effect of increasing the absorptive capacity of the remaining small bowel to approxi-
mately twice that anticipated for the same length of small bowel without an intact
ileocecal valve. Primarily as a result of mucosal hyperplasia and villous hypertrophy,
absorption by the residual intestinal segments of patients with short bowel syn-
drome can increase as much as four-fold. Therefore, in a patient with an intact
ileocecal valve, the total absorptive capability of the remaining bowel potentially can
be increased maximally about eight-fold.
The most common clinical conditions which precipitate massive small bowel
resections are those which compromise the vascular supply of the small intestine.
20-
22
These include venous thrombosis and arterial occlusion as a consequence of pri-
mary vascular disease, heart failure with attendant mesenteric low flow state, various
coagulopathies, volvulus, malrotation of the gut, and internal or external herniation
of the bowel with strangulation. Short bowel syndrome can also occur as a result of
necrotizing enterocolitis or massive atresia of the small intestine in newborn infants.
263
Nutritional and Metabolic Management of Short Bowel Syndrome
17
Inflammatory bowel disease involving large segments of the small bowel, or recur-
rent exacerbations of inflammatory bowel disease over a prolonged period of time,
can eventually result in the short bowel syndrome secondary to massive or multiple
intestinal resections. Excision of retroperitoneal malignancies which involve the su-
perior mesenteric vessels can mandate secondary resection of most or all of the small
bowel in order to accomplish palliation or cure. Major abdominal blunt or sharp
trauma involving transection, disruption or avulsion of the mesenteric vasculature
can result in ischemic necrosis of large segments of the small bowel, resulting in
short bowel syndrome. Post-irradiation or postoperative complications such as ex-
tensive severe radiation enteritis, multiple small bowel fistulas, and intestinal gan-
grene can also result in irreversible short bowel syndrome.
Pathophysiology
The intestinal absorption of water, electrolytes and other specific nutrients is
dependent upon the extent and site of the small bowel resection. The intestinal
phase of digestion occurs initially in the duodenum, where pancreatic enzymes and
bile acids promote digestion of all nutrients and enhance fat absorption. It is un-
common for the duodenum to be resected together with extensive segments of the
small bowel, primarily because of the differences in blood supply, however, total
duodenectomy leads to malabsorption of calcium, folic acid and iron.
1
Proteins,
carbohydrates, and fats are absorbed virtually completely in the first 150 cm
of the jejunum, therefore, only small quantities of these nutrients ordinarily
reach the ileum.
23
The small intestine acquires and handles about 8 liters of fluid daily, including
dietary ingestion and endogenous secretions. Normally, approximately 80% of the
water transported is absorbed in the small bowel, leaving approximately 1.5 liters of
fluid to traverse the colon. The colon usually absorbs about one to two liters of fluid
with maximal absorptive capacity of approximately six liters of fluid per day.
24
Be-
cause the ileum and colon have a large capacity for absorbing excess fluid and elec-
trolytes, proximal small bowel (jejunal) resections only rarely result in diarrhea. On
the other hand, extensive or total resection of the ileum results in a much greater
potential for malabsorption and diarrhea. Not only will such resections increase the
volume of fluid reaching the colon, but depending upon the length of ileum resected,
bile salt diarrhea (cholerrhea) or steatorrhea may ensue with subsequent loss of es-
sential fatty acids and fat soluble vitamins. If the ileocecal valve has been resected,
transit time is likely to decrease, and bacterial colonization of the small bowel will
eventually occur, further aggravating cholerrhea and steatorrhea. As the length of
ileal or colonic resections increases, essential absorptive surface area is lost, resulting
in proportionally increased dehydration, hypovolemia, and electrolyte derangements.
If the colon remains in continuity with the remaining small bowel following mas-
sive intestinal resection, malabsorbed bile salts can be deconjugated by colonic bac-
teria, stimulating increased colonic fluid secretion and further compounding existing
diarrhea. Following extensive ileal resection, the enterohepatic circulation is inter-
rupted and irreversible loss of bile salts results, with or without the colon in continu-
ity. Although the excess fecal losses stimulate hepatic synthesis of bile salts, a higher
incidence of cholelithiasis occurs in these patients. Because the transit time in the
ileum is usually slower than in the jejunum, residual intestinal transit is slowed, and
fecal output is diminished as the length of remaining ileum increases.
264
17
Following extensive small bowel resections, intestinal lactase activity may be de-
creased, resulting in lactose intolerance.
25
The presence of unhydrolyzed lactose causes
increased hyperosmolality in the intestinal lumen. Moreover, fermentation of lac-
tose by colonic bacteria produces a large amount of lactic acid that can further
aggravate osmotic diarrhea.
1
The water soluble vitamins (vitamin B-complex and C) and minerals (Ca
2+
, Fc
3+
,
Cu
2+
) are absorbed in the proximal small intestine, whereas magnesium diffuses
passively throughout the entire small bowel.
1
The ileum is the only absorption site
for vitamin B
12
and bile salts. Resection of the jejunum with preservation of the
ileum produces no permanent impairments of protein, carbohydrate, and electro-
lyte absorption.
26
The ileum can compensate for most absorptive functions, but not
for the secretion of jejunal enterohormones. Following jejunal resections, dimin-
ished secretions of cholecystokinin and secretin decrease gallbladder contraction and
emptying and decrease pancreatic secretion. Additionally, after jejunal resection,
gastric hypersecretion is greater than after ileal resection. This results from the loss
of inhibitory hormones such as gastric inhibitory polypeptide (GIP) and vasoactive
intestinal polypeptide (VIP), which are secreted in the jejunum, thus causing gas-
trin levels to rise, stimulating gastric hypersecretion.
27
Significant gastric hypersecre-
tion can be documented within 24 hours postoperatively, and the gastric and small
bowel mucosa can be injured by the high gastric acid output causing gastritis, ulcer-
ation and bleeding. Subsequently, the high salt and acid load secreted by the stom-
ach, together with the inactivation of digestive enzymes by the inordinately low
intraluminal intestinal pH, serves to compound the other causes of diarrhea associ-
ated with short bowel syndrome.
Ordinarily, the colon is a major site of water and electrolyte absorption, and as
the ileal effluent increases, the colon may increase its absorptive capacity to three to
five times normal.
28
Moreover, the colon has a moderate capacity to absorb other
nutrients, and concomitant colon resections can adversely affect the symptomatic
and nutritional courses of patients with massive small bowel resections. Malabsorbed
carbohydrates which reach the colon are fermented there by indigenous bacteria to
yield short chain fatty acids, principally acetate, butyrate and propionate.
29,30
The
short chain fatty acids can be absorbed by the colon in quantities representing up to
500 calories per day and enter the portal circulation to serve as a fuel source.
31,32
Although retention of the colon is highly desirable during massive bowel resections,
its presence can be associated with potential complications. In addition to cholerrheic
diarrhea, a patient with a massive small bowel resection and an intact colon often
develops hyperoxaluria and a tendency to form calcium oxalate renal stones. These
result from the increased absorption of dietary oxalate, which is normally rendered
insoluble by binding with calcium in the intestinal lumen and, therefore, ordinarily
unabsorbable. However, in patients with short bowel syndrome and steatorrhea,
intestinal calcium ion is bound preferentially to the increased quantities of unab-
sorbed fatty acids, leading to decreased binding and increased coloic absorption of
the oxalate.
10
Finally, preservation of the ileocecal valve is important in preventing abnormal
metabolic sequelae because the ileocecal valve not only slows intestinal transit and
passage of chyme into the colon, but prevents bacterial reflux from the colon into
the small bowel. Nutrients which reach the colonic lumen, especially vitamin B
12
,
become substrates for bacterial metabolism rather than being absorbed by the mu-
cosa.
1
Furthermore, bacterial overgrowth in the small bowel in patients with short
bowel syndrome appears to increase the incidence of liver dysfunction.
33
265
17
Nutritional and Metabolic Management
In the metabolic and nutritional management of patients with the short bowel
syndrome, three different but overlapping therapeutic periods having rather distinc-
tive characteristics can be designated arbitrarily (Table 1).
34
During the first two
months (immediate postoperative period), the clinical picture and course are domi-
nated by problems related to fluid and electrolyte balance, adjustment of organ
blood flow patterns, especially the portal venous flow, and other effects of the major
operative insult and its accompanying specific and general complications. During
the second period, from about two months up to two years postoperatively (bowel
adaptation period), efforts are directed toward defining maximum oral feeding tol-
erances for various nutrient substrates, encouraging and maximizing intestinal and
bowel adaptation, and determining and formulating the most effective patient-spe-
cific feeding regimens. Usually within two years, 90-95% of the bowel adaptation
potential has been accomplished, and only 5-10% further improvement in absorp-
tion and bowel adaptation can be anticipated. The third period (long-term manage-
ment period) constitutes the period after two years, by which time nutritional and
metabolic stability have ordinarily occurred. By this time, the patient has either
adapted maximally so the nutritional and metabolic homeostasis can be achieved
entirely with oral feeding, or the patient is committed to receiving specialized supple-
mental or complete nutritional support for the remaining life-span, either by ambu-
latory home TPN and/or specially prepared enteral or oral feedings.
Immediate Postoperative Period
During the immediate postoperative period, for up to two months, virtually all
nutrients, including water, electrolytes, fats, proteins, carbohydrates, and all vita-
mins and trace elements are absorbed from the gastrointestinal (GI) tract poorly, or
not at all.
34
Fluid losses via the GI tract are greatest during the first few days follow-
ing massive small intestinal resection, and anal or ostomy effluent frequently reaches
volumes in excess of five liters per 24 hours. In order to minimize life-threatening
dehydration, hypovolemia, hypotension and electrolyte imbalances, vigorous fluid
and electrolyte replacement therapy must be instituted promptly and judiciously.
Frequent vital signs, fluid intake and output, and central venous pressure measure-
ments together with regular hematologic and biochemical indices are mandatory in
monitoring the patient during this period of rapid metabolic change and instability.
All patients with short bowel syndrome exhibit some abnormalities in their liver
profiles, and the vast majority of them experience at least transient hyperbilirubine-
mia.
34
This has been advocated by some to be secondary to the translocation of
microorganisms and/or their toxins through the ischemic or gangrenous intestinal
mucosa into the portal vein and thence to the liver.
35,36
Others attribute the hyper-
bilirubinemia to impaired blood flow to the liver through the portal vein by as
much as 50% as a result of greatly diminished mesenteric venous return secondary
to the massive small bowel resection.
37
Still others attribute this phenomenon to a
combination of both factors and/or other etiologies.
38
Broad spectrum anaerobic
and aerobic antibiotic therapy should be instituted and maintained for several days
to one week following massive intestinal resection.
Typical patient management efforts during this period are directed toward achieve-
ment of four primary goals: fluid and electrolyte replacement, antisecretory/
antimotility therapy, antacid therapy, and total parenteral nutrition. During the first
24-48 hours, replacement therapy usually consists of 5% dextrose in lactated Ringers
266
17
Table 1. Synopsis of short bowel syndrome management
Immediate Postoperative Period
(First Two Months)
Fluid and Electrolyte Replacement
Lactated Ringers solution
Dextrose 5% in water
Human serum albumin (low salt)
K
+
, Ca
++
, Mg
++
supplementation
Strict intake and output
Daily body weight
Graduated metabolic monitoring
Antacid Therapy
Mylanta liquid
Camalox suspension
Amphogel suspension
Gelusil liquid
(30-60 ml via N-G tube q 2 hr
clamp N-G tube 20 min)
Antiulcer Therapy
Sucralfate liquid 1 gm po q 6 hr
(Clamp N-G tube 20 min)
Antisecretory/Antimotility Therapy
Cimetidine 300 mg IV q 6 hr
Ranitidine 150 mg IV q 12 hr
Famotidine 20 mg IV q 12 hr
Pantoprazole 40 mg IV daily
Codeine 60 mg IM q 4 hr
Loperamide 4-16 mg po daily
Lomotil 20mg po q 6 hr
Hyoscyamine sulfate 0.125 mg
sc q 4 hr
Cholestyramine 4 gm po q 8 hr
Total Parenteral Nutrition
1 liter on second postop day
Gradually increase dosage as tolerated
Supplement fluids, electrolytes
and colloids as needed
Bowel Adaptation Period
(First Two Years)
Progression of Oral Diet
Water, tea, broth
Simple salt solutions
Simple sugar solutions
Complex salt/sugar solutions
Dilute chemically defined diets
High carbohydrate, high protein
Modified fiber, low fat diet
Near-normal, normal diet
(First Two Years) (Contd)
Enteral Supplementation
Coconut oil 30 ml po tid
Safflower oil 30 ml po tid
Multiple vitamins 1 ml bid
Ferrous sulfate 1 ml tid
Ca gluconate 6-8 gm/day
Na bicarbonate 8-12 gm/day
Parenteral Supplementation
Electrolytes, Trace elements
Divalent cations (Mg, Zn)
Vit B
12
, Vit K, Folic acid
Albumin, Packed red cells
Fat emulsion
Antisecretory/Antimotility
Famotidine 20 mg po q 12 hr
ProBanthine 15 mg po q 4-6 hr
Dicyclomine 20 mg po q 6 hr
Omeprazole 20 mg po q day
Deodorized tincture of opium
10-30 gtts q 4 hr
Codeine 30-60 mg po q 4 hr
Paregoric 5-10 ml po q 4 hr
[Refer to column one for additional agents]
Growth Hormone/Glutamine
50,51
Long-Term Management
(After Two Years)
Apply Previous Principles
As indicated individually
Ambulatory Home TPN
Supplemental or Total
Continuous, Cyclic or
Intermittent
Surgical Management
Treat operative
Complications
Drain abscesses
Resect fistulas
Lyse adhesions
Reduce obstructions
Restore bowel continuity
Probable cholecystectomy
Intestinal Lengthening
Intestinal Transplantation
34
267
17
solution administered intravenously concomitantly with appropriate amounts of
potassium chloride and/or acetate, calcium chloride or gluconate, magnesium sul-
fate, and fat- and water-soluble vitamins. Low salt human albumin (12.5-25 g)
usually is added exogenously to the intravenous regimen every eight hours for the
first 24-48 hours postoperatively in order to maintain normal plasma albumin con-
centrations and normal plasma colloid oncotic pressure. In patients with severe di-
arrhea, zinc losses can increase to as much as 15 mg/day and require appropriate
aggressive parenteral replacement.
39
Anti-acid therapy can reduce the increased tendency for peptic ulceration, which
commonly occurs following massive small bowel resection. Antacids are given through
a nasogastric tube every two hours in doses of 30-60 ml, and the tube is clamped for
20 minutes before reapplying suction. Alternatively, or concomitantly, liquid sucralfate
can be given by mouth or via the nasogastric tube in a dose of one gram every six
hours, clamping the tube for 20 minutes after each dose. To counteract the
hypergastrinemia and associated gastric hypersecretion which follows massive small
bowel resection in the majority of patients, and H
2
receptor blocker is infused.
40
The
intravenous administration of 300-600 mg of cimetidine every six hours can have a
profound effect in reducing gastric acid and intestinal fluid production. Alterna-
tively, ranitidine 150 mg can be given IV every 12 hours, or preferably, famotidine
20 mg can be given IV every 12 hours or an intravenous form of a proton pump
inhibitor, pantoprazole, can be given daily in 40 mg doses. In selected short bowel
patients, somatostatin analog (octreotide) has reduced fecal losses when adminis-
tered in a dosage of 50-150 mcg IV or subcutaneously every six hours.
41,42
If diar-
rhea persists despite these measures, an opiate can be prescribed. Preferably, codeine
is given intramuscularly in doses of 60 mg every four hours. Improvement in fluid
and electrolyte management can also be achieved in selected patients with stomal
access to a distal defunctionalized bowel loop by reinfusing the chyme from the
proximal ostomy into the distal bowel segment.
43
Later in the course of the postop-
erative period, when the patient is tolerating liquids by mouth, antimotility therapy
can be achieved by giving loperamide 4-16 mg orally in divided doses daily,
cholestyramine 4 gm every four to eight hours and/or diphenoxlylate 20 mg every
six hours. Codeine 30-60 mg, paregoric 5-10 ml, or deodorized tincture of opium
(DTO) 10-30 drops every four hours orally can be used to impede bowel motility.
The major advantages of giving DTO are that it is readily absorbed by the upper
alimentary tract and that the patients bowel hypermotility and diarrhea can be ti-
trated to tolerable levels by adjusting the dosage up or down a few drops at a time to
optimize dose effectiveness and to minimize undesirable side effects.
By the second or third postoperative day, the patients cardiovascular and pulmo-
nary status have usually stabilized sufficiently to allow TPN to be initiated. The
average adult patient can usually tolerate two liters of TPN solution daily adminis-
tered by central vein. By titrating levels of plasma glucose and glycosuria, the daily
nutrient intake can be increased gradually to desired levels or to patient tolerance. In
a patient with diabetes mellitus, or in one who is glucose intolerant, crystalline
regular human insulin is added to the TPN solution in doses up to 60 units per
1000 calories. Following an operation of the magnitude of massive small bowel
resection, most patients require at least 3000 ml of TPN solution (about 3000 calories)
per day to maintain nutritional and metabolic homeostasis. Supplemental fluid and
electrolyte infusions may be necessary for several days or weeks to replace excessive
losses as diarrhea. The patient is offered a clear liquid diet as soon as the postoperative
268
17
condition is stabilized, and fecal output is controlled with antidiarrheal medica-
tions. It may take several days to several weeks before the patient is able to discon-
tinue TPN support in favor of oral or enteral feedings. It is essential to provide
adequate nutritional supplementation with TPN for as long as the patient requires
such support to maintain optimal nutritional status. The TPN ration is reduced
gradually in an equivalent manner as oral intake and intestinal absorption of re-
quired nutrients are increased. The patients diet is advanced slowly and gradually to
a low lactose, low fat, high protein, high carbohydrate composition according to
individual tolerances to the nutrient substrates and to the water volume and osmo-
lality of the dietary regimen.
44
During the period of bowel adaptation from two months to two years postop-
eratively, the patient is allowed to consume increasing amounts of water, simple salt
solutions and simple carbohydrates. Various fruit and other flavorings can be added
to 5% dextrose in lactated Ringers solution as a relatively inexpensive and practical
oral nutrient solution. Gradually, dilute solutions of chemically defined diets con-
taining simple amino acids and short chain peptides are given as tolerated in in-
creasing volumes and concentrations as bowel adaptation progresses toward a normal
or near normal diet consisting of high carbohydrate, high protein, and low fat and
comprised of foods most preferred by the patient as the next stage of nutritional
rehabilitation. Alternatively, the major nutrients can be provided as required in com-
mercially prepared modular feedings tailored to the needs of individual patients
until ordinary food is well tolerated. All essential vitamins, trace elements, essential
fatty acids and minerals are initially supplied in the patients balanced intravenous
nutrient ration. Subsequently the oral diet may be supplemented most economi-
cally by short- and medium-chain triglycerides in the form of coconut oil, 30 ml
two or three times daily; essential fatty acids as safflower oil, 30 ml two or three
times daily; multiple fat and water soluble vitamins in pediatric liquid form, 1 ml
twice daily; vitamin B
12
, 1 mg intramuscularly every four weeks; folic acid, 15 mg
intramuscularly weekly; and vitamin K, 10 mg intramuscularly weekly. Some pa-
tients may require supplemental iron, which can be administered initially by deep
intramuscular injection as iron-dextran according to the recommended
patient-specific dosage schedule, or as an IV infusion after testing the patient for
sensitivity. Alternatively, an oral liquid iron preparation can be given one to three
times daily.
A strong tendency for patients with short bowel syndrome to develop metabolic
acidosis usually requires the use of sodium bicarbonate tablets, powder, wafers or
liquid in doses of 8-12 g/day for as long as 18-24 months, but usually not for fewer
than six months. It is often helpful to alternate the form of sodium bicarbonate
prescribed in order to encourage maximal patient compliance. Because of the diffi-
culty in absorbing adequate dietary calcium, supplemental calcium gluconate should
also be prescribed as tablets, wafers, powder or liquid in doses of 6-8 g/day. As bowel
adaptation progresses, the doses of sodium bicarbonate and calcium gluconate can
be decreased concomitantly or discontinued. However such oral supplements may
be necessary for as long as two years or more in some patients in order to maintain
homeostasis. Occasionally, on the other hand, a patient may become severely aci-
dotic (pH 7.0-7.2) as a result of obviously copious diarrhea, but sometimes more
subtly, and may require urgent or emergency intravenous infusion of sodium
269
17
bicarbonate. Usually the patient responds promptly to the therapy within a few
hours and without untoward sequelae. Rarely, calcium gluconate must be given
intravenously as a supplement to correct recalcitrant hypocalcemia (<8.0 mg/dL).
Dietary advancement and nutrient supplementation must obviously be individual-
ized for each patient. When solid foods are given, they should be dry and followed 1
hour later with isotonic fluids to minimize diarrhea and to improve nutrient absorp-
tion. Lactose intolerance should be anticipated and treated as required with a low
lactose diet and/or lactase, 125-250 mg by mouth. Clearly, milk products should be
avoided as much as possible if intolerance persists.
As progress occurs during the bowel adaptation period of management of the
short bowel syndrome, fat can be increased in the diet as tolerated, and supplemen-
tation with short- and medium-chain triglycerides and essential fatty acids may no
longer be necessary. Serum-free fatty acid levels and triene:tetraene ratios are moni-
tored periodically to determine the efficacy of treatment and need for supplementa-
tion. Contrary to early reports, high fat diet apparently are comparable to high
carbohydrate diets when evaluated in reference to calories absorbed, blood chemis-
tries, stool or ostomy output, urine output and electrolyte excretions.
43
However it
has been suggested that enteral intake of fat should approach 50-100% greater than
expected goals to compensate for malabsorbed nutrients.
39
Patients who cannot tol-
erate or utilize a normal oral diet should be given a trial of continuous infusion of
enteral formula. Low residue, polymeric chemically defined or elemental diets offer
the putative advantage of high absorbability in the short bowel patient. However,
some investigators have recently shown no differences in caloric absorption, stomal
output of electrolyte loss among elemental, polymeric and normal diets in patients
with short bowel syndrome.
43,46,47
Depending upon the results of periodic hematologic and biochemical studies,
adjustments are made in the patients intake of sodium, potassium, chloride and
calcium.
48
Additionally, intermittent supplemental infusions of solutions contain-
ing magnesium, zinc, and copper may be required. As malabsorption and diarrhea
become less troublesome, the vitamin and trace element requirements may be satis-
fied by multivitamin capsules, tablets or chewable tablets containing therapeutic
doses of vitamins or minerals, one dose twice daily. Relatively large amounts of
magnesium, zinc, vitamin C and B-complex can be administered in the form of
several commercially available therapeutic vitamin and mineral preparations.
34
In some patients, it may be necessary periodically to correct individual nutrient
substrate deficiencies intramuscularly or intravenously for prolonged periods of time.
Intermittent infusions of human serum albumin and packed erythrocytes may be
required to treat recalcitrant hypoalbuminemia and anemia and to restore the plasma
albumin level and the hematocrit to normal. Cholestryramine can be administered
to counteract bile salt diarrhea if indicated, but intraluminal cholestyramine itself
can cause or aggravate diarrhea. Fatty acid, electrolyte, trace element, vitamin and
acid-base imbalances must be promptly corrected enterally or parenterally as re-
quired when manifested clinically or by laboratory assessment. Serum vitamin B12
levels must be monitored and its deficiency corrected immediately. Hyperoxaluria
should be assessed regularly, and if documented, foods containing high levels of
oxalate such as chocolate, spinach, celery, carrots, tea and colas should be restricted.
In patients with severe forms of short bowel syndrome in which little or no small
intestine is present distal to the duodenum, or in which the remaining small intes-
tine has residual disease, hypermotility and recalcitrant or intractable diarrhea may
270
17
require continuous long-term antimotility/antisecretory treatment with oral and/or
parenteral forms and dosages of the previously described pharmaceutical agents.
Additional oral medications which have been helpful in selected patients include
omeprazole, 20 mg daily; propantheline bromide, 15 mg every 4-6 h; dicyclomine
hydrochloride, 20-40 mg every 6 h; hyoscyamine sulfate, 0.125-0.250 mg every 4-6
h as needed.
Long-Term Management Period
Long-term management of the short bowel syndrome can be accomplished suc-
cessfully in most patients by conscientious attention to the principles and practices
outlined above. However, in a few patients who have undergone massive small bowel
resection, total or supplemental parenteral nutrition must be provided in a continu-
ous or cyclic manner for extended periods of time, and sometimes for life.
The metabolic management and nutritional therapy of patients with the short
bowel syndrome must be tailored specifically to each patient, and the clinical re-
sponses following massive intestinal resection depend upon many and varied fac-
tors. Patients with the short bowel syndrome pass through several stages of nutritional
and metabolic support during their recovery, convalescence and rehabilitation. Most
of them can ultimately be maintained on a normal or near normal diet. However,
depending upon the adaptability of their remaining bowel, they may have to settle
for receiving parenteral nutritional requirements via a modified oral diet, an enteral
total or supplemental diet supplemented with intravenous fluid and/or electrolyte
replacement, a parenteral nutrition regimen supplemented with a variable oral or
enteral diet, or reliance entirely upon total parenteral nutrition.
Almost all patients with the short bowel syndrome eventually develop gallstones,
most usually requiring cholecystectomy within two years following massive intesti-
nal resection if their gallbladder had not been previously removed. Indeed, the high
propensity of patients who have undergone massive intestinal resection to develop
stones in their gallbladders, has stimulated some physicians to advocate cholecystec-
tomy prophylactically at the time of bowel resection.
49
However, gallstone forma-
tion in the common bile duct and elsewhere in the biliary tree is also increased in
these patients even after cholecytectomy. Therefore surveillance with periodic ab-
dominal ultrasonography may be useful in identifying and monitoring echogenic
changes in the gallbladder and biliary tree.
Finally, some otherwise stable patients occasionally develop recalcitrant diarrhea
secondary to colonization or bacterial overgrowth of the residual small bowel seg-
ment, requiring stool culture and bacterial antigen studies followed by parenteral
treatment with appropriate antibiotics.
Growth Hormone, Glutamine, and Hormone Modified Diet
A rather extensive study has been completed to determine if growth hormone or
nutrients, given alone or together, could enhance absorption from the small bowel
after massive intestinal resection, especially in patients who continued to experience
malabsorption and require long-term parenteral nutrition.
50
The effects of high car-
bohydrate, low-fat diet, the amino acid glutamine, and growth hormone, adminis-
tered alone or in combination, were studied in 47 adult patients with short bowel
syndrome who were dependent on TPN to some extent for an average of 6 years.
The average age of the patients was 46 years, and the average residual small bowel
length was 50 cm in those with all or a portion of colon remaining, and 102 cm in
271
17
those with no colon remaining. During the 28 days of therapy, recombinant growth
hormone was given by subcutaneous injection at a dose ranging from 0.03 to 0.14
mg/kg/day (average dose 0.11 mg/kg/day). Supplemental glutamine was provided
by both the parenteral and enteral routes. The parenteral glutamine dosage averaged
0.6 g/kg/day whereas a standard daily dose of 30 gm glutamine was administered
orally in six equal portions of 5 gm mixed with a hypotonic cold beverage. In addi-
tion to the growth hormone and glutamine, all patients underwent extensive diet
modification and nutritional education, the details of which have been reported
extensively elsewhere.
31
On completion of the four week protocol, growth hormone
was discontinued, and the patients were discharged home on oral glutamine, 30
gm/day, and the modified oral diet.
The initial balance studies indicated improvement in absorption of protein by
39% accompanied by a 33% decrease in stool output with the regimen. In evalua-
tion of the long-term results, averaging one year and extending as long as five years,
40% of the study remain off TPN, and an additional 40% have reduced their TPN
requirements, with no change in TPN requirements in the remaining 20%. These
changes had occurred in a subset of patients that had previously failed to adapt to
the provision of enteral nutrients, and this therapy may offer an alternative to
long-term dependence on TPN for some patients with severe short bowel syndrome.
Subsesquently, a more comprehensive clinical study of greater than 300 patients has
been reported by the same group of investigators.
52,53
Surgical Considerations
Total parenteral nutrition is the mainstay of early, and sometimes late manage-
ment of the short bowel syndrome.
52
Prior to the widespread use of TPN, patients
often survived the initial surgical insult of massive small bowel resection and its early
complications only to die ultimately of fluid, electrolyte and nutritional imbalances.
Today, however, patients can usually be managed successfully and often rehabili-
tated with the judicious use of TPN. In this regard the surgeon is required to insert,
maintain and supervise a temporary and permanent indwelling central venous cath-
eter or catheter port for administration of TPN solutions.
As stated previously, massive small bowel resection is associated with a prompt
and inordinate increase in the secretion of gastrin and gastric acid. The resulting
hypersecretion can readily cause or aggravate existing gastritis, ulceration, bleeding,
diarrhea, and fluid and electrolyte depletion. Because the hypersecretion is thought
to be hormonally mediated, truncal vagotomy and pyloroplasty have been performed
in humans with good results.
1
Now that effective H2 receptor blockers have been
developed for clinical use, the surgical treatment of hypersecretion is seldom indi-
cated or required. Currently, vagotomy or other acid-reducing operations should be
reserved for those short bowel syndrome patients who develop complicated peptic
ulceration problems resistant to conservative medical therapy.
In patients with the short bowel syndrome, parenteral nutrition should be given
for at least 6-12 months to assure that optimal bowel adaptation has occurred before
contemplating the use of any surgical procedures to increase absorption of nutri-
ents.
35
In most short bowel syndrome patients, sufficient bowel adaptation occurs
during the first year following massive intestinal resection that parenteral nutrition
can be discontinued and the contemplated surgical intervention can be avoided.
Attempts to ameliorate the untoward effects of the short bowel syndrome surgi-
cally by interposing isoperistaltic or antiperistaltic bowel segments, intestinal valves
272
17
or recirculating loops; pacing the intestinal electrically; growing new intestinal mu-
cosa; and transplanting small intestine have been of limited additional value to date.
57
Therefore, no operative procedure for adjunctive management of the short bowel
syndrome currently is sufficiently safe and effective to recommend its routine use.
19
Long-term parenteral nutrition remains the cornerstone of successful management
of short bowel syndrome, and its judicious use is recommended in appropriate
amounts and formulations for as long as needed not only to insure maximal gas-
trointestinal adaptation and nutritional rehabilitation of the patient, but to support
the optimal size and function of the body cell mass.
Selected References
1. Allard J, Jeejeebhoy K. Nutritional support and therapy in the short bowel syn-
drome. Gastroenterol Clin N Am 1989; 18:589-601.
2. Detiel M, Wong KH. Short bowel syndrome. In: Deitel M, ed. Nutrition in Clini-
cal Surgery. 2nd ed. Baltimore: Williams & Wilkins, 1985:255-275.
3. Dudrick SJ, Jackson D. The short bowel syndrome and total parenteral nutrition.
Heart Lung 1983; 12:195-201.
4. Goutrebel M, Saint-Aubert B, Astre C et al. Total parenteral nutrition needs in
different types of short bowel syndrome. Dig Dis Sci 1986; 31:713-723.
5. Weser B. Nutritional aspects of malabsorption. Short gut adaptation. Clin
Gastroenterol 1983; 12:443-461.
6. Tilsom MD. Pathophysiology and treatment of short bowel syndrome. Surg Clin
N Am 1980; 60:1273-1284.
7. Dudrick SJ, Englert DM. Management of the short bowel syndrome. In: Miller
TA, Dudrick SJ, eds. The Management of Difficult Surgical Problems. Austin:
The University of Texas Press, 1981:225-235.
8. Dudrick SJ, ODonnell JJ, Englert DM. Ambulatory home parenteral nutrition
for short bowel syndrome and other diseases. In: Deitel M, ed. Nutrition in Clini-
cal Surgery. 2nd ed. Baltimore: Williams & Wilkins, 1985:276-287.
9. Trier JS, Lipsky M. The short bowel syndrome. In: Sleidenger MH, Fordtran JS,
eds. Gastrointestinal Disease: Pathophysiology, Diagnosis, Management, 4th ed.
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10. Weser B, Fletcher JT, Urban E. Short bowel syndrome. Gastroenterology 1979;
77:572-579.
11. Wilmore DW, Dudrick SJ. Effects of nutrition on intestinal adaptation following
massive small bowel resection. Surg Forum 1969; 20:398-400.
12. Wilmore DW, Holtzapple PG, Dudrick SJ et al. Transport studies, morphological
and histological findings in intestinal epithelial cells following massive bowel re-
section. Surg Forum 1971; 22:361-363.
13. Conn HJ, Chavez CM, Fain WR. The short bowel syndrome. Ann Surg 1972;
175:803-814.
14. Dudrick SJ. A clinical review of nutritional support of the patients. Am J Clin
Nutr 1981; 34:1191-1198.
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1989; 2:317-319.
17. Wilmore DW, Johnson DJ. Metabolic effects of small bowel reversal in treatment
of short bowel syndrome. Arch Surg 1968; 97:784-791.
18. Wilmore DW, Dudrick SJ, Daly JM et al. The role of nutrition in the adaptation
of small intestine after massive resection. Surg Gynecol Obstet 1971; 132:673-680.
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20. Garcia VF, Templeton JM, Eichelberger MR et al. Colon interposition for the
short bowel syndrome. J Pediatr Surg 1981; 16:994-995.
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J Gastroenterol 1987; 22:97-105.
23. Borgstrom B, Dahlquist A, Lundh G et al. Studies of intestinal digestion and ab-
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25. Ricotta J, Zuidema FD, Gadacz RT et al. Construction of an ileocecal valve and its
role in massive resection of the small intestine. Surg Gynecol Obstet 1981;
152:310-314.
26. Wright HK, Tilson MD. Short gut syndrome: pathophysiology and treatment.
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27. Strause E, Gerson E, Yalow RS. Hypersecretion of gastrin associated with the short
bowel syndrome. Gastroenterology 1974; 66:175-180.
28. Philips SF, Giller J. The contribution of the colon to electrolyte and water conser-
vation in man. J Lab Clin Med 1973; 81:733-746.
29. Bond JH, Currier BE, Buchwald H et al. Colonic conservation of malabsorbed
carbohydrates. Gastroenterology 1980; 78:444-447.
30. Bond JH, Levitt MD. Fate of soluble carbohydrate in the colon of rats and hu-
mans. J Clin Invest 1976; 57:1158-1164.
31. Haverstad T. Studies of short-chain fatty acid absorption in man. Scand J
32. Pomare EW, Branch WJ, Cummings JH. Carbohydrate fermentation in the hu-
man colon and its relation to blood acetate concentration in venous blood. J Clin
Invest 1985; 75:1148-1154.
33. Capton JP, Gineston JL, Herve MA et al. Metronidazole in prevention of cholestasis
associated with total parenteral nutrition. Lancet 1983; 1:446-447.
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Kirby DF, Dudrick SJ, eds. Practical Handbook of Nutrition in Clinical Practice.
Boca Raton: CRC Press, 1994:215-225.
35. Barnett WO, Oliver RI, Elliot RL. Elimination of the lethal properties of gangre-
nous bowel segments. Ann Surg 1968; 167:912-919.
36. Bounous G, McArdle AH. Release of intestinal enzymes in acute mesenteric is-
chemia. J Surg Res 1968; 9:33-348.
37. Ratych RE, Smith GW. Anatomy and physiology of the liver. In: Zuidema GD,
ed. Shacklefords Surgery of the Alimentary Tract, 3rd ed. Philadelphia: WB
Saunders, 1991:273-286.
38. Sarr WG, Tito WA. Intestinal obstruction. In: Zuidema GD, ed. Shacklefords
Surgery of the Alimentary Tract, 3rd ed. Philadelphia: WB Saunders, 1991; 372-413.
39. Woolf GM, Miller C, Kurian R et al. Nutritional absorption in short bowel syn-
drome: Evaluation of fluid, calorie and divalent cation requirements. Dig Dis Sci
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40. Cortot A, Fleming CR, Malagelada JR. Improved nutrient absorption after
cimetidine in short bowel syndrome with gastric hypersecretion. N Eng J Med
1979; 300:79-80.
41. Ladefoged K, Christiansen K, Hegnhoj J et al. Effect of long-acting somatostatin
analog SMS 201-995 on jejunostomy effluents in patients with severe short bowel
syndrome. Gut 1989; 30:943-949.
42. Nightingale J, Walker E, Burnham W et al. Short bowel syndrome. Digestion
1990; (suppl 1):77-83.
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43. Levy E, Frileux P, Sandrucci S et al. Continuous enteral nutrition during the early
adaptive stage of the short bowel syndrome. Br J Surg 1988; 75:549-553.
44. Ovesen L, Chu R, Howard L. The influence of dietary fat on jejunostomy output
in patients with severe short bowel syndrome. Am J Clin Nutr 1983; 38:270-277.
45. Woolf GM, Miller C, Kurian R et al. Diet for patients with short bowel: High fat
or high carbohydrate? Gastroenterology 1983; 84:823-828.
46. McIntyre P. The short bowel. Br J Surg 1985; 72:893-899.
47. McIntyre P, Fitchew M, Lennard-Jones J. Patients with a high jejunostomy do not
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50. Byrne TA, Persinger RL, Young LS et al. A new treatment for patients with
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syndrome. Experience with 160 patients. Ann Surg 1995; 222:600-605.
CHAPTER 1
CHAPTER 18
Pharmacologic Aspects of Short
Bowel Syndrome
Patricia Pecora Fulco, Donald F. Kirby
Short bowel syndrome (SBS) results when surgical removal or physiologic dys-
function alters the ability of the gastrointestinal tract to perform its usual functions
of digestion and absorption. The sequellae of this dysfunction can cause maldigestion
and malabsorption that lead to dehydration and potentially lethal metabolic de-
rangements often culminating in malnutrition and possibly death. There is a wide
spectrum of this syndrome that depends on the location and length of either resected
or dysfunctional intestine.
1
Acute and chronic phases of this syndrome exist and
depend upon the length of time from the inciting insult and the amount of adapta-
tion that evolves. The latter is dependent upon the health and integrity of the re-
maining intestine. The availability of total parenteral nutrition (TPN) has improved
survival during the acute phases and may be necessary during the adaptation phase
or even required life long.
As seen in Table 18.1, SBS can result from surgical bypass, intrinsic disease, and/
or extensive surgical resection. It is usually defined as having less than 150 cm of
small intestine with estimates of the actual length of the small intestine varying from
365-600 cm (12-20 feet) due to the variations in musculature and method of mea-
surement.
2,3
Thus, severe SBS not only affects how fluids, electrolytes and nutrients
are ultimately absorbed, but also the ability to absorb and metabolize medications.
Many of the severely affected SBS patients are dependent on central venous access
catheters to receive fluids, electrolytes and nutrition. These patients pose a unique
challenge to the clinician who must also administer medications for acute or chronic
needs.
4
This chapter will briefly review the pathophysiology of SBS and long term
adaptation, issues regarding intravenous access, patient variation, pharmacologic
routes of administration and special pharmacologic considerations in the TPN de-
pendent population.
Physiologic Considerations
The normal GI tract has an amazing absorptive capacity where 7-9 liters of fluid
from oral intake and intrinsic production are reduced to an average of 100-200 cc of
formed stool that is excreted daily. The small intestinal mucosa has coiled folds
which have small projections (villi) into the lumen and each villus has multiple cells
(microvilli) lining it providing a multiplication effect of the small bowel surface
area. In man, the surface area of the small intestine has been estimated to be equiva-
lent to the area of a doubles tennis court.
5
During the transit from mouth to anus
nutrients are digested into sizes that can be accepted by the mucosal enterocyte for
276
18
either immediate absorption or further digestion by brush border enzymes followed
by absorption.
The eventual severity of SBS depends on a number of factors:
1. Extent and location of resection (>80% less favorable);
2. absorptive capacity of the remaining small intestine;
3. presence or absence of the ileocecal valve;
4. function capacity of colon, if present; and,
5. time from onset of the syndrome.
6
Adaptation can take as long as 1-2 years to reach its maximal potential.
Site Specific Contributions
It is beyond the scope of this chapter to detail all the intricacies of intestinal
absorption, but it is important to understand some of the specialized functions of
the different regions of the GI tract. Figure 18.1 illustrates the areas of the GI tract
with some of their regular and specialized functions. The bowel not only absorbs
fluid and nutrients, but also secretes and excretes certain substances. The colon is
particularly efficient in absorbing sodium chloride and water while exchanging these
for potassium and bicarbonate to be excreted.
The stomach is not necessary for life except for its function in producing intrin-
sic factor. Without intrinsic factor vitamin B
12
should be provided parenterally, es-
pecially if ileal absorption sites are diseased or have been resected. The stomach also
functions in the slow release of food stuffs, which helps to maximize their mixing
with bile and pancreatic juice as digestion progresses. A substantial amount of diges-
tion occurs in the duodenum due to the high concentration gradient of enzymes
and bile present so that absorption ensues in the distal duodenum, jejunum, and
ileum. The duodenum is also highly efficient in absorbing iron and some of the
divalent cations such as calcium, magnesium and zinc. The ability to absorb these
cations does not appear to be dangerously reduced in severe SBS, but zinc may be
the most difficult to maintain at normal levels.
7,8
Isolated resection of the jejunum is well tolerated when the remainder of the
bowel is healthy. All absorptive functions can be performed by the ileum.
9
Since the
Table 18.1. Short bowel syndrome etiologies
Crohns disease
with or without surgery
Radiation therapy injury
with or without surgery
Surgery related
Bypass
Carcinomas
Congenital anomalies
Error
Obesity procedures
Strangulated hernias
Trauma
Vascular infarctions
Embolism or thrombosis
Volvulus
277
Pharmacologic Aspects of Short Bowel Syndrome
18
intrinsic motility is faster in the ileum, adaptation to jejunal resection includes fur-
ther slowing of ileal transit.
The ileum has specialized functions of absorbing vitamin B
12
and bile acids.
Diarrhea and/or steatorrhea can occur if there is not at least 100 cm of ileum, which
appears crucial for complete absorption of bile salts.
10
Altered fat absorption can also
negatively affect the absorption of fat soluble vitamins, as well as any medications
that depend on lipid transport systems.
The ileocecal valve provides a pressure gradient from the terminal ileum to the
large intestine. It is a specialized muscle that is responsive to -adrenergic agonists
and according to many sources its absence increases the severity of SBS.
11,12
The
valve is believed to be important in increasing transit time and in preventing bacte-
rial reflux, which can lead to bacterial overgrowth and reduced intestinal absorption.
11,13
The colon can have special importance in the overall fluid and electrolyte man-
agement of patients with SBS. It is highly efficient in absorbing water and sodium
Fig. 18.1. Specialized functions of the GI tract.
278
18
and excreting potassium and bicarbonate.
14
The colon can also absorb oxalate, which
can be important in the genesis of kidney stones.
6
In patients with extreme short
bowel, the presence of an ostomy may increase patient comfort and allow better
quantification of effluent losses.
Adaptation
The bodys adaptation to the insult of short bowel syndrome is quite crucial in
the patients eventual quality of life, but can take as long as two years to reach its
maximum potential. In the initial phase of SBS, survival is dependent on maintain-
ing fluid and electrolyte balance. This is immediately followed by providing nutri-
tion, usually parenterally, but also enterally, as soon as feasible. If there is residual
intestinal disease from the underlying etiology of the SBS, then this may hinder the
adaptation process. In this process there is dilatation and lengthening of the remain-
ing small bowel.
15
Adaptation is further characterized by hormonal changes, cellular
hyperplasia, villous hypertrophy, altered motility and intestinal lengthening, all of
which result in improved lumenal absorptive capacity.
16
It is important to provide
lumenal nutrients as soon as possible since villous atrophy can occur with TPN
alone, but in humans this is reversed by oral feeding.
17
All of the above adaptation
responses can have ramifications with regard to medication absorption, and absorp-
tion of some oral medications may improve with time.
Based on recent work by Gruy-Kapral and colleagues, it is now common to give
SBS patients conjugated bile acids to help improve fat absorption.
18
Calcium ab-
sorption was also increased without a significant increase in stool output.
The effects of glutamine and growth hormone are awaiting further trials. How-
ever, their use does seem to result in some modest improvements in electrolyte ab-
sorption, but no change in small bowel morphology, macronutrient absorption or
stool losses.
19
Intravenous Access in SBS Patients
While this chapter is not exclusively written for the SBS patient who is depen-
dent upon intravenous nutrition support, the principles will better apply to this
population since less severely affected SBS patients may absorb oral medications
better if they can maintain themselves without TPN. For the patient who is depen-
dent upon TPN for sufficient fluid, electrolytes and nutrients for survival, the cen-
tral venous catheter is a lifeline. Many variations are now available for use in the
hospitalized or home patient. A major decision will be whether the patient requires
a single lumen or multilumen catheter. For short-term use in the hospitalized pa-
tient, multilumen catheters may be vital when multiple medications are required.
However, these catheters are often subject to higher catheter-related sepsis rates.
20-22
Part of the reason for this is that these catheters are entered many times for various
medications and perhaps under less than sterile technique, but it has recently been
shown that bacterial translocation can be important in the genesis of catheter-re-
lated sepsis in the SBS population.
23
It is best to use as few lumens as possible and to
adhere to strict technique when using these catheters.
In home TPN patients it has been demonstrated that implantable devices are
not safer than standard tunneled catheters.
24
Tunneled

catheters

such as Hickman
and Groshong
catheters (Bard Access Systems, Inc., Salt Lake City, Utah) are the
most common in home patients, but a percutaneously placed subclavian catheter
(Hohn
catheter, Bard Access Systems, Inc., Salt Lake City, Utah) has been found
useful for short term patients requiring less than six weeks of parenteral therapy.
279
18
The use of heparin placed in the TPN solution or oral administration of low
dose warfarin can help decrease the incidence of venous thrombosis.
25-27
This be-
comes increasingly important as thrombosis usually means that the site will not be
usable again for intravenous access, and there are a limited number of large vessels
that can be used for this type of hyperosmolar infusion.
21
Patient Variation
Drug Absorption
The oral absorption of medications is affected by several factors, including whether
or not the gastrointestinal (GI) tract is intact or has been resected. The extent of
drug absorption is determined by the physiological capabilities of the remaining GI
tract, formulation, physicochemical properties, pharmacodynamics and pharmaco-
kinetics of the drug. Changes in any of these parameters will markedly determine
the amount of drug available to produce its pharmacodynamic effect. The overall
impact of changes in absorption will be the extent to which therapeutic effi-
cacy is achieved.
An increase in the variability of absorption is observed when a portion or all of
the GI tract is removed. A decrease in intestinal length will result in a decrease in
absorptive surface area. If all other factors affecting drug absorption were to remain
constant, the extent of absorption would be limited to the length of residual bowel.
However, not all factors affecting drug absorption remain constant when intestinal
resection occurs. Physiological changes in the mucosal integrity and intestinal mo-
tility occur, resulting in an increase or decrease in absorption, depending on how the
GI tract adapts to this anatomical change. Thus, GI physiology is directly affected
by GI anatomy, but the effects on drug absorption may not be the same.
The extent of a drugs absorption as determined by its formulation, physico-
chemical properties and pharmacokinetics, is evaluated with the assumption that
GI anatomy and physiology are normal. Resection of the GI tract will alter any or all
of these parameters, resulting in a single or multifactorial effect on absorption. Drugs
are formulated in a variety of ways to be released in various areas of the GI tract to
take advantage of the physicochemical requirements to enhance absorption. Such
modes of release include tablets, capsules, suspensions, elixirs, enteric coated tablets,
film coated tablets and sustained release tablets and capsules. However, a sustained-
release capsule that is designed to release medication throughout the entire small
intestine may not be therapeutically useful if there is not enough small bowel surface
area for absorption to effectively take place.
The physicochemical requirements that enhance a drugs absorption may in-
clude, but are not limited to,
1. solubility;
2. an acidic or alkaline environment;
3. the presence of bile acids;
4. the presence of an ileum; or,
5. the presence of site-specific receptors.
Removal of the section of bowel responsible for meeting these requirements could
result in minimal drug absorption. Physicochemical properties that enhance the
absorption of certain drugs are listed in Table 18.2.
Pharmacokinetic parameters that influence drug absorption include the site, ex-
tent, and rate of absorption. At the site of absorption, drugs bind to or localize in the
280
18
tissues. Depending on the physicochemical requirements of the drug, biotransfor-
mation may take place to allow for absorption. The molecule may become ionized
or an enzymatic process may take place to affect absorption. Circulation to the
absorption site will determine the extent and rate of absorption into the blood-
stream. Once absorbed, the drug will distribute to various body compartments. It
may or may not be metabolized before being eliminated.
Administration of some drugs via a jejunal tube, for example, markedly affects
their absorption, distribution, metabolism and elimination. Normally a drug dis-
solves in the stomach and is absorbed in the duodenum. Intrajejunal administration
of propranolol oral solution, for example, results in significantly higher serum con-
centrations of the drug.
28
The absorption of propranolol occurs in the duodenum
and then passes directly through the blood stream to the liver. A significant first-pass
metabolism occurs and markedly reduces the serum concentrations. With intrajejunal
administration the portal system (and first-pass metabolism) is bypassed, the drug is
absorbed, and higher serum concentrations result. This example demonstrates the
importance of the site, extent and rate of absorption on the pharmacokinetics
of propranolol.
Two other clinically significant factors that influence drug absorption are food
and other drugs.
29
The presence of food in the GI tract may increase or decrease the
extent and/or rate of absorption. A dose of theophylline oral syrup, for example,
may be completely absorbed, but the rate of absorption is slower, resulting in de-
creased peak serum concentrations. A dose of levofloxacin, administered with a dose
of a calcium-containing antacid, will be poorly absorbed (i.e., decreased extent of
absorption) because of calcium chelation with the drug.
30
A second type of drug-drug interaction that affects the relative absorption of
drugs involves the effects one drug may have on metabolism or elimination of an-
other. Once the drug is absorbed, metabolism may be increased or decreased result-
ing in serum concentrations that are lower or higher, respectively, than expected.
Phenobarbital, for example, may induce the metabolism of phenytoin, decreasing
serum concentrations of the latter. Cimetidine, for example, may inhibit the me-
tabolism of theophylline, thereby increasing the theophyllines serum concentration.
Table 18.2. Select drugs and the physicochemical properties that enhance
their absorption
Physicochemical Property Select Drugs
Acidic environment Ketoconazole
penicillin
Alkaline environment nitrofurantoin
procainamide
Bile acids cyclosporine
ergocalciferol
Drug-drug interactions ferrous sulfate
levofloxacin
Food-drug interactions penicillin
sucralfate
Ileal absorption cyanocobalamin
Receptor site dynamics diazepam
propranolol
281
18
When the small bowel is resected, the most significant impact on absorption
occurs because of the reduction or removal of the site of absorption. Consequently
the extent of absorption will change; the rate of absorption may be affected if the
necessary enzymatic transformation does not occur. The extent of this effect will be
directly proportional to the amount of bowel removed. Unfortunately, for the pa-
tient with SBS, drug absorption is almost always reduced, requiring the use of alter-
nate therapy or higher oral doses. Furthermore, the food-drug and drug-drug
interactions described above must be accounted for when administering medica-
tions to SBS patients via the oral route. Alternative routes may have to be considered.
Limited research has been conducted to quantify the pharmacokinetic effects of
bowel resection on drug absorption. The administration of oral doses of nortrip-
tyline, amitriptyline, procainamide, warfarin, digoxin, cyclosporine and tacrolimus
to patients with SBS has been reported.
31-43
In these case reports, various lengths and
segments of bowel had been resected. Serum concentrations were obtained to modify
dosing necessary to achieve a therapeutic concentration, as in the case of digoxin, or
desired therapeutic effect, as in the case of warfarin. The process of using serum
concentration determinations to manage therapy is the most useful information
presented. The information in these case reports is not generalizable due to their
limited utility.
Broyles et al discussed oral administration of nortriptyline to one SBS patient
with 5-6 feet of small intestine and 40-50 cm of colon remaining.
31
Normal serum
concentrations (50-140 ng/ml) were achieved with a nortriptyline dose of 25 mg
every morning and 50 mg every night. Approximately two months after initiating
therapy, the serum concentration was 90 ng/ml.
Robbins and Reiss administered amitriptyline buccally to a SBS patient with
approximately 18 inches of small bowel remaining.
32
Dosage titration to 75 mg of
amitriptyline lead to a therapeutic combined amitriptyline and nortriptyline con-
centration (100-250 ng/ml) for 12 consecutive months. Subjective improvement in
the patients depressive symptoms were also noted. In these two reports, following
serum nortriptyline or combined amitriptyline/nortriptyline concentrations
was an effective way to determine the extent of drug absorption and subse-
quent clinical response.
Felser and Hui evaluated oral administration of procainamide to one SBS pa-
tient with 6 cm of jejunum and 20 cm of terminal ileum remaining.
33
Serum trough
concentrations greater than 4 g/ml were achieved after 24 hours with a dose of 500
mg every four hours (therapeutic range of 4-12 g/ml) and suppression of the patients
ventricular arrhythmia was observed when in this range. Careful monitoring of se-
rum procainamide concentrations was instrumental in determining the extent of
absorption in this patient.
Four separate case reports describe experience with oral warfarin administration
to patients with SBS.
34,35,37,39
Mitchell et al describe the oral administration of war-
farin to one SBS patient with 100 cm of small bowel remaining.
39
The normal length
of the small intestine was approximated at 350-600 cm. Warfarin therapy was initi-
ated at 10 mg per day and adjusted to maintain therapeutic prothrombin time (PT)
values. Serum warfarin concentrations were not obtained. Absorption was assumed
based on the PT values observed, but was not quantified.
Lehman et al described oral administration of warfarin to one SBS patient with
12-15 cm of jejunum remaining.
34
After administering a loading dose of 20 mg, the
warfarin dose was titrated downward to maintain a PT between 1.5-2.0 times control.
282
18
By day 59 of therapy, a PT of 1.6 times control was maintained using a dose of 2.5
mg per day. Jejunostomy drainage collections were made after a 10 mg and 2.5 mg
dosage, at different times during therapy, to determine the amount of warfarin ab-
sorbed. The estimated percent of absorption was 92.8 and 96.1, respectively. This
compares to values obtained in healthy volunteers, having percentage absorption
greater than 90%. This is to be expected, since warfarin is nonpolar at pH 5.1 or less
and would be expected to be almost completely absorbed in the duodenum. In this
case, warfarin concentrations in the jejunostomy drainage, instead of serum concen-
trations, were used to determine absorption.
Kearns and OReilly described oral administration of warfarin to a SBS patient
with 30 cm of jejunum remaining.
37
After five weeks of therapy, a daily dose of 5 mg
was necessary to maintain a desired PT between 16-20 seconds. Serum and fecal
concentrations were obtained during the fasting and fed states to determine the
extent of absorption. The serum values observed were comparable or better than
those observed in normal patients. Neither warfarin nor its metabolites were re-
trieved from the stool samples. Hence, serum concentrations proved useful in quan-
tifying drug absorption.
Brophy et al described a warfarin-resistant SBS patient who needed anticoagula-
tion for recurring deep venous thrombosis.
35
The patient had a total duodenectomy,
gastrojejunostomy (unknown length of jejunem) with a completely retained ileum.
Anticoagulation was initiated with warfarin 5 mg daily and titrated to a dosage of
20 mg daily over a period of 14 days. No change in the International Normalized
Ratio was demonstrated with a peak value of 1.2. Warfarin serum concentrations
were not evaluated. This report emphasizes the pharmacokinetic properties of war-
farin. Warfarin is absorbed primarily within the proximal small bowel, specifically
the duodenum. All of the previous cases included patients with intact duodenum
with ultimately successful anticoagulation. These reports demonstrate that SBS pa-
tients may be successfully anticoagulated if the proximal small bowel, including the
duodenum, is retained.
Oral administration of digoxin has been reported in three separate patients with
SBS.
36,38,40
Beerman et al described a patient from which the distal jejunum and
ileum, approximately 4 meters, and ascending colon had been removed.
40
Radiola-
beled digoxin, 0.25 mg, was administered, followed by GI aspiration after three
hours. Aspirates were assayed to determine the absorption of radioactivity. Seventy-
two percent of the drug was retrieved from the duodenum, suggesting only 28%
absorption. Since only a single dose of digoxin was administered, the results of this
report are of limited clinical utility.
Krausz et al described a patient with the duodenum and only 15 cm of jejunum
remaining.
38
After a two day digitalization period, 0.25 mg daily was administered
as indicated. Serum digoxin concentrations were maintained within the therapeutic
range of 0.8-2.2 ng/ml. Renal clearance of the drug was normal. Therapeutic effi-
cacy, as evidenced by a decrease in heart rate, was achieved with no reported side
effects. Therapeutic serum concentrations suggest that the extent of absorp-
tion was adequate.
Vetticaden et al described a patient with the duodenum and 12-15 cm of je-
junum remaining.
36
Digoxin elixir, 0.5 mg, was administered for nine days, after
steady-state was achieved using 0.25 mg of digoxin intravenously. Serum and jejun-
ostomy drainage concentrations were assayed. The trough serum concentration was
0.77 ng/ml and the cumulative amount of digoxin in the drainage, after 24 hours,
283
18
was 0.302 mg. This suggests that approximately 60% of the 0.5 mg dose was ab-
sorbed. Since the trough serum concentration was less than the therapeutic concen-
tration of 0.8 ng/ml, a higher dose of digoxin may be necessary to achieve a therapeutic
serum concentration.
The oral administration of cyclosporine and tacrolimus in SBS patients has been
reported.
41-43
Roberts et al described two patients in whom therapeutic serum con-
centrations of cyclosporine could not be achieved when administered orally.
41
How-
ever, desired concentrations were achieved with intravenous therapy. Whittington
et al found a relationship between the length of the small intestine and the oral dose
of cyclosporine necessary to achieve therapeutic serum concentrations in children
after liver transplant.
42
Patients received both intravenous and oral cyclosporine to
maintain a therapeutic serum concentration. As the intravenous dose was decreased,
the oral dose was increased. Large doses of oral cyclosporine were required to achieve
therapeutic concentrations; these doses were inversely proportional to the length of
the small bowel. That is, the shorter the small bowel, the larger the dose required to
achieve serum concentrations in the therapeutic range.
Thielke et al described the pharmacokinetic evaluation of cyclosporine,
microemulsion cyclosporine and tacrolimus in a SBS patient with approximately
two feet of small intestine.
43
Single doses of 250 mg cyclosporine, 250 mg
microemulsion cyclosporine and 5 mg tacrolimus were administered on separate
occasions. The results demonstrated undectable blood concentrations with conven-
tional cyclosporine. Both microemulsion cyclosporine and tacrolimus pharmacoki-
netic parameters were slightly reduced compared to normal reference values. The
results suggested that increased doses of the microemulsion cyclosporine formula-
tion or tacrolimus may be successfully orally administered with blood concen-
tration evaluation.
Quantifying Drug Absorption
The cases described above substantiate the usefulness of determining drug con-
centrations, in serum and other body fluids, to evaluate the extent of absorption in
the SBS patient. For many medications, a therapeutic range for serum concentra-
tions has been established; however, the efficacy of other medications may be inde-
pendent of the serum concentration. Regardless of the establishment of a therapeutic
range, the ability to quantitatively and qualitatively measure drug concentrations in
various body fluids may be of tremendous help to the clinicians managing the SBS
patient. Quantitative measurements reflect the approximate amount of drug in the
sample. Qualitative measurements reflect the presence of a drug only in the sample.
Most hospital toxicology laboratories are capable of determining concentrations
of aspirin, acetaminophen, tricyclic antidepressants, anticonvulsants, cyclosporine,
tacrolimus, digoxin, warfarin, barbiturates, methylxanthines, benzodiazepines, opi-
ate agonists, and class 1a antiarrhythmics (e.g., procainamide, quinidine). Body fluid
concentrations of other drugs may be measured, both qualitatively and quantita-
tively, at other laboratories. Table 18.3 offers a representative, but not exhaustive,
list of drugs other than the common ones listed above, that may be measured.
Routes of Administration
Medications may be administered by several routes and categorized as either
enteral, parenteral or topical, as shown in Table 18.4. Enteral drug delivery includes
oral, buccal, sublingual, gastric tube, jejunal tube and rectal routes of administration.
284
18
Table 18.3. Qualitative and quantitative assessment of drug absorption
Drug Qualitative Quantitative
acyclovir X
allopurinol X
atenolol X
bethanechol X
brompheniramine X X
captopril X
carbidopa X
chlorthiazide X
chlorpheniramine X X
cimetidine X X
clonidine X
colchicine X
dapsone X
diclofenac X
diflunisal X
diltiazem X X
dipyridamole X
enalapril X
ergotamine X
famotidine X
fenoprofen X
fluphenazine X
glipizide X
glyburide X
haloperidol X X
hydralazine X
hydrochlorothiazide X
hydroxychloroquine X
ibuprofen X X
indomethacin X
ketoprofen X
labetalol X
levadopa X
lisinopril X
lithium X
loperamide X
meclizine X
meclofenamic acid X
mercaptopurine X
methocarbamol X
methyldopa X
metoclopramide X
metolazone X
metoprolol X X
metronidazole X
naltrexone X
naproxen X
nifedipine X X
oxybutynin X
pentazocine X X
285
18
In the SBS patient, buccal, sublingual, and rectal administration may be suitable
routes since the small intestine has been resected. Enteral drug delivery is the least
expensive, and should be utilized whenever possible, even if higher doses of medica-
tion need to be administered to obtain the desired effect. However, many oral dos-
age forms have neither been formulated nor administered sublingually, buccally, or
rectally. Consequently, other methods of drug delivery must be utilized.
Parenteral drug delivery includes subcutaneous, intra-arterial, intramuscular,
intrathecal, intraperitoneal, intravenous, and intraventricular routes of administra-
tion. Of the parenteral routes, subcutaneous (SC), intramuscular (IM), and intrave-
nous (IV) administration of medications to SBS patients are the most common.
Prolonged release of drug from the administration site e.g., depot formulations may
decrease the frequency of dosing a drug when it is administered IM or SC. In fact,
some medications may be given IM as infrequently as every 28 days. IV delivery of
medications may either be continuous or intermittent. Continuous infusions are
usually used for medications requiring a constant serum concentration and having a
very short half-life. Intermittent infusions are usually used for medications requir-
ing peak and trough serum concentrations, such as antibiotics.
Table 18.3. Qualitative and quantitative assessment of drug absorption
(continued)
Drug Qualitative Quantitative
pentoxyfylline X
perphenazine X X
phenylbutazone X
phenylpropanolamine X X
piroxicam X
probenecid X
propoxyphene X X
propranolol X X
propylthiouracil X
pseudoephedrine X
ranitidine X
rifampin X
sulfamethoxazole X
terbutaline X
terfenadine X
thioridazine X X
thiothixene X X
tolbutamide X X
tolmetin X
trifluoperazine X X
trihexyphenidyl X
trimethoprim X
triprolidine X
verapamil X X
The above list was compiled from the following sources: 1) 1991 Professional
Service Manual. American Medical Laboratories, Inc., Fairfax, Virginia; 2) January
1990 Professional Manual. National Medical Services, Willow Grove,
Pennsylvania.
286
18
Topical drug delivery includes respiratory, nasal, ophthalmic, otic, implantable,
mucous membrane and skin routes of administration. Drugs administered to the
mucous membranes that do not include the buccal, sublingual and rectal routes
may be in the form of vaginal suppositories, creams, ointments and aerosols. Drugs
administered to the skin may be in the form of ointments, creams, gels, pastes,
powders, or transdermal patches. In many cases, topical drug delivery is intended
for its topical effect; however, systemic absorption of medications via the topical
route is necessary in some cases.
Buccal and Sublingual Administration
Buccal administration of a medication refers to placement of a solid oral dosage
form (e.g., tablet) into the cheek, where it dissolves and is absorbed. Sublingual
administration refers to placement under the tongue. Absorption from the buccal
and sublingual sites is enhanced when the mucosal pH and lipid solubility increase
until the pH is 2 units above the pKa of the drug, then absorption tapers off.
44
The
advantages of these sites of administration for SBS patients include the following:
1. high systemic and lymphatic vascularity allows for rapid absorption and
onset of effect;
2. therapy may be interrupted abruptly if necessary;
Table 18.4. Common methods of drug delivery
Enteral
Oral
Buccal
Sublingual
Rectal
Parenteral
Subcutaneous
Intra-arterial
Intramuscular
Intrathecal
Intraperitoneal
Intravenous
Intermittent vs. continuous
Intraventricular
Pulmonary
Aerosol
Dry-powder
Topical
Eye
Implantable
Mucous membrane
Skin
Ointment
Transdermal
Cream
Reprinted with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN
1993; 17:180-186.
287
18
3. direct delivery to the systemic circulation occurs, bypassing first-pass he-
patic and intestinal metabolism;
4. the tablet may be retained for an extended period of time to provide a
sustained effect; and,
5. intestinal absorption is not necessary to achieve the desired therapeutic
effect.
44
Buccal and sublingual administration may be limited when
1. the tablet is accidentally chewed or swallowed;
2. the dosage form dissolves too quickly; and,
3. the taste of the tablet is not pleasing to the patient.
Medications that may be administered by the buccal and sublingual routes are
listed in Table 18.5.
44-82
Rectal Administration
Rectal administration refers to the placement of a dosage form, whether liquid
or solid, into the rectum. Rectal suppositories and enemas have been specifically
formulated for such administration. Some of these formulations are commercially
available; others have to be compounded extemporaneously. When a suppository
cannot be prepared, some liquids which have been formulated for oral and intrave-
nous use may be given rectally. Drug absorption from the rectum is determined by
the drug form administered, the surface area of the rectum, the pH of the rectum,
the pK
a
of the drug, and the extent of first-pass metabolism that may occur. It may
be enhanced when the drug is in solution and is highly lipophilic.
The advantages of rectal administration are recognized when a patient is acutely
ill and neither oral nor intravenous administration is desirable. In the chronically ill
patient, such as the SBS patient, rectal administration may preclude the less desir-
able intramuscular or intravenous route. Rectal administration may also lead to en-
hanced bioavailability as a result of decreased first pass metabolism.
46,83
For example,
metoprolol, an agent with extensive first pass metabolism, has demonstrated in-
creased serum concentrations when administered rectally as compared to oral ad-
ministration.
83
The disadvantages of the rectal route include the following:
1. an unpredictable extent of absorption;
2. an unpredictable onset of action;
3. difficulty in achieving therapeutic serum concentrations; and,
4. difficulty maintaining the medication in the rectal cavity until it is ab-
sorbed.
Medications that have been administered rectally include antiemetics, antide-
pressants, anticonvulsants, antihypertensives, antipyretics, anti-inflammatories, seda-
tive/hypnotics and laxatives. Table 18.6 lists specific medications; some are not
commercially available, but may be compounded by a pharmacist.
45,83-129
Subcutaneous Administration
Subcutaneous (SC) administration is the direct parenteral injection of a medica-
tion into the top half-inch of skin. The extent and rate of drug absorption will be
determined by the site of injection and the extent of vascular circulation to the area.
In most cases, the medication will be absorbed more slowly than in intravenous (IV)
administration, but not as slowly as the intramuscular (IM) route. The advantages
of SC administration are recognized when the oral or IV routes are neither available
nor desirable and when a prolonged duration of effect may be desired. The
288
18
disadvantages of SC administration include pain on injection, unpredictable peak
serum concentrations and tissue hypertrophy that may occur after multiple injec-
tions. Table 18.7 lists medications that may be administered using the SC route.
130-133
Intramuscular Administration
Several medications prepared for IV use may be given by the IM route; however,
some may be administered as depot injections. Depot injections are administered
deep into a muscle, primarily the deltoid, gluteals or the thigh. These drugs are
formulated to allow a dose of medication to be released slowly over an extended
period of timeas long as a month in some cases. Absorption, therefore, is slow and
continuous giving a steady concentration of drug in the serum. The advantages of
such administration include decreased frequency of injections, fewer dermal com-
plications, an alternate route when the oral and intravenous routes are not desirable
and a prolonged duration of effect. The disadvantages of IM depot injection include
pain on injection and difficulty reversing the drugs therapeutic or adverse effects
once administered. Table 18.8 lists medications that may be administered by IM
depot injection.
134-135
Continuous Infusion
Intravenous, or direct, administration of medications into the systemic circula-
tion allows for complete drug absorption. When no other alternatives are available,
some medications may have to be administered by continuous infusion to the SBS
patient. When a continuous effect is desired and a medication has a short elimina-
tion half-life, a constant IV infusion may be required. The advantages of continuous
infusion include continuous effect and use when the oral route is not desirable. The
disadvantages of continuous infusions include the requirement for continuous in-
travenous access, interrupted therapeutic effect when the infusion is disrupted, an
increased risk for thrombophlebitis and extravasation at the site of infusion and
higher costs. The medications most commonly infused include opiate analgesics,
heparin, immunosuppressants, insulin and H
2
-antagonists. Table 18.9 lists medica-
tions administered by continuous infusion.
136
Some of these medications may be
admixed with TPN and administered simultaneously.
Table 18.5. Drugs that can be used by buccal and sublingual routes*
Buccal Sublingual
amitriptyline alprazolam methyltestosterone
amphetamine buprenorphine midazolam
fentanyl captopril morphine
methylamphetamine desmopressin nifedipine
methyltestosterone ergoloid mesylates nitroglycerin
midazolam ergotamine mesylate prazepam
morphine fentanyl propranolol
nicotine hyoscyamine sulfate sotalol
nitroglycerin isosorbide dinitrate triazolam
pemoline lorazepam
prochlorperazine
testosterone
*References 44-82
289
18
Oral and Nasal Inhalation
Medications may be inhaled by either the oral or nasal route and be adminis-
tered by using a nebulizer or inhaler. The process of nebulization involves the dis-
persion of liquid medication via oxygen or compressed air into a mask from which
the patient breathes orally and/or nasally. Inhalers are provided for either nasal or
oral use. The nasal, and some oral, inhalers deliver medication that is dispersed via a
propellant. Other oral inhalers involve the use of dispersing powdered drug from a
capsule that is placed inside an activating device or dry powder that is released from
a breath-actuated inhaler. In every case, the topical effect of the medication brings
about a therapeutic systemic effect. In some cases, the amount of drug absorbed
systemically is significant enough to cause side effects, but they are not nearly as
significant as those resulting from oral or systemic administration.
The advantages of administering medications by inhalation include minimal
systemic effect and they do not require a functioning GI tract. The disadvantages
Table 18.6. Drugs that can be used by rectal administration*
acetaminophen methadone
allopurinol methohexital
aminophylline metoclopramide
amitriptyline metoprolol
aspirin metronidazole
atropine midazolam
bisacodyl mineral oil
bumetanide morphine
carbamazepine N-acetylcysteine
chloral hydrate nalbuphine
chlorpromazine naproxen
cimetidine nifedipine
clonazepam omeprazole
clonidine ondansetron
codeine oxybutynin
dextroamphetamine paraldehyde
diazepam pentobarbital
diclofenac phenobarbital
digoxin piroxicam
dimenhydrinate prochlorperazine
docusate progesterone
doxepin promethazine
ergotamine propranolol
fluoxetine propylthiouracil
glycerin sodium phosphate
hydrocortisone sodium polystyrene
ibuprofen sorbitol
indomethacin sulfasalazine
insulin sumatriptan
isoproterenol temazepam
ketoprofen thiopental
lactulose trimethobenzamide
levodopa/carbidopa valproic acid
*References 45,83-129
290
18
are usually limited to the patients ability to properly administer the doses and the
irritation to the throat/nares that may occur with the oral/nasal inhalers. Table 18.10
lists medications that may be administered by nasal and/or oral inhalation.
137-156
Topical Administration
Topical routes include ointments, transdermal systems, implantable devices, and
creams that can be used on the skin and some are used vaginally. Table 18.11 sum-
marizes the topical medications available.
157-181
Transdermal drug administration refers to the delivery of medication from a
drug reservoir through the skin and into the systemic circulation. The degree of
Table 18.7. Drugs that can be used by subcutaneous injection*
bethanecol heparin
buprenorphine insulin
corticotropin insulin aspart
dalteparin insulin glargine
danaparoid insulin lispro
deferoxamine interferon
desmopressin isoproterenol
dihydroergotamine morphine
enoxaparin naloxone
ephedrine prochlorperazine
epinephrine pyridostigmine
erythropoietin somatostatin
ethacrynic acid terbutaline
G-CSF thyrotropin
GM-CSF tinzaparin
glucagon triamcinolone
vitamin K
*References 130-133
Table 18.8. Drugs that can be used by intramuscular depot injection*
aurothioglucose
benzathine penicillin
bromocriptine
estradiol
estradiol + testosterone
fluphenazine decanoate
haloperidol decanoate
methylprednisolone
medroxyprogesterone
octreotide
testosterone
*References 134-135
291
18
Table 18.9. Drugs that can be used by continuous intravenous infusions
cimetidine
famotidine*
fentanyl
heparin
hydromorphone
insulin
meperidine
morphine
octreotide
ranitidine
tacrolimus
*In vitro compatibility data only.
136
Table 18.10. Drugs that can be used by nasal and oral inhalation*
albuterol lidocaine
amikacin metaproterenol
amphotericin liposomal methylprednisolone
atropine midazolam
azelastine mometasone
beclomethasone naphazoline
budesonide nedocromil
butorphanol nicotine
colistin nitroglycerin
cromolyn sodium oxymetazoline
deferoxamine oxytocin
desmopressin acetate pentamidine
dexamethasone propylhexedrine
ephedrine phenylephrine
epinephrine propranolol
ergotamine salmeterol
fentanyl sufentanil
flunisolide sumatriptan
fluticasone terbutaline
gentamicin tetrahydrozoline
glycopyrrolate tobramycin
ipratropium triamcinolone
isoetharine vasopressin
isoproterenol zanamivir
levalbuterol
*References 137-156. Adapted and updated with permission from McFadden MA,
DeLegge MH, Kirby DF. JPEN 1993; 17:180-186.
292
18
drug absorption is comparable to that of a continuous infusion without the use of
an IV catheter. The advantages of transdermal drug delivery include the following:
1. provides a steady serum concentration of drug;
2. does not require GI tract for absorption;
3. it has less variability in absorption when compared to GI absorption;
4. therapy may be discontinued abruptly if necessary;
5. dosing may be as infrequent as once weekly; and,
6. patient adherence may be better.
181
The disadvantages of these systems are primarily related to the limited number
of medications which may be administered transdermally.
Special Considerations
Home Antibiotics
Patients with SBS may require central venous access to provide adequate nutri-
tion and to administer intravenous medications. In-dwelling catheters pose a sig-
nificant risk of infection. This, coupled with the potential for other infections, may
necessitate the use of intravenous antimicrobials. In an effort to minimize cost, pa-
tients may be managed at home with IV antimicrobial therapy. Common catheter-
related infections result from Staphylococcus aureus (S. aureus ) and Candida species
(C. species) including C. albicans and Torulopsis glabrata (T. glabrata). Other infec-
tions caused by Gram-negative organisms may need to be managed as well. In many
cases, S. aureus is resistant to methicillin, requiring the use of vancomycin. Oxacillin
or nafcillin may be used if the organism is sensitive. Amphotericin B is the drug of
choice for sepsis caused by C. species. Fluconazole is an acceptable alternative in the
case of a C. albicans line infection. C. krusei and T. glabrata are primarily fluconazole-
resistant species and necessitate the use of amphotericin.
182
The aminoglycosides
and third generation cephalosporins are commonly utilized to manage infections
caused by Gram-negative organisms. Table 18.12 lists some useful antimicrobials
for outpatient therapy home use based on their dosing regimens, solution stability
and the bacterial/fungal coverage.
30,182-197
Table 18.11. Drugs that can be used by topical route
I. Ointment
nitroglycerin
II. Transdermal patches*
clonidine estradiol fentanyl
nicotine nitroglycerin salicylic acid
scopolamine testosterone
III. Implantable devices
levonorgestrel
IV. Cream
betamethasone capsaicin clotrimazole
conjugated estrogen fluocinonide hydrocortisone
miconazole nystatin triamcinolone
terconazole
*References 157-181. Reprinted with permission from McFadden MA, DeLegge
MH, Kirby DF. JPEN 1993; 17:180-186.
293
18
Table 18.12. Useful antibiotics for home therapy
Antibiotic Name Half-Life* Dosing Interval Special Information
Amikacin 2-3 hours Every 8-24 hours Monitor serum concentra-
tions and renal function
Amphotericin up to 15 days Every 24 hours Monitor renal function and
potassium, phosporus and
magnesium
Cefazolin 1-2 hours Every 8 hours Gram + coverage including
methicillin sensitive S. aureus
Ceftazidime 1.5-2 hours Every 8 hours Good coverage
Pseudomonas aeruginosa and
acinetobacter
Ceftriaxone 5-11 hours Every 12-24 hours Good gram + coverage, but
not enterococci, listeria or
methicillin resistant S. aureus,
many pseudomonas resistant
Cefoxitin < 1 hour Every 6 hours Gram coverage including
anaerobic bacteria
Ciprofloxacin 3-4 hours Every 12 hours Gram coverage including
Pseudomonas aeruginosa
Clindamycin 2-3 hours Every 8 hours Gram + aerobic and
anaerobic coverage; diarrhea
with Clostridium difficile
Gatifloxacin 7-14 hours Every 24 hours Gram + and gram- coverage
including Streptococcus
pneumoniae
Gentamicin 2-3 hours Every 8-24 hours Monitor serum concentra-
Levofloxacin 6-7 hours Every 24 hours Gram + and gram- coverage
including Streptococcus
pneumoniae
Nafcillin < 1 hour Every 4-6 hours Gram + coverage including
methicillin sensitive S. aureus
Oxacillin < 1 hour Every 4-6 hours Gram + coverage including
methicillin sensitive S.
aureus; strong association
with phlebitis
Ticarcillin- 1 hour Every 4-6 hours Gram + coverage including
Clavulanate methicillin sensitive S.
aureus; Gram - and
anaerobic coverage including
Bacteroides fragilis
Tobramycin 2-3 hours Every 8-24 hours Monitor serum concentra-
Vancomycin 4-6 hours Every 12-24 hours Monitor renal function and
serum concentrations when
appropriate
*References 30,182-197. Reprinted with permission from McFadden MA, DeLegge
MH, Kirby DF. JPEN 1993; 17:180-186
294
18
Culture and sensitivity data are always important in the final decision of antimi-
crobials to assure that the patient is being effectively managed. The dosage regimen,
solution stability, and toxicity must also be considered to provide optimal care.
183-185
Minimizing the number of doses that need to be administered will decrease cost and
increase patient compliance.
194
The implementation of portable multiple-dose elec-
tronic infusion pumps have allowed easier antimicrobial administration.
183
These
infusion pumps deliver medication via drug reservoirs for either intermittent or
continuous infusions. These pumps negate the need for IV administration sets for
each dose. The cost of these systems are increased but a wider variety of antimicro-
bials may be utilized in the outpatient setting.
183
Monitoring serum concentrations and renal function is encouraged with the use
of the aminoglycosides. Assessment of renal function is also necessary with vanco-
mycin. Vancomycin trough concentrations should only be measured if renal func-
tion deteriorates or a poor clinical response is demonstrated.
198
Amphotericin B
may have significant effects on renal function and electrolyte homeostasis; routine
monitoring is suggested.
Some TPN vendors who supply TPN for the home patient use two-in-one infu-
sions while other companies use three-in-one infusions. Table 10.13 shows com-
patibility data of whether the antimicrobial may be co-infused or put into the
TPN directly.
195
Cyclic Infusion Techniques
The infusion of total parenteral nutrition (TPN) over a 24-hour period is com-
monly practiced when a patient is in the hospital. This practice may not be optimal
for the outpatient, particularly when a relatively active lifestyle may be maintained.
If the SBS patient has central venous access, the duration of TPN infusion may be
decreased from the usual 24 hour period to a 10-12 hour period. Several approaches
may be taken to achieve this goal. One method may involve maintaining the same
volume and dextrose concentration while decreasing the infusion time a couple hours
each day until the patient tolerates a 10-12 hour infusion. The rates of infusion may
be increased or decreased when initiating and discontinuing the TPN infusion, re-
spectively. However, Krzywda et al suggest that patients may tolerate abrupt initiation
and discontinuation of 3-in-1 TPN without significant hyper- or hypoglycemia.
196
Home Infusion Devices
The infusion of IV fluids, medications and TPN at home may be accomplished
by the use of several devices. Standard infusion pumps may be utilized to administer
large volumes of fluid, particularly TPN and fat emulsion. H
2
-antagonists that have
been admixed with the TPN would consequently be delivered by the same method.
Antibiotics, provided in piggyback form or in concentrated drug reservoirs, could
be co-infused with an IV fluid or TPN using the same device. However, when anti-
biotics are provided in predrawn syringes, the use of a syringe pump may be more
practical, especially when the extra fluid from the IV infusion and piggyback may
compromise patient care.
Narcotic analgesics, including fentanyl, hydromorphone, meperidine and mor-
phine, may be infused for management of chronic pain. This may be accomplished
using microinfusion devices that allow fairly concentrated solutions to be adminis-
tered continuously. Still other infusion devices are designed to allow for continuous,
subcutaneous administration. The medication most commonly infused by this
295
18
Table 18.13. Medication administration with TPN
Medication 2 in 1 3 in 1
Co-Infusion In Solution Co-Infusion In Solution
Acyclovir No ND* ND ND
Amikacin Yes ND No ND
Aminophylline Equivocal Yes ND Yes
Amiodarone ND ND ND ND
Amphotericin No ND ND ND
Amphoterin cholesterol
sulfate complex ND ND ND ND
Ampicillin Equivocal Equivocal Yes ND
Azithromycin ND ND ND ND
Aztreonam Yes ND ND ND
Cefazolin Equivocal Yes Yes ND
Cefepime ND ND ND ND
Cefotaxime Yes Yes ND ND
Cefoxitin Yes Yes Yes ND
Ceftazidime Yes Yes ND ND
Ceftriaxone Yes Yes ND ND
Cefuroxime Yes Yes ND ND
Cidofovir ND ND ND ND
Cimetidine Yes Yes ND Yes
Ciprofloxacin No ND ND ND
Clindamycin Yes Yes Yes ND
Cyclosporine Equivocal ND ND ND
Digoxin Yes ND Yes ND
Doxycycline Yes ND ND ND
Erythromycin Yes ND Yes ND
Famotidine Yes Yes ND Yes
Fentanyl Yes ND ND ND
Fluconazole Yes ND ND ND
Foscarnet Yes ND ND ND
Furosemide Equivocal ND Yes ND
Ganciclovir Equivocal No ND ND
Gatifloxacin ND ND ND ND
Gentamicin Equivocal Yes Yes ND
Heparin Yes Yes ND ND
Hydromorphone Yes ND ND ND
Imipenem-Cilastin Yes No ND ND
Insulin Yes Yes ND ND
Iron Dextran Equivocal Yes ND Equivocal
Levofloxacin ND ND ND ND
Linezolid ND ND ND ND
Meperidine Yes Yes ND ND
Meropenem ND ND ND ND
Methicillin Yes Yes ND ND
Metoclopramide No Yes ND ND
Metronidazole Yes ND ND ND
Morphine Yes Yes ND ND
Nafcillin Yes Yes ND ND
Ofloxacin Yes ND ND ND
296
18
method is insulin. In the case of chronic iron toxicity, deferoxamine may also be
infused by this method.
Conclusion
The chronic care of the SBS patient can be extremely rewarding, yet challenging.
It may often tax the ingenuity of the most resourceful clinician. The availability of
newer drugs and delivery systems has made it easier, but it is clear that more work is
needed in the pharmacologic approach to patients with limited GI absorption. The
new millenium holds the promise of even greater advancements and improvements
in the quality of life for these patients.
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Medication 2 in 1 3 in 1
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Oxacillin Yes ND Yes ND
Penicillin G K
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Penicillin G Na
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CHAPTER 19
Nutritional Support in Inflammatory
Bowel Disease
John H. Seashore, Melissa F. Perkal
Introduction
Crohns disease and ulcerative colitis are chronic remitting diseases of unknown
etiology characterized by abdominal pain, diarrhea and other gastrointestinal symp-
toms. Both diseases, but Crohns in particular, are associated with nutritional defi-
ciencies for a variety of reasons including malabsorption, increased nutrient losses,
increased energy requirements and inadequate nutrient intake. Acute malnutrition,
evidenced by weight loss, anemia and hypoalbuminemia, is common during acute
attacks of inflammatory bowel disease (IBD). A smaller number of patients have
chronic malnutrition with cachexia and multiple nutrient deficiencies. Malnutrition
may be responsible for considerable morbidity and even mortality in inflammatory
bowel disease (IBD), although there is no evidence that it exacerbates either condition.
The classic papers by Dudrick and Wilmore in 1968 describing the first success-
ful method for total parenteral nutrition sparked a resurgence of interest in clinical
nutrition and led to the development of new techniques and formulas for both
parenteral and enteral nutrition.
1,2
There has been intense interest in the role of
nutritional therapy in IBD during the 25 years since. Much of the literature is based
on anecdotal, retrospective or uncontrolled data, and spontaneous remissions and
exacerbations are characteristic of IBD which makes it difficult to know whether a
specific treatment is responsible for observed improvement. However, the large
amount of information and the available prospective, randomized, controlled stud-
ies make it possible to draw some general conclusions.
Malnutrition in Inflammatory Bowel Disease
Incidence
Acute malnutrition, as evidenced by weight loss of more than 10% or serum
albumin less than 3 g/dl, has been reported in 30-60% of patients during flare-ups
of Crohns disease.
3,4
Chronic malnutrition, or undernutrition is less common but
probably occurs in about 10% of adult patients. Ulcerative colitis is characterized by
long periods of well being and periodic severe flare-ups of disease. It is not surpris-
ing, then, that acute malnutrition occurs in 50-75% of patients, but chronic malnu-
trition is quite rare.
Approximately 85% of children have weight loss during acute attacks of Crohns
disease, and 65% suffer weight loss during flares of ulcerative colitis.
4
Chronic
malnutrition is a particular problem in children because of their unique growth
307
Nutrition Support in Inflammatory Bowel Disease
19
requirements. About 20% of patients have onset of IBD in childhood, usually
during adolescence, when children normally have a rapid increase in skeletal growth
and muscle mass, and undergo sexual maturation.
5
Growth failure occurs in 15-30%
of children with Crohns disease and 10% of children with ulcerative colitis.
5,6
Mechanisms of Malnutrition
Table 19.1 lists a host of factors which may contribute to malnutrition in pa-
tients with IBD.
Malabsorption
Malabsorption is most likely in the face of extensive mucosal disease, decreased
transit time from active disease, multiple resections resulting in short bowel syn-
drome, or bacterial overgrowth which occurs in up to 30% of patients with Crohns
disease.
8
Carbohydrate absorption, measured by D-xylose studies, was reported to
be abnormal in 16-40% of adults and children with Crohns disease.
8,9
Lactose in-
tolerance is the most common manifestation of malabsorption in IBD and has been
assumed by many clinicians to be nearly universal. However, decreased lactase levels
in jejunal biopsy specimens could be demonstrated in only 9-12% of patients.
10
Transient lactose intolerance is probably somewhat more common during acute
attacks of disease. The hydrogen breath test, a sensitive indicator of lactose malab-
sorption, was abnormal in 15% of children with ulcerative colitis and 34% of chil-
dren with Crohns disease.
11
Extensive ileal disease or resection may disrupt the enterohepatic circulation and
lead to depletion of the bile salt pool resulting in fat and fat soluble vitamin malab-
sorption. Many patients with bile salt deficiency have difficulty maintaining a nor-
mal weight. Deficiency of vitamins A, D, E, and K have been reported, but the
incidence is not known.
9
Vitamin B12 is absorbed in the terminal ileum indepen-
dent of bile salts and may also become depleted.
9
Serum zinc levels are low in IBD
patients as in other diarrheal diseases.
12,13
Many of the common medications used to treat IBD may exacerbate malabsorp-
tion. Corticosteroids inhibit calcium absorption, sulfasalazine impairs folate absorp-
tion by competitive inhibition and cholestyramine binds bile acids and aggravates
bile salt deficiency.
Increased Gastrointestinal Losses
Acute or chronic GI bleeding from the inflamed mucosal surfaces is very com-
mon in IBD. The bleeding may be occult or gross, the latter more prominent in
ulcerative colitis. Iron deficiency anemia is therefore common, but since other mi-
cronutrient deficiencies can cause anemia (folate, B
12
), further evaluation may be
necessary. Mean corpuscular volume less than 80 and a serum ferritin less than 18
mg/ml are the best evidence of iron deficiency anemia.
14
The inflamed mucosa characteristic of IBD may lead to an exudative enteropa-
thy and loss of protein from the gut, above and beyond protein malabsorption. This
excessive protein loss may exacerbate hypoalbuminaemia and other protein defi-
ciency. Increased losses of protein from the gut have been demonstrated by abnormal
fecal excretion of
51
chromium labeled albumin or clearance of alpha-1-antitrypsin.
15
The diarrhea seen during acute attacks of IBD is multifactorial in origin, but is
in part a secretory diarrhea causing active loss of water and electrolytes through
the diseased mucosa. Excessive losses of trace metals, including, zinc, copper and
magnesium have also been reported.
16,17
308
19
Increased Nutritional Requirements
Fever associated with active disease, sepsis, peritonitis or abscess increases en-
ergy expenditure substantially and therefore increases caloric requirements.
18
In the
absence of fever, however, most of the evidence suggests that patients with IBD do
not have an increased caloric requirement.
19
Motil et al showed that Crohns disease
patients have the same whole body nitrogen flux, rates of protein synthesis and
breakdown and net protein retention as normal controls.
20
Chan, et al found that
the measured energy expenditure(by indirect calorimetry) in patients with Crohns
disease was virtually identical to that predicted by the Harris-Benedict equation for
normal adults.
21
Inadequate Oral Intake
This is the single most important reason for nutritional deficiency. Nausea, cramps
and diarrhea tend to be worse after eating and may condition patients to food avoid-
ance. The anorexia which accompanies many chronic illnesses may contribute. Spe-
cific complications including obstruction and fistula clearly impair eating. Self-se-
lected or physician-recommended diets may restrict intake by eliminating desired
foods and by interfering with palatability. The most compelling evidence that inad-
equate intake is responsible for malnutrition comes from studies showing that chil-
dren with growth failure can achieve normal growth rates when their diet is supple-
mented with parenteral or enteral nutrition.
Table 19.1. Possible causes of malnutrition in inflammatory bowel disease
Inadequate intake
Anorexia, altered taste, avoidance behavior
Abdominal pain, diarrhea, nausea, vomiting
Restrictive diets
Malabsorption
Diminished digestive function secondary to decreased bile salt concentration or
bacterial overgrowth
Decreased absorptive surface area secondary to extensive disease and/or previous
bowel resections
Drug-induced malabsorption(e.g., steroids/calcium; sulfasalazine/folate;
cholestyramine/fat-soluble vitamins
Increased gastrointestinal losses
Protein-losing enteropathy
Gastrointestinal bleeding
Electrolyte and mineral loss
Increased nutritional requirements
Fever, fistula, infection
? corticosteroid therapy
Need for repletion of body mass
Reproduced with permission of WB Saunders Co from Perkal, MF and Seashore,
JH. Nutrition and inflammatory bowel disease. Gastroenterology Clin NA, 1989;
18(3):567-578.
7
309
19
Nutritional Support in Inflammatory Bowel Disease
Patients with inflammatory bowel disease are at risk for developing nutritional
deficiencies which may in turn increase morbidity and mortality. Maintenance of
good nutrition is a desirable goal, but the best methods, timing and route of nutri-
tional support are not always clear. The role of nutritional therapy in IBD can be
considered in the following areas.
Nutritional Management of Acute Attacks and Induction
of Remission
Corticosteroids have long been the mainstay of medical treatment for IBD. In
the National Cooperative Crohns disease Study, treatment of active Crohns disease
with prednisone achieved a 47% rate of remission of symptoms compared with
26% in placebo treated patients.
22
Truelove described treating severe attacks of IBD
with a period of bowel rest and intravenous steroids with good results.
23
This ap-
proach has become commonplace in the management of IBD. However, even healthy,
well nourished adults may develop evidence of malnutrition after 10 days NPO.
Patients who are already malnourished from IBD should not be allowed to starve for
more than a few days. Finally, most patients who fail medical therapy require sur-
gery which is better tolerated in the nutritionally repleted patient. For all these rea-
sons, it is prudent to give parenteral nutrition to patients who are NPO during
treatment with steroids and bowel rest.
The concept of bowel rest in the treatment of gastrointestinal inflammatory pro-
cesses is based on several theoretical considerations. Peristalsis is decreased in the
absence of enteral feeding so there is less physical movement of the bowel which
could function as a medical splint to aid in healing of the inflammatory process.
Withholding oral feedings minimizes gastrointestinal secretions. In the absence of
digestion and absorption, the metabolic work and oxygen consumption of the gut
mucosa is minimal, which may also permit better healing. It has been suggested that
the multiplicity of foreign antigens introduced into the gut with oral feeding may
worsen the disease.
24
There is no direct evidence to support these hypotheses, but
bowel rest has been widely used in the treatment of gastrointestinal disease.
The introduction of total parenteral nutrition (TPN) in 1968 made it possible
to provide intravenous nutrition for more than a few days. There has been con-
siderable interest over the years in using longer periods of bowel rest for treating
IBD leading to the concept of TPN as primary therapy. Early experience was en-
couraging and led to widespread use of a 3-12 week period of bowel rest with in
hospital and home TPN. Greenberg, et al reported a 77% remission rate in 43
patients, 79% of whom remained well for 2 years.
25
A subsequent prospective but
non-randomized study of 100 patients from the same institution again reported a
77% remission rate in hospital and 54% of patients still in remission at 1 year.
26
Most of the patients continued to receive steroids during TPN. Other workers
have not been able to duplicate these results, however. Reported remission rates
have been from 30-70%.
27-35
More important, remissions have not generally been
sustained, relapses or surgical intervention occurring in 15-80% of patients within
1-2 years. Muller et al reported that 83% of patients had remission and avoided
surgery acutely, but that the recurrence rate was 65% at 2 years and 85% at 4
years.
36
This relapse rate was 4 times higher than that following surgical resection.
One of the few prospective, randomized, controlled studies was reported by
Dickinson, et al who found no difference in outcome between those patients
310
19
treated with standard medical therapy alone and those treated with medical therapy
plus TPN.
37
While most of the studies in the literature are retrospective and uncon-
trolled and the definitions of disease severity, remission and relapse vary somewhat,
certain conclusions seem appropriate. A prolonged period of bowel rest and TPN
may be more effective in inducing remission than the standard 10 day course of
treatment, but the cost and complications of TPN must be considered. Remission is
not well sustained compared with long term steroid therapy or surgical resection.
The role of TPN is adjunctive rather than primary.
The concept of bowel rest has been challenged in recent years for several rea-
sons.
35,38,39
As noted above, there is no hard evidence that bowel rest works. Second,
there is accumulating evidence that prolonged bowel rest is damaging to the gut.
Small bowel mucosal atrophy as measured by villous height, DNA content and
mucosal wet weight, occurs in patients who are NPO and receiving TPN.
40,41
It is
now recognized that mucosal atrophy may be associated with bacterial translocation
from the bowel lumen to the portal circulation and may be a source of sepsis in TPN
patients.
42
Intraluminal nutrients, especially glutamine, appear to be critical to main-
tain the health of the small bowel mucosa.
41,43
Third, recent studies suggest that bowel rest may not be necessary in the treat-
ment of acute episodes of IBD. OMorain, et al in 1980 reported substantial clinical
improvement in 27 patients treated with an elemental diet with or without steroids
for acute exacerbations of Crohns disease.
44
Morin, et al induced remission in 10
newly diagnosed children with moderately severe Crohns disease using elemental
diet without steroids.
45
Since then, a number of prospective, randomized controlled
studies have confirmed that elemental diets, with and without steroids, are effective
in inducing remission during acute attacks of IBD.
46-52
Remission rates in these
studies range from 60-90%. Elemental diet was equal or superior to steroids,
46-48,50
bowel rest, TPN and bowel rest
49,52
or polymeric diet,
51
in inducing remission in
both children and adults. Results were generally maintained for up to 3 months, but
most of these studies did not provide long-term follow-up. One retrospective study
that did report long term follow up data showed a 22% relapse rate at 6 months,
then an 8-10% annual relapse rate thereafter.
53
A third study from the Toronto
group, this one prospective and randomized, found no significant differences in
outcome among groups treated with:
1. TPN, bowel rest and steroids,
2. elemental diet and steroids, and
3. regular diet plus steroids.
54
In this study, remission was maintained in over 50% of patients for up to 2 years.
Teahon, et al showed that the abnormal permeability of the bowel mucosa found in
active Crohns disease was reversed during treatment with an elemental diet, sug-
gesting improved integrity of the mucosal barrier.
55
These studies clearly demonstrate that bowel rest is not essential in the manage-
ment of acute attacks of IBD. Elemental diets are superior in most cases and obviate
the need for TPN with its attendant cost and risks. However, there is still a place for
a short course of TPN and bowel rest in patients who fail other therapy.
Nutritional Management in the Maintenance of Remission
Once remission has been achieved, the goal of treatment is to keep patients
symptom free while they return to their usual activities and diet. Dietary manage-
ment in this phase remains controversial. Restrictive diets often lead to inadequate
311
19
nutrition because of exclusion of favorite foods or unpalatability and should be avoided
unless there is good evidence of need and efficacy.
24,39
A low residue or low fiber diet
has traditionally been recommended in IBD, but there is no scientific evidence that
it works. Levenstein et al randomized patients to either a regular or a low fiber diet
and found no difference in symptoms or relapse.
56
Heaton et al treated a group of
patients with a diet low in refined carbohydrate and high in fiber content.
57
They
found a lower incidence of hospitalization and surgery in the diet treated patients
compared with historical controls taking a regular diet. A subsequent larger, ran-
domized study failed to confirm this observation.
58
Many clinicians advise their
patients to eat a regular diet, avoiding only those foods which bother them. Alun-
Jones provides some evidence for this approach in a small randomized study
59
and a
larger non-randomized study
49
in which one new food was introduced each day.
Any food which caused symptoms was eliminated from the patients diet. The ma-
jority of the patients were sensitive to 1-4 foods, the most common being wheat,
dairy products, corn, yeast, tomatoes, citrus and eggs. A prospective multicenter
trial using a similar exclusion diet technique found a 2 year relapse rate of 62%
compared with 79% in patients treated with steroids and regular diet.
60
Growth Failure in Children
About 20 % of patients with inflammatory bowel disease have onset of symp-
toms in childhood.
5
Children suffer the same nutritional consequences of IBD as
adults, namely acute weight loss, chronic undernutrition and micronutrient defi-
ciencies. In addition, children normally are growing, especially during the pubertal
growth spurt, and significant numbers of children with IBD have impaired linear
growth and delayed sexual maturation. Growth failure occurs in 15-40% of chil-
dren with Crohns disease and 10% of children with ulcerative colitis.
4,61-63
Growth
failure, as opposed to weight loss, is most commonly defined as a height for age less
than the 5th percentile on standard growth curves. A single static measurement of
growth, however, may represent constitutional short stature rather than the effect of
disease. Estimating predicted adult height from mean parental height may be help-
ful. Even better is to obtain old height measurements and plot the childs growth
history over time on the standard growth charts. Adult height can be predicted fairly
accurately if a child has been growing steadily along a particular percentile curve. If
height begins to cross percentiles over a year or two, the child almost certainly has
growth failure from disease. The most accurate method to assess growth failure is to
plot linear growth (cm/year) on normal growth velocity curves
64
A child whose lin-
ear growth is less than the 3rd percentile (2 SD below the mean) may be considered
to have growth failure. Growth velocity measurements are particularly useful to as-
sess the nutritional effects of treatment. The majority of studies in the literature,
however, have used height for age percentile as the initial definition of growth fail-
ure and changes in height percentile as the outcome measurement.
The etiology of growth failure in children is not entirely clear and may well be
multifactorial. The nutritional consequences of IBD discussed earlier could cer-
tainly contribute to poor growth, but these are usually operative during acute attacks
of the disease, whereas growth failure is a chronic problem. One of the striking obser-
vations about Crohns disease in children is that growth failure often predates gas-
trointestinal symptoms by a year or more.
65
In one study, 46% of children with
Crohns disease had a decrease in height velocity before the onset of symptoms,
66
which
suggests the presence of a systemic factor. It is not uncommon for children who
312
19
eventually develop Crohns disease to be referred to an endocrinologist for evalua-
tion of short stature. Endocrine evaluation is invariably normal. Several studies have
shown normal pituitary and adrenal function, and normal secretion of thyroid hor-
mone, growth hormone and somatomedin.
6,67,68
Thus, there is no evidence of an
endocrine basis for growth failure in Crohns disease.
Corticosteroids are a mainstay of therapy for moderate to severe Crohns disease
and have well known antianabolic properties. Long term treatment with high dose
corticosteroids may contribute to growth failure,
69
but patients who require high
dose therapy are more likely to have severe disease and poor nutrition, and it is not
clear that corticosteroid use is an independent variable. Most patients are treated
with relatively low dose and/or alternate day steroids which are less likely to impair
growth.
70,71
Motil et al found no association between corticosteroid use and rates of
protein synthesis or breakdown
20
The most likely explanation for growth failure is inadequate nutrition. Several
balance studies have shown that children with Crohns disease and growth failure
spontaneously take in only 50-80% of their estimated caloric requirements.
6,67,72
Some studies also suggest that energy expenditure may be higher than normal in
these children which would further compound the effect of poor intake.
73
It is par-
ticularly difficult for adolescents to eat enough to achieve normal pubertal growth
rates. The most convincing evidence that inadequate intake is responsible for growth
failure is the excellent response to caloric supplementation which has been docu-
mented in numerous studies.
Layden et al first demonstrated enhanced growth in children with Crohns dis-
ease using bowel rest and total parenteral nutrition for 4-6 weeks.
73
Kelts et al
67
and
Strobel et al
74
also reported increased growth velocity during TPN. Some, but not
all, of these children had continued improved growth for up to a year after TPN was
stopped. Subsequent studies by Morin et al,
75
Kirschner et al
72
and Motil et al
20
have
shown that the same result can be achieved using enteral supplementation. Dietary
counseling and the use of high calorie snacks and liquid oral supplements may be
sufficient to achieve adequate nutrition in some children. If growth is still not ad-
equate, administration of a defined formula diet at night through a nasogastric tube
will usually work.
76
Parenteral nutrition as primary treatment for growth failure
should be reserved for children who have documented failure of enteral supplements.
It is particularly important to attend to the nutritional needs of adolescents dur-
ing the period of rapid growth and sexual maturation beginning at puberty. Perma-
nent short stature may result if the epiphyses close before normal pubertal growth is
complete. Small size and delayed appearance of secondary sex characteristics can be
emotionally devastating to teenagers who are already struggling with the problems
of chronic disease. Control of the disease by medical and/or surgical therapy and
careful monitoring of caloric intake and growth rates are essential.
Perioperative TPN
Morbidity and mortality rates following major abdominal surgery are clearly
higher in malnourished patients than in those who are nutritionally replete.
77-79
Since
many patients with inflammatory bowel disease have significant malnutrition, it is
logical to assume that nutritional support in the perioperative period might decrease
postoperative complications. Unfortunately, there are no prospective studies which
examine the role of either preoperative or postoperative TPN in patients with IBD.
Mullen, et al reported a retrospective series of general surgical patients with a variety
313
19
of gastrointestinal conditions including some with IBD.
80
Among patients who were
malnourished preoperatively, the complication rate was significantly lower in those
who had received at least 7 days of preoperative TPN.
81
Other studies show no
benefit from preoperative TPN.
82,83
Most patients scheduled for elective surgery for
IBD are only minimally malnourished, and there are no data to support preopera-
tive TPN. Many patients come to surgery urgently after failure of medical therapy
for acute exacerbation or complication of IBD and these patients often have a sig-
nificant period of time with inadequate enteral intake of calories. TPN during this
time may prevent or treat malnutrition and in turn reduce the morbidity of subse-
quent surgery.
84
Whether surgery should be deferred to allow a period of preopera-
tive TPN must be decided on an individual basis. Severely malnourished patients
might benefit, but other patients may have worsening nutritional status from ongo-
ing fever and loss of blood and protein from the gut.
85
Routine postoperative TPN
is not indicated, but it is appropriate to give TPN to patients who have moderate to
severe malnutrition or whose postoperative course may be prolonged.
86
Enterocutaneous Fistula
Entero-enteral and entero-vesical fistulas are well known complications of Crohns
disease as a result of chronic inflammation and transmural disease. Entero-cutane-
ous fistulas may occur spontaneously but are more common as a postoperative com-
plication. Entero-cutaneous fistulas are much less common in ulcerative colitis and
are almost always postoperative. Loss of fluid and electrolytes, rapid transit time,
malabsorption and bypass of distal bowel all contribute to malnutrition in patients
with fistulas, particularly fistulas from the proximal gastrointestinal tract. Wound
healing is impaired in patients with moderate to severe malnutrition; the longer the
fistula persists, the worse the malnutrition and the ever diminishing likelihood of
spontaneous closure, in the absence of nutritional support. The devastating conse-
quences of enterocutaneous fistulas were well described by Edmunds, et al, who
reported a 63% rate of malnutrition and a 59% mortality rate in patients with
enterocutaneous fistula from a variety of causes, including Crohns disease.
87
Death
is usually due to a combination of malnutrition and failed attempts at surgical clo-
sure of the fistula.
Since the introduction of TPN, there has been considerable interest in the role
of nutritional support in the management of patients with enterocutaneous fistulas,
and early reports of spontaneous closure using TPN to restore and maintain normal
nutritional status were encouraging.
88-90
Various retrospective series of patients with
fistulas from a spectrum of causes have shown spontaneous healing in 20-80% of
patients treated with bowel rest and nutritional support, as reviewed by Meguid.
91
The reported mortality in these series was 5-28%. However, there have been no
prospective or randomized studies, so it is not known how much of the improve-
ment compared with historical controls is a result of TPN and how much to other
factors such as improved general care, ICUs, newer antibiotics, etc.
The results with enterocutaneous fistulas in inflammatory bowel disease have
been less encouraging. The rate of spontaneous permanent closure of fistulas has
ranged from 10-50%.
26,29,32,80
This is perhaps not surprising since chronic inflam-
mation and infection are well known impediments to healing. High dose intrave-
nous steroids to treat active IBD may also interfere with healing.
In the absence of prospective studies, it is not possible to draw firm conclusions
about the treatment of enterocutaneous fistulas in IBD. Given the high incidence of
314
19
malnutrition in these patients, it is imperative to provide some sort of nutritional
support which can often be as an enteral elemental diet for distal small bowel or
colonic fistulas, but usually should be as TPN and bowel rest for proximal fistulas.
Whether nutritional support has a primary therapeutic benefit above and beyond its
adjunctive role is uncertain. It seems reasonable to offer a short course(2-6 weeks) of
nutritional support with or without bowel rest, combined with medical treatment
of active disease and appropriate management of infection. If the fistula has not
closed in that time, surgical treatment is usually indicated.
Short Bowel Syndrome and Home TPN
A small but significant number of patients with Crohns disease(rarely ulcerative
colitis) are nutritional cripples and become dependent on TPN. Some patients have
intractable symptoms, non-closing fistulas, high output stomas or other complica-
tions of the disease, and are unable to eat because of symptoms or cannot maintain
adequate nutrition with enteral feeding alone. Other patients have diffuse disease
throughout the gastrointestinal tract and are poor candidates for operation. Still
others have had multiple resections leaving them with short gut syndrome and chronic
malnutrition. Prolonged TPN both in the hospital and at home may be life-saving
for these unfortunate patients. In the large Home TPN Registry maintained by the
Oley Foundation, Crohns disease is the second most common indication for home
TPN, accounting for 17% of all patients through 1987.
92
The reported experience
with long-term TPN is similar to that already described for short to medium dura-
tion TPN, which is that the patients nutritional status improves, but the overall
course of the disease is not changed. Fleming reported a small group of patients who
had severe, intractable Crohns disease who were treated with home TPN for up to
17 months.
93
Weight and albumin improved, but none of the patients achieved
sustained remission. Strobel treated 17 adolescents with home TPN(2-12 months)
for moderately severe Crohns disease and also found improved nutrition, including
increased growth velocity and catch up growth in 10.
74
One-third of the children
had sustained remission of symptoms for a mean of 331 days, but the majority had
persistence or relapse requiring ongoing medical or surgical treatment. More re-
cently, the Cleveland Clinic group reported 41 patients with Crohns disease who
were treated by bowel rest and home TPN for 1-8 years after failure of medical and
surgical treatment.
94
Nutritional status as measured by albumin and transferrin,
improved in most patients as did quality of life scores. However, the frequency of
operations did not change compared with the pre-TPN period, and the frequency
of hospitalization actually increased, primarily due to complications related to the
TPN. It is clear that TPN is effective in restoring and maintaining good nutrition
but has little primary therapeutic benefit. Patients with severe IBD ultimately need
definitive medical or surgical treatment of their disease, and a prolonged course of
TPN hoping to avoid such treatment is probably fruitless. A modest course of treat-
ment to replete a malnourished patient, to allow intra-abdominal inflammation to
settle down, or to provide time to prepare the patient for operation may be useful
but should not be prolonged unduly. Long-term home TPN is reserved for those
few patients who have failed all conventional treatment or who are not candidates
for surgery.
Summary
Nutrition and inflammatory bowel disease are inextricably related. The nutri-
tional requirements of these patients need constant attention. Micronutrient
315
19
deficiencies are relatively common and require dietary supplementation. Macronu-
trient deficiency may lead to acute or chronic protein-calorie malnutrition, and
increased morbidity and mortality. Growth failure is a particular problem in adoles-
cent children. Nutritional support, either enteral or parenteral, is effective in treat-
ing or preventing malnutrition and is an essential part of management. Enteral nu-
trition is at least as effective as TPN to induce remission, maintain remission and to
treat growth failure; it is also safer and less expensive, and protects the integrity of
the intestinal mucosal barrier. There is no clear evidence for a primary therapeutic
role for TPN in these patients; prolonged courses of bowel rest and TPN do not
alter the ultimate course of the disease. Definitive medical or surgical treatment
should be provided once the patient is nutritionally repleted and stable. Nutritional
support is an important adjunct perioperatively and in the management of compli-
cations including enterocutaneous fistula and short bowel syndrome. Prolonged,
potentially lifelong, TPN at home is lifesaving and provides a reasonable quality of
life for patients with short bowel syndrome or whose disease is refractory to medical
and surgical therapy.
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70. Sadeghi-Nejad A, Senior B. The treatment of ulcerative colitis in children with
alternate-day corticosteroids. Pediatrics 1969; 43(5):840845.
71. Whittington PF, Barnes V, Bayless TM. Medical management of Crohns disease
in adolescence. Gastroenterology 1977; 72(6):1338-1344.
72. Kirschner BS, DeFavaro MV, Jensen W. Lactose malabsorption in children and
adolescents with inflammatory bowel disease. Gastroenterology 1981;
81(5):829-832.
73. Layden T, Rosenberg J, Nemchausky et al. Reversal of growth arrest in adolescents
with Crohns disease after parenteral alimentation. Gastroenterology 1976;
70(6):1017-1021.
74. Strobel CT, Byrne WJ, Ament ME. Home parenteral nutrition in children with
Crohns disease: an effective management alternative. Gastroenterology 1979;
77(2):272-279.
75. Morin CL, Roulet M, Roy CC et al. Continuous elemental enteral alimentation in
children with Crohns disease and growth failure. Gastroenterology 1980;
79(6):1205-1210.
76. Belli DC, Seidman E, Bouthillier L et al. Chronic intermittent elemental diet im-
proves growth failure in children with Crohns disease. Gastroenterology 1988;
94(3):603-610.
77. Studley HO. Percentage of weight loss - a basic indicator of surgical risk in patients
with chronic peptic ulcer. Nutr Int 1936; 106:458-460.
78. Thomas L, Robert D. Nutritional status and body composition in critically ill
patients. Correlation between results and mortality. Am J Clin Nutr 1979;
32:510-511.
79. Seltzer M, Slocum B, Cataldi-Betcher E et al. Instant Nutritional Assessment:
Absolute Weight Loss and Surgical Mortality. J Parenteral Enteral Nutr 1982;
6(3):218-221.
80. Mullen JL, Hargrove WC, Dudrick SJ et al. Ten years experience with intravenous
hyperalimentation and inflammatory bowel disease. Ann Surg 1979;
187(5):523-529.
81. Mullen JL, Buzby GP, Matthews DC et al. Reduction of operative morbidity and
mortality by combined preoperative and postoperative nutritional support. Ann
Surg 1978; 192(5):604-613.
82. Higgens CS, Keighley MRB, Allan RN. Impact of preoperative weight loss and
body composition changes on postoperative outcome in surgery for inflammatory
bowel disease. Gut 1984; 25:732-736.
319
19
83. Lashner BA, Evans AA, Hanauer SB. Preoperative total parenteral nutrition for
bowel resection in Crohns disease. Dig Dis Sci 1989; 34(5):741-746.
84. Dempsey DT, Mullen JL, Buzby GP. The link between nutritional status and clini-
cal outcome: can nutritional intervention modify it? Am J Clin Nutr 1988;
47352-356.
85. Werlin SL, Grand RJ. Severe colitis in children and adolescents: diagnosis, course,
and treatment. Gastroenterology 1977; 73(4):828-832.
86. Rombeau JL, Barot LR, Williamson CE et al. Preoperative total parenteral nutri-
tion and surgical outcome in patients with inflammatory bowel disease. Am J Surg
1982; 143:139- 143.
87. Edmunds Jr LH, Williams GM, Welch CE. External fistulas arising from the gas-
trointestinal tract. Ann Surg 1960; 152(3): 445-466.
88. Chapman R, Foran R, Dunphy JE. Management of intestinal fistulas . Am J Surg
1964; 108:157-164.
89. MacFayden BV, Dudrick SJ, Ruberg RL. Management of gastrointestinal fistulas
with parenteral hyperalimentation. Surgery 1973; 74(7):100-105.
90. Eisenberg HW, Turnbull Jr RB, Weakley FL et al. Hyperalimentation as prepara-
tion for surgery in transmural colitis (Crohns disease). Dis Colon Rectum 1974;
17(4):469-475.
91. Meguid MM, Campos AC, Hammond WG. Nutritional support in surgical prac-
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92. Howard L, Heaphey L, Fleming CR et al. Four years of North American Registry
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agement. JPEN 1991; 15(4):384-393.
93. Fleming CR, McGill DB, Berkner S. Home parenteral nutrition as primary therapy
in patients with extensive Crohns disease of the small bowel and malnutrition.
Gastroenterology 1977; 73(5): 1077-1081.
94. Galandiuk S, ONeill M, McDonald P et al. A century of home parenteral nutri-
tion for Crohns disease. Am J Surg 1990; 159:540-545.
CHAPTER 20
Nutrition Support of Acute Pancreatitis
Introduction
Acute pancreatitis ranges in severity from a minimal edematous in-flammation,
which usually resolves spontaneously and completely, to a fulminant process that
can progress to an often fatal, necrotizing hemorrhagic pancreatitis. Mild forms of
pancreatitis are manifested by abdominal pain, nausea, vomiting, and anorexia and
may be confused with many other gastrointestinal disorders. About l0-20% patients
with acute pancreatitis develop severe necrotizing pancreatitis, which is character-
ized by profound hemodynamic, cardiovascular, pulmonary, renal, hematologic, and
metabolic aberrations and is associated with high mortality.
1,2
Total parenteral nutri-
tion (TPN) and metabolic support are essential in patients with severe acute pancre-
atitis and should be started as soon as possible when the patient has developed more
than two of Ransons prognostic criteria. When prescribing nutrient substrates in
acute pancreatitis, consideration must be given to their specific effects on pancreatic
enzyme secretion, as well as their general effects on nutritional and metabolic ho-
meostasis. This chapter deals with the pathophysiology of acute pancreatitis includ-
ing the effects of alcohol, biliary disease, oxygen-derived free radicals, and the role of
pancreatic ischemia in inducing acute pancreatitis. Furthermore, associated meta-
bolic changes, nutritional support with TPN as an essential component of the care
of these patients, and rationales for the use of TPN, as well as the effects of the
nutrient substrates in this disorder are elaborated.
Pathophysiology of Acute Pancreatitis
A variety of factors can predispose a patient to acute pancreatitis. Depending on
the population studied, a history of alcohol abuse and biliary tract disease is found
in 80-90% of patients with acute pancreatitis. In addition to these primary causes of
acute pancreatitis, other operative, traumatic, metabolic, infectious, and pharmaco-
logic factors have been implicated in the pathogenesis of this disease (Table 20.1).
The mechanism by which these multiple factors initiate and sustain pancreatic in-
flammation have not been established. It is apparent, however, that pancreatic en-
zymes are activated from within the pancreas and are released into the interstitium
of the pancreas, leading to the subsequent autodigestion of the gland, which may
have devastating effects on its function. The activated pancreatic enzymes subse-
quently enter the bloodstream and leak into the peripancreatic tissue producing
characteristic fat necrosis and exudation. Activation and release of proteolytic en-
zymes (trypsinogen, chymotrypsinogen, proelastase, and phospholipase A) are stimu-
lated by a variety of factors, such as endotoxins, exotoxins, ischemia, anoxia, trauma,
3
2
1
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u
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r
i
t
i
o
n

S
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t

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2
0
Table 20.1. Causes of acute pancreatitis
Nutritional Operative, Infectious Drugs Others
and Metabolic Traumatic,
Obstructive
Alcohol ingestion Intra-abdominal operations Mumps Steroids Idiopathic
Biliary tract disease ERCP Viral hepatitis Azathioprine Systemic lupus
Hypertriglyceridemia Biopsy of pancreas Coxsackie Virus Thiazides erythematosus
Tropical pancreatitis Kidney transplant Echovirus Estrogens Necrotizing angiitis
Hypercalcemia Abdominal trauma Ascariasis Tetracycline Thrombocytopenic
Hyperparathyroidism (open or blunt) Mucoplasma Valproic acid purpura
Renal failure CABG Rotavirus Chlorthalidone Vascular disease
Fatty liver of pregnancy Translumbar aortography Ethacrynic acid (mesenteric
Biliary sludge Neoplastic obstruction Procainamide thrombosis)
of ampulla of Vater L-asparaginase Hereditary
Crohns disease Sulfamethoxaz Food allergy
Duodenal diverticulum ole-Trimethoprin
Penetrating peptic ulcer Oleic acid
Pancreatic divisum
Gastrostomy tube
Foreign body in the duodenum
322
20
viral infections, lysomal hydrolases, etc. Trypsin activates all of the pancreatic zy-
mogens that participate in autodigestion, which starts with erosion of the cellular
membranes and may end with extensive destruction of pancreatic tissue.
It appears, at least in experimental pancreatitis, that the secretion of zymogen
granules is blocked in individual acinar cells.
3
In turn, this blockade results in the
fusion of zymogen granules with intracellular lysosomes. Consequently, lysosomal
enzymes activate the zymogen proenzyme trypsinogen, yielding active intracellular
trypsin which is capable of cellular autodigestion.
4
The findings of acinar cell zy-
mogen granule enlargement and the formation of large auto-phagosomes during
acute pancreatitis were confirmed by pathologic examination of human tissue by
electron microscopy.
3
The constellation of morphologic changes in acute pancreati-
tis may include interstitial edema, proteolysis, vascular damage with pancreatic hem-
orrhage, fat necrosis, and parenchymal necrosis. The ultimate consequences may be
abscess formation, infection, sepsis, and pancreatic failure, which can progress to
multiple organ systems failure and death.
Alcohol and Biliary Disease
Many theories have been proposed to explain the cause and progression of acute
pancreatitis. Alcohol, the major cause of acute pancreatitis, is thought to induce
pancreatic enzyme secretion by way of chlorhydric-acid-induced secretin release and
increased ampullary sphincter tone. Alcohol is thought to cause pancreatitis by:
a. pancreatic enzyme extravasation, which is facilitated by an increase in
pancreatic ductal permeability during exocrine hypersecretion and par-
tial ampullary obstruction;
b. protein plugging of a pancreatic duct, which may initiate extravasation
and injury; and
c. transient hypertriglyceridemia. Toxic levels of free fatty acids released from
the lipolysis of triglycerides may damage acinar cells or induce endothe-
lial injury.
The mechanism by which biliary tract disease causes pancreatitis is not clear.
Recent experiments in animals suggest that pancreatic duct obstruction is the criti-
cal event that triggers acute pancreatitis in the opossum, however, bile duct obstruc-
tion alone or the reflux of bile into the pancreatic duct are important determining
factors in the development of acute pancreatitis.
5
Furthermore, bile reflux into the
pancreatic duct, via a common biliopancreatic channel, is not necessary for the de-
velopment of pancreatitis and does not worsen the severity of pancreatitis associated
with pancreatic duct obstruction.
5
Oxygen-Derived Free Radicals
The cellular and molecular mechanisms involved in the actual pancreatic injury
and extrapancreatic organ involvement are unknown. Regardless of experimental
models of acute pancreatitis (gallstones, ischemia, or alcohol), endothelial injury
and increased capillary permeability have been documented. Alterations in the pan-
creatic microvasculature have been attributed to increased activity of oxygen-de-
rived free radical activity. These unstable but highly reactive toxic metabolites of
molecular oxygen have wide-ranging effects on cells and tissues, including peroxidizing
lipids, denaturing enzymes and proteins, and accelerating tryptic activity. The
effects of oxygen-free-radical activity, and inhibition with superoxide dismutase,
were examined recently in experimental pancreatitis.
6
In this study, chemilumines-
cence (a phenomenon based on emission of light during chemical reactions that
323
20
depends on oxygen-free-radical activity) was used as an index of oxygen-free-radical
activity. Rats treated with superoxide dismutase, the activity of which depends on
scavenging free radicals, after induction of severe hemorrhagic pancreatitis with so-
dium taurocholate, had significantly reduced chemiluminescence and hyper-
amylasemia. Increased oxygen-free radical activity paralleled evolving pancreatitis,
and superoxide dismutase was thought to have a therapeutic role in pancreatitis.
Whether superoxide dismutase will induce the same effects if administered systemi-
cally remains to be seen. However, when experimental pancreatitis was induced in
dogs by the intraductal infusion of activated trypsin and taurocholate, pretreatment
with catalase and superoxide dismutase prevented the rise in mean blood pressure,
moderated the rise in pulmonary vascular resistance, and decreased the rate and
extent of the fall in cardiac index.
7
Furthermore, with an ex vivo blood-perfused
canine lung lobe, the lung injury induced by -chymotrypsin was significantly at-
tenuated by pretreatment with a combination of the reactive oxygen scavengers,
superoxide dismutase and catalase.
8
However, pretreatment of the lobe with super-
oxide dismutase alone did not protect the lobe from -chymotrypsin-induced in-
jury in this study.
8
The data suggest that reactive oxygen metabolites may play some
role in extra-abdominal organ manifestations, such as early cardiopulmonary changes
of acute pancreatitis, in addition to local effects.
Pancreatic Ischemia in Experimental Acute Pancreatitis
Necrosis of pancreatic and peripancreatic tissue is a key factor in the evolution of
pancreatitis from mild to severe. The question as to whether necrotizing injury is
caused by enzymes or ischemia is receiving more and more attention.
9
That ischemia
is the initiating or aggravating factor in acute pancreatitis is well documented. Hem-
orrhagic-necrotizing pancreatitis has been produced with intra-arterial injection of
8 m to 20 m microspheres that irreversibly obstruct terminal arterioles. On the
other hand, obstruction of larger, more proximal vessels results only in pancreatic
edema.
10
Furthermore, ischemia superimposed on pancreatic edema leads to necro-
tizing pancreatitis. The relationship between splanchnic hypoperfusion and acute
pancreatitis has been identified,
11
and changes in pancreatic microcirculation dur-
ing acute pancreatitis are well documented.
9
These specific disturbances of pancre-
atic microcirculation are characterized by heterogeneous and low capillary blood
flow and increased blood viscosity. Possible contributory mechanisms for these
changes include chemical-induced vasoconstriction, injury to a vessel wall, intravas-
cular coagulation, and increased endothelial permeability resulting in pancreatic
edema, hemoconcentration, and impaired venous drainage. Protecting the pancreas
from secondary injury caused by the early ischemic phase of acute pancreatitis, or
correcting existing changes in microcirculation by restoring volume with a dextran
preparation and increasing pancreatic perfusion, may prove to be the indicated treat-
ment at the early stages of this potentially fatal disease.
9
Metabolic Changes and Other Complications
in Acute Pancreatitis
Regardless of the cause and mechanism of acute pancreatitis, a broad spectrum
of systemic disturbances can ensue secondary to circulating hydrolytic enzymes and
toxins, compounding the severity of local or regional disturbances (Table 20.2).
Local activation of inflammatory cells may result in the systemic release of inflam-
matory mediators that not only relate to the severity of the pancreatitis, but that can
3
2
4
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e

B
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y

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2
0
Table 20.2. Potential complications of acute pancreatitis
Local and Regional Systemic
Pancreatic phlegmon METABOLIC PULMONARY
Pancreatic abscess Hypoproteinemia Pleural effusion
Pancreatic pseudocyst Hypoalbuminemia Atelectasis
Pain Hyperglycemia Pneumonitis
Rupture Hypertriglyceridemia Mediastinal abscess
Hemorrhage Hypocalcemia Adult respiratory distress syndrome
Obstruction of GI tract Hypomagnesemia
(stomach, duodenum, colon) Hyperamylasemia RENAL
Paralytic ileus Hyperlipasemia Oliguria
Pancreatic ascites Hyperbilirubinemia Azotemia
Disruption of main pancreatic duct Abnormal liver function Renal artery and/or renal vein thrombosis
Leaking pseudocyst Pancreatic encephalopathy
Involvement of contiguous organs Fat necrosis HEMATOLOGIC
by necrotizing pancreatitis Decreased BCAA/AAA ratio Anemia
Massive intraperitoneal hemorrhage Thrombocytopenia
Thrombosis of blood vessels CARDIOVASCULAR Disseminated intravascular coagulopathy
Bowel infarction Hypotension
Common bile duct obstruction Hypovolemia CNS
Sudden death Psychosis
Nonspecific ST-T changes in Fat emboli
electrocardiogram simulating
myocardial infarction
Pericardial effusion
325
20
subsequently influence gut permeability. Among the inflammatory products identi-
fied in early pancreatitis, granulocyte elastase and interleukin 6 (IL-6) correlate best
with severity of pancreatitis and mortality of the disease.
12
These products and other
mediators, such as interleukin-1, tumor necrosis factor (TNF), or histamine, may
directly or indirectly alter gut permeability by damaging intestinal mucosa. Increased
gut macromolecular permeability in early acute pancreatitis has recently been docu-
mented and also correlates with the extent of injury in patients with burns.
13,14
Fur-
thermore, a direct relationship between gut permeability and the severity of pancre-
atitis has also been shown, although the clinical implications of enhanced gut
permeability in this disease is still ill-defined. The gut permeability that was seen
only in the presence of pancreatitis was thought to be a response to changes in
homeostasis or to the acute inflammatory reaction initiated by the pancreas.
Although acute pancreatitis originates locally, extensive tissue destruction may
generate profound systemic metabolic derangements, adversely affecting multiple
organ systems accompanied by hemodynamic and cardiovascular changes. Acute
pancreatitis induces hypermetabolism with increased protein hypercatabolism. Of-
ten, this disease occurs in patients with severe nutritional depletion secondary to
extensive alcohol intake, chronic liver or biliary tract disease, and protein malnutri-
tion. The increased metabolic rate further accelerates depletion of endogenous pro-
tein and fat stores. The severity of the metabolic disorders or nutritionally related
complications correlates well clinically with the severity and duration of acute pan-
creatitis. Resting energy expenditure (as a percent of predicted energy expenditure)
was significantly (p<.02) greater in patients with pancreatitis complicated by sepsis
(120% 11%) than in patients with non-septic chronic pancreatitis (105% 14%).
15
Patients with severe acute pancreatitis (more than three prognostic signs) had a mean
energy expenditure of 126% to 149% of predicted energy compared with those
having two or less prognostic signs (111% 15%) (p<.03).
15
Patients with severe
acute pancreatitis, defined by poor general physical condition, multiple organ sys-
tems failure, positive peritoneal signs, ascites, pancreatic enlargement with exudate
confirmed by non-invasive imaging techniques (ultrasound, CAT scan or magnetic
resonance imaging), and at least two abnormal clinical chemistries, usually present
with significant metabolic alterations.
16,17
Biochemical Abnormalities
Patients with severe acute pancreatitis present with metabolic, cardiovascular,
and hemodynamic features similar to those observed in sepsis. In addition to glu-
cose intolerance, ureagenesis is increased, net protein catabolism is accentuated by
70%-80%, and in some patients with acute pancreatitis, net nitrogen losses increase
to as much as 20 g to 40 g/day.
18,19
Decreased levels of total plasma proteins and
rapid turnover proteins, together with a marked decrease of the branched-chain
amino acid/aromatic amino acid (BCAA/AAA) ratio, further illustrate a
hypercatabolic state with significant protein breakdown. Significant decreases in
plasma essential amino acids, with marked reductions of almost all amino acids in
the liver and increased uptake of endogenous amino acids by the skeletal muscle
mass, have been reported clinically and experimentally.
17
Other biochemical abnormalities are also present and are considered to be useful
indicators of the severity of acute pancreatitis. Gross elevations in plasma concentra-
tions of the pancreatic enzymes usually accompany severe forms of the disease. How-
ever, although widely used in the clinical setting, the degree of elevation of plasma
326
20
amylase does not correlate well with the degree of severity of acute pancreatitis.
20
However, the ratio of the amylase clearance to the creatinine clearance has not been
found to be reliable in diagnosing acute pancreatitis.
Other enzymes that may be elevated in severe acute pancreatitis include plasma
lipase, phospholipase A, elastase, trypsin, chymotrypsin, and acid catalase. Plasma
levels of glucose, bilirubin, alkaline phosphatase, lactic dehydrogenase, and triglyc-
erides become moderately to highly elevated as the severity of the disease increases.
Increased plasma concentration of pancreas-specific protein (PASP) has been
found in acute pancreatitis and offers some promise as a novel assay for pan-
creatic cellular damage.
21
Recently, an acute-phase protein, the pancreatitis-associated protein (PAP), has
been found to be increased at least l00-fold in pancreatic tissue during the acute
phase in experimentally induced pancreatitis in rats.
22
This new protein was first
observed 6 hours after induction of experimental pancreatitis with taurocholate or
cerulein, reached maximal levels at 48 hours, and disappeared during recovery (day
5). This molecule is synthesized on the rough endoplasmic reticulum and stored in
zymogen granules before being secreted as are other pancreatic secretory proteins.
Other substances produced by the pancreas are reported to be increased during
acute pancreatitis. Among them, serum pancreatic phospholipase A
2
(PLA
2
), which
is secreted by pancreatic acinar cells as an enzymatically inactive proenzyme (pro
PLA
2
) but that is activated by trypsin, is significantly increased in patients with
acute pancreatitis and in the active phase of chronic pancreatitis. This enzyme is also
increased in patients in the early stage of pancreatic cancer; however in the terminal
state of pancreatic cancer, the serum PLA
2
level is low.
An important biochemical abnormality resulting from acute pancreatitis is the
depletion of intravascular albumin. Consequently, circulating protein-bound cal-
cium decreases, precipitating hypocalcemia, which may be accompanied by increased
plasma levels of parathormone and calcitonin.
23
In addition, plasma magnesium
levels decrease in patients with the more severe forms of acute pancreatitis. Other
trace elements are depleted
24
as a result of long standing secondary malnutrition and
not primarily because of the pancreatitis itself.
Lung Injury
Acute respiratory distress syndrome is a well recognized complication of acute
pancreatitis. Although the mechanism of action is unknown, the effects of pancre-
atic elastase in pulmonary vascular injury has been suggested.
25
Recent studies have
found that circulatory pancreatic proteases (alpha-chymotrypsin) can cause acute
lung injury that is mediated, at least in part, by toxic oxygen metabolites that are not
of neutrophil origin.
8
Elevated levels of free fatty acids or phospholipase associated
with pulmonary surfactant destruction, which consequently leads to the develop-
ment of atelectasis and fluid exudation, have been proposed as possible mechanisms
of injury.
26
Chymotrypsin may trigger proteolytic conversion of xanthine dehydro-
genase into the oxygen radical-producing xanthine oxidase in pulmonary artery en-
dothelial cells. Furthermore, alpha-chymotrypsin may stimulate radical oxygen me-
tabolite production in pulmonary endothelial cells.
8
Nutritional Management in Acute Pancreatitis
The severity of acute pancreatitis depends on the action of elevated pancreatic
enzymes associated with an inflammatory response of variable intensity that is
327
20
mediated by the activation of proteolytic systems and inflammatory cells. The preva-
lence of specific nutritional deficiencies in patients with acute pancreatitis depends
also on a number of other factors. Among them, the cause of the pancreatitis and
the severity of the disease, combined with premorbid nutritional status are the most
important. Because almost 80-90% of episodes of acute pancreatitis are short and
self-limited, exceptional nutritional measures in these patients are rarely indicated.
However, in those patients with severe pancreatitis who manifest more than two
adverse prognostic factors
27-30
(Table 20.3) at admission or who experience them
subsequently during the first 48 hours of hospitalization, individualized nutritional
support should be started as soon as possible.
The current general therapeutic principles in the nutritional management of
acute pancreatitis involve: aggressive nutritional support, essential to insure optimal
provision of nutrient substrates, and reducing pancreatic exocrine secretion and
maintaining the gastrointestinal tract and the pancreas at rest. Several reports
have confirmed that total parenteral nutrition (TPN) has substantially reduced mor-
bidity and mortality in this disease.
31-35
In one series, TPN reduced mortality from
26.1% to 14%.
33
In another study of 29 patients with moderate to severe pancreati-
tis, those receiving TPN had a mortality rate of 7% whereas those receiving only
conventional intensive therapy but without TPN had a mortality rate of 45%.
17
Yet others found no distinct advantage to the use of early TPN in acute pancreatitis
as measured by the number of days before oral feeding was started, length of hospi-
tal stay, and number of complications.
36
This failure to show an advantage of
TPN early in the course of acute pancreatitis may be secondary to the study
population and design, and perhaps the composition of TPN formula. Most
of the patients had mild pancreatitis, which would resolve anyway, and in patients
with fulminant pancreatitis and in those with multiple organ systems failure, nutri-
tional support was not carefully and individually tailored. The high rate of cath-
eter-related infections in this study was not explained.
Recently, TPN was found to be beneficial in patients with complex metabolic
alterations resulting from severe acute pancreatitis and in patients with underlying
malnutrition, before or after surgical intervention.
37
Thus, early aggressive nutri-
tional support is strongly recommended in these subgroups of patients. This recom-
mendation is based primarily on the potential benefits of TPN in acute pancreatitis,
which include, among others, the preservation or restoration of nutritional status in
patients who have not been fed for long periods, yet who are in a hypercatabolic
state with increased caloric and nitrogen demands, and on the beneficial impact of
TPN on the disease process by suppressing pancreatic secretion.
The Effects Of Nutrient Substrates
The effects of specific nutrient substrates on the exocrine pancreas and the best
route of their administration have been debated. Ingested nutrients stimulate
exocrine pancreatic secretion by activating enterohepatic reflexes and enteral hor-
mones and by directly affecting the pancreas. Total parenteral nutrition not only
provides all the nutrients but bypasses the effects of enterohepatic reflexes and en-
teral hormones. Intravenous infusion of 20% dextrose or 30% dextrose and 12%
amino acid solution significantly inhibited the secretion of secretin-pancreozymin
stimulated pancreatic juice and amylase in dogs with chronic fistulas.
38
Intravenous
administration of some amino acids, individually or in combination, also depressed
pancreatic exocrine secretions.
38,39
Moreover, it is well known that free amino acids
infused into the duodenum also decrease pancreatic secretion.
328
20
Inhibition of Pancreatic Secretion
Somatostatin is considered to be the best inhibitor of pancreatic secretion, and
its use in the treatment of acute pancreatitis, to directly inhibit pancreatic secretion,
is becoming standard clinical practice. In a large multicenter study, somatostatin,
when used with TPN, yielded the best results in a group of patients with necrotiz-
ing-hemorrhagic pancreatitis.
40
In humans, somatostatin inhibits HCL-induced and
alcohol-induced secretin secretion; inhibits cholecystokinin release; markedly in-
hibits pancreatic enzyme secretion; may reduce duodenal output of trypsin, chy-
motrypsin, and amylase by 65% to 90%; affects gut motility; slows gallbladder and
gastric emptying rates; and reduces the sphincter of Oddi basal pressure.
41
To sup-
press or neutralize pancreatic enzymes, the synthetic anti-proteases (gabexate mesilate
and nafamostat mesilate) have also been used to treat acute pancreatitis. In a recent
study, these two agents were useful in the treatment of experimental acute pancreati-
tis.
42
The strongest depressant of pancreatic exocrine secretion, other than soma-
tostatin and glucagon, is the infusion of hypertonic salts and dextrose into the je-
junum. On the other hand, hydrochloric acid, meat extracts, antral distention, fat,
protein, calcium, and magnesium all increase pancreatic exocrine secretion.
In acute experimental pancreatitis, pancreatic exocrine secretion has been found
to be suppressed.
43
The secretory blockade was found in different models of acute
pancreatitis and reflected the severity of the disease. Cholecystokinin-stimulated
secretion was almost abolished in vivo and in vitro at the time of maximal histologi-
cal damage.
43
Clinical studies indirectly evaluating pancreatic secretory function in-
dicated that pancreatic secretion is reduced in most patients between 3 and l0 days
after the onset of pancreatitis,
44
but secretions gradually improve in most patients
after a few months, although, in patients with severe necrotizing pancreatitis, com-
plete functional recovery may take more than one year.
45
Because pancreatic secre-
tion, especially pancreatic secretory response to cholecystokinin, is reduced during
Table 20.3. Factors adversely influencing survival in acute pancreatitis
I. At admission to hospital
Age >55 years
Hypotension
Abnormal pulmonary findings
Abdominal mass
Hemorrhagic or discolored peritoneal fluid
Increased serum LDH levels (> 350 IU/dL)
SGOT >259 U/dL
Leukocytosis (> l6,000/mm
3
)
Hyperglycemia (>200 mg/dL, no diabetic history)
Neurologic deficit (confusion localizing signs)
II. During initial 48 h of hospitalization
Fall in hematocrit > 10% with hydration and/or hematocrit <30%
Necessity for massive fluid and colloid replacement
Hypocalcemia (< 8 mg/dL)
Arterial PO
2
< 60 mm Hg with or without adult respiratory distress syndrome
Hypoalbuminemia (< 3.2 g/dL)
Base deficit > 4 mEq/L
Azotemia
329
20
acute pancreatitis, experimentally and possibly clinically, this secretory blockade
might, at least in part, explain why acute pancreatitis is not treated effectively by inhib-
iting secretion with atropine, cimetidine, glucagon, calcitonin, and somatostatin.
41
Rationale for TPN in Acute Pancreatitis
The indications for the use of TPN in severe acute pancreatitis are multiple and
usually urgent.
28,32,46,47
Not only may the nutritional status of these patients deterio-
rate rapidly, but prolonged ileus, respiratory and renal failure, severe metabolic aber-
rations, and multiple major surgical interventions will interfere with adequate oral
or enteral feeding, further complicating existing malnutrition. Indeed, providing
complete nutrient substrates via TPN while allowing pancreatic rest has been an
effective modality of nutritional support and has reduced morbidity and mortality
in these patients.
48-50
Other investigators
17,34
have concluded that the use of TPN in
the treatment of acute severe pancreatitis has decreased complications, has effec-
tively suppressed exocrine secretion, and has been an essential adjunct to conven-
tional intensive care. Adequate nutrition provided parenterally not only promotes
restoration of damaged pancreatic tissue, but enhances spontaneous closure of pan-
creatic fistulas,
48,51
and stimulates and maintains immunocompetence, thus poten-
tially improving the patients general condition before and after surgery. This will
allow surgical treatment of late-stage complications, such as pseudocyst, pancreatic
abscesses or fistulas.
52
Additionally TPN bypasses the cephalic, gastric, and intesti-
nal phases of pancreatic secretion, reducing by up to 50% the pancreatic acinar
nuclear volume, cell volume, and synthetic activity and substantially reducing the
basal pancreatic and proteolytic and bicarbonate secretions.
28,53,54
If, on the other
hand, the patient undergoes pancreatic debridement, surgeon should obtain long
term gut access by placing a surgical jejunostomy or at least a naso-jejunal feeding
tube, and start enteral feedings as soon as possible.
Dextrose and Amino Acids
Intravenous nutritional formulations should be selected on the basis of the ef-
fects that the individual nutrient substrates have on pancreatic secretions. Each nu-
trient has a different specific effect and a different potency for stimulating the re-
lease of each peptide hormone. Intravenous hypertonic dextrose suppresses both the
fluid volume and the proteolytic enzyme concentration of pancreatic secretion, an
action attributed in part to increased serum osmolality. The effect of amino acids in
suppressing pancreatic exocrine secretion is also well known. Even though patients
with severe acute pancreatitis are metabolically similar to septic patients with sig-
nificantly depressed uptake of the exogenous carbohydrate load, dextrose remains
the nutrient of choice as the main energy source in acute pancreatitis.
Patients with hemorrhagic necrotizing pancreatitis show persistent nitrogen loss
with low intracellular glutamine concentrations in skeletal muscle,
17
in addition to a
marked decrease in the BCAA/AAA ratio that correlates inversely with the progres-
sion of the disease.
38
Therefore, administering highly concentrated amino acid solu-
tions, augmented with extra valine, isoleucine, alanine, and arginine, which are sig-
nificantly decreased in plasma and tissue, has been recommended in the nutritional
support of patients with severe acute pancreatitis.
38
Nitrogen balance and amino
acid profiles have also improved when metabolically stressed patients were given
BCAA enriched solutions.
55
330
20
Lipids
The use of intravenous lipids as an energy source during acute pancreatitis has
been controversial.
56
Although infused intravenous lipid emulsions may appear to
be a safe and effective calorie source and may be helpful in acute pancreatitis com-
pounded by severe lung failure and by an elevated pCO
2
, each patient must be
closely monitored because fat infusion may aggravate pancreatitis in a significant
number of patients.
57
Intravenous fat administration has actually been identified as
the cause of pancreatitis in a patient with Crohns disease being treated with lipid-
based TPN, and patients receiving lipid-based TPN formulations have been known
to have significantly elevated serum AST.
56
A reduction in survival rate occurred in
patients receiving lipid emulsion combined with dextrose compared with patients
who received dextrose as their only energy source in the parenteral nutrition regi-
men.
17
Lipid emulsions should be avoided in patients with acute pancreatitis and
abnormal triglyceride metabolism . In laboratory animals with acute severe pancre-
atitis, studies with infused radioactive lipid emulsions have indicated that uptake of
the emulsion with production of CO
2
was slightly to moderately depressed, de-
pending on the structure of the fatty acids.
38
Others
50
have suggested that excess free
fatty acids damage capillary membranes and cause the consequent release of pancre-
atic enzymes, implying that elevated fatty acid levels may promote pancreatic exo-
crine secretion. Increased plasma triglyceride levels also cause acute pancreatitis.
Another clear contraindication to the use of intravenous lipid emulsions as the ma-
jor energy source in patients with acute pancreatitis is a lipid disorder (type I, IV and
V hyperlipoproteinemia). Because intravenous lipids also significantly increase pan-
creatic output in the form of bicarbonate and protein concentrations,
58
it appears
that the best dietary formulation for patients with severe pancreatitis is a fat-free
intravenous solution of crystalline amino acids and hypertonic dextrose to which
appropriate daily requirements of electrolytes, vitamins, minerals and trace elements
have been added.
Administration and Monitoring of TPN
Total parenteral nutrition is administered continuously over 24 hours, with ap-
propriate adjustments to infusion rate and nutrient concentration and composi-
tion.
46
Conscientious and meticulous biochemical and hematologic monitoring of
these patients is necessary to identify and promptly prevent and treat any renal fail-
ure, hepatic decomposition, or fluid, electrolyte and trace element imbalances that
might accompany unrelenting disease. Restoring nitrogen balance has a striking
beneficial influence on survival of the patient with severe pancreatitis, whereas
failure to achieve nitrogen balance has been associated with a ten-fold increase in
mortality (2.5% vs. 2l.4%, p<.0l).
56
H
2
receptor blockers should be added to the
infusion in standard intravenous doses to thwart gastric secretion, and human insu-
lin should be added as needed to control hyperglycemia. Both are compatible with
TPN formulations. Patients with severe necrotizing hemorrhagic pancreatitis may
require rather large amounts of insulin to maintain normal blood glucose levels,
especially in the presence of uncontrolled infection, occult abscesses or frank sepsis,
and diabetic ketoacidosis, alone or in combination.
The preferred route of nutritional support depends on the acuity and severity of
the disease, as well as an understanding of the physiology of pancreatic stimulation.
While parenteral nutrition has become a standard component of therapy in the
treatment of severe acute pancreatitis, enteral feedings, preferably immune-enhancing
331
20
diets, should be used whenever possible. Enteral feeding may supply nutrients if the
major responses to cephalic, gastric, and intestinal phases of pancreatic stimulation
are bypassed by infusion distal to the duodenum. Significant increases in pancreatic
secretions and protein output mediated by CCK-PZ stimulation are induced with
intraduodenal infusion of elemental diets in dogs;
59
therefore, intrajejunal feeding is
the method of choice. However, small bowel obstruction, enteritis, entero-enteric
and entero-cutaneous fistulas, or severe paralytic ileus often preclude enteral feeding
in patients with severe pancreatitis.
Maintenance of intestinal mucosal integrity and the gut mucosal barrier has
been suggested as a potential benefit of enteral feeding.
60
However, the most practi-
cal feeding method in patients with severe pancreatic inflammation, abscesses, and
fistulas is TPN. Failure to reduce pancreatic stimulation and to reverse malnutrition
as a major complication of severe acute pancreatitis may profoundly affect survival
of these patients.
56
Total parenteral nutrition should be continued until the symptoms abate, pan-
creatic encephalopathy and ileus resolve, and all serious metabolic derangements
disappear. Only when enteral intake can maintain optimal nutrition without exac-
erbating the symptoms of pancreatitis should TPN be discontinued.
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lishers, 1990.
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22. Klein V, Iovanna JL, Rohr G et al. Characterization of a rat pancreatic secretory
protein associated with pancreatitis. Gastroenterol 1991; 100:775-782.
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24. William RB, Russel RM, Dutta SK. Alcoholic pancreatitis - patients at high risk of
acute zinc deficiency. Am J Med 1979; 66:889-893.
25. Lungarella G, Gardi C, De Santi MM et al. Pulmonary vascular injury in pancre-
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inhibition of pulmonary phospholipid synthesis. Am J Surg 1987; 153:54-61.
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ease. Ann Surg 1984; 200:627-631.
28. Pitchumoni CS, Scheele GA. Interdependence of nutrition and exocrine pancre-
atic function. In: Go VLW, Dimagno EP, Gardner JD et al, eds. The pancreas:
biology, pathobiology and disease, 2nd ed. New York: Raven Press 1993:449-473.
29. Ranson JHC. Etiological and prognostic factors in human pancreatitis: a review,
Am J Gastroenterol 1983; 77:663-668.
30. Ranson JHC. Prognostication in acute pancreatitis. In: Glazer G, Ranson JHC,
eds. Acute pancreatitis, Bailliere Tindal, 1988.
31. Blackburn GL, Williams LF, Bistrian B et al. New approaches to the management
of severe acute pancreatitis. Am J Surg 1976; 131:114-124.
32. Copeland EM, Dudrick SJ. Intravenous hyperalimentation in inflammatory bowel
disease, pancreatitis and cancer. Surg Ann 1980; 12:83-101.
33. Feller JH, Brown RA, Toussaint GPM et al. Changing methods in the treatment of
severe pancreatitis. Am J Surg 1974; 127:196-201.
34. Funakoshi A, Yamada Y, Migita Y et al. Simultaneous determination of pancreatic
phospholipase A
2
and prophospholipase A
2
in various pancreatic diseases. Dig Dis
Scien 1993; 38;3: 502-506.
35. Goodgame JT, Fischer JE. Parenteral nutrition in the treatment of acute pancreati-
tis: effect on complications and mortality. Ann Surg 1977; 186:651-658.
36. Sax HC, Warner BW, Talanimi MA et al. Early total parenteral nutrition during
acute pancreatitis: lack of beneficial effects. Am J Surg 1987; 153:117-124.
37. Robin AP, Campbell R, Palani CK et al. Total parenteral nutrition during acute
pancreatitis: clinical experience with l56 patients. World J Surg 1990; 14:572-579.
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38. Ohyanagi H, Usami M, Nishimatsu SH et al. Metabolic changes and their man-
agement in acute pancreatitis. In Tanaka T, Okada A, eds.. Nutritional support in
organ failure. Amsterdam: Elsevier Science Publishers, 1990:351-363.
39. Saitoh Y, Honda T, Matsuno S et al. Effect of eight amino acids on the exocrine
and endocrine function. Tohoku J Exp Med 1979; 129:257-272.
40. Ladas SD, Raptis SA. Conservative treatment of acute pancreatitis: the use soma-
tostatin. Hepato-Gastroenterol 1992; 39:466-469.
41. DAmico D, Favia G, Biasiato R et al. The use of somatostatin in acute pancreati-
tis: results of a multicenter trial. Hepato-Gastroenterol 1990; 37:92-98.
42. Dobosz M, Sledzinski Z, Babicki A et al. Synthetic antiproteases in acute pancre-
atitis. Mount Sinai J Med 1992; 59:43-46.
43. Niederau C, Niederau M, Lthen R et al. Pancreatic exocrine secretion in acute
experimental pancreatitis. Gastroenterol 1990; 99:1120-1129.
44. Mitchell CJ, Playforth MJ, Kelleher J et al. Functional recovery of exocrine
pancreas after acute pancreatitis. Scand J Gastroenterol 1983; 18:5-8.
45. Angelini G, Pederzoli P, Caliary et al. Long-term outcome of acute necrohemorrhagic
pancreatitis. Digestion 1984; 30:131-137.
46. Latifi R, McIntosh JK, Dudrick SJ. Nutritional management of acute and chronic
pancreatitis. Surg Clin North Am 1991; 73:579-595.
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nutrition in acute pancreatitis. In: Hollender LF, ed. Controversies in Acute pan-
creatitis. Berlin: Springer-Verlag, 1982:293-296.
48. Dudrick SJ, Wilmore DW, Steiger E et al. Spontaneous closure of traumatic
pancreatoduodenal fistulas with total intravenous nutrition. J Trauma 1970;
10:542-553.
49. Variam FP. Central vein hyperalimentation in pancreatic ascites. Am J Gastroenterol
1983; 78:178-181.
50. White TT, Heinbach DM. Sequestrectomy and hyperalimentation in the treat-
ment of hemorrhagic pancreatitis. Am J Surg 1976; 132:270-275.
51. Rowlands BJ, Dudrick SJ. Nutritional support of the infected patient. In: Powanda
MC, Canonica PG, ds. Infection: The Physiologic and Metabolic Responses of the
Host. Amsterdam: Elsevier Science Publishers, 1981:359-397.
52. MacFadyen BV, Dudrick SJ, Ruberg RL. Management of gastrointestinal fistulas
with parenteral hyperalimentation. Surgery 1973; 74:100-105.
53. Johnson LR, Schanbacher LM, Dudrick SJ et al. Effect of long-term parenteral
feeding on pancreatic secretion and serum secretin. Am J Physiol 1977;
233:E524-E529.
54. Paviat WA, Rodgers W, Cameron JL. Morphologic analysis of pancreatic acinar
cells from orally fed and intravenously fed rats. J Surg Res 1975; 19:267-276.
55. Havalo T, Shrouts E, Cerra F. Nutritional support in acute pancreatitis. Gastroenterol
Clinic North Am 1989; 18:528-541.
56. Sitzman FJ, Steinborn PA, Zinner MJ et al. Total parenteral nutrition and alter-
nate energy substrates in treatment of severe acute pancreatitis. Surg Gyn Obstet
1989; 168:311-317.
57. Leibowitz AB, OSullivan P, Iberti TJ. Intravenous fat emulsions and the pancreas:
a review. Mount Sin J Med 1990; 59:38-42.
58. Konturek SJ, Tasler J, Cieszkowski M et al. Intravenous amino acids and fat stimu-
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59. Wolfe BM, Keltner FM, Zkraminski DL. The effect of an intraduodenal el-
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from gut. J Surg Res 1987; 42:536-.
CHAPTER 21
Nutritional Management of Chronic
Pancreatitis: Current Concepts
Rifat Latifi, Paul G. Perch and Stanley J. Dudrick
Introduction
Chronic pancreatitis is characterized histologically by progressive, destructive,
irregular, and irreversible fibrosis of the pancreas. Ultimately, it is manifested by
intermittent or persistent abdominal pain and signs and symptoms related to the
loss of pancreatic exocrine and endocrine functions, including maldigestion and
malabsorption, diarrhea, steatorrhea, and azotorrhea with subsequent muscle wast-
ing, weight loss, and pancreatic diabetes. The recurrent inflammatory process re-
sults in constrictive fibrosis and destruction of pancreatic tissue, leading to a significant
reduction of pancreatic cell mass. An anatomical and functional deterioration of the
pancreas progresses with each recurrence of inflammation. The most prominent
complaints are persistent dull epigastric pain radiating to the back particularly in
the region of the upper lumbar vertebrae, accompanied by anorexia, nausea, vomit-
ing and diarrhea that are intensified by eating. These unpleasant, uncomfortable
and often recalcitrant signs and symptoms regularly result in the systemic complica-
tions of malabsorption and malnutrition, multiple operations, narcotic dependency,
and associated debilitating psychological and social problems.
In addition, chronic pancreatitis may be manifested by a number of well-recog-
nized secondary complications such as common bile ductobstruction, gastric outlet
or duodenal obstruction, pancreatic ductstones, strictures or obstruction, pancre-
atic pseudocysts, pancreatic fistulas, (pancreatico-pleural, pancreatico-enteric,
pancreatico-cutaneous), portal vein thrombosis and splenic vein thrombosis.
12
These
serious conditions often indicate the need for complex surgical interventions, which
further aggravate overall poor nutritional and metabolic status of these patients.
Other less common complications associated with chronic pancreatitis include gas-
trointestinal bleeding, ascites, pleural effusion, development of carcinoma, retinal
changes, metastatic fat necrosis, intermedullary calcification and parotid hypertro-
phy. Physiologic changes in gallbladder motility and CCK secretion are also associ-
ated with pancreatic insufficiency due to chronic pancreatitis.
53
It has also been
demonstrated that the chronic inflammatory process in chronic pancreatitis alters
the distribution and function of immunocompetent peripheral blood lymphocytes.
49
The pancreas has multiple important functions, treating a patient who has lost
pancreatic function and has persistent and intractable abdominal pain represents a
very difficult challenge for all involved. Correcting nutritional deficiencies and
maintaining optimal nutritional and metabolic status for these patients is of utmost
335
Nutritional Management of Chronic Pancreatitis
21
importance in achieving a favorable outcome. This chapter reviews current concepts
in nutritional and metabolic support of patients with chronic pancreatitis, with
special attention to the role of exogenous pancreatic enzyme administration for the
optimal enhancement of digestion and absorption.
Etiologic and Risk Factors of Chronic Pancreatitis
The most common cause of chronic pancreatitis is excessive and prolonged alco-
hol consumption (about 75% of all cases). The remaining 25% of patients with
chronic pancreatitis have idiopathic, nutritional, hereditary, post-traumatic, con-
genital or metabolic etiologies.
3
Among the metabolic initiating factors, hyperpar-
athyroidism, hyperlipidemia, diabetes mellitus, and renal failure are the most
common. Other less common conditions or etiologies which are known to induce
chronic pancreatitis include pancreas divisum, cystic fibrosis, Ehlers-Danlos syn-
drome, vascular insufficiency, Crohns disease, and tuberculosis. The precise role of
gallstones or dysfunction of the sphincter of Oddi in the etiology of chronic pancre-
atitis remain controversial but it appears at the least to be a significant collateral
factor. Although many alcoholic patients also smoke, an independent and separate
causal relationship between smoking and chronic pancreatitis may exist, especially
in men. Other factors placing the patient at increased risk for chronic pancreatitis
include protein deprivation, cyanogenetic glycosides in cassava and chronic cyanide
toxicity (from smoking or cassava).
1
Deficiencies of trace elements such as zinc,
selenium, or copper may also play a role in the development of chronic pancreatitis.
Regardless of the original cause of chronic pancreatitis, recurrent inflammation
can lead to an obstructive process in the minor ducts. The morphologic changes
observed at the microscopic level include acinar cell apoptosis, ductular prolifera-
tion and fibrosis. In addition the pancreatic ducts exhibit tortuosity and periductal
fibrosis. These alterations are the suspected result of a defensive assault against el-
evated pancreatic duct pressures.
58
Eventually, ductal obstruction leads to a general-
ized deleterious effect throughout the entire organ with atrophy of both the acinar
and islet cells. The tissue remodeling that occurs appears to be correlated with the
up regulation of the lectins, galectin-1 and galectin-3.
59
However, these morpho-
logic changes will only result in the clinical manifestation of pancreatic exocrine
insufficiency if more than 90% of the gland has been destroyed and pancreatic li-
pase and trypsin output has decreased to less than 10% of normal.
Nutritional Deficiencies in Chronic Pancreatitis
In pancreatic failure caused by chronic pancreatitis, incomplete digestion of nu-
trients secondary to deficiencies of proteolytic, lipolytic, and amylolytic enzymes
occurs gradually but progressively. As dietary fat, protein, and vitamins are lost in
the stool, full-blown malabsorption eventually occurs with diarrhea, steatorrhea,
and azotorrhea. In normal individuals, fecal fat content does not change appreciably
after the ingestion of a high-fat diet. In contrast, the patient with chronic pancreati-
tis may have normal fecal fat levels while consuming a normal-fat diet, but will have
a high fecal fat level after ingesting a high-fat meal. Incomplete triglyceride diges-
tion is generally believed to be the primary cause of steatorrhea and eventual weight
loss. The patient with chronic pancreatitis may also reach a stage in which not only
fat is lost in the stool, but also incompletely hydrolyzed proteins resulting in im-
paired visceral and skeletal protein synthesis and muscle wasting. Deficiencies of the
fat soluble vitamins, A, D, E and K, are occasionally manifested as syndromes that
336
21
include night blindness, osteomalacia, neuropathy and coagulopathy, respectively.
Vitamin B
12
malabsorption and its secondary hematologic and neurologic effects
can occur secondary to deficiency of pancreatic protease, which is necessary to de-
grade the proteins bound to vitamin B
12
R-binding protein. Deficiencies of other
nutrients and essential minerals such as iron, magnesium, zinc, copper, and sele-
nium also occur.
4
Pancreatic Diabetes
Although islet cells account for only1-2% of the total pancreatic cellular mass,
this is ordinarily sufficient to maintain glucose homeostasis in the body. In chronic
pancreatitis patients, qualitative changes occur with fibrotic infiltration into the
islets of Langerhans, often splitting the islets into separate lobules.
5-7
Fasting serum
insulin levels in patients with chronic pancreatitis are normal to mildly elevated,
whereas insulin release is reduced after glucose stimulation, indicating a depletion of
insulin reserve. These effects on serum insulin levels have been hypothesized to be
secondary not only to a decrease in islet cell mass, but also to fibrosis that adversely
affects islet integrity by impairing local circulation and glucose diffusion. Beta cells
exhibit more susceptibility to sclerotic changes than cells.
6
Studies to date have
not demonstrated abnormalities in the function or number of cells in chronic
pancreatitis. Abnormalities in glucose metabolism in chronic pancreatitis occur as a
result of a combination of diminished production of endogenous insulin together
with insulin resistance.
8
Furthermore, new evidence also suggests that the insulin
mediated reduction of the facilitative glucose transport protein GLUT2 is impaired
in chronic pancreatitis and may also contribute to impaired glucose tolerance.
48
The overall incidence of impaired glucose tolerance in chronic pancreatitis varies
between 40-90%, yet overt diabetes develops in only 20-30% of these patients.
9
The usual onset of apparent diabetes in patients with chronic pancreatitis occurs
between 7 and 15 years after the initial diagnosis of pancreatitis.
Pancreatic diabetes may not differ clinically from other forms of diabetes, but
nonetheless has unique characteristics. Unlike other diabetics, chronic pancreatitis
patients generally have low plasma cholesterol and lipid levels, especially if steator-
rhea is pronounced. Furthermore, although regarded as insulin dependent, pancre-
atic diabetes has a number of metabolic characteristics that distinguish it from Type
I diabetes. For example, long-term complications such as retinopathy and nephr-
opathy are less frequent.
10
Vasculitis also an infrequent finding in pancreatic diabe-
tes. Keto-acidosis and diabetic coma occur only rarely, and when it occurs, the coma
is usually hyperosmolar and nonketotic.
Diagnosis of Malabsorption in Chronic Pancreatitis
A reduction in exocrine pancreatic cell mass results from the irreversible pancre-
atic fibrosis which occurs inevitably with chronic pancreatitis. Under normal condi-
tions, the acinar cells synthesize pro-teolytic, lipolytic, and amylolytic enzymes that
are secreted ultimately into the pancreatic ducts. However, small amounts of these
pancreatic enzymes are secreted into the bloodstream when their intraductal passage
has been partially or completely obstructed. As fibrosis progresses, the integrity of
the pancreatic tissue is disrupted, and large amounts of these enzymes diffuse into
the blood stream causing plasma amylase, lipase, and trypsin levels invariably to
become elevated. However, in chronic pancreatitis the plasma pancreatic enzyme
levels vary with the course and severity of the disease. The progressive destructive
337
21
fibrosis of the gland eventually causes plasma enzyme levels to decrease as the num-
ber of remaining functioning acinar cells capable of secreting digestive enzymes is
significantly reduced. During a relapse of chronic pancreatitis, the plasma enzyme
levels often rise transiently, but rarely to the levels seen in acute pancreatitis. On the
other hand, patients with chronic pancreatitis who have pseudocysts frequently
present with elevated plasma enzyme levels.
The two principal biochemical techniques for investigating exocrine pancreatic
function in patients with pancreatic inflammation involve direct and indirect meth-
ods. Direct function tests measure the composition of pancreatic secretions (bicar-
bonate and enzymes) obtained by intubation of the duodenum either in the normal
state or following a 90-minute intravenous infusion of secretin and cerulein.
11
Dem-
onstration of subnormal pancreatic enzymes or bicarbonate secretion is diagnostic
of chronic pancreatitis, however, pancreatic cancer must be excluded.
Indirect testing estimates the diminished digestive capability in pancreatic insuf-
ficiency by measuring plasma chymotrypsin and trypsin.
12
These tests are able to
demonstrate only severely decreased exocrine function, which is characteristic of
late stages of chronic pancreatitis, but not early stages of the disease. Other measure-
ments of intraluminal digestion such as stool examination for undigested meat fi-
bers, or determining enzyme effectiveness by fecal fat quantitation or plasma amino
acid levels following hormonal stimulation may also be useful in assessing pancre-
atic insufficiency.
13
In general, if pancreatic function tests are carried out appropri-
ately, they are reliable in documenting the severe exocrine insufficiency of chronic
pancreatitis. For example, direct intubation of the duodenum has a sensitivity of
97% and a specificity of 98%.
11
The
14
C-triolein breath test has been shown to be
sensitive and sufficiently specific to screen for fat malabsorption. More recently the
cholesterol 13C-octanoate breath test has been introduced and offers unique possi-
bilities. Unlike direct duodenal intubation, this new technique measures the overall
functional level of lipase activity in the intestinal lumen.
14
However, the relevance of
these tests is greater in the management of mild or moderate cases of chronic pan-
creatitis, in which they can not only predict the necessity for supplemental enzyme
therapy, but also stage the severity of the disease.
12
Although the previously
outlined studies are reliable in diagnosing chronic pancreatitis, none the less
these procedures can be cumbersome, time consuming, unpleasant for patients
and potentially dangerous.
Principles of Clinical Management of Chronic Pancreatitis
Regardless of whether an episode of pancreatitis is an initial presentation of acute
pancreatitis or an acute exacerbation of chronic pancreatitis, the preeminent symp-
tom is usually a rather constant, severe, and unrelenting pain in the epigastrium and
mid-abdomen that penetrates directly posterior to the vertebral column and is ag-
gravated by oral ingestion. Postprandial abdominal pain is very common in chronic
pancreatitis, and fear of pain may further contribute to reduction of food intake.
Persistent anorexia, nausea, and vomiting will eventually lead to weight loss,
as discussed earlier.
The nutritional management of chronic pancreatitis depends on the stage of the
disease. For critically ill patients in the acute phase, absolute restriction of all food
intake is required in order to minimize and to prevent exacerbations of the disease
by preventing stimulation of the gland. Nutrients should be supplied by total
parenteral nutrition (TPN) to ensure maximal rest of the pancreas and to maintain
338
21
an optimal nutritional and metabolic status. For less severely ill patients who are
able to maintain nourishment by mouth, the main goals of judicious dietary inter-
vention are: to correct existing nutrient deficiencies, to compensate for exocrine
pancreatic deficiency, and to attempt to relieve or obviate pain.
The initial approaches to treatment of such patients is dependent to some extent
upon the nature and severity of the pancreatitis, on the training and experience of
the responsible physicians, and on the resources and technology available.
15-17
The most mild forms of pancreatitis can usually be managed conservatively by
admitting the patient to the hospital and instituting a regimen of adequate analge-
sia, H
2
receptor blockers, and a low-fat diet. Should severe pain and vomiting persist
or should the patients general condition deteriorate, more aggressive management
may be required which may include prohibition of oral intake, nasogastric suction,
and various invasive diagnostic and drainage procedures. Excessive alcohol intake
and/or dietary indiscretions are the most frequent precipitating factors of acute ex-
acerbations of chronic pancreatitis. Thus, it is essential to insist upon absolute absti-
nence from alcoholic beverages in all patients with chronic pancreatitis not only for
the purposes of prophylaxis and treatment of the primary disorder, but to maintain
long-term optimal nutrition status. Dietary carbohydrates should be limited in pa-
tients manifesting glucose intolerance. On the other hand, protein is usually well
tolerated in patients with chronic pancreatitis. A high protein, high carbohydrate
diet is the primary nutritional goal, supplemented with medium-chain triglycerides
as tolerated. TPN should be instituted when these measures fail to meet nutritional
requirements. In addition to providing adequate energy and protein intake, other
important components of comprehensive oral therapy include multiple vitamins,
minerals, trace elements and pancreatic enzymes.
Enteral Feeding
Hypercatabolism associated with chronic pancreatitis can lead to prolonged nega-
tive nitrogen balance, making nutritional support vital to these patients. A trial of
pancreatic rest is considered beneficial because it results in reduction of pancreatic
secretions and minimizes exposure of damaged tissues to endogenous proteolytic
enzymes. The fundamental goal of therapy in chronic pancreatitis, therefore, is to
provide optimal nutritional support with minimal stimulation of pancreatic exo-
crine secretory function while allowing the inflammatory process to resolve. Whereas
oral feeding of regular food obviously stimulates pancreatic exocrine secretion, oral
elemental diets produce much less pancreatic volume and enzyme secretion.
18,19
If
elemental diets are infused by tube into the duodenum rather than into the stom-
ach, the volume of pancreatic secretions is reduced further, but without a concomi-
tant decrease in enzyme secretion, in a manner similar to the response produced by
intravenous CCK infusion.
20,21
The effects of jejunal infusion of elemental diets
have been variable and controversial.
22,23
It appears, however, that pancreatic rest
with enteral feeding can be best achieved if elemental diets are in fused intrajejunally
or nasojejunally rather than intragastrically or intraduodenally. Obviously, the deci-
sions regarding the route and type of feeding must be individualized. Although
patients with mild forms of chronic pancreatitis can often be managed with
intrajejunal feeding of an elemental formula, satisfying the requirements for calories
and protein may be difficult to achieve enterally, primarily because enteral feeding
must be introduced at low volumes and concentrations and increased gradually and
slowly, and intestinal intolerance of the feedings may require that the infusion be
339
21
reduced to a less than optimal rate and volume. Moreover, enteral feeding is often
precluded by ileus or some other gastrointestinal malfunction, often related to a
complication of the primary disease. Should a patient require operative intervention
for any reason, a feeding jejunostomy should be inserted for postoperative nutrient
infusion controlled by a continuous pump equipped with safety monitors and alarms.
Total Parenteral Nutrition
TPN has become an important adjunct to conventional medical and surgical
therapy, particularly in a patient having an acute exacerbation of chronic pancreati-
tis. TPN can replenish previously acquired nutritional deficiencies and restore im-
mune function to normal, thus reducing morbidity and increasing survival.
24
During
anacute exacerbation of chronic pancreatitis, time honored supportive management
requires the cessation of all oral intake. Nasogastric tube aspiration may further
reduce the stimulatory effect of intraluminal contents on pancreatic secretions. These
measures obviously compound existing nutritional depletion, which may be reduced
or obviated by early initiation of TPN. An additional beneficial effect of TPN is that
the nutrient infusion greatly reduces both the volume and enzyme content of pan-
creatic exocrine secretion to basal levels. In general, TPN is usually indicated early in
the course of severe disease and early post operatively, wit h gradual conversion to
enteral feeding as the patient s condition improves.
Nutrient Substrates in Chronic Pancreatitis
Amino Acids
TPN regimens should consist initially of only dextrose and amino acids together
with essential vitamins, minerals and trace elements until levels of serum triglycer-
ides and lipids have been determined. Although daily energy requirements can be
estimated by various techniques with appropriate activity factors and stress factors
added, the total nonprotein calorie ration required is usually less than 2500 kcal/
day. Since the calorie:nitrogen ratio should be approxi-mately 100:1, the total pro-
tein provided should be approximately 2-2.5 g/kg/day. In patients with severe pan-
creatitis, the changes in skeletal muscle protein metabolism and amino acid
concentrations are similar to those observed in patients following major operations
or major trauma, during sepsis, or with multiple systems organ failure.
24
The total
free amino acid pool decreases to about 40% of normal, and intracellular skeletal
muscle glutamine declines to levels as low as 15% of normal. These changes in
specific amino acid concentrations indicate that parenteral infusion of replacement
nutrient solutions richin branched chain amino acids and/or in glutamine may sup-
port the underlying metabolic derangement and may be beneficial clinically to pa-
tients with severeforms of pancreatitis. No clinical studies to date, however, have
demonstrated that the administration of branched chain amino acid preparations,
nor of glutamine, have a beneficial effect on the ultimate outcome of severe
chronic pancreatitis.
Dextrose
In seriously ill patients with pancreatitis, glucose clearance and utilization may
be significantly impaired and below maximal capacity. Accordingly, intravenous dex-
trose substrates should never be administered in excess of the maximal capacity to
metabolize glucose (4-5 mg/kg/min). Moreover, if dextrose is infused in an amount
exceeding the glucose utilization rate, hepatic steatosis will inevitablydevelop.
25
340
21
Therefore, dextrose should provide no more than 60% of a patients total caloric
needs and should not be infused at a rate greater than 3.0 mg/kg/min.
8
Insulin can
be added to the nutrient mixture or, if preferred, in a separate infusion as required to
achieve this goal without exceeding it. Serum glucose levels should be closely moni-
tored, and insulin should be added either as a separate peripheral infusion ordirectly
to the TPN solution in order to maintain the serum glucose level below 200 mg/dL.
Lipids
The use of lipid emulsions in the nutritional management of patients with chronic
pancreatitis continues to be controversial primarily because of the etiologic associa-
tion of hyperlipidemia with pancreatitis.
26-30
Because some patients may have a pre-
viously unrecognized lipid disorder or impaired ability to metabolize lipids, the
administration of lipid emulsions to patients with pancreatitis requires careful con-
sideration and observation. Patients who have had previous episodes of pancreatitis
may have an impaired ability to clear circulating lipid and may, therefore, be suscep-
tible to the development of hyperlipidemia while receiving an infusion containing
fat emulsion. Thus, it is imperative to determine serum lipid levels both before
infusion in patients with pancreatitis and after infusion to demonstrate adequate
clearance of the lipid from the plasma. Numerous clinical trials have reported the
relative safety of administration of intravenous fat emulsions in patients who have
pancreatitis and in whom hypertriglyceridemia was not an etiologic factor for their
disease. If it is determined that the serum triglyceride level is normal and intrave-
nous lipids are desirable to meet caloric needs, the TPN regimen should supply no
more than 1.5 g fat/kg/day, and the fat should not provide more than 30% of total
nonprotein calories.
Enzyme Treatment of Exocrine Pancreatic Insufficiency
Pancreatic exocrine insufficiency, endocrine insufficiency and pain are leading
manifestations of chronic pancreatitis.
2
Because of the large functional reserve of the
gland, steatorrhea secondary to incomplete digestion of ingested fats does not occur
in exocrine pancreatic insuf ficiency until approximately 90% of pancreatic secre-
tory function is lost, at which point exogenous pancreatic enzyme administration
becomes necessary for maintaining adequate digestion and absorption.
A variety of commercially available pancreatic enzyme preparations allow suc-
cessful supplemental or replacement therapy in exocrine pancreatic insufficiency or
failure. Pancreatin, which is derived from porcine or bovine pancreas, by alcohol
extraction, is a major source of these enzymes. Lipase-augmented pancreatin, known
generically as pancrelipase, may reduce steatorrhea more effectively than pancreatin
on an equal-weight basis.
31
In addition, a vegetable-derived form of pancreatin is
available for patients with sensitivities to porcine or bovine protein.
Based on normal pancreatic secretion after maximal stimulation with cerulein
and secretin, a secretory capacity of 10% corresponds approximately to 100,000
units of lipase activity.
46
Accordingly, effective control of steatorrhea will ordinarily
require the administration of at least 100,000 units of lipase per day. Therapeutic
success has been documented by a 50% reduction in stool fat with this dosage, and
a 70% reduction with a dosage of 200,000 units of lipase per day. Only rarely is
complete restoration of lipid hydrolysis possible, and as much as 100,000 units of
lipase are required per meal. Most pancreatic preparations containonly 3,500 to
10,000 units of lipase per dose,
32
requiring patients to take a large number of tablets
341
21
daily. However, a high potency enzyme tablet is now available that contains 22,500
units of lipase and 180,000 units each of protease and amylase, respectively.
Degradation in an acid environment is the major problem with these enzyme
preparations, especially lipase which is irreversibly denatured at a pH <4.33. Im-
proved digestive efficiency has been achieved by the simultaneous administration of
antacids or H
2
receptor blocking agents, thereby substantiating the clinical relevance
of acid degradation. Patients with refractory steatorrhea may benefit by the addition
of H
2
antagonists and proton pump inhibitors to their pancreatic enzyme replace-
ment therapy.
52
Enteric coated preparations that release the hydrolytic enzymes at a
pH above 5.5 have been developed and are currently available. The current recom-
mendations for using the ph-sensitive pancreatin microspheres are at a dose of 25,000
to 40,000 units per meal.47 Nonetheless, these preparations still lose much of their
activity along the gastrointestinal tract because only approximately 22% of trypsin
activity and 8% of lipase activity delivered by pancreatin have been found postpran-
dially past the ligament of Treitz.
34
In addition, because fiber has been shown to
inhibit pancreatic enzymes in vitro and in vivo, a fiber enriched diet should not be
given together with pancreatic enzymes.
12
Side effects of pancreatic enzymes may occur, but only rarely are of clinical sig-
nificance. Allergies to porcine preparations are possible and should be considered
following any immediate hypersensitivity reaction to powdered pancreatic extracts.
35
Oral pancreatic extracts can form insoluble complexes with folic acid and, by im-
pairing folate absorption
36
can affect iron absorption, especially in patients with
cystic fibrosis.
37
Hyperuricemia and hyperuricosuria can also occur in patients using
these preparations.
Most patients respond well to pancreatic enzymes. With failure of the patient to
respond to exogenous pancreatic enzymes, one must consider the patients noncom-
pliance, incorrect diagnosis (or overlooking other diseases or conditions ), incorrect
prescription of medication, or incorrect choice of pancreatic enzyme preparation.
38
Total elimination of steatorrhea may be prevented by the concomitant existence of
other factors and diseases that cause steatorrhea, such as celiac sprue, giardiasis, and
bacterial overgrowth; incomplete gastric emptying of the pancreatic enzyme prepa-
ration and food; low micellar concentrati on of bile salts; and susceptibility of lipase
to gastric acidity and chymotrypsin hydrolysis.
38
The Role of Exogenous Pancreatic Enzymes
in Pain Management
It has been hypothesized that enzyme preparations relieve pain accompanying
chronic pancreatitis.
39-41
The cause of this pain is poorly understood but is thought
to be secondary to multiple factors including ductal hypertension and obstruction,
recurrent auto-digestion, and increased nerve infiltration.
40
Alterations in
intaduodenal bile acids and plasma CCK concentrations may also be implicated in
the pathogenesis of pain.
54
In addition increased proliferation of peripheral mono-
nuclear cells and their demonstrated increase release of in vitro tumor necrosis fac-
tor-alpha and interleukin-10 have been hypothesized to contribute to pain
development.
55
In several controlled studies, most patients experienced a reduction in pain with
administration of pancreatic enzyme supplements that increased the levels of in-
traluminal proteases.
40-42
More profound effects of pain relief were noted with mod-
erate pancreatic insufficiency than with severe pancreatic insufficiency.
42
Greater
342
21
relief of pain was achieved in patients who ingested the enzymes adlibitum in re-
sponse to the pain in addition to ingesting thei rprescribed standard doses of diges-
tive enzyme tablets.
41
The effect of acid-protected porcine pancreatic extracts on
pain was studied in a prospective placebo-controlled, double-blinded, multicenter
study.
43
In 43 patients with chronic pancreatitis, pain improved in most patients
irrespective of study group, thus the two treatment arms did not significantly differ.
Nonetheless, most authorities recommend that enzyme preparations, taken as re-
quired to relieve pain in patients with chronic pancreatitis, should be given at least a
two-month trial. If the pain does not decrease within that time, treatment should be
discontinued if analgesia rather than digestive enzyme replacement has been the
only reason for prescribing the medication.
The choice of enzyme replacement therapy depends on the dominant symptoms
present. If used for relief of pain only, enzymes high in protease are more desirable;
however, if used for amelioration of malabsorption, enzymes high in lipase and low
in protease should be used. In patients having both pain and malabsorption, prepa-
rations with high lipase and trypsin but without chymotrypsin should be used.
38
Antioxidant therapy with a complex of L-methionine, beta-carotene, vitamin C,
vitamin E, and organic selenium may also have a positive effect in patients who
suffer from pancreatic inflammatory pain.
50
Efforts to limit the stimulation of the exocrine pancreas by decreasing CCK
release through dietary modulation may be beneficial in relieving postparandial pain.
51
The Effect of Exogenous Enzymes
in Gastrointestinal Hormones
The effect of exogenous pancreatic enzymes on the enteropancreatic axis is com-
plete.
44
The feedback control of pancreatic secretion clearly depends on the dose
and the site of the administration of exogenous enzymes. Intraluminal duodenal
perfusion of pancreatic enzymes inhibits protease activity in patients with chronic
pancreatitis. This protease-mediated negative feed back of pancreatic secretion ap-
pears to be controlled largely by a duodenal mechanism. When infused into the
duodenum, exogenous pancreatic enzymes have no effect on gastrin release. On the
other hand, they do affect gastric inhibitory polypeptide (GIP) and following exog-
enous exocrine enzyme replacement in patients with chronic pancreatitis, increased
levels of GIP have been measured.
45-47
Conclusion
Chronic pancreatitis is a complex disorder induced by different causes, but mani-
fested by exocrine and endocrine insufficiency. Multiple nutritional and metabolic
derangements result from maldigestion and malabsorption, resulting in malnutri-
tion with severe weight loss. Persistent abdominal pain and potentially multiple
various complications requiring surgical intervention further diminish the patients
already compromised quality of life. Caring for this group of patients demands con-
scientious teamwork, persistence and dedication. Although very important, nutri-
tional support is only one aspect of comprehensive care. Nutritional management
ranges from simple dietary manipulation, with or without administration of
digestive enzymes, to enteral supplementation with modular or chemically defined
diets to total parenteral nutrition, depending on the stage, severity, manifestations
and complications of the disease.
343
21
Thus, close follow-up of patients with chronic pancreatitis is necessary and should
include:
25
1. individually tailored dietary counseling;
2. conscientious monitoring of glucose metabolism;
3. judicious administration of pancreatic enzyme supplements which must
be tailored to meet the need for adequate disease and possibly pain control;
4. control of gastric hyperacidity;
5. reduction of intestinal hypermotility;
6. definitive surgical management of biliary lithiasis; and
7. absolute abstinence from alcohol.
Even with all these measures, chronic pancreatitis can be a disabling disease. As
the pathophysiology of this complex process becomes better defined and under-
stood, new avenues for treatment likely to be developed. At the frontier, pancreatic
regeneration and autoislet transplantation are in their infancy but may prove prom-
ising for managing these chronically ill patients.
56,57
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3. Holt S. Chronic pancreatitis. South Med Jour 1993; 86:201-206.
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11. Gullo L. Direct pancreatic function test (duodenal intubation) in the diagnosis of
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13. Hosoda S. Evaluation of digestion-absorption test for measuring exocrine pancre-
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exogenous cholecystokinin on the exocrine pancreatic and biliary secretions in man.
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MC, Canonica PG, eds. Infection: The Physiologic and Metabolic Responses of
the Host. Amsterdam: Elsevier, 1981:359-397.
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chronicpancreatitis. Surg Clin North Am 1991; 71:579-595.
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101:1-14.
27. Cameron JL, Capuzzi DM, Zuidema GD et al. Acute pancreatitis with hyper-
lipemia: Evidence for a persistent defect in lipid metabolism. Am J Med 1974;
56:4382-487.
28. Gossum AV, Memoyne M, Greig OD et al. Lipid-associated to total parenteral
nutrition in patients with severe acute pancreatitis. J Parenter Enteral Nutr 1988;
12:250-255.
29. Davidoff F, Tishler S, Rosoff C. Marked hyperlipidemia and pancreatitis associ-
ated with oral contraceptive therapy. N Engl J Med 1973; 289:552-553.
30. Guzman S, Nervi F, Llanos O et al. Impaired lipid clearance in patients with pre-
vious acute pancreatitis. Gut 1985; 26:888-891.
31. Noseworthy J, Colodny AH, Erakalis AJ. Pancreatitis and intravenous fat: An as-
sociation in patients with inflammatory bowel disease. J Pediatr Surg 1983;
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32. Howard J M. Treatment of pancreatic malabsorption syndrome. In: Howard JM,
Jordan GL Jr, Reber HA, eds. Surgical Diseases of the Pancreas. Philadelphia: Leaand
Febiger, 1987:522-527.
33. Otte M, Ridder P, Pageforde J. In vitro Intersuchungen zur Pankreas-Enzym-sub-
stitution. Dtsch Med Wochenschr 1987; 112:1498-1502.
34. Heizer WD, Cleveland CR, Iber FL. Gastric inactivation of pancreatic enzyme
supplements. Bull Johns Hopkins Hosp 1965; 116:261-270.
35. DiMagno EP, Malagelada JR, Go VLW et al. Fate of orally ingested enzymes in
pancreatic insufficiency. Comparison of two dosage schedules. New Engl J Med
1977; 296:1318-1322.
36. Otte M, Riddler P, Gutowski HD. Substitutions Behandlung der Pankreas
Inaffinuffzienz mit Pankreatin-Fertigarz Neien. Inter Prax 1989; 29:185-189.
37. Dutta SK, Russell RM, Iber FL. Impaired acid neutralization in the duodenum in
pancreatic insufficiency. Dig Dis Sci 1979; 24:775-780.
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38. Zempsky WT, Rosenstein BJ, Carrol JA et al. Effect of pancreatic enzyme supple-
ments on iron absorption. Am J Dis Child 1989; 143:969-972.
39. Lankisch PG. Enzyme treatment of exocrine pancreatic insufficiency in chronic
pancreatitis. Digestion 1993; 54(Suppl 2):21-29.
40. Ihse I, Andersson R, Axelson J. Pancreatic pain: Is there a medical alternative to
surgery? Digestion 1993; 54(Suppl 2):30-34.
41. Ihse I, Permeth S. Enzyme supplementation for pain in chronic pancreatitis. In:
Berger HG, Buchler M, Ditschuneit H et al, eds. Chronic pancreatitis. Berlin:
Springer-Verlag, 1990:354-357.
42. Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in
chronic pancreatitis. Dig Dis Sci 1983; 28:97-102.
43. Ramo OJ, Puolakkaimen PA, Seppalok et al. Self-administration of enzyme sub-
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44. Mossner J. Is there a place for pancreatic enzymes in the treatment of pain in
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45. Malfertheimer P, Dominguez-Munoz JE. Effect of exogenous pancreatic enzymes
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50. De las Heras Castano G, Garcia de la Paz A, Fernandez MD et al. Use of antioxi-
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Lab Invest 2000 Aug; 80(8):1233-41.
CHAPTER 22
Nutritional Support in Liver Failure and
Liver Transplantation
Rifat Latifi
Introduction
Liver transplantation (LT) has evolved into the most successful form of treat-
ment for end-stage liver disease (ESLD), with operative survival exceeding 90% for
the firstgraft, retransplant free survival greater than 85% at one year,
1,2
and pre-
dicted actuarial survival over 75%.
3
Although the indications for LT have become
more standardized (in adults as well as in children), 89% of adult patients undergo-
ing LT have advanced cirrhosis (secondary to primary cholestatic liver disease, alco-
holism, hepatitic C/non-A-non-B, autoimmune hepatitis, 0 or hepatitis B), followed
by fulminant hepatic failure (5.5% -7.0%), metabolic disease (4%), malignant and
benign neoplasms (3%-6% and 0.5% respectively), biliary atresia (0.5%), and other
miscellaneous indications (1.8%-2%).
3
On the other hand, the most common indi-
cations for LT in children are extrahepatic atresia (>50%) and alpha-1-antitrypsin
deficiency (9%-14%), followed by metabolic diseases (12%-13%), cirrhosis (7%)
and other indications.
4
Patients who have undergone LT, or are awaiting LT, represent the most complex
medical challenges. These patients are often plagued with multiple comorbid dis-
eases and require meticulous, well-planned and executed, highly individualized
medical care. Since the liver plays a major function in metabolic homeostasis, nutri-
tional and metabolic support becomes one of the most important therapeutic inter-
ventions. Malnutrition and its associated sequella are common features in patients
with chronic liver disease in general, and most patients awaiting LT are no excep-
tion. Malnutrition in this group of patients is a consequence of increased nutrient
requirements in the presence of hypermetabolism, anorexia and inadequate oral
intake, associated with concomitant impaired digestion, absorption, and assimila-
tion of nutrients.
Maintaining adequate nutrition represents a significant therapeutic challenge,
considering the profound metabolic alterations that impair the incorporation of
nutrient substrate into tissue. A vicious cycle then occurs, in which the patient is
profoundly hypoproteinemic, reflecting the depleted stores and synthetic activity of
the liver, and hypercatabolic, while at the same time provision of protein may result
in hyperammonemia and aggravation of existing encephalopathy. Although poor
nutritional status increases morbidity and mortality perioperatively, it is difficult to
correctly identify and quantify the impact of individual nutrient therapy on patients
with ESLD requiring LT.
347
Nutrition Support in Liver Failure and Liver Transplantation
22
Malnutrition in Patients with Chronic Liver Disease
The complex metabolic derangements that accompany liver failure reflect the
magnitude of the problems associated with liver failure (Table 22.1).
5
The frequency
and the degree of malnutrition varies among patients studied.
6
In one study, malnu-
trition was present in all 74 patients undergoing LT.
7
Patients with primary biliary
cirrhosis retained their hepatic synthetic function better than others despite extreme
wasting of muscle and fat.
8
Others
9
found malnutrition present less frequently (79%)
and no differences in nutritional status with regard to the etiology of chronic liver
disease. The etiologic factors of malnutrition in chronic liver disease are multiple
and synergistic in nature.
10
Among these factors, anorexia, nausea, vomiting, poor
dietary habits, malabsorption, frequent large volumes therapeutic paracenteses, and
inadequate protein and caloric intake are the most common. The mechanisms of
malnutrition varies and may include catabolism and altered hepatic metabolism of
key nutrients: carbohydrates, fat and protein.
10-12
The hepatocellular dysfunction that causes unique changes of protein, carbohy-
drate and fat metabolism becomes more prominent during the fasting state,
10,11
when a starvation type metabolism develops. Hepatic glycogen depletion occurs
rapidly (10-12 h instead of 36-48 h) resulting in accelerated and premature protein
catabolism.
Hepatic glucose production and peripheral glucose oxidation are significantly
decreased. This prevents fasting hypoglycemia. Serum free fatty acids are increased
secondary to increased peripheral lipolysis, which in turn stimulates ketogenesis.
12
Ketogenesis, however, ultimately fails with worsening of liver failure. In addition to
protein, fat, and carbohydrate metabolic abnormalities, impaired hepatic function
results in vitamin and mineral deficiencies. When patient condition deteriorates
and nutrient metabolism becomes insufficient to maintain body homeostasis, as in
the late stages of cirrhosis, or infulminant hepatic failure, liver transplantation be-
comes the only current, long-term live saving intervention.
Hepatic Encephalopathy
When the liver fails or blood is shunted past the liver, hyperammonemia results
and brain function deteriorates. This frequent complex syndrome in patients with
ESLD, known as hepatic encephalopathy, is manifested by varies signs and symp-
toms that range from rapidly developing delirium, convulsions and coma in acute
failure to more gradually impairment of intellect that eventually leads to stupor and
coma in chronic liver failure
13
(Table 22.2). Progression and severity depend on
whether the disease is in an acute or chronic stage and on the magnitude of the
insult to the liver. Although, the exact biochemical mechanisms and neurochemical
pathways of this complex condition are not known, one or more of several mechanisms
may adversely affect the brain function of patients with liver failure
14
(Table 22.3).
The blood-brain barrier (BBB) consists of tight junctions of endothelial cells in
the cerebral capillary bed. If substances are to affect the brain and tissues, they must
penetrate this barrier. Transport of substrates through the BBB is strictly regulated
and depends on their lipid solubility and on specific transport systems. For example,
amino acids and glucose have their own unique and distinct carrier systems for
transportation into the brain. The effectiveness of this physiologic barrier protects
the organisms from the potentially adverse effects of serious metabolic changes. In
HE, however, the BBB commonly breaks down, as demonstrated by the uptake of
substances that otherwise are not taken up by the brain.
15
In addition, hepatic
348
22
encephalopathy significantly alters the BBB which affects specific transport systems
of neutral amino acids, glucose, ketone bodies, and basic amino acids. Transport of
neutral amino acids into the brain significantly increases, whereas the transport of
glucose, ketone bodies, and basic amino acids decreases.
16,17
On the other hand,
BBB alteration may be consequence of a generally nonspecific increased permeabil-
ity, which can expose the brain to a variety of neurotoxic substances circulating in
the blood and possibly cause cerebral edema.
Portal-systemic shunting of blood is associated with hyperammonemia, increased
glutamine concentration in the brain, an altered plasma neutral amino acid pattern,
and high levels of several large neutral amino acids in the brain. An altered amino
acid pattern is caused by liver disease as much as by portal-systemic shunting. The
amino acids of great importance in hepatic encephalopathy are tyrosine, phenylala-
nine, and tryptophan because they are involved in the synthesis of the catechola-
mines dopamine, noradrenaline, and serotonin and are potential precursors of false
neurotransmitters, such as octopamine or tryptamine.
18
These amino acids together
Table 22.1. Metabolic alterations in chronic liver disease*
Alteration Mechanism
Increased plasma glucagon Portosystemic shunting
Impaired hepatic degradation
Hyperammonemia
Increased plasma aromatic Hyperinsulinemia
amino acids Increased peripheral insulin resistance
Decreased effective insulin to glucagon ratio
Impaired hepatic function
Increased plasma epinephrine Impaired hepatic function
and cortisol
Decreased liver and muscle Accelarated glycogenolysis
carbohydrate Impaired glycogenesis
Accelarated gluconeogenesis Hyperglucagonemia
Hyperglycemia Portosystemic shunting
Increased glucose production
Decreased insulin-dependent glucose uptake
Decreased insulin-dependent hepatic glycolysis
Hyperammonemia Deamination and accelerated bacterial
degradation of protein in the colon
Increased plasma aromatic Decreased hepatic clearance
amino acids Increased release into circulation
Hypoalbuminemia, hyperbilirubinemia
Decreased incorporation of aromatic amino acids
into proteins
Increased plasma methionine, Decreased hepatic clearance
glutamine, asparagine, histidine
Decreased plasma Hyperinsulinemia
branched-chain amino acids Excessive uptake
Increased use of BCAA as energy source
*Adapted from Latifi R, Killam J, Dudrick SJ: Nutritional support in liver failure. Surg Cli
North Am 1991; 71:567-578.
349
22
with leucine, isoleucine, valine, methionine, threonine, and histidine compromise
the group of large neutral amino acids that have a common blood-brain transport
system. Other amino acids, such as glutamate, aspartate, taurine, and glycine, can
also act as neurotransmitters. Because some of these amino acids are precursors for
neurotransmitters and other potentially neuroactive substances, high central ner-
vous sytem levels of these amino acids may contribute to the development of en-
cephalopathy. Changes in the blood-to-brain transport of neutral and basic amino
acids, in part, may be caused by an increase in the V-max of the respective carrier
system, which is possible a consequence of hyperammonemia.
19
Amino Acids in Hepatic Encephalopathy
Hepatic encephalopathy is associated with increased plasma and brain concen-
trations of the aromatic amino acids (AAA): phenylalanine, tyrosine and tryptophan
(free form) and decreased concentrations of the branched-chain amino acids (BCAA):
valine, leucine and isoleucine.
18-23
Because large neutral amino acids share a com-
mon transport carrier in crossing the BBB, decreased BCAA concentrations in the
blood may in fact facilitate increased transport AAA into the brain.
23
High concen-
trations of the aromatic amino acids and methionine could limit the cerebral uptake
of BCAA because the higher AAA concentrations result in greater competition at
the BBB for the carrier-mediated transport system used by BCAA. When brains of
normal dogs were perfused with AAA a hepatic-like coma and an abnormal neu-
rotransmitter pattern were induced. These findings are, in part, responsible for the
false neurotransmitter-amino acid hypothesis of hepatic encephalopathy.
18
The
hepatic-like coma induced by AAA may be prevented when AAA and BCAA were
infused simultaneously.
24
During liver failure or diversion of the blood around the liver, amines and their
amino acid precursors accumulate in the circulation and enter the brain and
the peripheral autonomic nervous sytem, replacing the true neurotransmitter
Table 22.2. Clinical grading of hepatic encephalopathy
Grade Mental Status and Tremors EEG Findings
I. Prodome Euphoria, occasional depression; Usually no EEG
fluctuant, mild confusion; slowness changes
of mentation and affect; slurred
speech; disordered sleep rhythm;
tremor slight
II. Impending coma Accentuation of state I: Generalized
drowsiness; inappropriate behavior; slowing pattern,
inability to maintain sphincter control; abnormal
tremor present (easily elicited)
III. Stupor Asleep most of the time but can be Abnormal
roused; incoherent speech; marked
confusion; tremor usually present
(patient may not be able to cooperate)
IV. Deep cerebral coma May or may not respond to painful Abnormal
stimuli, and tremor usually absent
350
22
norepinephrine with weak or false neurotransmitters, such as octopamine, tyrosine,
phenylethylamine, of phenylethanolamine. On the other hand, patients with liver
failure have increased levels of norepinephrine and the other catecholamines.
25
None-
theless, it is thought that this imbalance of neurotransmitters has serious conse-
quences which may be manifested as brain dysfuction and high cardiac output, low
peripheral vascular resistance states, as well as hepatorenal syndrome. Whether amino
acid imbalance precipitates encephalopathy, possibly, by promoting the synthesis of
toxic aromatic amines, is not clear, but attempts to correct this imbalance have been
the rationale for metabolic and nutritional therapy of patients with liver failure in
which the protein ration is enriched with BCAA and low in AAA is administered
(Tables 22.4,5).
The administration of BCAA to rats with portocaval shunts reduces the concen-
tration of tryptophan, serotonin, and 5-HIAA in brain indoles.
20
Formation of false
or weak adrenergic neurotransmitters may contribute to hepatic coma, pos-
sibly by displacing norepinephrine and dopamine from their storage granules
at nerve terminals.
Nutritional Assessment
Accurate assessment of nutrition status of patients with chronic liver disease is
very important, albeit characterized by many encumbrances to performing and in-
terpreting clinical and biochemical studies. Identifying and differentiating the im-
pact of malnutrition from the effects of liver disease and the therapy represent the
main predicament. Common methods of determining the nutritional status of these
patients have obvious practical limitations. Total body weight and measurements of
tricepts skinfold thickness and mid-arm circumference are influenced by ascites and
edema. Hypoalbuminemia is an important indicator of nutritional status and a good
index of hepatic functional reserve. The absolute rate of albumin synthesis is signifi-
cantly lower in patients with cirrhosis and correlates well with the Child-Turcotte
score and with its Pugh modification. However, when analyzed separately the rate of
albumin synthesis does not correlate with serum albumin concentration, intravas-
cular albumin mass, or with other clinical indexes of liver function or integrity.
Hypoalbuminemia decreases the colloid oncotic pressure, which contributes to the
Table 22.3. Mechanisms that may affect brain function in
hepatic encephalopathy
Mechanisms Consequences
Disruption of integrity of the Exposure of the brain to undesireable
brain-blood barrier neuroactive compounds
Alterations of specific transport systems Increased transport of neutral amino
acids
Decreased transport of glucose,
ketone bodies, and basic amino acids
Accumulation of neurotoxic substance Functional alterations of the brain
in the blood
Changes in the substrate supply Alterations and catabolism of normal
neurotransmitters in the brain
Lack of nutrients, e.g., glucose Impairment of brain energy metabolism
351
22
accumulation of ascites and edema, a persistent characteristic of decompensated
liver function. Close metabolic monitoring of these patients is of utmost impor-
tance. In addition to routine biochemical indices which include transferring,
prealbumin and retinol-binding protein, plasma levels of vitamins, trace elements
and apolipoprotein A-IV may be useful in a comprehensive nutritional assessment.
The new metabolic tool that is coming in the clinical practice is the measure-
ments of the hepatic mitochondrial redox potential,
26
but its role in CLD has not
been studied to date. The hepatic mitochondrial redox potential represents the ratio
of acetoacetate to -hydroxybutyrate and can be expressed and measured as the
arterial blood ketone body ratio (AKBR). The AKBR is not a specific measurement
of liver insufficiency, but does allow the severity of liver damage to be graded and
reflect the state of perfusion of splanchnic bed. Different clinical and biologic phe-
nomena are associated with a decrease in the AKBR, of which most prominent are
enhanced catabolism, impaired oxygen utilization, hypoperfusion and deterioration
of the immune response.
Protein malnutrition is a characteristic feature of patient with cirrhosis. More-
over, functional alterations and histologic abnormalities of the liver are known con-
sequences of malnutrition. Protein deprivation profoundly depletes liver protein
stores and adversely affects the breakdown and conversion of polysomes to free ribo-
somes. On the other hand, in chronic liver disease, alterations in visceral protein
synthesis, cellular immunity, and total lymphocyte count may be present indepen-
dently of protein malnutrition. Plasma protein levels correlate inversely with the
degree of liver damage and are its best indicators. Serum concentrations of AAA can
indicate the severity of chronic and acute liver disease as well. Furthermore, because
patients with hepatic encephalopathy have the lowest BCAA:AAA ratio, this deter-
mination may serve as an index of liver function impairment. Other markers such as
lean body mass and fat stores are not reliable indicators of structural liver damage.
Measurement of nitrogen balance has its limitation, because it is difficult to differ-
entiate impaired hepatic protein synthesis from accelerated breakdown of endog-
enous protein.
Standard tests of hepatic metabolic capacity and blood flow (aminopyxine breath
test, galactose elimination capacity and clearance of idiocyanine green) are less sen-
sitive indicators of prognosis than the Child-Pugh classification of liver disease.
7
The recognized, but less applied clinically prognostic nutritional index, which relies
mostly on plasma protein lacks the predictive value in patients with ESLD.
8
Table 22.4. Use of branched-chain amino acids in hepatic encephalopathy
When gluconeogenesis and ketogenesis are depressed, BCAAs* may furnish as much
as 30% of energy requirements for skeletal muscle, heart and brain.
The BCAAs may regulate the movement of other amino acids across the myocyte
membrane.
The BCAAs increase hepatic protein synthesis when given with glucose and decrease
aromatic amino acid concentrations.
Theoretically, BCAAs may improve peripheral catecholamine synthesis.
The BCAAs complete with aromatic amino acids for transport across the blood-brain
barrier.
*BCAA=Branched-chain amino acids
352
22
Peritransplant Nutrition: Support
In a retrospective study of 160 adults with liver transplant, malnutrition score
was one of the six variables that highly correlated with patient survival. High malnu-
trition score was associated with increased postoperative morbidity and mortality.
27
The degree of postoperative malnutrition has been shown to predict the postopera-
tive morbidity and mortality in liver transplant patients.
9
This study demonstrated
a relationship between moderate to severe malnutrition and increased morbidity
(increased requirements for ventilatory support, and ICU and hospital stay) and
mortality.
9
Identifying the correct caloric and protein requirements in patients before and
after undergoing LT is not an easy task. In a prospective study of 16 adults patients
scheduled to undergo LT, nitrogen balance, 24-hour urinary cratinine, 3-methyl
histidine and resting energy expenditure (REE) were determined before transplan-
tation and on days 1,2,5,14 and 28 posttransplant.
28
Only 15% of patients in this
study achieved a positive balance, although parental nutrition (containing 1.29 gm/
protein/kg, 30% and 70% of calories were given as fat and dextrose respectively)
was started within 24 hours. Calculation of malnutritional needs on this study was
based on the Harris-Benedict equation, and parenteral feeds were continued until
solid oral intake reached 1200 calories in 24 hours in females and 1500 in males.
These investigators have suggested to use the Harris-Benedict formula for calcula-
tion of nutritional requirements and to add 20% more calories in order to provide
nutritional support in LT patients.
In another, most recent study,
29
150 patients with ESLD undergoing LT pro-
spectively were assessed and followed for an average of 46 months after LT. Body
composition analysis (24 hour urinary creatinine excretion, anthropometric mea-
surements and bioelectrical impedance analysis), changes of REE and other vari-
ables were analyzed. Patients with severe hypermetabolism (changes in REE >20%)
and reduced body cell mass (<35% of body weight) had reduced survival after LT.
Based on the degree of hypermetabolism and malnutrition a prognostic risk profile
Table 22.5. General treatment of hepatic encephalopathy
Identify and treat other medical problems
Balance protein intake
Avoid antidepressants and hypnotics unless severe mania is present
Avoid extensive paracentesis or abrupt removal of fluids by dialysis
Avoid vigorous diuresis
Avoid use of acetazolamide
Slowly correct hyponatremia
Do not overhydrate
Monitor hemodynamic status and blood gases closely
Monitor arterial blood ketone body ratio
Avoid lumbar puncture if possible
Supplement vitamins
Avoid use of strong cathartics
353
22
predicted the survival. Patients with high risk profile had a 5-year survival of 88%
(P<.01). Others, have also found that nutritional status indices predict survival after
LT in children.
30
Although nutritional assessment in adult patients with ESLD is difficult and
complex, and the current indices cannot be applied optimally to all patients, it is
clear that hypermetabolism and malnutrition are present in a significant number of
patients undergoing LT and that perioperative nutritional and metabolic status of
these patients has great prognostic value.
Metabolic Changes
Hypermetabolism as a systemic manifestation of cirrhosis is closely related to
splanchnic hemodynamics and malnutrition.
31
Following LT patients are in a
hypercatabolic state, however their postoperative metabolic state (as measured by
REE) is a reflection of their preoperative state.
32,33
The degree of hemodynamic
abnormality, when studied intraoperatively, correlates with the stage of the disease.
34
LT does not reverse the existing splanchnic and systemic hemodynamic abnormali-
ties of ESLD completely.
31
The splanchnic hyperemia persists for at least two weeks,
and the closure of porto-collateral circulation occurs at a much slower rate, even
though the portal pressure returns to normal.
35
Total liver blood flow markedly
increases after LT, although the effects of persistent high liver blood flow on me-
tabolism are not known.
31
Immediately following LT (in the first 6 hours ) glucose utilization by the graft is
impaired until mitochondrial redox potential improves.
36
During this period, the
liver preferentially uses fatty acid oxidation for ATP generation. After 6 hours, if
transplanted liver have normal function, substrate utilization shifts from fat to glu-
cose. On the other hand, failing grafts will continue to utilize fat. These significant
metabolic changes may be followed by the serial measurements of arterial ketone
body ratio (acetoacetate/3-beta-hydroxybuturate) or AKBR. The AKBR reflects the
hepatic mitochondrial redox potential (oxidized nicotinamide adenine dinucleotide
(NAD)/reduced nicotinamide adenine dinucleotide (NADH). The ketone body ratio
reflects one of the most fundamental regulatory factors of energy production in the
liver. The AKBR changes may be used to predict the function of transplanted liver.
Low values of AKBR associated with low levels of ketone bodies should be regarded
as a strong indicator of graft failure.
37,38
Furthermore, fatty acid oxidation and keto-
genic pathways are accelerated to compensate for energy deficits immediately after
LT. Administration of small quantities of glucose in post operative period has been
suggested.
38
Glucose infusion may be increased as mitochondrial redox potential
recovers (AKBR >0.07). Low AKBR values (<0.07) have been associated with in-
creased mortality and morbidity.
39
Following LT low levels of some amino acids
such as glutamine, asparagine, citrulline and taurine have been reported.
40,41
All of the existing studies have involved patients undergoing standard cadaveric
donor LT. The use of partial liver grafts is becoming increasingly common, however.
These grafts are typically less than 50% of normal adult liver mass. The ability of
these organs to utilize nutrient substrates in the early postoperative period has
not been systematically studied and the optimal nutritional support for these
patients in unknown.
Nutrition Status of Donors
The nutritional status of donors has not received adequate attention, although it
has been suggested that the nutritional state of the donor may affect the outcome of
354
22
LT.
42
Often times organ donors receive little, if any, nutritional support during their
hospitalization, and are subjected to acute starvation that may last for days in an
ICU. This period could substantially deplete the liver energy stores. The role of
acute nutritional repletion on the outcome of LT was examined experimentally.
42
Donor pigs were divided into three groups and pretreated for seven days before
harvesting their livers. Group I was given intravenous saline; Group II was fed orally
regular animal diet; and Group III was fasted, but given 20% glucose intravenously.
Harvested livers were stored for four hours in cold Euro-Collins solution before
transplantation. The glycogen content of the liver at harvesting was consumed com-
pletely in Group I, but was well preserved in Groups II and III. The ATP content of
the liver in all three groups were similar at harvesting and were markedly reduced
four hours after cold preservation. The amount of ATP recovered one hour after
reperfusion was 26% of that before preservation for Group I, and 48% and 73% for
Goups II and III, respectively. The mean survival for Group III was 37.2 days vs 5.8
0.7 days and 9.8 2.0 days in Group I and II (P<0.01). Other investigators,
43,44
have also shown that livers from nutritionally repleted animals have improved func-
tion when compared with livers from fasted animals after cold preservation. It has
been demonstrated that glycogen stores could be rapidly repleted in pigs by intraportal
infusion of glucose over 3 hours.
45
Studies in humans using this technique
46
have
shown that glycogen stores in human allograft are good and glycogen is needed
throughout the transplantation procedure. Futhermore, newly synthesized gly-
cogen is superior to preformed glycogen and glycogen repletion improves out-
come of liver transplantation in humans.
It appears that glucose infusions lower peak transaminase levels, and protects
against the effects of prolonged warm ischemia.
46
Rapid hepatic glycogenation was
shown to be beneficial in maintaining adenine nucleotide levels in a large animal
model.
47
Moreover, livers harvested from hyperglycemic donors receiving insulin
infusion during the procurement operation have significantly lower reperfusion hepa-
tocellular injury.
48
On the other hand, others have reported that livers from fasted
rats were more tolerant to long-term hypothermia than livers from fed donors.
49,50
More contrasting data were reported recently, were both extensive donor fasting and
glucose feeding enhanced outcome in LT.
51
Nonetheless, prevention of the nutritional status of the donor liver prior to har-
vesting may be a method to improve function of the livers for transplantation, as the
evidence suggests that nutritional status of organ donors matters. Furthermore, nu-
tritional modulation of hepatic reperfusion may have greater influence on liver pres-
ervation of LT, and nutritional supplementation may precondition the liver.
52
Until
a large human randomized clinical trial answers this question definitively, organ
doors should be treated principally the same as other critically ill patients: once fully
resuscitated, start the nutritional support, and when possible use the gastrointestinal
tract to deliver nutrition. Based on animal studies, during prolonged pretransplant
period, a higher percentage of glucose infusion may have theoritical advantage.
How to Feed Liver Transplant Patients
Attempts to reverse malnutrition in patients with advanced cirrhosis are very
complex and often are compounded by nutrient substrate intolerance and encepha-
lopathy requiring some protein restriction. The principle question to be answered is
not do these patients need to be fed, but rather how to do it and when to start? Until
recently TPN was the preferred form of postoperative nutritional support in LT as it
355
22
provides all the nutrients even in a face of significant gut dysfunction. In a random-
ized prospective, partially blinded, study, 28 patients were studied for seven days
following liver transplant.
53
Patients were randomized into three groups: Group I
(N=10) was given isotonic intravenous fluids with glucose; Group II (N=8) was
given standard TPN providing 1.5 g/protein/kg/day; and Group III (N=10) isoca-
loric isonitrogenous TPN fortified with 3.5% branched-chain amino acids. All pa-
tients were similar with regard to their disease stage, muscle wasting, albumin levels
and jaundice. Nitrogen balance was significantly improved in both TPN groups
(Group I vs Group II, P<0.0001; Group I vs Group III, P<0.0011). Furthermore,
both TPN groups were extubated earlier than the control and had a shorter ICU
stay (an average 2.4 days), although these differences did not achieve statistical sig-
nificance. This study
53
demonstrates that patients post LT can tolerate aggressive
nutritional support and protein load of 1.5 gm/kg/d without evidence of precipitat-
ing encephalopathy. Urea nitrogen and creatinine were also not effected by protein
intake. Achievement of nitrogen balance in patients with liver transplant has been
reported previously.
54,55
Since TPN has its inherent potential problems (metabolic, infectious, mechani-
cal) the provision of nutrients enterally when possible is an attractive concept. The
efficacy and the tolerance of early enteral feeding via a double-lumen nasojejunal
tube, placed at the time of transplant, was studied in 14 LT patients.
56
These pa-
tients were compared with 10 patients who received TPN as a main of provision of
nutritional support. Tube feeding was started within 18 hours after transplantation,
while TPN within 24 hours for most patients. These investigators concluded that
with early tube feeding after LT, the nutritional status can be maintained as effi-
ciently as with TPN, although nitrogen balance studies were not performed. All
patients in this study underwent studies of intestinal absorptive capacity and intes-
tinal permeability before and after transplant. These studies showed no significant
differences in intestinal permeability between the enterally and parenterally fed pa-
tients within the first seven days of provision of nutritional support.
56
This tech-
nique of provision of early enteral feeding may be difficult to achieve in cases when
choledocho-enteric biliary drainage is performed. In another study,
57
early enteral
feeding immediately after LT was shown to be safe but early postoperative feeding
did not effect the ICU or hospital stay, or ventilatory dependence. Thirty one (out
of 51) patients completed the study. Tube feeding was tolerated well by 14 patients
and these patients had a better nitrogen balance on post transplant day 4 than con-
trol (P<.03) and greater cumulative 12-day nutrient intake (P<0.002) and lower
viral infection rate (P<.05). The major deficiency of this study is that the control
group received no nutritional support until they were able to eat.
The means and technique of delivering enteral feedings has been a matter of
debate.
58
Because of associated discomfort of the nasojejunal tubes to the patient
and other technical difficulties, routine placement of feeding jejunostomies at the
same time of transplant has been recommended.
59
Many surgeons avoid this proce-
dure due to the high incidence of complications and infrequent need for prolonged
tube feeding. Although 15% of the patients had some type of complication related
to placement of J-tubes, placement of these tubes at the time of operation can be
done safely, with very low risk of serious complications and without adding signifi-
cant operative time. J-tubes may, however, be best reserved for those patients who
are at risk for prolonged postoperative malnutrition (i.e., prolonged ventilation).
356
22
Naoenteric tubes are generally well tolerated in the short term and do not carry
potential the risk of J-tubes.
Based on these and other studies, enteral nutrition should be the primary mode
of nutrition support whenever possible. When to start the feeding is another ques-
tion. In general if the patients is fully resuscitated as documented by normal lactic
acid, base excess and gastric pHi (when measured) enteral nutrition support may be
started and advanced as tolerated. On the other hand, TPN should be reserved for
patients that cannot be fed enterally or their resuscitation is prolonged and/or com-
plicated by multiple returns to the operating room, for those with prolonged ileus,
abdominal distention, abdominal sepsis, or chylous ascites.
60
Conclusion
Malnutrition is very common in patients undergoing liver transplantation and
poor nutritional status is associated with increased morbidity and mortality. Correc-
tion and prevention of malnutrition and metabolic support of these patients in their
perioperative period is of utmost importance. Enteral feeding should be initiated as
soon as possible after LT. Enteral feeding should be used, even when all nutritional
needs cannot be met with this technique, and requires supplementation with TPN.
Use of specialized nutritional formulas need to be evaluated further, while individu-
alized dietary consult with the patient and the family is of great importance and
should be part of the therapeutic interventions.
61
The use of type and the amount of
lipids in nutrition support of patients with liver failure and transplant have not been
studied. It is clear, however that too much lipids, or when most of lipids are given in
a form of omega-6-fatty acids have deleterious effects on the immune status of the
critically ill patients. The nutritional therapeutic interventions should be oriented
toward reducing patient's protein catabolism and to provide sufficient nutrient sub-
strates in a form of amino acids and dextrose to improve nitrogen balance without
aggravating the hepatic encephalopathy.
7
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CHAPTER 23
Nutritional Support in Renal Transplantation
Susan T. Crowley, Richard Formica and Antonio Cayco
Introduction
Because of the high prevalence and adverse impact of malnutrition in the
pretransplant end stage renal disease (ESRD) population, the effects of renal trans-
plantation on the nutritional state of the recipient is of interest. This Chapter re-
views the available published literature on selected aspects of nutrition in the kidney
transplant recipient (KTR). Because of their correlation with increased risk of mor-
bidity and mortality and their high prevalence among KTRs, the treatments of pro-
tein malnutrition and dyslipidemia are examined. The impact of vitamin
supplementation on modification of another potential cardiovascular risk factor in
the KTR, hyperhomocysteinemia is also considered. Finally, because serious mor-
bidity secondary to osteoporosis in the KTR has been recognized, bone metabolism
in the KTR is discussed.
Protein Malnutrition and Nitrogen Balance
The attributable impact of the restoration of renal function on nitrogen balance
in the KTR has been confounded by the requisite use of immunosuppressive therapy.
The latter has been well known to independently influence protein turnover. In
particular, glucocorticoids have been repeatedly shown to increase protein catabolic
rate (PCR) and result in negative nitrogen balance. Over a decade ago, multiple
investigators demonstrated that PCR doubled within 6-11 days post-renal trans-
plantation, independent of protein intake and in parallel with changes in steroid
dose. Studies reported that despite restoration of renal function and intake of at
least 1.2 gm protein/kg IBW/day, glucocorticoid therapy had a major impact on
PCR and was associated with dramatic nitrogen wasting.
Fortunately, it has been demonstrated that protein wasting is a not an invariable
consequence of glucocorticoid therapy. In nondiabetic renal transplant patients, in-
creased dietary protein intake (1.5 gm/kg/day) in the immediate postoperative pe-
riod diet accompanied by 30-35 kcal/kg/day of caloric intake is able to effect neutral
nitrogen balance, whereas more protein restricted patients develop negative nitro-
gen balance. Thus, dietary manipulation is effective in maintaining nitrogen bal-
ance, even in the immediate post-transplant period when high dose steroid therapy
is typically utilized.
More aggressive dietary protein supplementation has been shown to be a means
of further reducing negative nitrogen balance associated with high-dose steroids in
the early post-transplant period. In one study, isocaloric diets of approximately 30
kcal/kg/day, adjusted for the differences in the protein content of the diets, were
361
Nutrition Support in Renal Transplantation
23
consumed by 12 nondiabetics, randomized to either the control (1 gm/kg/day) or
experimental (3 gm/kg/day) diet. Over the study period of four weeks, both groups
lost a mean of 3 kg, yet a net increase of 4.5 kg of lean body mass was noted in the
experimental group. For both groups, nitrogen balance was directly proportional to
the nitrogen intake. Regression analysis of daily protein intake and nitrogen balance
suggested that neutral nitrogen balance was achieved at an intake of 1.3 gm protein/
kg/day. Thus, in the setting of adequate caloric intake, it is possible to improve
nitrogen balance by protein supplementation without suffering undue side effects
such as clinically significant hyperkalemia or azotemia.
Dietary protein intake recommendations in the long term KTR requires a bal-
ance between the potentially beneficial and the potentially detrimental effects of a
high protein diet. Diminished muscle mass, as evidenced by reduced forearm muscle
circumference, has been demonstrated in a significant proportion (38%) of diabetic
and nondiabetic patients even two years after successful renal transplantation, when
consuming 1 gm/kg/day protein and 25-35 kcal/kg/day. This occurs despite im-
provement in other nutritional parameters (weight, serum albumin) and minimal
steroid use.

It has also been shown, by computerized tomographic assessment of
mid-thigh muscle area, that marked muscle atrophy occurs in the otherwise stable
kidney transplant patient. Given the apparent extent of muscle wasting and protein
malnutrition in the stable KTR, dietary protein restriction for any reason would
appear questionable.
Some investigators however, have postulated that chronic rejection is a
forme-fruste of hyperfiltration induced vascular damage. Over the long term, there-
fore, a normal or high protein diet might potentially be detrimental to renal graft
survival by exacerbating hyperfiltration. A short-term study examining the effect of
a low protein (0.55 gm/kg/day) diet on a small cohort of KTRs revealed that urinary
protein excretion significantly diminished during low protein dietary intake, and
neutral nitrogen balance was achieved.

However, significant declines in serum total
protein, albumin, as well as transferrin occurred which would suggest that this was
too restrictive a diet to maintain overall protein balance.
Whether dietary protein restriction in the long term renal transplant recipient is
adequate to maintain nitrogen balance has been investigated by others as well.

Among
a small cohort of long term nondiabetic KTRs with moderate renal insufficiency
consuming a diet containing 0.6 gm protein/kg/day with a caloric intake of 30 kcal/
kg/day, no significant changes in inulin-measured glomerular filtration rate or sero-
logic nutritional parameters were noted over a four week follow-up period. While
nitrogen balance did not significantly change ( baseline = -0.88 1.14 gm/day; at
three weeks = -1.59 0.5 gm/day) nitrogen balance did correlate with protein in-
take (r=0.42, p< 0.05). Furthermore, caloric intake was positively correlated with
nitrogen balance, with near-neutral nitrogen balance being achieved in subjects con-
suming greater than 25 kcal/kg/day, regardless of protein intake. Thus, there ap-
pears to be a threshold for caloric intake (28 kcal/kg/day) which must be met to
maintain weight and neutral nitrogen balance.
Because it appears difficult to achieve a protein-restricted diet without compro-
mising essential caloric intake, protein restriction should probably be avoided in the
renal transplant recipient. A diet containing at least 1 gm/kg/day of protein and
25-35 kcal/kg/day appears to be the best compromise in the stable, long term renal
allograft recipient (Table 23.1).
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23
Dyslipidemia
Cardiovascular disease remains a leading cause of death in renal transplant re-
cipients. In Europe, among long term KTRs, coronary artery disease is responsible
for 32% of deaths, approximately equivalent to the number of deaths caused by
infection.

In the United States, 18% of all long-term KTRs die of coronary artery
disease. Despite these findings, there are few studies elucidating the risk factors for
cardiovascular disease in the kidney transplant patient.
A recent retrospective review of 54 long term KTRs demonstrated significantly
greater LDL and TC levels in KTRs vs. normal controls. Furthermore, blood lipid
levels in KTRs with coronary artery disease were significantly greater than in KTRs
without coronary disease suggesting an association between blood lipids and athero-
genesis in the transplant population, analogous to their relationship in the general
population. In another study, a Cox proportional hazard analysis of vascular disease
risk factors for a large cohort of both cyclosporine and non-cyclosporine treated
KTRs, determined that low serum high density lipoprotein (HDL) level was an
independent relative risk factor for ischemic heart disease. Thus, in addition to other
traditional risk factors for coronary artery disease, such as diabetes mellitus and
hypertension that KTRs may have, it seems reasonable to conclude that elevated
serum lipids place these patients at increased risk of cardiovascular disease and that
lipid lowering strategies may be beneficial (Table 23.2).
The incidence of hyperlipidemia post transplantation is high; approximating
40% in one large study of over 500 subjects. The cause of hyerlipidemia in the KTR
has multiple factors (Table 23.3). Diabetes mellitus, insulin resistance and weight
gain all play a role. Additionally, immunosuppressive medications have a role. Pred-
nisone has been shown to increase serum lipids in patients with systemic lupus
erythematosis in a dose-related fashion. For each 10 mg increase in dose, prednisone
increased TC by 7.5 mg/dl. In KTRs, prednisone has also been shown to increase
LDL and TC while reducing HDL.
Blood lipids are also affected by cyclosporine. In a trial evaluating the effective-
ness of cyclosporine in treating psoriasis, TC and triglycerides were significantly
increased during cyclosporine treatment and diminished after discontinuation of
cyclosporine. Studies in KTRs have shown cyclosporine treatment to be associated
with a significant increase in serum lipids. However, because of concomitant use of
prednisone, the attributable effect of cyclosporine on blood lipids in these studies
could not be independently assessed.
With regard to treatment of dyslipidemias, it has been well established that reduc-
tion of TC and LDL in hypercholesterolemic patients in the general population signifi-
cantly reduces the number of coronary events and coronary deaths. This has been
Table 13.1. Suggested dietary protein intake in the KTR
Time Period
Postoperative Long-Term
Protein 1.5 gm/kg/d 1 gm/kg/d
Calories 30-35 kcal/kg/d 25-35 kcal/kg/d
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23
shown in both primary and secondary prevention trials. It has also been established
that reduction of TC and LDL in patients in the general population who have coro-
nary artery disease but, whose cholesterol is in the normal range by western stan-
dards, also reduces coronary artery disease endpoints. In all of these trials success
was achieved through the combined use of dietary modification and HMG CoA
reductase inhibitors.
The use of the HMG CoA reductase inhibitors, lovastatin and fluvastatin, has
been shown to be safe and effective in reducing TC and LDL, and in raising HDL in
KTRs receiving azathioprine and/or cyclosporine and prednisone. Of note, in pa-
tients being treated with cyclosporine, HMG CoA reductase inhibitors did not change
cyclosporine blood levels.

Side effects such as muscle aches, frank myositis or labora-
tory abnormalities in creatinine phosphokinase, AST or ALT were minimized by
reducing the maximum dose of the statin in KTRs to 20 mg per day.

It should be
pointed out that although these medications have been shown to be safe and effec-
tive in lowering TC and LDL as well as in raising HDL in KTRs, long-term efficacy
and a survival benefit have not yet been demonstrated in this population. It is still a
reasonable assumption however, that serum lipid lowering therapy in the hyperlipi-
demic KTR is beneficial because there is no evidence to suggest that elevated serum
lipids in the KTR behave differently than in the general population.
There is limited published research concerning the use of alternative lipid lower-
ing agents in the renal transplant population (Table 23.4). A second line agent that
has been shown to be very effective at reducing TC, LDL, and triglycerides, and can
raise HDL in cyclosporine and noncyclosporine treated KTRs is nicotinic acid.

While
most patients in one study tolerated the dose of 1 gm twice a day without undue side
effects, conclusions about safety must be limited due to the small number of subjects.
Similarly, experience with the use of the bile acid sequestrant cholestyramine, is
limited. Bile acid sequestrants significantly reduce TC and LDL in hypercholester-
olemic patients but, there has been concern about impairment of cyclosporine ab-
sorption by the sequestrants. In one small study in KTRs, cholestyramine taken as a
single 4 gm dose at least 4 hours after the last dose of cyclosporine did not affect the
absorption of cyclosporine from the gastrointestinal tract. However, no information
Table 13.2. Cardiovascular risk factors in the KTR
Hypertension
Dyslipidemialow HDL
Diabetes Mellitus
Hyperhomocysteinemia?
Table 13.3. Causes of hyperlipidemia in the KTR
Medications:
Prednisone, Cyclosporine
Diabetes Mellitus
Insulin Resistance
Obesity
364
23
on efficacy of lipid lowering was provided. The strict compliance required to prop-
erly use cholestyramine, the large amount needed, the somewhat unpleasant taste,
and the constipation associated with its use diminish enthusiasm to evaluate this
agent further.
Based on epidemiological evidence from the Greenland Eskimo population, who
have a very low rate of CAD and a fish-rich diet, fish oil tablets have also been used
in an effort to reduce blood lipids.

In one study conducted in KTRs however, the
administration of fish oil tablets had no effect on TC, LDL, or HDL.

Fish oil did
significantly reduce serum triglycerides and decrease platelet adhesion in response to
ADP which may be beneficial in reducing atheromatous plaque thrombus forma-
tion. The only significant side effect from fish oil consumption was fishy eruction,
which, overtime, the participants in the study reportedly grew accustomed to.
Vitamin Supplementation
In addition to lipid lowering agents, vitamin supplementation has been pro-
posed as an intervention to lower the risk of coronary artery disease in patients at
risk. Folic acid supplementation, in particular, has been the subject of considerable
investigation. Folic acid is a requisite factor in one of the metabolic pathways of the
sulfur-containing amino acid, homocysteine (HCY), which was first linked with
accelerated atherosclerosis nearly three decades ago. In vitro evidence suggests that
HCY can both directly and indirectly, via enhancement of lipid peroxidation, pro-
duce endothelial injury. Epidemiological investigations have demonstrated a strong
correlation between elevated plasma HCY levels (hyperhomocysteinemia) and the
frequency of vascular disease. In fact, hyperhomocysteinemia has been shown to be
an independent risk factor for primary as well as secondary cardiovascular disease in
the general population.
Increased levels of plasma HCY have been demonstrated in a variety of acquired
disease states including folate deficiency and renal insufficiency. Present in 75% of
Table 13.4. Treatment of hyperlipidemia*
Agent Note
HMG Co-A r.i.s Preferred agent
(ex. lovastatin, fluvastatin) Reduces TC, LDL
No change in CYA level
Myositis
Max dose of statin 20 mg qd
Nicotinic Acid Reduces TC, LDL, TG
Increases HDL
Safety?
Cholestyramine Reduces TC, LDL
Impaired CYA absorption?
Compliance?
Fish oil Reduces TG
Decreases platelet adhesion
Fishy eruction
* in addition to dietary fat reduction
365
23
ESRD patients in one study, hyperhomocysteinemia was 33 times more common in
ESRD patients than in controls, and was far more common (2- to 15-fold) than
traditional risk factors for cardiovascular disease.

Longitudinal follow up to
determine if HCY levels correlate with incident cardiovascular disease rates in
ESRD is ongoing.
The effect of restoration of renal function through transplantation and of the
administration of folic acid supplements on homocysteine metabolism in the KTR
has been recently examined. In 27 long-term, non-cyclosporine treated KTRs with
creatinines ranging from normal to 0.5 mmol/l, plasma HCY level in the KTR was
inversely proportional to renal clearance.

In addition, it was possible to reduce HCY
levels via folate supplementation (1-5 mg/day) as similarly demonstrated in normal
patients, dialysis patients, and in patients with renal insufficiency.
Immunosuppressive therapy may have an independent effect on HCY metabo-
lism. Specifically, cyclosporine therapy can raise plasma HCY independently of re-
nal function and may abrogate the HCY lowering effect of folic acid via interference
with the folate dependent metabolism of homocysteine.
Despite the aforementioned studies, the clinical relevance of hyper-
homocysteinemia to cardiovascular disease in the KTR population is unclear. In a
previous multivariate analysis of cardiovascular risk factors in stable long-term renal
transplant patients, HCY levels were not considered. Past cross-sectional compari-
son of HCY levels in KTRs with and without cardiovascular disease demonstrated
significantly greater HCY levels in transplant patients with cardiovascular disease
compared to patients without it. Since comparisons were uncontrolled for differ-
ences in time at which sampling of plasma HCY and the cardiovascular event oc-
curred, and lacked matching for other cardiovascular risk factors, conclusions about
causality could not be firmly drawn. Hence, the contributory role of
hyperhomocysteinemia in the development of cardiovascular disease in the KTR
requires further investigation.
Vitamin supplementation with alpha tocopherol, vitamin E, as a means of re-
ducing cardiovascular disease risk has also been a subject of considerable investiga-
tion in the general population. In vitro, vitamin E supplementation increases the
resistance of LDL to oxidation which may result in improved endothelial cell va-
sodilator function, decreased foam cell formation, and decreased chemotactic sig-
nals for monocytesall proposed mechanisms which contribute to the atherogenic
process. In addition, growing epidemiological evidence suggests that vitamin E supple-
mentation reduces the risk of myocardial events and possibly reduces the risk of
death from myocardial infarction in the general population. However, no data cur-
rently exists to support the efficacy or safety of supplemental vitamin E in the kid-
ney transplant population.
Bone Metabolism
Kidney transplantation is the second most frequently used modality of renal
replacement therapy in the United States, serving the needs of 27.1% of the end-stage
renal disease population. As KTRs live longer, long term complications, such as post
transplantation bone disease start to impact on patient morbidity.
Osteoporosis is a condition wherein bone density is reduced such that fracture
risk is dramatically increased. Significant declines in vertebral bone mineral density
(BMD) have been observed not only during the first years after kidney transplantation,
but continuously for rates up to -1.7% per year for several years post transplantation.
366
23
In a recently conducted cross-sectional study among long-term KTRs, the preva-
lence of osteoporosis at the hip or spine was 42%. Osteoporosis has been reported
not only in KTRs but in heart and liver transplant recipients as well. These findings
suggest that the loss of bone is quite prevalent and may be attributed not entirely to
previous renal osteodystrophy but to transplantation itself.
Various mechanisms have been proposed to explain the pathogenesis of bone
loss in KTRs (Table 23.5). Bone mass is governed by the two dynamic and opposing
forces of bone resorption and bone formation. Previously, bone loss during the first
year post transplantation, was attributed to a decrease in bone formation rate, or a
low bone turnover state, as a result of corticosteroid therapy. Recently however,
long-term KTRs more than a year after transplantation were found to have a high
bone resorption and turnover state. Furthermore, their high bone resorption rate
was correlated with reduced BMDs. The etiology of this accelerated resorption of
bone tissue remains unknown. Despite the restoration of normal renal function and
calcium homeostasis by a functioning allograft, a hyperplastic parathyroid gland
could occasionally fail to involute and lead to persistent hyperparathyroidism. This
residual hyperparathyroidism could cause the high bone resorption and turnover
which would eventually lead to bone loss. The immunosuppressive drugs, cyclosporine
and FK506, have also been shown to cause a high turnover bone loss. Vitamin D
deficiency does not appear to be a major cause of reduced bone mass in KTRs with
decent allograft function. Several studies have consistently shown adequate stores of
25(OH)-Vitamin D and 1,25 (OH)2-Vitamin D in KTRs even in those with re-
duced BMD.
Several treatment regimens have been evaluated to reduce the high turnover bone
loss associated with transplantation. The agents, calcitonin (40 IU IM daily) or
disodium etidronate (400 mg/day p.o. for 15 days every three months), increased
vertebral BMD in liver transplant patients compared to the untreated historical
control group. In a randomized study, a regimen consisting of 40 g of 25(OH)
-Vitamin D3 and 3 grams of calcium taken daily significantly minimized the reduc-
tion in the lumbar, femoral and total body BMD in KTRs. However, these studies
are limited by their relatively short duration of follow up. Further studies are needed
to evaluate and compare the long-term efficacy and safety of these different regi-
mens in the prevention and treatment of post transplant bone disease.
Summary
Malnutrition is highly prevalent in the pretransplant ESRD population and is
associated with increased morbidity and mortality. Hence, attention to nutritional
prescription in the perioperative period is particularly important to avoid compound-
ing an already compromised nutritional state. The well known protein catabolic
effect of glucocorticoid therapy can be abrogated by ensuring adequate caloric and
dietary protein intake. Optimally, the protein and caloric intake in the perioperative
period should be at least 1.5 gm protein/kg/day and 30-35 kcal/kg/day.
The optimal long-term dietary prescription of the KTR is controversial. Mainte-
nance of nitrogen balance needs to be balanced by the theoretical risk of hyperfiltration
induced by dietary protein loading. In summary, because it appears difficult to achieve
a protein restricted diet without compromising essential caloric intake, protein re-
striction should probably be avoided in the long term renal transplant recipient. A
diet containing 1 gm/kg/day and 25-35 kcal/day appears to be the best compromise
in the stable renal allograft recipient.
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A major cause of mortality in the KTR remains cardiovascular disease which has
been linked to markers of malnutrition in other populations, specifically to alter-
ations in lipid metabolism. In conjunction with a low fat diet, careful pharmaco-
logical therapy with HMG CoA reductase inhibitors appears to be safe and effective
in the short-term treatment of dyslipidemias in the transplant patient. Since there is
currently no evidence to suggest that lipids in the KTR behave differently than in
the general population, it is reasonable to assume that KTRs will benefit from serum
lipid reduction until a treatment outcomes study suggests otherwise.
An alternate nutritional parameter that may be associated with enhanced cardio-
vascular disease risk in the KTR, hyperhomocysteinemia, should also be considered.
In non-cyclosporine treated KTRs, hyperhomocysteinemia can be modified by nu-
tritional supplementation with folic acid. Since folate supplementation is relatively
innocuous, modest repletion (5 mg/day) should be considered in this group. The
utility of folate supplementation in the vitamin-replete cyclosporine treated KTR is
less clear.
Bone disease remains a significant cause of morbidity in the long-term renal
allograft recipient. Further studies are needed to evaluate and compare the long-term
efficacy and safety of different regimens in the prevention and treatment of post
transplant bone disease. Several therapeutic interventions hold promise for attenu-
ating the debilitating bone-associated side effects of immunosuppressive medications.
Because of limited original research concerning nutrition in the KTR, the true
impact of altered nutrition in the KTR is poorly understood. Additional investiga-
tions correlating measures of nutrition to specific renal transplant patient and al-
lograft outcomes are needed.
Selected References
1. Ikizler TA, Hakim RM. Nutrition in end-stage renal disease. Kidney Intl 1996;
50:343-357.
2. Cogan MA, Sargent JA, Yarbrough SG et al. Prevention of prednisone-induced
negative nitrogen balance:effect of dietary modification on urea generation rate in
patients on hemodialysis receiving high-dose glucocorticoids. Ann Int Med 1981;
95:158-161.
3. Whittier FC, Evans DH, Dutton S et al. Nutrition in renal transplantation. Am J
of Kidney Dis 1985; 6(6):405-411.
4. Miller DG, Levine SE, DElia JA et al. Nutritional status of diabetic and nondia-
betic patients after renal transplantation. Am J Clin Nutr 1986; 44:66-69.
5. Horber FF, Zurcher RM, Herren H et al. Altered body fat distribution in patients
with glucocorticoid treatment and in patients on long-term dialysis. Am J Clin
Nutrition 1986; 43:758-769.
6. Salahudeen AK, Hostetter TH, Raatz SK et al. Effects of dietary protein in pa-
tients with chronic renal transplant rejection. Kidney Intl 1992; 41;183-190.
Table 13.5. Causes of bone loss in the KTR
Residual Hyperparathyroidism
Medications
Corticosteroids
Cyclosporine
FK506
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7. Windus DW, Lacson S, Delmez JA. The short-term effects of a low-protein diet in
stable renal transplant recipients. Am J Kidney Dis 1991; 17(6): 693-699.
8. Kasiske BL, Guijarro C, Massy ZA et al. Cardiovascular disease after renal trans-
plantation. J Am Soc Nephrol 1996; 7:158-165.
9. Hilbrands LB, Demacker PNM, Hoitsma AJ et al. The effects of cyclosporine and
prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipi-
ents. J Am Soc Nephrol 1995; 5:2073-2081.
10. Goldberg R, Roth D. Evaluation of fluvastatin in the treatmentof hypercholester-
olemia in renal transplant recipients taking cyclosporine. Transplantation 1996;
62:1559-1564.
11. Lal SM, Hewett JE, Petroski GF et al. Effects of nicotinic acid and lovastatin in
renal transplant patients: A prospective, randomized, open-labeled crossover trial.
Am J Kidney Dis 1995; 25:616-622.
12. Jensen RA, Lal SM, Diaz-Arias A et al. Does cholestyramine interfere with
cyclosporine absorption? A prospective study in renal transplant patients. ASAIO
J 1995; 41:M704-706.
13. Urakaze M, Hamazaki T, Yano S et al. Effect of fish oil concentrate on risk factors
of cardiovascular complications in renal transplantation. Trans Proc 1989;
21:2134-2136.
14. Nygard O, Nordrehaug JE, Refsum H et al. Plasma homocysteine levels and mor-
tality in patients with coronary artery disease. New Engl J Med 1997; 337:230-236.
15. Arnadottir M, Hultberg B, Vladov V et al. Hyperhomocysteinemia in cyclosporine-
treated renal transplant recipients. Transplantation 1996; 61(3):509-512.
16. Kirkman RL, Strom TB, Weir MR et al. Late mortality and morbidity in recipi-
ents of long-term renal allografts. Transplantation 1982; 34:347-351.
17. Pichette V, Bonnardeaux A, Prudhomme L et al. Long-term bone loss in kidney
transplant recipients: A cross-sectional and longitudinal study. Am J Kidney Dis
1996; 28:105-114.
18. Cayco AV, Wysolmerski J, Simpson C et al. Posttransplant bone disease: Evidence
for a high bone resorption state. J Am Soc Nephrol 1997; 8:549A.
19. Valero MA, Lonaz C, Larrodera L et al. Calcium and biphosphonates in bone loss
after liver transplantation. Calcif Tissue Int 1995; 57:15-19.
20. Talalaj M, Gradowska L, Marcinowska-Suchowierska E et al. Efficiency of preven-
tive treatment of glucocorticoid-induced osteoporosis with 25-hydroxyvitamin D
3
and calcium in kidney transplant recipients. Transplant Proc 1996; 28:3485-3487.
CHAPTER 1
CHAPTER 24
Biology of Nutrition Support
in the Critically Ill Patient
Rifat Latifi, Selman Uranes
Introduction
The vocabulary and the practice of nutrition support of critically ill patients
have changed significantly in recent years, and new era of nutri-pharmaceutics has
become integral part of patients care. The question to be answered is not any longer
should critically ill patients be fed or not, but rather when to feed and what to feed
them. The benefit of early institution of enteral or parenteral nutrition in the overall
management of critically ill patients has been well established. Following injury,
energy requirements are greatly increased to sustain the increased metabolism and
wound repair. Similarly protein requirements are also greatly increased to provide
substrate for protein synthesis. In this situation, provision of calories and nitrogen
in a ratio of 150:1 has been shown to be most efficacious in achieving a positive
balance. However it is not yet completely understood whether improved nitrogen
balance in patients receiving TPN is achieved by an increase in protein synthesis or
a decrease in protein (muscle) catabolism. Irrespective of these results, it is
well established that TPN is associated with improved nitrogen balance in criti-
cally ill patients.
In general, the optimal route of providing nutrition in critically ill patients has
been established: use the gastrointestinal tract whenever possible. If, on the other
hand, a patient will not receive all needed nutrient substrates and calories enterally,
then nutrition should be provided parenterally. Because of recent advances, in iden-
tifying and recognizing fundamental metabolic changes of key nutrient substrates in
critically ill patients, nutritional formulas are being designed to overcome these
changes and support the organism during critical illness, infection, trauma or severe
sepsis. Example of such approach to nutritional support of critically ill patients is
the provision of immune-enhancing formulas (IEF) that have been shown to im-
prove immune response in laboratory animals and in critically ill patients. These
enteral formulas contain increased amounts of peptides, arginine, glutamine, vita-
mins E, A, and C, nucleotides and nucleosides, branched- chain amino acids and
omega 3-fatty acids. It is suggested that these key nutrients can modulate and affect
a variety of inflammatory, metabolic, and immune processes if given in doses higher
than those recommended. Based on current evidence derived from randomized pro-
spective controlled trials, early provision of nutrition in critically ill patients is a
Level I recommendation,
1
however the controversy exists on what type of nutrition
formula should be used.
370
24
Protein and Nitrogen Metabolism in Critically Ill Patients
Severely injured and critically ill patients characteristically demonstrate signifi-
cant muscle losses and consequently are in negative nitrogen balance. During criti-
cal illness, dietary amino acid requirements are increased two to three times as a
result of hypercatabolism and inefficient reutilization of endogenous nitrogen. Fur-
thermore, amino acids are redistributed from peripheral tissues to splanchnic organs
to maintain protein synthesis in the gut mucosa and immune system. Although
different tissues have varies rates of protein synthesis and, respond differently to
stress and trauma, both muscle protein and albumin synthesis rate correlate with the
metabolic status and severity of the disease. A brief period of accentuated proteoly-
sis, ureagenesis and negative nitrogen balance is tolerated by the stressed, but
well-nourished patient. If the patient is malnourished prior to injury or surgery, or
develops a complication that precludes adequate oral intake or if a patient sustain a
prolonged catabolic phase, then special nutritional support is indicated.
Metabolic response to injury is the striking increase in protein catabolism along
with a marked increase in urinary losses of nitrogen, phosphorus, sulfur, potassium,
magnesium, and creatinine. Skeletal muscle and nitrogen losses following injury
may occur secondary to actual destruction of tissue by injury, blood loss, and exu-
dates from wounds, and muscle wasting secondary to atrophy. The process of in-
creased nitrogen losses is complex and correlates with increased metabolic rate, which
peaks several days after injury and gradually returns towards normal over several
weeks.
1-5
This phenomenon occurs consistently following major fractures or major
blunt injury, burns, sepsis and various other injuries.
6-10
The mechanism for net
protein increase is not entirely clear, although hormonal effect of insulin resistance,
cortisol effects, and proinflammatory cytokines activity have synergistic effects. Di-
minished activity of antioxidants such as gluthatione may effect protein stability
within the cell it self. Metabolic response to severe surgical illness is associated with
mobilization and utilization of nutrient substrates such as fatty acids, amino acids
and glucose. Although, there is a well orchestrated redistribution of body protein
from carcass to visceral organs, the rates of tissue protein synthesis varies with differ-
ent trauma, but correlates with clinical status and overall metabolic indices and is
clearly exacerbated during criticall illness and directly is influenced by the illness it
self, the PO
2
, pH, and hemoglobin.
11
An increased muscle protein catabolism fol-
lowing injury has been demonstrated by measuring the excretion of 3-methyhistidine,
which serves as an index of muscle protein catabolism.
9
As protein is broken down,
3-methylhistidine is released and excreted unchanged by the kidneys especially fol-
lowing critical injury, burns, postoperative trauma, infections and other critical
illness.
10
The primary origin of the 3-methylhistidine is skeletal muscle, but some of
it is derived from the smooth muscle of the gastrointestinal tract. During periods of
starvation and bowel rest, the intestine may become the source for large portion
muscle losses and increased amount of excreted 3-methylhistidine.
Amino Acid Metabolism
Although plasma amino acid levels have been measured in critically ill and in-
jured patients in an effort to identify specific changes related to the catabolic re-
sponse, the results have been inconsistent.
12
The mobilization of amino acids from
muscle protein leads to an irretrievable loss of nitrogen from the body in the form of
urea, ammonia, uric acid, creatinine and other excreted compounds. If left uncor-
rected, the adverse consequences for the critically ill patient are a rapid loss of muscle
371
Biology of Nutrition Support in the Critically Ill Patient
24
mass and subsequent marked debility. All amino acids are required for optimal pro-
tein synthesis; however, alanine and glutamine are the major carriers of nitrogen
from muscle, constituting as much as 70% of the amino acids released from skeletal
muscle following injury.
13
Alanine is a major substrate for production of glucose by
the liver, and during that conversion, the nitrogen released is incorporated into urea.
This represents the final breakdown step of the protein and results in an irreversible
loss of nitrogen from the bodys metabolic pool. Glutamine, a nonessential amino
acid, serves as an important respiratory substrate for the enterocytes and other rap-
idly dividing cells, including the bone marrow, endothelial cells, and proliferating
cells in wounds and areas of inflammation.
14,15
Following surgical interventions, glutamine consumption by the gastrointestinal
tract is greatly increased.
16,17
Glutamine has been identified as primary fuel for
enterocytes, and for other rapidly dividing masses of cells where it is converted to
alanine The utilization of glutamine by the intestine as an oxidative fuel has a spar-
ing effect on glucose. During the sepsis, glutamine depletion is even more severe
and lasts longer than that associated with the hypercatabolism following injury. In
sepsis, the lung and the kidney, in addition to the skeletal muscle, becomes an organ
of net glutamine release.
18,19
Furthermore, during the sepsis the liver has increased
glutamine uptake, and becomes the primary organ for glutamine utilization.
19
In
the presence of endotoxemia, glutamine may be used in the liver for gluconeogen-
esis, ureagenesis and synthesis of proteins, nucleotides, and glutathione.
20,21
Following surgery, severe injury or sepsis, the rapid fall in the concentration of
glutamine in the plasma and in the intracellular pool is greater than that of any
other amino acid and is inversely correlated with the severity of the underlying in-
sult. It is reversed only late in the course of recovery.
21
This marked decline in
glutamine concentrations in blood and tissues during critical illness indicates that
glutamine is being consumed at a greater rate than endogenous synthesis. Thus, it
has been hypothesized that glutamine is a conditionally essential nutrient, especially
following injury. Glutamine supplementation has been shown to exert trophic ef-
fects on intestinal mucosa. TPN solutions enriched with glutamine
22
increase jeju-
nal mucosal weight, nitrogen and DNA content, and significantly decrease atrophy
of the villi. Furthermore, glutamine prevents deterioration of gut permeability,
23
and has been proven beneficial for patients with intestinal mucosal injury secondary
to chemotherapy and radiation.
24,25
Reduction of hepatic steatosis,
26
pancreatic at-
rophy
27
and in bacterial translocation from the gut,
28
associated with standard TPN
solutions have been reported with the use of glutamine supplemented TPN solutions.
Glutamine also improves the nitrogen balance and reduces the skeletal muscle glutamine
loss in patients following elective cholecystectomy
29
and other major surgeries. Admin-
istration of glutamine in TPN as glutamine-containing dipeptides has decreased the
incidence of infections in bone marrow transplant patient.
31
Arginine is considered a nonessential amino acid in the diet of healthy adults
because the endogenous synthetic pathways provide adequate amounts of this amino
acid. Arginine stimulates release of growth hormone and prolactin, and also induces
a marked release of insulin.
32
Supplementing the diet with arginine has been shown
to improve weight gain, increase nitrogen retention, and accelerate wound healing
in animals and in human beings.
33
The trophic effects of arginine on the immune
system in human beings have also been demonstrated.
34
In both animals and human
beings, plasma arginine levels decreases significantly following a burn injury.
35
Ex-
perimentally, arginine and glutamine as well as dehydroepiandrosterone reversed
372
24
the susceptibility to infections caused by prednisone and may be useful agents for
preventing infections in patients treated with steroids.
36
Branched-Chain Amino Acids (BCAA)
Following injury and sepsis, an energy deficit that may develop in skeletal muscle
is met by an oxidation of the BCAA. BCAA oxidation is increased after trauma and
sepsis, and evidence indicates that skeletal muscle is the major site of BCAA degra-
dation.
37-41
Most recent study has demonstrated that when critically ill patients,
unable to be fed enterally, were given total parenteral nutrition fortified with BCAA
of 23% and 45% respectively, as compared with standard TPN which provided 1.5
g/kg/day of protein, they had significantly lower morbidity and mortality (42). The
decrease in mortality correlated with higher doses of BCAA to or > 0.5 g/kg/day).
Furthermore, BCAA rich parenteral nutrition formulas have been shown to correct
the plasma amino acids imbalance that consistently exist in critically ill patients, and
improves plasma concentrations of pre-albumin and retinol binding protein
in septic patients.
In a series of trauma patients, nitrogen retention, transferrin level and lympho-
cyte counts were all improved with BCAA supplementation. Since the concentra-
tion of BCAA is low in septic patients, probably as a result of over utilization,
supplementation of feeding regimen with BCAA may be beneficial.
Nucleotides and Nucleic Acids in Nutritional Support
Nucleotides, as building blocks of DNA and RNA, are essential to genetic mecha-
nism, protein synthesis, regulation and structure. These low molecular weight, highly
biological compounds, are involved in virtually all biochemical processes.
43-61
They consist of a nitrogenous base, a 5-carbon sugar, and at least one phosphate
group. RNA and DNA are high-molecular-weight compounds that are made up of
long chains of nucleotides. They form the genetic code and are essential for protein
synthesis. They function as an energy source in cellular metabolism and as interme-
diates in biosynthetic and oxidative pathways. The synthesis of nucleotides is a ma-
jor activity of the cell. Next to protein synthesis, nucleotide synthesis consumes
more amino acids than any other biologic activity. Nucleotides contain either pu-
rine or pyrimidine bases. Adenine, inosine, and guanine, are purine bases, while
thymidine, cytosine and uracil are pyramidine bases. Purine nucleotides are
synthesi zed de novo from gl utami ne, gl yci ne, aspar tate, CO2, and
phosophoribosylpyrophosphate (PRPP), while pyrimidines are synthesized from
aspartate or glutamine, NH
3
, and CO
2
. Purine nucleotides, with their high-energy
phosphate side chains are fundamental to cellular energy metabolism and are inter-
mediaries in biosynthetic and oxidative pathways. Purine nucleotide biosynthesis
produces inosine monophosphate (IMP). IMP is synthesized by the de novo path-
way of purine biosynthesis from glycine and is then converted to AMP and GMP.
The three main sources of nucleotides are: dietary nucleotides, salvage of nucle-
otides released by intracellular metabolism, de novo synthesis from amino acids and
sugars. The addition of a pentose sugar to a nitrogen base produces a nucleoside.
Depending on which sugar is added to the nitrogen base, a nucleoside can be ribo-
nucleoside or a deoxyribonucleoside. Nucleosides are produced by intracellular
metabolism and are used for purine biosynthesis via the salvage pathway. The most
common pathway is the resynthesis of IMP from inosine, which is a product of
adenosine nucleotide metabolism.
373
24
The adenosine monophosphate (AMP), adenosine diphosphate (ADP) and ad-
enosine triphosphate (ATP), are energy sources and participants in carbohydrate,
protein, and lipid synthesis. Nucleotides are required in all cells undergoing prolif-
eration, but they are especially important in tissues with rapid cell proliferation such
as intestine, liver, and lymphoid tissue. T lymphocytes require nucleotides to main-
tain a normal cellular immune response. Various tissues in the body, such as liver,
are capable of synthesizing nucleotides de novo. When tissues are unable to synthe-
size purine nucleotides, purines are transported from another tissue. For example,
adenosine is released from the liver and taken up by the lung in large amounts.
The small intestinal mucosa requires a constant supply of nucleotides to produce
DNA and RNA. In these rapidly proliferating cells, the content of DNA and RNA
must double for cell division to occur. However, in these cells, the enterocyte has a
limited capacity for de novo biosynthesis. The small intestine must rely on the sal-
vage pathway to synthesize nucleotides from nucleosides. The nucleosidesinosine,
adenosine, and so on, come either from the blood, or from luminal nucleosides. The
latter may come from the diet, and the sloughing of enterocytes, or from bacterial
breakdown. In addition, nucleotides themselves can be absorbed from the in-
testinal lumen.
It is clear that the small intestinal mucosa relies partially on intestinal nucle-
otides and nucleosides to meet synthetic demands. There are at least two significant
implications. The first is that diets that contain no nucleotides or nucleosides may
not offer sufficient support to the intestinal diets that contain no nucleotides or
nucleosides may not offer sufficient support to the intestinal mucosa in some cir-
cumstances. This includes many enteral diets, especially elemental diets, and in-
cludes all varieties of total parenteral nutrition (TPN). The second implication is
that nucleotide or nucleoside supplementation could be beneficial to critically ill
patients. This type of supplementation has been implemented clinically in certain
enteral products. Nucleotides exert multiple protective actions on the intestinal
mucosa and facilitate repair of injured mucosa. Experimental rats receiving TPN
supplemented with nucleotides showed higher protein and DNA content in intesti-
nal mucosa, increased maltase activity, higher villous height, and more proliferative
activity in crypt cells compared with rats receiving nucleotide-free TPN. In mice,
intraperitoneal and oral administration of a mixture of nucleotides and nucleosides
reduced bacterial translocation and improved repair of mucosal injuries.
Clinically, the frequency of diarrhea in children was reduced from 68% to 52%
when milk formulas were supplemented with nucleotides. While the basis for this
protective action is unclear, although it is known that dietary nucleotides enhance
intestinal epithelial proliferation and differentiation.
The metabolic fate of any exogenously administered nucleotide depends on its
entry position in the overall pathway of purine metabolism. Nucleic acids undergo
partial hydrolysis in the stomach, after which they are subjected to pancreatic nu-
clease to yield nucleotides. Phosphodiesterases and alkaline phosphatases cleave phos-
phate groups to form nucleosides. The presence of charged phosphates in nucleotides
impedes their transport across cell membranes. Phosphates remove the charged phos-
phates and together with nucleotidase facilitate transport across the cell membrane.
Dietary nucleotides converge in the cell cytoplasm in the form of nucleosides, which
are then used in the salvage pathway to reform nucleotides. Nucleotides may be
supplied either enterally or parenterally. Parenterally administered purine and py-
rimidine derivatives are effectively used throughout the salvage pathway. TPN
374
24
formulas supplemented with a mixture of nucleotides and nucleosides can promote
ulcer healing in rats by restoring villous architecture and accelerating cell prolifera-
tion. TPN supplemented with a mixture of nucleotides and nucleosides in animals
undergoing massive intestinal resection resulted in significantly higher residual jeju-
nal total mucosa weight, protein, DNA, RNA, and the ratio of proliferating cells per
crypt a compared with a standard TPN formula. The clinical use of nucleotides in
liver disease has been suggested in order to improve healing of the liver. Experimen-
tal studies have suggested beneficial effects. A mixture of nucleotides and nucleo-
sides given subcutaneously prevented ethionine-induced liver injury by suppressing
the accumulation of triglycerides in the liver, reducing the increase of liver enzymes,
and preventing the decrease of hepatic ATP concentration. In rats undergoing a
70% hepatectomy, supplementation of TPN regimens with nucleotides and nucleo-
sides improved both nitrogen balance and whole body protein turnover. Nucleotide
supplementation was beneficial in galactosamine induced liver injury by reducing
the extent of injury histologically and by improving clinical biochemical liver indi-
ces. Currently, nucleotides are not included in standard TPN solutions, however
there are now enteral formulas fortified with nucleotide (in addition to arginine,
omega-3 fatty acids, and glutamine) that are intended to enhance the immune sys-
tem in patients receiving them.
The immunologic role of nucleotides has been studied mainly in experiments
with nucleotide-free diets. In the early 1980s it was observed that renal transplant
patients receiving standard nucleotide-free TPN had better graft function with few
rejection episodes and required lower doses of immunosuppressants. Once on a
regular diet, these patients required increased doses of immunosuppressants to main-
tain graft function and prevent rejection. Clearly, the patients were immunosup-
pressed on TPN.
It was postulated that lack of preformed nucleotides in TPN was a cause of this
immunosuppression. Animal studies have demonstrated the effects of nucleotide-free
diets. Such diets diminish T cell mediated immune responses such a delayed-type
cutaneous hypersensitivity to various antigens, decreased mitogenic response, and
reduced interleukin-2 production. There is also evidence of decreased survival from
systemic infections caused by Staphylococcus aureus and Candida albicans in ani-
mal fed a nucleotide-free diet. The increased susceptibility to systemic infections has
been shown to reverse with RNA supplementation. Furthermore, nucleotide defi-
ciency reduces splenic stem cell proliferation. This can be reversed with RNA supple-
mentation. Dietary nucleotides modulate T helper cell mediated antibody
production and have a preferential effect on antigen-driven T helper cell-mediated
immune response. Nucleotides and nucleosides are major and essential components
of all cells. The metabolic rate of nucleotides is accelerated in hypermetabolic condi-
tions such as sepsis, trauma, or surgical stress. Substantial evidence suggests that
these nutrients are conditionally essential for normal stress responses. The condi-
tions that increase nucleotide requirements are rapid cellular proliferation and
include hepatic injury or resection, intestinal development and adaptation fol-
lowing massive intestinal resection, and other nonspecific challenges to the
host immune system.
Nucleotides are a component of several immune-enhancing formulas that also
contain glutamine, arginine, and omega 3-fatty acids. These formulas have been
shown to be beneficial in multiple clinical trials. Glutamine, arginine, nucleic acid,
and omega 3-fatty acid supplemental enteral feeding in severe trauma patients
375
24
reduced major infection rate, decreased the use of antibiotics, and shortened hospi-
tal stays, In a prospective, randomized, placebo-controlled, double-blinded,
multicenter trial of patients in the surgical intensive care unit, early enteral feeding
supplemented with arginine, nucleotides, and omega 3-fatty acids was shown to
reduce postoperative and wound complications. Septic patients fed early enterally
with the same supplemented diet (in another double blinded multi-center study)
had a substantial reduction in the hospital stay. No clinical study has examined the
beneficial effect of isolated nucleotide supplementation in enteral feeding formulas
critically ill or trauma patients. However, as a component of an immune-enhancing
formula, nucleotides have a role in nutritional support of the critically ill. Nucle-
otides should not be administered as a calorie source, only as a promoter of protein
synthesis and cellular immunity. It seems likely that nucleotides will become an
essential component of nutri-pharmacologic intervention in critically ill and trauma
patients. Published studies have used different terms to describe various nucle-
otide supplementation regimens including nucleotides, polynucleotides,
nucleotide-nucleoside mixtures, RNA, and purines and pyrimidines
Purine nucleotides with their high-energy phosphate chains are fundamental to
cellular energy metabolism and are intermediaries in biosynthetic and oxidative path-
way. Nucleotides exert multiple protective actions on intestinal mucosa and facili-
tate repair of injured mucosa. They prevent ethionine-induced liver injury by
suppressing accumulation of triglycerides in the liver, reducing the increase of liver
enzymes, and preventing the decrease of hepatic ATP concentration. In rats under-
going a 70% hepatectomy, supplementation of TPN with nucleotides and nucleo-
sides improved both nitrogen balance and whole body protein turnover. Furthermore,
nucleotide supplementation was beneficial in galactosamine-induced liver injury by
reducing the extent of injury histologically and by improving clinical biochemical
indices. The turnover rate of nucleotides is accelerated in hypermetabolic condi-
tions such as sepsis, trauma or surgical stress. Substantial evidence suggests that
these nutrients are conditionally essential for normal stress response.
Omega 3-Fatty Acids
The ability of omega 3-fatty acids to incorporate into a cell membrane and their
use during the inflammatory process, as well as their ability to modify the inflam-
matory response, is the rationale for their use in dietary formula in critically ill
patients.
62
Omega 3-fatty acids affect cytokine production, decrease both tumor
necrosis factor (TNF ) and IL-1 synthesis and significantly modulate the inflam-
matory response in adult respiratory distress syndrome (ARDS).
63
Growth Hormone
Growth hormone has been shown to attenuate the protein catabolic response
after major surgery, induce nitrogen retention in patients undergoing gastrointesti-
nal surgery with epidural anesthesia and TPN, and attenuate forearm glutamine,
alanine, 3-methylhistidine and total amino acid efflux. Moreover, growth hormone
has been shown to preserve both muscle protein synthesis and the decrease in
muscle-free glutamine, and improve the whole-body nitrogen economy after sur-
gery.
64
In addition, growth hormone has been shown to reduce skeletal muscle re-
lease of glutamine. Most recently growth hormone and insulin-like growth factor 1
was shown to promote intestinal uptake and hepatic release of glutamine in sepsis.
65
Use of growth hormone in critically ill patients, however, has become controversial
66-74
376
24
While GH administration was shown to accelerate protein gain in stable adult pa-
tients receiving aggressive nutritional support, and attenuate the catabolic response
to injury, surgery, and sepsis, more recently
GH treatment in critically ill patients has been associated with increased mortal-
ity and morbidity. In a prospective, multi-center, double blind, randomized
placebo-controlled trial, patients treated with high dose GH (0.1 mg/kg body weight)
had higher mortality rate then patients who did not receive GH (p<0.001).
66
Be-
cause of conflicting results of studies, administration of high dose GH is not recom-
mended in critically ill patients.
Immune-Enhancing Enteral Nutrition: Clinical Evidence
Enteral formulas fortified with immune-enhancing substrates are associated with
significant reduction in the risk of infectious complications as well as reduction of
overall hospital stay. Providing adequate standard enteral or parenteral nutrition
support does not necessarily protect critically ill patients from developing nosoco-
mial infections. Since most critically ill patients are immuno-commpromized modu-
lating or enhancing their immune status with nutrient substrates has great
potential.
75-80
It has been demonstrated that certain nutrients can modulate inflam-
matory, metabolic and immune processes. Amino acids such as arginine and
glutamine, improve body defenses, tumor cell metabolism, increase wound healing
and reduce nitrogen losses. RNA and omega 3-fatty acids also modulate the im-
mune function. To this end, supplementation of enteral diets in critically ill patients
with specific immuno-nutrients such as arginine, glutamine, nucleotides, nucleo-
sides, and omega 3-fatty acids in critically ill patients have been shown to be clini-
cally beneficial. These immune-enhancing formulas improve immune response
experimentally as well as clinically. Studies performed in burn, trauma, or surgical
patients have shown outcome advantages with reduction in infections, total compli-
cations, or length of stay. The majority of the prospective, randomized, clinical trials
published to date used formula fortified with arginine, RNA, omega-3 and omega-6
fatty acids. Although various formulas are used they all were associated with im-
proved outcome. The mortality rate however, has not been reduced by the use of
these immune-enhancing formulas.
The effect of the first immune-enhancing formula on the length of hospital stay
and complication rate of critically ill and septic patients was studied in a multi-center
study of 296 traumas, post-surgery and septic patients.
75
The patients in this study
had entry requirements of an APACHE II score greater then 10 and therapeutic
intervention score (TIS) greater than 20, and were stratified by age (less than 60 or
greater than 60 years) and whether they had sepsis or systemic inflammatory re-
sponse syndrome (SIRS), highlighted by fever and leukocytosis. One hundred
sixty-eight patients were randomized to receive the fortified formula, while 158 were
fed with isonitrogenous enteral diet. Both groups tolerated early feeding well, had a
low tube-feeding related complication rate, and achieved similar nitrogen balance.
Patients receiving diet supplemented with arginine, nucleotide and fish oil had higher
levels of plasma arginine and ornithine concentration. Furthermore, their plasma
fatty-acids profiles demonstrated higher concentration of linoleic acid in patients
with common formula (control group) while patients receiving immune-enhancing
formula had higher concentrations of eicosapentaenoic acid and docosahexaenoic
acid. There were no differences in mortality between the groups, however both groups
had overall lower than expected mortality. Moreover, patients who received at least
377
24
821 mL/day of enteral diet had an average length of hospital stay reduced by 8.1
days. Most beneficial effects were demonstrated in severely and septic patients with
reduction of length of hospital stay by 10 predicted days along with a major reduc-
tion in frequency of acquired infections (p< 0.01). In a subgroup of septic patients
in whom early enteral feeding goals were achieved, the median length of stay was
reduced by 11.5 days. In a group that was stratified as SIRS, there were no statistical
differences in benefits between the groups. These investigators concluded that early
enteral feeding in severely ill patients is safe and is associated with significant ben-
efits, especially if patients were septic.
75
Another immune-enhancing enteral diet containing glutamine reduced septic
complications in patients with severe trauma.
76
This study, unlike the previous study,
had an isonitrogenous (INIC) control not receiving the immune enhancing diet
(IEF). In a prospective, blinded study 35 severely injured patients with abdominal
trauma supplemented with glutamine, arginine, nucleotides, and omega-3 fatty ac-
ids, or INIC diet (N=18). Nineteen other patients without enteral access served as a
control. Significantly fewer major infections complications (6%) developed in pa-
tients that received IEF than in patients receiving INIC diet (41%, p = 0.02) or the
control group (58%, p = 0.002). The hospital stay, antibiotic use, and the develop-
ment of intra-abdominal infections were significantly lower in IEF group. Patients
that were not fed had the highest rate of complications.
In another prospective, randomized, placebo, double blind, multicenter study of
surgical intensive care patents that underwent upper gastrointestinal surgery, clini-
cal outcome and costs were compared.
77
Early enteral feeding with arginine, dietary
nucleotides, and omega-3 fatty acids was associated with significant reduction in the
frequency rate of late post-operative infection and wound complications. Further-
more, the treatment cost was substantially reduced in the immune-nutrition group
as compared with the control group. Immuno-nutrition (Impact, Novartis Nutri-
tion, Minneapolis, MN) was given to 77 patients, while an isocaloric and
isonitrogenous diet was given to 77 patients. Enteral feeding was initiated within
12-24 hours after surgery and advanced to a target volume of 80 mL/hr by
post-operative day 5. There were no differences in early post-operative complica-
tions between the groups: however, there were significantly fewer late complications
were significantly fewer in immune-nutrition group.
Achieving nutritional goals early in critically ill patients with immune-enhancing
enteral diet has been shown to greatly reduce morbidity and shorten time on me-
chanical ventilation.
78
These investigators studies 390 critically ill surgical and medical
patients. Of the 101 patients achieving early enteral nutrition (within 72 hours), 50
patients fed with Impact had a significant reduction in requirements for mechanical
ventilation compared with controls. There was also an associated reduction in the
length of hospital stay. The administration of immune-enhancing enteral nutrition
had no clear benefits over standard high-protein enteral diets in burn patients, and
was even found to increase the incidence of adult respiratory distress syndrome.
41
Recent prospective double- blind, randomized trial of patients with major burns
(>50% body surface) demonstrated that supplemental intravenous glutamine in-
fused continuously over 24 hours was significantly better than just isonitrogenous
amino acid solutions. In this study, 26 severely burned patients (20%-90% were
randomized to either intravenous glutamine (0.57 g/kg/body weight) or
isonitrogenous amino acid solutions (to give patients 0.57 g/kg/body weight, with-
out glutamine) administered continuously in addition to enteral nutrition support,
378
24
or enteral and parenteral nutrition, for those patients unable to achieve nutritional
goals with enteral nutrition alone. The study group receiving glutamine had lower
incidence of Gram-negative bacteremia (8% vs 43%; p=<0.04), and significant im-
provements in serum transferrin and prealbumin at 14 days after the injury (p<0.01
and 0.04, respectively). Furthermore, there was a trend toward lower mortality, de-
creased bacteremia incidence, and antibiotic usage in glutamine group.
79
Other studies
have shown similar results in multiple trauma patients, where use of glutamine was
associated with significant reduction in the incidence of bacteremia, septic episodes,
and pneumonia.
80
Patients treated with glutamine, had no episodes of Gram- nega-
tive bacteremia, where as the 54% of all bacteremia and 63% of sepsis were caused
by Gram-negative bacteria. Although the mechanism is not entirely clear, it appears
from both these studies that glutamine protects from Gram- negative bacteria in
these most critically ill patients.
Meta-analysis of 11 randomized controlled clinical trials of enteral nutrition with
immune-enhancing formula) that included 1009 patients,
81
concluded that nutri-
tional support supplemented with key nutrients (arginine, glutamine, branched-chain
amino acids, nucleotides, and omega-3 fatty acids) results in a significant reduction
in the risk of developing infectious complications and reduces the overall hospital
stay in critically ill patients and in patients with gastrointestinal cancer.
Although multiple studies have shown beneficial effect of IED, non- the less
their use is not wide spread yet. A consensus panel from a recent conference on
immune-enhancing enteral therapy,
82
recommend the use of IED in the following
patients: a) severely malnourished patients (albumin <3.5 g/dL) undergoing upper
GI surgery, or patients with albumin <2.8 g/dL, undergoing lower GI surgery; b)
patients with blunt or penetrating torso trauma with an ISS of >18/or or abdominal
trauma index >20. Although there are insufficient data to recommend use of IED,
non the less patients undergoing elective aortic surgery with preexisting chronic
pulmonary disease, or those undergoing major head and neck surgery with preexist-
ing malnutrition, severe head injury patients (GCS <8 with an abnormal CT scan),
burns patients (>30%, third degree) and ventilatory dependent patients at risk of
subsequent infections may benefit from early IED use.
Summary
The biology of nutrition support has become much better understood, although
we far from knowing all we need to know in this complex field. Amino acids are a
key component of the nutritional and metabolic management of critically ill pa-
tients. As our current knowledge of the altered regulation of amino acid metabolism
in critically ill patients increases, the formulation and administration of more effec-
tive parenteral and enteral therapeutic feeding regimens will inevitably evolve. The
use of specific amino acids in pharmacological doses and in special combinations
and ratios is likely to be beneficial to critically ill patients. A working knowledge of
the multiple and complex functions of amino acids is essential to the competent and
efficacious practice of medicine. Because derangements in amino acid metabolism
are common in pathologic states and are detrimental to optimal metabolic function,
reversal of these path physiologic alterations by optimal nutritional support will be
obligatory if the outcome of critically ill patients is to be significantly improved.
Metabolic changes of amino acid pool and milieu simply cannot be ignored any
more, and will need to be taken in account when creating new formulation of nutri-
ent formulas, enteral as well as parenteral. Standardization of methodology of
379
24
studying end points of nutrition support, clinical criteria for specialized nutrient
substrate such as those fortified with BCAA, patients selection and other variables
will resolve the contradictory findings of future clinical studies. The main difficulty
in obtaining evidence-based data in surgical nutrition support, when different nu-
trient substrates are used, lie the patients selection criteria and study end point, as
well as multiple other variables. The use of specific immune-enhancing formulas
with amino acids in higher pharmacological doses and in special combinations and
ratios is beneficial to critically ill patients.
One should compare nutrition support and advances that need to be made with
other fields such as management of anemia in critically ill patients. Today one can
manage anemia virtually without transfusing blood using genetically created recom-
binant erythropoietin (Procrit
- Ortho Biotech).
83
So, just as we can support ane-
mic patient with substrates that will stimulate bone marrow to produce blood and
blood products, without transfusing blood, we should strive to use in the future
genetically altered nutrient substrates that will mimic, or better off, substitute the
perfect nutrient substrates for most critically ill patients and correct exactly the cel-
lular imbalances caused by the injury, severe sepsis or other disorders. Derangement
in amino acid metabolism, nucleotides, vitamins and trace elements are common in
critically ill patients. Reversal of these pathophysiologic alterations by optimal nu-
tritional support with immune-enhancing formulas is obligatory if the outcomes of
critically ill patients are to be significantly improved. Ideally the formula used for
nutrition and metabolic support in critically ill patients should contain high doses
of arginine, glutamine, taurine, BCAA, nucleotide and nucleoside, omega 3-fatty
acids, zinc, selenium, and vitamins A, E, C. It is also important for this formula to
be inexpensive and should be available in the enteral as well parenteral form.
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CHAPTER 25
Nutrition Support in Patients
with Pulmonary Failure and ARDS
Vanessa Fuchs, A.K. Malhotra and Rifat Latifi
Malnutrition and Lung Functions
Malnutrition is a leading cause of impaired respiratory muscle strength, endur-
ance and contractility, as well as lung function and their dynamics. In addition,
malnutrition causes deleterious changes in the structure and function of the dia-
phragm muscle mass and thickness which are reduced in proportion to the reduc-
tion in body weight. While the diseases associated with somatic wasting cause atrophy
of the respiratory muscles, respiratory muscle strength and endurance are reduced
more dramatically than the weight loss. Patients suffering from chronic obstructive
pulmonary disease (COPD) frequently exhibit profound malnutrition both as a
consequence of and result of their disease. Patients with acute respiratory failure,
secondary to sepsis, trauma, or intrinsic lung disease, may rapidly progress to a state
of nutritional embarrassment due to multiple factors. Furthermore, patients with
ARDS, or those sufferings from conditions rendering them susceptible to develop
ARDS, similar to other critically ill patients, have increased caloric requirement, are
hyperglycemic and have triglyceride intolerance, and overall net increase in protein
catabolism. Subsequently most patients with pulmonary failure have an attendant
compromise in nutrition status. Malnutrition may precede or follow respiratory
failure and if nutritional status is not preserved or malnutrition reversed with ag-
gressive nutritional support, the condition will progress into severe malnutrition
with significant clinical deterioration.
1
Malnutrition can adversely affect lung func-
tion and the adverse effects of such malnutrition include: decreased ventilatory drive,
decreased respiratory muscle function, alterations of lung parenchyma and depressed
lung defense mechanism. The incidence of post-operative pneumonia or atelectasis
is higher in protein-depleted patients as compared with well-nourished patients.
2,3
Anatomy of Respiratory Failure
Three categories of pulmonary failure are of special clinical interest: acute respi-
ratory failure (ARF) or acute respiratory distress syndrome (ARDS) and chronic
obstructive pulmonary disease (COPD), and post operative
Acute Respiratory Failure
Acute respiratory failure (ARF) occurs when the respiratory system is no longer
capable of providing sufficient oxygenation or is unable to eliminate enough CO
2
.
Several disorders including alveolar edema, fungal infections, lung cancer, tuberculosis
385
Nutrition Support in Patients with Pulmonary Failure and ARDS
25
and COPD may cause acute respiratory failure, which is classified in three types.
Type I respiratory failure is hypoxemic, caused mostly by shunting, thus is unre-
sponsive to supplemental oxygen therapy. Alveoli are basically flooded with puru-
lent material such is in pneumonia, blood in lung contusion, or edema in ARDS
caused by sepsis, aspiration, massive transfusion, shock, severe pancreatitis, fat em-
boli syndrome or amniotic fluid emboli. While many scoring systems have been
used in an attempt to define the severity of ARF, the PaO
2
/FiO
2
(P/F) ratio is most
useful. When this ratio is between 300 and 200 there is acute lung injury, and when
this ratio drops below 200, then this is considered ARDS. If, on the other hand, the
P/F ratio is <100, this is considered to be a severe ARDS. Because Type I respiratory
failure causes significant respiratory dysfunction with decreased lung compliance,
and dramatic increase in work of breathing, the majority of patients with ARF re-
quire some form of mechanical ventilation. Chronic pulmonary failure is character-
ized by abnormal expiratory flow that does not change markedly over several months.
Because expiration is obstructed, breathing requires more effort and more energy.
Type II of respiratory failure is characterized by elevation of CO
2
which is caused by
hypoventilation as a result of loss of respiratory drive, impaired mechanics of breathing
or simply excessive work load. Type III respiratory failure occurs mainly in the post-
operative patients, and is typically associated with hypoxemia and hypoventilation.
While this type of ARF is considered to be mainly from atelectasis and decreased
movement of diaphragm, which could progress in to pneumonia, the weakness of
diaphragmatic muscle secondary to perioperative malnutrition should be strongly
considered.
Chronic Respiratory Failure
Two major causes of COPD are chronic bronchitis and emphysema. Often this
type of respiratory failure is termed acute on chronic respiratory failure, when a
patient with relatively compensated respiratory failure experiences an insult such as
trauma or infection and deteriorates in full respiratory failure requiring mechanical
ventilatory support. This group of patients is at increased risk for significant malnu-
trition since increased metabolic demands and reduction of nutrient substrate in-
take result in a malnutrition state.
1,4,5
Chronic obstructive pulmonary disease (COPD) is associated with a variety of
nutritional and metabolic abnormalities. These abnormalities include protein and
caloric malnutrition, associated muscular atrophy, alteration in carbohydrate me-
tabolism, and altered respiratory drive. In addition, COPD is often associated with
hypermetabolism that is caused by an increase in the work of breathing. During
pulmonary failure, superimposed starvation may rapidly lead to worsening of respi-
ratory muscle function and inability to wean mechanical ventilatory support. It has
been demonstrated that during the period of acute illness and starvation, that muscle
degradation occurs primarily as a result of decreased protein synthesis and increases
muscle protein catabolism.
6,7
It has been also shown that malnutrition and immu-
nity may play a very important role in the pathogenesis of COPD. Furthermore,
malnourished patients have lower cellular immune function, although their humoral
immune function was similar to healthy subjects.
8
Acute Respiratory Distress Syndrome (ARDS)
ARDS is a common, devastating syndrome of lung injury affecting both surgical
and medical patients. It is estimated that approximately 75 per 100,000 populations
386
25
will suffer from ARDS. Although ARDS was described for the first time in 1967, it
was not until 1994 that a new definitions was created by the American-European
Consensus Conference Committee, that defined ARDS as a syndrome occurring
particularly in subset of patients with severe of acute lung injury (ALI), character-
ized by a constellation of clinical, radiological, and physiologic abnormalities that
cannot be explained by, but may coexist with left arterial or pulmonary capillary
hypertension. In particular, this syndrome must have acute onset, bilateral infil-
trates on chest radiography, pulmonary- artery wedge <18 mm Hg, and P/F ratio
less than 200.
9-11
There are numerous predisposing factors and clinical disorders associated with
development of the ARDS, including direct acute lung injury (aspiration, pneumo-
nia or inhalation injury), and indirect causes such as sepsis, severe multiple traumas,
shock, massive blood transfusion, and pancreatitis. Other less common causes of
ARDS are pulmonary contusion, fat emboli, near- drowning, and reperfusion pul-
monary edema after lung transplantation or pulmonary embolectomy, cardiopul-
monary bypass and drug overdose.
11
Overall mortality from ARDS is typically
reported to be greater than 50%, mainly because of underlying predisposing illness,
sepsis, or multiple organ dysfunctions. The primary reason for high mortality is
multiple organ system failure and sepsis, rather than primary respiratory causes,
although death may be related to the lung injury with high tidal volumes therapy.
12
The long-term consequences of ARDS are often very serious, although full return of
pulmonary function in a patient who survives ARDS is seen, with pulmonary func-
tion returning to normal within 6-12 months. If on the other hand, patient had
suffered long period of ventilatory support, sepsis, then the residual impairment of
lung function is present although may be asymptomatic. Currently patients with
ARDS are supported with mechanical ventilation and other supportive measures
directed at reducing and reversing the lung injury, such as low tidal volumes, pres-
sure control ventilation with or without inverse ratio ventilation and other tech-
niques such as prone positioning of the patients and aggressive pulmonary toilet.
Failure of standard advanced therapeutic measures to resolve ARDS have prompted
the use of other techniques such as tracheal gas insufflations, inhaled nitric oxide,
extra corporeal membrane oxygenation (ECMO) or partial liquid ventilation. Most
impressive progress in ventilatory support of patients with ARDS was reported re-
cently.
12
In an randomized, multicenter trial patients with acute lung injury and
ARDS, mechanical ventilation with lower tidal volume than traditionally used low
tidal volumes decreased mortality rate and decreased ventilatory days. Patient with
ALI and ARDS, were enrolled in a study that compared ventilatory support involv-
ing high tidal volume (12 ml per kg body weight) with low tidal volume (6 ml per
kg). The primary outcomes were the death before discharge home and breathing
without assistance. The trial of 861 patients was stopped because patients with lower
tidal volumes had significantly lower mortality rate (31% vs 39.8%; p=0.007) as
well as had fewer days in the ventilator (12+/-11 vs 10+/-11;P=0.007), than those
with high tidal volume. Most of these techniques, however, do not address the main
issue in ARDS: the molecular basis for the condition and, as such are supportive
only. Until such treatment becomes available, we will continue to support these
patients with multiple modalities, hoping to reduce effectively high morbidity and
mortality of ARDS.
387
25
Nutritional Assessment
Respiratory Quotient
In the process of converting the macronutrients such as protein, fat and carbo-
hydrates to energy, oxygen is consumed and carbon dioxide is produced.
13,14
Utiliza-
tion of caloric sources is estimated from the respiratory quotient (RQ), which is the
ratio of carbon dioxide produced to oxygen consumed. The RQs produced from
carbohydrate, fat, and protein is 1.0, 0.7, and 0.8, respectively. For a given amount
of oxygen consumed, more carbon dioxide is produced from metabolism of carbo-
hydrates then from fat or protein. Metabolism of fat yields the lowest RQ (0.7). The
RQ of a typical mixed diet is 0.85.
Since patients with COPD and respiratory failure suffer from carbon dioxide
retention and oxygen depletion in the blood, the goal of therapy is to decrease the
blood level of carbon dioxide. Administration of a diet with and increased propor-
tion of fat calories and decreased carbohydrate calories can reduce carbon dioxide
production and RQ, thus diminishing ventilatory requirements. The end result is
desirable both for the patient with COPD, for whom hypercapnia may lead to res-
piratory failure, and for patient with respiratory failure who must be weaned from
mechanical ventilation.
Although providing sufficient protein for anabolism is important, the overfeed-
ing of protein should be avoided. Protein intake has little effect on carbon dioxide
production but has been demonstrated to augment the ventilatory drive mecha-
nism. High protein diets will stimulate ventilatory drive and minute ventilation in
normal persons. An increase in respiratory drive can be beneficial for patients able to
respond to stimulus. However, for patients unable to increase minute ventilation,
the stimulus can increase the work of breathing and cause dyspnea.
15,16
Excess nutrient administration in patients on mechanical ventilation could ag-
gravate respiratory failure by augmenting CO
2
production.
17-19
Thus, provision of
caloric intake that exceeds metabolic requirements can lead to net lipogenesis with
associated RQ >1. At the same token, estimation of energy requirements of patients
with respiratory disease can be difficult.
20-23
In normal subjects only a small fraction
of REE is devoted to supporting the metabolic activity of respiratory muscles. Both
COPD patients and patient with respiratory failure of various causes have increased
work of breathing. Therefore, commonly used prediction models for estimation of
metabolic requirements, which typically use parameters attempting to estimate the
lean tissue mass, may have limited accuracy in the patient with pulmonary disease.
While indirect calorimetry can be used as an assessment of energy expenditure to
predict metabolic needs more accurately, there is a specific equation to predict en-
ergy requirements for COPD patients.
Men (11.5 x weight (kg) + 952
Women (14.1 x weight (kg) + 515
Energy requirement may be estimated based on indirect calorimetry. However,
the most accurate method for determination of estimated caloric requirements is
the indirect measurement of actual energy expenditure with a metabolic chart, al-
though these devices are subject to significant error because of short sampling time,
usually 10 to 15 minutes.
The goals of nutritional support and nitrogen requirements of patients with
pulmonary disease are not significantly different from other patients. The optimal
support entail establishing neutral or positive nitrogen balance. This is usually
388
25
accomplished by giving 0.16 to 0.24 g of nitrogen per kilogram per day for mild to
moderate stress and 0.32 g/kg per day for marked stress. The composition of nutri-
ent substrates however should be directed to the individual disease process, in order
to address the basic molecular needs as well as derangement at the molecular level.
The goal of nutritional assessment is to identify those patients at high risk for an
adverse outcome. Once identified, the nutritional assessment parameters can be
used to identify the response of selected patients to an intervention program. Effec-
tive screening tools must be safe, cost effective, wildly applicable, an accurate in
predicting adverse sequale.
Anthropometrical measurements are limited by the assumption of uniform dis-
tribution of total body fat. However, they remain useful in patients with end stage
pulmonary disease (ESPD) because they identify an adverse nutritional effect that is
not evident with the monitoring of body weight alone. Weight gain in patients with
ESPD may be interpreted as favorable, but weight gain of primarily fat mass is
unlikely to be beneficial. The use of anthropometrical assessment can provide valu-
able insight into the patients progress during a rehabilitation program if measured
and interpreted correctly.
Hepatic secretory proteins such as albumin, prealbumin, transferrin, and
retinol-binding protein are often measured as part of a comprehensible nutritional
assessment program as indicators of visceral protein stores. Malnourished ESPD
patients generally do not present with decrements in these parameters, based on a
number of clinical trials of nutritional support in COPD patients, and routine se-
rum measurements are probably not indicated.
An alternative approach to nutritional assessment involves a more functional
assessment. Examples of these are adductor policis muscle for a functional nutri-
tional assessment owing the ready accessibility of the ulnar nerve for neural stimula-
tion. The respiratory muscles demonstrate similar neurophysiologic properties to
peripheral muscles during electrical stimulation; a simpler, less precise alternative to
neurophysiologic testing is the use of voluntary tests of maximal muscle strength,
such as handgrip dynamometry or respiratory muscle pressure. Handgrip dynamom-
etry provides an inexpensive and simple method of assessing muscle function and is
easily obtained in the output setting; it can be incorporated into an initial assess-
ment with little difficulty and used serially to confirm strength changes by nutrition
and exercise. Muscle mass is a difficult parameter to assess in ESPD patients. A
standard index is the 24-hour collection of urinary creatinine. This measurement
requires a controlled diet and meticulous collection of the urine sample, making it
impractical in the outpatient setting. When the more practical indices of muscle
mass such as body weight or arm muscle circumference are compared with urinary
index, the correlation is poor.
Another functional assessment tool is a measurement of immune function. Un-
dernourished COPD patients demonstrate abnormalities in these markers that ap-
pear to improve following the institution of nutritional support. Although useful,
this test may be affected by multiple factors such as such as aging, corticosteroid use,
chronic infection, and malnutrition, all of which are typically present in the patient
with ESPD. This relationship limits the ability of these functional assessment tools
to identify patients at nutritional risk, although the tools are still valuable for assess-
ing the response to a nutritional intervention program. All physiological and his-
torical findings are used to identify the specific nutritional problems of the individual
patient and to develop a comprehensive care plan.
13-20
Patients with obstructive disease
389
25
(COPD) and those who suffer from adult respiratory distress syndrome (ARDS) are
at high nutritional risk.
16,21
Merely providing adequate calories to the severely ill
ventilated patient is not sufficient. Specialized nutrition support regimens for pa-
tients with respiratory disease should include carbohydrate doses below the maxi-
mal oxidative rates for glucose and omega 3-fatty acid fat emulsions as a daily
continuous infusion.
21
Early enteral feeding is clearly most beneficial.
Molecular Basis Nutritional Management
In order to help patients with ARDS as well as those with COPD, we must
understand the pathophysiology of this complexes disease process, especially in pa-
tients with ARDS. The molecular basis of inflammatory process and lung injury has
been advanced significantly in recent years.
10,11
While the issue is far from being
resolved, the evidence of neutrophil predominance in the pulmonary edema fluid
and bronchoalveolar lavage obtained from patients with ARDS and animal models
has been accumulated, although ARDS may develop in neutropenic patients as well.
10
At the same time, a complex cadre of prroinflammatory cytokines is activated lo-
cally or systemically and initiate or exacerbate the inflammatory response in ALI
and ARDS. Most important though is the balance between the pro-inflammatory
and anti-inflammatory cytokines. If this process can be reversed effectively or pre-
vented than one will expect that ARDS will not progress into fibrosing alveolitis or
fibrotic lung injury, as this finding clearly corresponds with increased mortality.
Interleukin-1 (IL-1) is known to promote the development of fibrosing alveolitis,
and procollagen III peptide, a precursor of collagen synthesis that is elevated very
early in the course of disease process. The strategies to improve the resolution of
ARDS should be closely related to arrest the inflammatory process of lung injury.
Fluid and hemodynamic support of these patients, surfactant therapy, use of in-
haled nitric oxide and other vasodilators and glucocorticoids as well as use of other
anti-inflammatory agents are part of the current pharmacological armamentarium
in the treatment of ARDS. However, the concept that we may feed patients with a
specially formulated diet, that will maintain optimal nutritional status, prevent or
reverse malnutrition, and at the same time reverse effectively or arrest the inflamma-
tory process of sepsis or other causes induced acute lung injury is certainly
very appealing.
For practical purposes we will separate nutritional management of patients with
COPD and those with ARDS. Although most patients with COPD, except those
with acute on chronic respiratory failure do not require special dietary measure-
ment. While nocturnal nasoenteric feeds are well tolerated by most patients and
results in weight gain, the termogenic effect of a large meal may include significant
metabolic demand and ventilatory workload due to excess CO
2
production and
could precipitate acute respiratory failure.
22
In COPD patients with acute respira-
tory failure, a hyper caloric nutrition may induce complications that result mainly
from an excessive CO
2
production. The use of a specially formulated lipid enriched
diet has been recently proposed in these patients to facilitate weaning from ventila-
tory support. Nutritional regimen providing optimal calorie and protein is associ-
ated with weight gain, nitrogen retention, and improvement in muscle.
physiologic parameters.
On the other hand, for the patient with severe pulmonary disease or requiring
mechanical ventilation, the over-provision of carbohydrate may have serious
theoretical sequale, although practically this is not very common. As part of the
390
25
conversion of excess carbohydrate to fat, additional CO
2
is produced. To maintain
acid-base balance, the excess CO
2
must be eliminated, thus increasing the amount
of respiratory work. This process has been shown to increase VO
2
, VCO
2
, VE, REE,
and ventilatory response to hypoxia, hypercapnea, and respiratory work.
23
In order
to avoid this, the optimal amount of carbohydrate utilization has been determined.
It has been shown that patients do not oxidize more than 5 to 7 mg glucose/kg body
weight/min given intravenously. Higher rates of administration can lead to fat stor-
age. In septic patients, the maximal amount of glucose oxidized may even be lower.
Initially, the excess glucose is used to replete glycogen stores in the liver. Because this
is a finite pool of glucose, it is quickly replenished and the body converts all excess
glucose into triglyceride. Therefore, in most circumstances, the rate of infusion should
not exceed 4 to 5 mg/kg/min. In average size patient, daily provision should not be
greater than 300 to 400 g/day.
23
Another interesting point of nutritional therapy in
pulmonary failure is the achievement of most accurate combination and proportion
of nutrients.
22
When nutrient substrates provision in both enteral and parenteral
formulas is properly calculated and provided, caloric goals can be achieved with less
potential for carbohydrate overfeeding. To avoid the provision of all non-protein
calories as carbohydrate, approximately 30% of caloric requirements are usually sup-
plied as lipids. The provision of lipids, traditionally as long chain triglycerides, has
been associated with immunological abnormalities including reticuloendothelial
system dysfunction, impaired phagocytosis, increased gram-positive bacterial sur-
vive and depression of cardiac function.
While the lipids are useful to prevent essential fatty acids deficiency, the amount
and the type of fatty acids provided is very important element of nutritional support
of patient with respiratory failure. This may be true for other critically ill patient as
well. A recent study compared hemodynamic and gas exchange alterations in septic
patients with ARDS receiving long-chain triglycerides (LCT) versus medium chain
triglycerides (MCT). The results showed that, in septic patients with respiratory
failure, LCT administration was associated with more significant changes of Qva/
Qt, MPAP and P/F ratio compared to an infusion of an LCT/MCT 1:1 emulsion.
Clinically, these transient alterations might cause serious problems in patients with
marginal arterial oxygenation and cardio-respiratory impairment.
14
High fat, low
carbohydrate enteral feeds appeared to be beneficial in patients with acute respira-
tory failure requiring ventilatory support.
24
Furthermore, there have been experimental studies in which it was demonstrated
that supplementation of parenteral nutrition with -linolenic acid increased dihomo
-linolenic acid, and prostaglandin E, increased the plasma arachidonic acid ratio,
and favorably reduced the ratio of thromboxane B
2
and 6-ketoprostaglandin F 1
in injured rats. These reflect the potential capacity of -linolenic acid enriched emul-
sions to increase dihomo -linolenic, fatty acid precursor of anti-inflammatory
eicosanoids, prostaglandin E
1
; and to modulate arachidonic acid-deviated prostag-
landin after injury.
25
In another study, the researches demonstrated that dietary fish
oil and borage oil suppressed intrapulmonary proinflamatory eicosanoid biosynthe-
sis and attenuates pulmonary neutrophil accumulation in endotoxic rats. Fish oil
and fish and borage oil when compared with corn oil may ameliorate
endotoxin-induced acute lung injury by suppressing the levels of proinflammatory
eicosanoids (but not TNF or MIP-2) in broncho-alveolar lavage fluid and reduc-
ing pulmonary neutrophil accumulation.
26
In addition dietary fish oil and borage
oil significantly alter the fatty acid composition of lung phospholipids by decreasing
391
25
arachidonic acid and increasing eicosapentanoic acid (EPA) with fish oil and in-
creasing dihomo-gama-linolenic acid when fish oil and borage oil were used in com-
bination.
26
These changes are consistent with suppression of eicosanoids associated
with SIRS. There is evidence that incorporation of EPA into phospholipids shifts
eicosanoid metabolism to the less biologically actively 3-series prostaglandins and
5-series leukotrienes.
27-29
Others have shown that following enteral feeds, as short as only three days; there
is significant incorporation of EPA and GLA with displacement of arachidonic acid
in lung alveolar macrophage phospholipids.
30
Leukotrienes are considered to be the
mediators in lung inflammation and have also been found to be in high concentra-
tions in the bronchoalveolar lavage fluid of patients with ARDS. Inhibition of
leukotriene B
4
formation significantly reduces lung microvascular permeability and
edema formation in experimental animals. Fish oil and borage oil diet was shown to
reduce the synthesis of B
4
leukotriene. Lower levels of leukotriene B
4
reduces the
effect of neutrophils and increased microvascular protein permeability in endotoxic
rats. Most importantly animals fed with this diet, did not mount the expected re-
sponse in eicosanoid production when challenged with endotoxins.
26
Entirely specialized diets enriched in eicosapentanoic acid (EPA) and -linolenic
acid, precursors of trienoic and monoenoic eicosanoids, respectively, have proven to
attenuate cardiopulmonary dysfunction during acute injury in pigs. These diets
improve gas exchange and O
2
delivery, presumably in part through a modification
of thromboxane B
2
(TxB
2
) production with decrease in pulmonary vascular resis-
tance and an increase in cardiac index, and acute lung injury (ALI).
31
Using this
background,
24-32
a prospective, multicenter, double-blind, randomized controlled
trial was reported recently.
33
One hundred and forty-six patients with ARDS were
randomized to receiving enteral tube feeds with either eicosapentaenoic acid (EPA)
and gamma- linolenic acid (GLA) or isonitrogenous isocaloric standard diet for at
least 4-7 days. Patients who were fed with EPA+GLA had significantly lower neu-
trophils in the bronchoalveolar lavage, significantly improved in the P/F oxygen-
ation ratio, had lower ventilatory variables (Fio2, PEEP, minute ventilation) than
controls. Furthermore, patients fed with EPA and GLA had fewer days in a ventila-
tor support and a decreased stay in the ICU. In addition, only 8% of patients with
ARDS fed EPA+GLA developed multiple organ system failure when compared to
28% of the controlled group. The beneficial effects of the EPA+GLA diet on neu-
trophil recruitment, gas exchange, requirement for mechanical ventilation, ICU stay
and reduction in development of multiple organ system failure were clearly demon-
strated. Specialized diet with EPA+GLA and antioxidants modulates neutrophil
mediated lung injury, and it is thought the mechanism of action is anti-inflammatory
and vasodilator properties of EPA and GLA.
Chronic Obstructive Pulmonary Disease (COPD)
The occurrence of weight loss in obstructive lung disease has been described in
50% of COPD patients who require hospitalization. Positive energy balance in weight
losing COPD patients is associated with nitrogen retention and weight gain. These
finding distinguishes the patient with COPD from other diseases models associated
with hypercatabolism, such as sepsis or trauma, in which positive balance does not
produce nitrogen retention. Studies associated with positive energy and nitrogen
balance have produced improvements in measured muscle strength parameters, as
well as walking distance, dyspnea, and quality of life.
21,23,34
COPD flares are often
392
25
associated with increased respiratory muscle metabolism, inactivity, limited caloric
intake, systemic inflammation, and frequent steroid use. When approaching the
patient with ESPD and ongoing weight loss, the contribution of these individual
factors must be addressed and appropriate solutions incorporated into the treat-
ment plan. Nutrition counseling to address the planning, preparation and the use of
nutritionally adequate meal plan, food supply at home, the use of nutritional supple-
ments, and other details is essential to the success of any intervention program. The
benefits of altering fat-to-carbohydrate ratios in the provision of non-protein calo-
ries in ambulatory COPD patients remain to be proven. However, there are studies
that attempt to surpass daily caloric requirement with nutritional manipulation in
favor of a low carbohydrate, high fat diet may be an important consideration for
patients with COPD. When compared to standard liquid diets, a diet with a high
percentage of fat results in decrease carbon dioxide production and retention. In
another study in which it was study the effects of refeeding a high fat enteral diet
versus a high carbohydrate one in patients with COPD, the authors showed that the
high fat diet resulted in lower oxygen consumption and carbon dioxide production
than the high-carbohydrate formula. They concluded that metabolic response to
each regimen was primarily related to dietary content and composition. These func-
tional changes were primarily related to feeding duration.
24
Nutrition intervention for COPD patients should be viewed as complementary
to the other components of a comprehensive rehabilitation program. There is strong
evidence that the onset of weight loss is a poor prognostic indicator, and that mod-
est weight gain facilitated improves in muscle function. Excessive weight gain, espe-
cially of body fat, would likely have deleterious effect in these patients and should be
avoided. Investigations that address the mechanisms of weight loss in an effort to
better understand the decline of patients with severe emphysema are indicated.
Summary
General goals of nutritional therapy in the patient with respiratory failure in-
clude maintenance of lean body mass and positive nitrogen balance. Weight gain
should be reserved for more protracted phase of respiration failure, such as malnour-
ished patients requiring long-term ventilatory support. The key for the treatment of
those patients is mainly not to overfeed them, especially with carbohydrates, and to
reassess them as frequent as possible in order to adjust their diet according to their
nutritional requirements depending on their disease and state. Nutrition therapy is
an important part of the treatment of patients with pulmonary failure and should be
taken into consideration since the onset of the disease, and should be monitored
throw the evolution of these patients.
Selected References
1. Pinard B, Geller E. Nutritional support during pulmonary failure. Crit Care Clin
1995; 11(3):705-15.
2. Dureuil B, Matuszczak Y. Alteration in nutritional status and diaphragm muscle
function. Reprod Nutr Dev 1998; 38(2):175-80.
3. Ferrari-Baliviera E, Pierdominici S. Effects of nutritional status on respiratory sys-
tem. Minerva Anestesiol 1989; 55(11):443-50.
4. Grant J. Nutrition Care of patients with acute and chronic respiratory failure.
NCP 1994; 9:11-17
5. Blair G, Sharpe L. Nutrition support in Respiratory Disorders. NCP
1989.4:173-175
393
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6. Ireton-Jones C, Borman K, Turner W. Nutrition considerations in management of
ventilator-dependent patients. NCP 1993; 8:60-64
7. Branson R, Hurst J. Nutrition and respiratory function: Food for thought. Resp
Care 1988; 33(2):89-92.
8. Song Y, Kang XM, Xia XR. The nutritional status and immune function of pa-
tients with chronic obstructive pulmonary disease. Chung Hua Nei Ko Tsa Chih
1993; 32(1):33-6.
9. Bernard GR, Artigas A, Brigham KL et al. The American-European consensus
conference on ARDS: Definitions, mechanism, relevant outcomes and clinical trial
coordination. Am J Respir Crit Care Med 1994; 149:818-24
10. Ware BL, Matthay M. The acute respiratory distress syndrome. NEJM 2000;
342:1334-1349.
11. Tobin MJ. Culmination of an era in research on the acute respiratory distress syn-
drome. NEJM 2000; 342:1360-1361
12. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. NEJM 2000; 342;1301-1308.
13. Pingleton S, Harmon G. Nutritional management in acute respiratory failure. JAMA
1987; 257(22):3094-3099.
14. Smirniotis V, Kostopanagiotou G, Vassiliou J et al. Long chain versus medium
chain lipids in patients with ARDS: Effect on pulmonary homodynamic and gas
exchange. Intensive Care Med 1998; 24(10):1029-33.
15. Azkenazi J, Weissman C, Rosenbaum H et al. Nutrition and respiratory system.
Crit. Care Med 1982; 10(3):163-72.
16. Blair G, Sharpe L. Nutrition support in respiratory disorders. Nutr Clin Prac 1989;
4:173-175
17. Cerra FB, Hypermetabolism, organ failure and metabolic support- clinical review.
Surgery 1987; 101:1-14
18. Clemmer TP, Orme JF. Nutritional support in the adult respiratory distress syn-
drome. Clin Chest Med 1982; 3:101-8.
19. Spector N. Nutritional Support of the ventilator dependent-patient. Nurs Clin
North Am. 1989; 24:2
20. Glodstien SA, Thomashow B, Azkenazi J. Functional changes during nutritional
repletion in patients with lung disease. Clin Chest Med 1986; 7(1):141-151.
21. Mowatt-Larssen CA, Brown RO. Specialized nutrition support in respiratory dis-
ease. Clin Pharm 1993; 12(4):276-92
22. Ryan CF, Road JD, Buckley PA et al. Energy balance in stable malnourished pa-
tients with chronic obstructive pulmonary disease. Chest 1993; 103(4):1038-44.
23. Donahue M. Nutritional aspects of lung disease. Resp Care Clin North America.
1998; 4(1):85-111.
24. Al-Saady NM, Blackmore CM, Bennet ED. High fat, low carbohydrate, enteral
feeding lowers PaCO
2
and reduces the period of ventilation in artificially venti-
lated patients. Int Care Med 1989; 15:290-295.
25. Karlstad M, DeMichelle S. Effects of intravenous lipid emulsions enriched with
-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after
burn and endotoxin injury in rats. Crit Care Med 1993; 21(2):1740-49.
26. Mancusco P, Whelan J. Dietary fish oil and fish and borage oil suppress intrapul-
monary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neu-
trophil accumulation in endotoxic rats. Crit Care Med 1997; 25:1198-1206.
27. Lee TH, Mencia-Huerta J, Shih C, et al: Characterization and biologic properties
of 5,12-dihydroxy derivatives of eicosapentaenoic acid including leukotriene B
5
and double lipoxygenase product. J Biol Chem 1984; 259:2383-2389
28. Fischer S. Weber PC. Prostaglandin I
3
is formed in vivo in man after dietary
eicosapentaenoic acid. Nature 1984; 307:165-168
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29. Needleman P, Raz A, Minkes MS et al. Triene prostagladins: Prostacyclin and throm-
boxane biosynthesis and unique biological properties. Proc Natl Acad Sci USA
1979; 76:944-948
30. Palombo JD, DeMichele SJ, Lyndon E et al. Rapid modulation of lung and liver
macrophage phospholipids fatty acids in endotoxemic rats by continuous enteral
feeding with n-3 and gamma-linolenic acids. Am J Clin Nutr 1996; 63:208-219.
31. Mancusco P, Whelan J, DeMichele SJ et al. Effects of eicosapentaenoic acid and
gamma-linolenic acid on lung permeability and alveolar macrophage eicosanoid
synthesis in endotoxic rats. Crit Care Med 1997; 25:523-532
32. Murray M, Kumar M, Gregory TJ et al. Enteral diet enriched with eicosapentaenoic
acid and gamma-linolenic acid attenuate cardiopulmonary dysfunction in a por-
cine model of acute lung injury. Am J Physiol 1995; 269:H2090-H20997.
33. Gadeck JE, DeMichele SJ, Karlstad MD et al. Effect of enteral feeding with
eicosapentaenoic acid, -linolenic acid, and antioxidants in patients with acute
respiratory distress syndrome. CCM 1999; 27:1409-1420
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Resp Care Clin North Am 1997; 3(1):69-91.
CHAPTER 1
CHAPTER 26
Nutritional Support for the Burned Patient
G.J.P Williams, Michael J. Muller and David N. Herndon
Introduction
Weight loss of 30% was common among burned patients prior to the advent of
adequate nutritional support and was partly responsible for high mortality rates
associated with moderate or large size burns.
1
Metabolic rates of burn patients can
be double that of normal individuals. This can cause marked wasting of lean body
mass within a few weeks of injury and failure to satisfy the increased energy and
protein requirement results in impaired wound healing, cellular dysfunction, de-
creased resistance to infection and, ultimately, death.
In 1949, a 49% TBSA burn caused 50% mortality in patients aged 0-14years.
2
Modern techniques of immediate total burn excision, rapid wound closure, and
adequate early enteral feeding have made a great impact on mortality. Today, a 98%
TBSA burn has a 50% mortality in the same age group.
4
The hypermetabolic re-
sponse to the burn injury is driven by a series of interconnecting physiologic and
biochemical changes that are themselves promoted by the presence of the wound.
This chapter will describe the hypermetabolic response and then the hormonal and
metabolic responses that drive hypermetabolism. An approach to the estimation of
the nutritional requirements of burn patients and some of the practical issues in-
volved in delivery of nutritional support will be outlined. Recent advances in phar-
macological support will also be summarized.
Hypermetabolism in Burns
The response to burn injury is similar to the stress response provoked by any
critical illness or severe injury. However, its extended duration is unique. Burned
patients pass through an ebb phase immediately after injury that lasts two or three
days. During this time, metabolic rate and cardiac output are decreased. After the
ebb phase comes the flow or hypermetabolic phase. This may last up to twelve
months (Fig. 26.1)
4
and can be associated with a rise in resting metabolic rate to
200% of normal values.
5
Hypermetabolism, hyperdynamic circulatory response,
marked protein catabolism, nitrogen wasting, amino acid mobilization, accelerated
lipolysis, fluid retention, insulin resistance, hyperglycemia, hyperthermia,
immunodepression and poor wound healing are characteristic of this phase.
6
Early investigators believed that post-burn hypermetabolism was due to energy
generated to offset heat loss due to evaporation through the water-permeable eschar.
Evaporative water loss can be as high as 3,500cc m
2
of body surface area burned per
hour.
7
Since the heat of water evaporation is 0.576 kcal/ml, this represents a consid-
erable amount of energy. When evaporative water loss was prevented through the
396
26
use of a water-impermeable membrane, burned patients remained hypermetabolic.
8
Furthermore, burned patients remain hypermetabolic at an environmental tempera-
ture of 33C, at which point the energy of evaporation comes from the environ-
ment.
9,10
Nursing patients in rooms heated to this temperature reduced the degree
of hypermetabolism, but did not abolish it.
11,12
Local and systemic infection will increase hypermetabolism. More effective antimi-
crobial therapy, early burn wound excision and wound closure with skin substitutes in
cases where autograft is unavailable reduces burn wound sepsis. This undoubtedly
has the added benefit of reducing energy requirements for many patients.
Figure 26.1. Indirect calorimetry was used to measure energy expenditure in a resting state
at admission, full healing, and 6, 9, and 12 months after burn. At all time points, the energy
expenditure was higher than the basal metabolic rate predicted for age-, sex-, weight-, and
height-matched individuals by the Harris-Benedict equation. Error bars represent 95%
confidence intervals.
397
26
The central nervous system plays a key role in the initiation and maintenance of
the hypermetabolic state. Hyperpyrexia is a result of an upward reset of the tempera-
ture control centre in the hypothalamus.
13
Large wounds, such as those seen with
burn injury, induce activated leukocytes to elaborate mediators such as histamine,
cytokines and thromboxanes in sufficient quantity to produce measurable serum
levels.
14,15
It is well recognized that inflammatory mediators such as bacterial endo-
toxin and various cytokines, such as interleukin-1 and tumor necrosis factor-a, stimu-
late the hypothalamus directly.
16-20
They increase the thermoregulatory set-point and
alter endocrine function.
21,22
The importance of the central nervous system in stimu-
lating the stress response to burn injury is demonstrated in individuals with a con-
comitant head injury or who are unconscious due to barbiturates or alcohol
intoxication when they develop an attenuated stress response consequent to their
neurological impairment.
13,23,24
Physiologic Responses to Burn Injury
Hormonal Response
Cortisol, glucagon and the catecholamines are characterized as counter-regula-
tory, anti-insulin or stress hormones. After injury, they are all elevated and all have
synergistic effects.
25
Catecholamines are thought to be the mediators of hyperme-
tabolism and their production following thermal injury is under hypothalamic con-
trol.
26
Norepinephrine levels are raised two- to ten-fold in proportion to burn size.
27
A close correlation exists between the increase in plasma catecholamines and meta-
bolic rate.
11,28
Catecholamine levels remain elevated until wound repair is complete.
Catecholamines cause increased glycogenolysis, hepatic gluconeogenesis and
glucogenic precursor mobilization, promote lipolysis, peripheral insulin resistance
and inhibit insulin release.
29
Glucagon production by pancreatic a cells is elevated in
burned individuals.
30
Insulin and hyperglycemia decrease glucagon secretion.
31
The
effect of glucagon on glucose production depends on changes in the molar ratio of
glucagon to insulin. Injury results in adrenergic stimulation of glucagon release.
This results in mobilization of glycogen stores and enhancement of gluconeogen-
esis. Continued adrenergic stimulation of glucagon prevents suppression of its re-
lease during hyperglycemia. Glucagon may substitute for thyroid hormone during
the period of postburn hypermetabolism.
32
Glucagon increases hepatocyte cyclic
adenine monophosphate (cAMP) and promotes gluconeogenesis, glycogenolysis,
lipolysis and ketogenesis in the liver.
Cortisol production can rise 10-fold in severely burned patients. Following burn
injury, the amplitude of the circadian rhythm of plasma cortisol levels is diminished
and sometimes absent.
32
Cortisol stimulates gluconeogenesis, increases proteolysis
and alanine production, sensitizes adipocytes to the action of lipolytic hormones
(catecholamines) and has an anti-inflammatory action. It also causes insulin resis-
tance. Cortisol facilitates the action of catecholamines and helps maintain cardio-
vascular stability during stress.
33
Cortisol synergizes with catecholamines and glucagon
to divert glucose utilization from skeletal muscle to central organs, such as the brain.
The mechanisms of synergy of cortisol, glucagon and catecholamines are varied.
Cortisol may induce inhibition of catechol-o-methyl transferase and block re-up-
take of catecholamines by the sympathetic nerve ends.
34
Cortisol also increases b-
receptors.
35
Glucagon increases intracellular cyclic AMP levels by a non-b-receptor
mechanism and catecholamines are adrenoreceptor agonists. The net effect is to
398
26
increase the availability of the substrates required for gluconeogenesis (glycerol,
pytuvate, lactate, alanine) and maintain blood glucose levels at or above fasting lev-
els until recovery.
36
Metabolic Response to Burn
Substrate cycling may exist when opposing, non-equilibrium reactions, catalyzed
by different enzymes, are active simultaneously.
37
It involves the use of high-energy
phosphate bonds in ATP, with the net result being heat production. There is no
change in the amount of the substrate or the products, but energy expenditure is
increased in order to resynthesize the ATP. This process is therefore known as fu-
tile or wasteful substrate cycling. One such example is a glucose-lactate-glucose
metabolic sequence known as the Cori cycle.
Burned extremities metabolize a large amount of glucose to lactate and pytuvate.
38
The inflammatory cells in burn wounds (leukocytes and fibroblasts) primarily me-
tabolize glucose in an anaerobic fashion.
39
The anaerobic metabolites of glucose
(lactate and pytuvate) are then returned to the liver along with gluconeogenic amino
acids released from muscle tissue for the synthesis of additional glucose. Burned
patients have a significant rate of hepatic uptake of lactate and pytuvate, which are
generated from anerobic metabolism of glucose peripherally. The liver synthesizes
glucose from these substrates which is then reutilized as an energy source by the
leukocytes and fibroblasts in the wound.
38,40
Thus, burned patients have an acceler-
ated Cori cycle in which glucose is synthesized by the liver and metabolized through
anaerobic metabolism by the various cells present in the burn wound. Not surpris-
ingly, the hyperglycemia that follows burn injury is usually proportional to burn size.
41,42
Glucose is an important energy source for burned patients, and large amounts of
glucose are required to avoid excessive protein catabolism. Unfortunately, there are
limits to the amount of glucose which burned patients can metabolize. They begin
to develop difficulties when the rate of infusion exceeds 4 mg/kg/min. Lipids and
proteins are then utilized to meet the remaining metabolic requirements.
43,44
The stress response causes increased lipolytic activity and results in elevated se-
rum levels of free fatty acids and glycerol and a decreased rate of ketogenesis.
45-47
Since ketone bodies are one of the primary energy sources utilized to decrease pro-
tein catabolism, this would indicate that burned patients may require increased
amounts of carbohydrate and protein in their diet in order to prevent protein ca-
tabolism and achieve positive nitrogen balance.
48
The metabolism of fatty acids by
the cyclooxygenase enzyme system is significantly increased in burned patients.
Protein breakdown and synthesis rates are both elevated following burn injury,
but the rate of protein breakdown is elevated in excess of protein synthesis, resulting
in net protein/nitrogen loss.
49
There is increased efflux of amino acids, especially alanine, glutamine and phe-
nylalanine, from muscle following burn injury.
50,51
Plasma levels of all amino acids
are decreased, except for phenylalanine. This was felt to be due to a disproportionate
rate of release by muscle tissue. Alanine efflux occurs from muscle tissue distant
from the site of burn injury indicating a generalized response.
50
The branched-chain
amino acids (valine, leucine and isoleucine) supply nitrogen for transamination of
pytuvate to produce alanine, which is subsequently utilized for glucose production.
Glutamate is converted to glutamine by the action of glutamine synthetase before
conversion to alanine and ammonia in the gut mucosa. Alanine is transported to the
liver for gluconeogenesis, and ammonia is converted to urea and subsequently ex-
creted in the urine.
48,52
399
26
In summary, the wound releases a variety of mediators which stimulates a hor-
monal response which in turn drives biochemical processes to produce glucose, waste
energy, and cannibalise skeletal muscle. Grossly emaciated, weak patients whose
wounds are slow to heal is the end result. Immediate institution of adequate nutri-
tional support is vital to ameliorate this process.
Nutritional Support
Caloric Requirements
Caloric needs can be estimated using formulae created by the retrospective analysis
of maintenance of body weight or by measurement of metabolic rate using indirect
calorimetry. Accurate provision of calories is important. Overfeeding leads to respi-
ratory failure from excess CO
2
production, hepatomegaly from fatty infiltration and
increased blood urea nitrogen. Underfeeding causes increased loss of lean body mass,
muscle wasting, poor wound healing and increased susceptibility to infection.
Total energy expenditure (TEE) is made up of basal metabolism, diet-induced
thermogenesis and energy consumed by muscular activity. In burned patients, futile
substrate cycling, shivering, anxiety and pain all increase total energy expenditure.
Direct calorimetry measures actual heat elaborated when the subject is placed in a
sealed, insulated chamber. Indirect calorimetry uses the stoichiometric relationship
between oxygen consumption and carbon dioxide production during respiratory
gas exchange analysis. This can be done as a bedside procedure with a mobile meta-
bolic cart, which measures the concentration of oxygen and carbon dioxide in the
inspired and expired gas, and the volume of gas exchanged.
53
The oxygen consump-
tion and carbon dioxide production are determined and equations used to calculate
the energy expenditure.
54
These measurements should be performed in the resting
state (at least one hour following activity) and in the same absorptive state. If per-
formed in a fasting state, basal metabolic rate or basal energy expenditure is mea-
sured. As many burned patients undergo continuous feeding, a measurement taken
during this process also accounts for the thermic effect of food and is known as
measured resting energy expenditure (REE). Metabolism of different substrates yields
known ratios of carbon dioxide production to oxygen consumption. These ratios
are known as the respiratory quotient (RQ). Fat oxidation produces an RQ of 0.7
while glucose oxidation gives an RQ of 1.0. A respiratory quotient of greater than
1.0 indicates net fat synthesis. This can occur with overnutrition and may lead to
hepatic steatosis.
55
Alternatively, low RQ readings indicate inadequate nutrition.
56
Extrapolation of measured resting energy expenditure to total energy expendi-
ture over 24 hours requires multiplication by an activity factor. Total energy expen-
diture can be quantified with infusion of two stable isotopes of water, H
2
18
O and
2
H
2
O and is known as the doubly-labeled water technique.
2
H
2
O is lost from the
body at a rate proportional to water flux alone while H
2
18
O is lost in water and in
CO
2
during rapid equilibration through carbonic anhydrase. The difference in turn-
over rates gives total CO
2
production, and total energy expenditure can be calcu-
lated if dietary intake is known. Application of this technique in severely burned
children during convalescence revealed total energy expenditure exceeded measured
resting energy expenditure by a factor of 1.18 0.17.
57
Analysis of the determinants of measured resting energy expenditure has shown
that the predicted basal energy expenditure (PBEE) based on the Harris-Benedict
equation (Table 26.1),
58
total body surface area and body weight correlated signifi-
cantly with REE. Burn size and time after burn only accounted for 24% and 21%
400
26
respectively, of the variation in the elevation in REE above PBEE.

The following
equation will predict the energy required to ensure that 95% of burned children will
receive sufficient calories to reach a state of energy balance: TEE = (1.55 x PBEE) +
(2.39 x PBEE
0.75
). In most cases, this is close to: TEE = 2 x PBEE. Therefore, 2 x
PBEE is probably a reasonable starting point.
59
The Harris-Benedict equation may be inaccurate in burned patients as it is based
on body weight, which is difficult to accurately assess following burn. When using
indirect calorimetry, two factors should be considered: energy expenditure may be
less than energy requirement if malabsorption or diarrhea is present and indirect
calorimetry loses accuracy at FiO
2
> 60 torr or if a gas leak occurs. If performed
accurately and in a similar state, indirect calorimetry represents the most reliable
method of estimating energy requirements. Measured resting energy expenditure
multiplied by an activity factor of 1.2-1.35 will provide the total energy expenditure
appropriately for the majority of patients.
60
Although mobile metabolic carts are the ideal, they require a sizeable financial
outlay initially and a trained technician to use and maintain them. Therefore, many
units will depend on feeding formulae to calculate requirements (Table 26.2 for
adults and Table 26.3 for children).

The Curreri formula is based on only nine pa-
tients over the first 20 days of recovery.
61
In fact, the only patient in the group who
lost weight received only 20% of requirements while weight was maintained in the
other patients whose energy intake was significantly less than that prescribed by the
formula. The pediatric formulae have been derived from retrospective analyses of
Table 26.3. Galveston formula to estimate caloric requirements for children
with burns
Age Maintenance Plus Burn
< 1 year 2100 Kcal/m
2
TBSA/day + 1000 Kcal/m
2
TBSAB/day
1-12 years 1800 Kcal/m
2
2
TBSAB/day
12-18 years 1500 Kcal/m
2
2
TBSAB/day
TBSA = Total Body Surface Area; TBSAB = Total Body Surface Area Burned
Table 26.2. Curreri formula to estimate caloric requirements for adults
with burns
Age Maintenance Plus Burn
16- 60 years 25 Kcal/Kg + 40 Kcal/% burn
> 60 years 25 Kcal/Kg + 65 Kcal/% burn
Table 26.1. Harris Benedict equation for predicted basal energy expenditure
Males BMR = 66.47 + (13.75 x W) + (5.0 x H) - (6.76 x A)
Females DMR = 655.10 + (9.56 x W) + (1.85 x H) - (4.6% x A)
W = Weight in Kg; H = Height in CM; A = Age in years
401
26
dietary intake, which was associated with maintenance of body weight average over
hospital stay.
62-67
It has been shown that resting energy expenditure rarely exceeds predicted basal
metabolic rate by more than 50%, in patients with burns > 45%, if treated with
modern techniques.
68
This means that adult patients will rarely require more than
3,500 Kcal/day.
Dietary Composition
Carbohydrates
The major source of calories for thermally injured patients should be carbohy-
drates. However, glucose intolerance can be a significant problem. Plasma insulin
levels are usually elevated in burned patients but they are overshadowed by eleva-
tions of glucagon and cortisol producing the so-called diabetes of injury. In addi-
tion, the patients caloric requirements may exceed the bodys ability to assimilate
glucose. This is estimated at approximately 7gm/kg/day or 2,240 kcal for an 80kg
man.
68
Patients often require significant amounts of exogenous insulin to improve
glucose absorption but refractory hyperglycemia may sometimes force reduction of
administered calories.
Protein
Protein availability is essential to adequate wound healing. Protein malnutrition
is associated with decreased rates in gain of strength of the skin, abdominal wounds
and intestinal anastomoses. More specifically, a shortage of protein blunts fibroblas-
tic proliferation, neoangiogenesis, collagen synthesis and wound remodeling.
70,71
It
is therefore essential that negative nitrogen balance be avoided. The ideal amount of
protein which should be provided in the diet of burned patients has not yet been
determined. Increasing protein intake in burned patients from 1.4 g protein/kg/day
to 2.2g protein/kg/day did not alter nitrogen balance.
72
Another study showed that
increasing the percentage of protein in the diet of burned patients resulted in a
number of immunologic benefits. They compared patients receiving 16.5% of their
calories as protein to those receiving 23% of their calories as protein. Although
neither group was able to achieve the desired caloric intake, the group receiving the
higher protein content was found to have significantly higher serum levels of IgG,
transferrin, and complement factor 3. More importantly, they experienced fewer
bacteremic days and had a significantly lower mortality rate.
73
However, protein
should not be given primarily as an energy source. Calculated energy requirements
must be supplied as non-protein calories. Current recommendations call for 1.5-2.0
gm protein/kg/day in adults and up to 3.0 gm protein/kg/day in children.
74,75
This
should result in a calorie:nitrogen ratio of 100:1 or less.
Amino Acids
Arginine is an integral substrate of the urea cycle and is not considered an essen-
tial amino acid, but under periods of severe stress it is thought to become an essen-
tial dietary nutrient. An experimental deficiency in arginine in the traumatized rat
produced decreased collagen deposition and decreased wound breaking strength.
76
Arginine is not only important to wound healing in deficiency, it also appears to
promote wound healing when given as a supplement. High arginine levels were
shown to improve wound healing in rats as demonstrated by increased collagen
deposition. In healthy humans, it was shown to increase the deposition of total
402
26
protein and hydroxyproline (an indicator of collagen content) into wound cylin-
ders. Supplemental arginine has also been shown to decrease skin weight loss under
stress, therefore, retaining more dermal protein for wound healing. It also promotes
retention of nitrogenous calories and decreased protein catabolism. Arginine ap-
pears to achieve most of its stimulatory action secondarily via the hypothalamic-
pituitary axis as a secretagogue of insulin, glucagon, prolactin and growth hormone
because these effects are absent in hypophysectomized rats. In support of these mecha-
nisms, arginine supplementation appears to be most effective in the first three days
of wound healing, the period of inflammation and fibroblast migration and activa-
tion. On the cellular level, there has been demonstrated an altered metabolism of
arginine in wounded tissue. Although arginase is present in fibroblasts only in very
low levels, its presence is significant in macrophages and in extracellular wound
fluid, presumably released from dying macrophages. Arginase catalyzes the conver-
sion of arginine to ornithine, which is a precursor of proline. Arginine supplemen-
tation in an experimental burn model
77
and in post surgical cancer patients
78
improved indices of immune function of a collagen precursor. In this fashion, supple-
mental arginine may directly enhance collagen production in the wound.
79-84
Glutamine is also an amino acid thought to play an integral role in wound heal-
ing. It is known that it is utilized in substantial amounts by macrophage metabo-
lism.
85
Glutamine is considered to be a major fuel of rapidly dividing cells, such as
fibroblasts, enterocytes and stimulated lymphocytes.
86,87
Cultures of fibroblasts re-
quire more glutamine to survive than any other amino acid, and the glutamine
metabolized is primarily oxidized to carbon dioxide to provide a source of energy.
Fibroblasts may even derive more energy from glutamine metabolism than from
glucose.

Glutamine is also important in the production of collagen because glutamate,
a primary metabolite of glutamine, is the primary precusor to proline in pure fibro-
blast cultures. Glutamine is the preferred fuel of the small bowel enterocyte.
89
Sepsis
has been shown to decrease glutamine uptake by the small bowel enterocyte, which
may result in barrier failure,
90
and the addition of gultamine to the nutritional regi-
men has been theorized to improve barrier function.
Methionine and cysteine have important roles in antioxidant production. Sulf-
hydryl group produced directly from cysteine, or indirectly from methionine, act as
oxygen free radical scavengers. Cysteine and glutamine form glutathione, which is a
strong sulfhydryl-reducing substance and is required in the synthesis of the
leukotrienes. Their presence is, therefore, required to limit lipid penoxidation.
91
Lipids
The hormonal environment of the burned patient limits the extent to which
lipids can be utilized as energy. Peripheral lipolysis, mediated through the catabolic
hormones, is a principal component of the metabolic response to injury. Released
free fatty acids circulate to the liver where they are oxidized for energy and re-esteri-
fied to triglyceride. They are either deposited in the liver or further packaged for
transport to other tissues. In the burned patient processing of lipid by the liver can
be overwhelmed by the increasing amounts of circulating fat leading to fatty depo-
sition. This may be further complicated by overfeeding which can contribute to
hepatomegaly. Cyclooxygenase activity leads to an increased rate of production of
the physiologically active prostaglandins that have immunosuppressive activity. One
means of limiting this effect is to supply dietary lipids such as Omega-3 fatty acids,
which are metabolized by the cyclooxygenase enzyme system to yield PGE
3
. The
403
26
more common dietary fatty acids are of the Omega-6 group and are metabolized to
yield PGE
1
and PGE
2
PGE
1
and

PGE
2
have been reported to have significant immu-
nosuppressive properties while PGE
3
has been reported to be immunologically in-
ert. It has, therefore, been hypothesized that by replacing the Omega-6 fatty acids
obtained from standard vegetable and animal oils with the Omega-3 fatty acids
from fish oil, postburn immunosuppression might be avoided or reversed.
92
Vitamins
Vitamin C
Vitamins and trace minerals play a part in polymorphonuclear and macrophage
chemotaxis during inflammation.
93
Macrophage function is impaired by ascorbic
acid deficiency.
94
During the proliferative and maturation phases of wound healing,
vitamin C acts as a necessary electron donor in the hydroxylation of proline and
lysine residues in the collagen precursor procollagen. Scurvy is characterized by weak-
ening and dehiscence of previously healed wounds. Collagen in scar tissue is in a
continuous process of revision with reabsorption and manufacture of new collagen.
Ascorbic acid deficiency leads to defective cross-linking, thus weakening the scar.
Supplemental ascorbic acid delivery has been demonstrated to have two comple-
mentary effects on healing. Within the first 24 hours, there is a reduction in the
degradation of intracellular collagen and after 24 hours, supplementation increases the
synthesis of collagen protein and favors its release into the extracellular medium.
95,96
Vitamin A
Vitamin A is usually stored in the liver in large amounts, however, it is known to
be the most commonly depleted vitamin. Vitamin A has been shown to affect cell
morphology, and its influence on epithelial cell differentiation and mucus produc-
tion may be humoral. Vitamin A binds to specific intracellular receptor protein
which carry the vitamin to the nucleus where it affects the gene expression of
glycosyltransterases, fibronectin and perhaps even transglutaminases.
97
It also ap-
pears necessary as a cofactor in collagen synthesis and cross-linking. T lymphocyte
function is enhanced by Vitamin A.
98
Supplemental Vitamin A also increases fi-
broplasia and collagen accumulation in wounds and increases the differentiation rate
of fibroblasts.
99
Vitamin E
Vitamin E is an antioxidant and free radical scavenger, which appears to act in
preventing the oxidation of cell membrane polyunsaturated phospholipids.
100,101
It
is a promising means of counteracting the oxidative changes induced by injury.
Cutaneous burn wounds have increased xanthine oxidase activity which produces
damaging oxygen radicals and hydrogen peroxide. In turn, hydroxyl ion release leads
to distant organ lipid peroxidation and systemic inflammation. These changes can
be limited experimentally with xanthine oxidase, thromboxane synthetase inhibi-
tors and prostaglandin antagonists.
102
Malondialdehyde levels, an indicator of lipid
peroxidation, are increased in the wound, serum and lung in burns.
103
Levels of
naturally occurring antioxidants such as vitamin E are decreased, due to consump-
tion by both regional and systemic inflammation.
104
404
26
Vitamin B Group
The B vitamin group is central to the metabolism of all cells because they are
coenzymes in reactions necessary for energy metabolism. Riboflavin is a coenzyme
in the oxidation-reduction reactions involved in fatty acid synthesis and oxidation,
amino acid oxidation, electron transport, xanthine oxidase function and glutathione
reductase function.
105
Pantothenic acid functions as part of coenzyme-A, and
phosphopantetheine is involved in the Krebs cycle as well as in -oxidation of fatty
acids. It also appears to play an important role in collagen production by the wound.
Alone, it has been shown to increase skin strength and the fibroblastic content of
scar tissue.
106
Minerals
Iron
Iron plays an important role in the oxygen-carrying proteins hemoglobin and
myoglobin. It also acts as a cofactor for a number of important enzymes. Burn
patients are susceptible to iron deficiency although blood transfusions do deliver a
significant amount of iron.
Zinc
Zinc has been known to be an essential element of the mammalian diet since the
early decades of this century.
107,108
Zinc oxide has been used in surgical dressings for
a long time. Zinc deficiency impairs the rate of epithelialization and lessens the gain
in wound strength through impaired amino acid utilization.
109
A hypercatabolic
state induces hyperzincuria, which can progress to zinc depletion.
110,111
In addition
to substantial urinary loss, a redistribution of zinc occurs after tissue injury and
surgical stress. Zinc uptake is increased in the wound, liver, spleen and lung while
zinc levels decrease in plasma and skin.
112,113
Zinc supplementation has not been
shown to accelerate wound healing in non-burned, normal subjects.
114
Burned pa-
tients have substantial sequestration in the wound and high urinary loss and should
benefit from zinc supplementation.
Selenium
Selenium has an influence on wound healing through its presence in selenium-
dependent glutathione peroxidase.
115
This enzyme protects the cell from oxidative
damage by catalyzing the reduction of hydrogen peroxide. Selenium deficiency may
also affect wound healing by altering macrophage and polymorphonuclear cell func-
tion. A state of selenium deficiency often occurs in burned patients and is thought
to be secondary to topical silver preparation.
116
Route of Administration
Enteral Nutrition
The route of delivery of nutrients is almost as important as their composition.
Ischemic mucosal erosions in the stomach and duodenum are seen within hours of
significant burn injury and are most likely present throughout.
117
Ileus results from
ischemia that is reversed by reperfusion and is obviously dependent upon adequate
fluid resuscitation. A pernasal, transgastric jejunal tube advanced past the ligament
of Treitz allows enteral feeding to commence well before gastroduodenal function is
restored. This seems to diminish the extent and duration of ileus.
118
Furthermore
405
26
when used in combination with a nasogastric tube to ensure gastric emptying, there
is no reason to subject the patient to preoperative periods of fasting.
Experimental models have shown attenuation of catecholamine elaboration and
maintenance of gut mucosal integrity with immediate enteral, but not parenteral,
nutrition. Immediate enteral feeding in a clinical trial was associated with a 3%
daily incidence of vomiting, no aspiration pneumonia and delivery of calculated
needs by the third postburn day.
119
Other studies have shown that when continuous
enteral tube feeding were started immediately following burn injury, the postburn
hypermetabolic response was prevented, and elevations of serum glucagon, cortisol
and catecholamines failed to develop.
120,121
Intestinal permeability, as assessed by lactulose mannitol absorption
122
and poly-
ethylene glycol,
123
is increased in a burn size-dependent fashion early after injury.
Thereafter, infection will induce increased intestinal permeability.
124,125
Passage of
these macromolecules implies that bacterial translocation or leak of endotoxin can
occur.
126,127
Burn size-dependent increases in levels of circulating endotoxin and
cytokines, such as IL-1, TNF, and IL-6 occur post-burn,
128-130
and may originate for
the gut. Animals who receive immediate enteral feeding do not develop gut mucosa
atrophy, while they do develop it when enteral feeding is delayed. Gut mucosa atro-
phy allows translocation of bacteria and endotoxin into the portal circulation.
131
Postburn ileus affects the stomach and colon, sparing the small bowel.
132
Therefore,
duodenal or jejunal tube feeding can be commenced early in the postburn period,
and preferably within the first six hours.
Parenteral Nutrition
Enteral feeding is far preferable to total parenteral nutrition in the critically ill
patient.
133
Parenteral nutrition in burned patients increases mortality three-fold and
decreases the amount of enteral calories tolerated.
134,135
Therefore, total parenteral
nutrition is indicated only if there is an absolute contraindication to enteral feeding,
such as pancreatitis or ischemic enterocolitis.
The same rationale for calorie, protein, carbohydrate and lipid composition of
enteral diet can be applied to parenteral nutrition. Obviously, vitamins and trace
elements need to be added as appropriate. Carbohydrate is usually provided as dex-
trose (glucose) which gives 3.4 Kcal/g. Free amino acids, to a concentration of around
5%, which includes all essential amino acids, provide the protein requirement. Supple-
mentation with arginine, glutamine (as di-peptide) and branched chain amino acids
(leucine, isoleucine and valine) is theoretically inviting. Essential fatty acid defi-
ciency can be avoided by providing 10% of daily calories as lipid.
Rigid compliance with aseptic principals for handling lines and insertion sites is
mandatory. If complications, such as bacterial endocarditis and pyogenic throm-
bophlebitis, are to be avoided, lines must be changed every 72 hours.
Assessment of Nutritional Support
Assessment of pre-morbid nutritional state is an essential step and provides baseline
information. Heavier, more muscular subjects, and subjects whose definitive surgi-
cal treatment is delayed are at the greatest risk for excess catabolism after burn.
Sepsis and excessive hypermetabolism are also associated with protein catabolism.
136
Daily intake of total calories and macronutrients, regular weighing and routine labo-
ratory tests, such as electrolytes, glucose and protein, provide most information re-
quired. Further laboratory assessment such as prealbumin or retinol-binding protein
and total lymphocyte count can be added.
137
A total lymphocyte count less than
406
26
1,800/ml indicates malnutrition, but is unreliable in the presence of infection or
during the early resuscitation phase.
138
Nitrogen balance assessments are cumber-
some and require fastidious performance to eliminate inaccuracies. As such, they are
more often a research tool. Static measurements of serum concentrations of markers
of nutritional status, such as prealbumin, albumin, transferrin, cholesterol, triglyc-
eride, calcium and ascorbic acid, are not as reliable as functional testing
139
and often
indicate a poor nutritional state when none exists. Having a dedicated dietician as
part of the burns team who is responsible for monitoring daily dietary intake and
weight trends is essential. As the patient recovers and has changing needs, weekly
measurements of resting energy expenditure using metabolic carts will allow for
adjustments in administered calories. New techniques for measuring body composi-
tion, such as Dual energy x-ray absorptiometry scanning, enables accurate determi-
nation of body composition and will be a useful adjunct in the future.
Hormonal Manipulation of Burn Hypermetabolism
The metabolic response to burn injury is produced by increased levels of cata-
bolic hormones including catecholamines, cortisol and glucagon. Attempts to re-
duce hypermetabolism have focused on agents that block or counteract their effects.
These anabolic agents can be divided into three groups. The first group includes
anabolic proteins such as growth hormone, insulin and insulin-like growth factor.
The second group includes anabolic steroids such as oxandrolone. The third group
includes antagonists of the mediators of hypermetabolism such as propranolol and
glucocorticoid blockers. Whilst some of these agents have shown promising results
in clinical trials, the hormonal milieu that accompanies the burn injury is complex
and further research is needed to confirm the efficacy and safety of these drugs.
Growth Hormone and Insulin-Like Growth Factor
Hyperaminoacidemia is a major stimulus to net protein synthesis in normal sub-
jects.
140
In burned patients, however, hyperaminoacidemia fails to completely re-
verse net protein catabolism, possibly because of defective trans-membrane amino
acid transport.
141
This may be the result of decreased growth hormone (GH) and
insulin-like growth factor 1 (IGF-1) levels following burn injury.
142
GH promotes protein synthesis by increasing the cellular uptake of amino acids
and accelerating nucleic acid and accelerating nucleic acid translation and transcrip-
tion, thereby enhancing cell proliferation. Fatty acids are released from the hydroly-
sis of fat for conversion to acetyl Co-A, an essential energy-producing molecule for
the tricarboxylic acid cycle. Through the preferential use of adipose tissue for energy
production, there is a decrease in body fat with the result that protein is spared from
catabolism.
143-144
Recombinant GH and IGF-1 have been shown to increase trans-membrane amino
acid transport in-vitro,
145
reverse diet-induced protein catabolism,
146
attenuate post-
surgical amino acid efflux from skeletal muscle
147
and accelerate skin graft donor site
wound healing by 25% in severely burned children. GH was shown to reduce the
healing time of the second and third donor site compared with a placebo group as
well. The significance of these results is that massively burned children can be taken
to the operating room for further skin grafting about two days earlier if treated with
GH. The use of GH results in a significant decrease in time required to close a burn
wound. When adjusted for percentage of total body surface area burned (% TBSA),
the treated group took 0.54 0.04 days/% TBSA, (mean 3 SEM), and the placebo
group took 0.80 0.09 days/% TBSA to achieve total wound closure. This represents
407
26
a decrease from 46 to 32 days to achieve total wound closure for a patient with a
burn size of 60% TBSA.
148
Donor sites healed faster in the growth hormone-treated group perhaps due to
the resultant three-fold increase in 1GF-1 levels. GH treatment also accelerates wound
healing in adults, in infants aged less than two years, and in very severely burned
children who present late for treatment and are consequently in an advanced state of
emaciation.
149,150
Studies in severely burned subjects indicated that those receiving
GH had an increased protein turnover with elevation of both protein synthesis and
breakdown, but with synthesis exceeding breakdown. This resulted in a net reduc-
tion in protein loss of 50% compared with controls.
151
Children who are not in their growth-spurt years have a decrease in their height-
velocity growth curves for more than two years following severe burns. However,
recent studies have shown that children with severe burns treated with growth hor-
mone (0.2mg/kg/day) during the acute phase of their management continued to
have normal growth curves following their injury.
152
Furthermore, following severe burns, administration of growth hormone in low
doses (0.05mg/kg/day subcutaneously) for one year after hospital discharge increased
total body weight, linear growth, lean body mass and bone mineral content com-
pared to an equivalent group receiving placebo (Fig. 26.2, Fig. 26.3).
153
Insulin
Insulin has been shown to promote muscle anabolism in healthy volunteers by
either stimulating protein synthesis,
154,155
or inhibiting protein breakdown.
156
In
burned patients it has been shown that over short periods of time, submaximal
insulin administration also produces muscle anabolism via net muscle protein syn-
thesis. This is achieved with normal feeding by efficient reuse of intracellular amino
acids.
157
Currently, clinical studies are underway using exogenous insulin infusions
to produce euglycemic hyperinsulinemia for the duration of hospital stay in an at-
tempt to reduce muscle breakdown. Whenever exogenous insulin is administered, careful
monitoring is required to minimize the potential for precipitating hypoglycemia.
Oxandrolone
Oxandrolone is an oral synthetic testosterone analogue. Compared with test-
osterone, it has minimal virilizing activity and little hepatotoxicity.
158,159
Oxandrolone
has been used in acute and rehabilitating adult burn patients with promising results
in terms of weight gain and urinary nitrogen balance.
160,161
Recently it has been
shown to improve net muscle protein synthesis in children malnourished due to
delay in burn treatment.
162
Current clinical trials are underway investigating its use
during the acute phase of burn treatment. Whilst growth hormone can produce
hyperglycemia and insulin can induce hypoglycemia, oxandrolone has minimal side
effects and has the additional advantage of being given as a tablet. These features are
sure to encourage further study.
-Blockade
Elevated catecholamine levels in burn patients have been implicated in myocar-
dial dysfunction similar to that seen with pheochromocytoma, myocarditis, cardi-
omyopathy and focal myocardial necrosis. Children who succumb to burn injuries
often have hepatomegaly with marked fatty change from catecholamine-induced
lipolysis.
163
The modulation of these potentially harmful effects has been attempted
with blockers.
408
26
and -adrenergic blockade has been shown to decrease the metabolic rate of
burned patients. Selective -2 blockade with clenbuterol increases skeletal muscle
mass experimentally.

Selective -1 blockade with metoprolol (2 mg/kg/day) signifi-
cantly reduced cardiac work but did not affect protein or lipid metabolism.
164
Propranolol, a nonselective blocker, decreased myocardial oxygen requirements
without affecting cardiac output or whole-body oxygen delivery or consumption
when administered to massively burned patients.
165
Patients were noted to be calmer
when on this treatment.
166
Doses of 1-2 mg/kg/day are required to achieve a 25%
reduction of the elevated heart rate. The patients were still able to respond appropri-
ately to cold stress and to an isoproterenol challenge, which supported the conten-
tion that limited -blockade causes decreased myocardial work while cardiovascular
responsiveness to stress was retained.
167
Propranolol administration decreased lipolysis but also resulted in increased urea
production in fasted patients. This was partially reduced by feeding.
166
This effect
was thought to be due to increased protein catabolism to provide substrate for glu-
coneogenesis as -1 receptor blockade of adipocytes decreased lipolysis and led to
decreased glycerol and free fatty acid availability. Further research is needed to deter-
mine the effect of propranolol on muscle protein in the acute phase of burn treatment.
Figure 26.2. Changes in bone mineral content from baseline at discharge.
409
26
Glucocortioid Blockers
Glucocorticoids can be blocked either by decreasing production with agents such
as Ketoconazole or by competitive inhibition with agents such as RU-486. Studies
are currently in progress to determine if glucocorticoid levels can be decreased with
Ketoconazole to the extent that metabolism is altered but current regulatory diffi-
culties with the availability of RU-486 have hampered the investigation of this agent
in modifying hypermetabolism.
Summary
Burn patients have increased nutritional requirements due to hypermetabolism.
Enteral feeding initiated as early as possible after injury, decreases mortality. Total
calorie requirements for hypermetabolic patients are best estimated by indirect calo-
rimetry to find the resting energy expenditure (REE). Total energy expenditure (TEE)
is then calculated by multiplying the REE by 1.35. If REE measurements are not
available, an activity factor of 1.55 on the predicted basal energy expenditure (PBEE)
from the Harris and Benedict equation should provide adequate calories for virtu-
ally all burned patients without excessive overfeeding.
Figure 26.3. Change in lean body mass from baseline at discharge.
410
26
Most standard formulae used to estimate calorie requirement overestimate needs
for large burns. The Curreri formula provides a good guide for burned adults but
not for children. Retrospective analyses of total calorie intake, daily calorie intake
and lowest weight loss in burned children have produced a series of formulae based
on age and body surface area. Application of these formulae has resulted in mainte-
nance of body weight to within 5% of pre-injury weight.
Feeding should be started as early as possible in the post burn period. Nutrition
should be delivered enterally via the nasojejunal route until the patient is able to
tolerate the required calorie intake orally. Parenteral feeding should be avoided if
possible. Calculated energy requirements should be given as non-protein calories
but protein requirements may be as great as 3 gm/kg/day in children. Continuous
reassessment of nutritional status is essential.
Appropriate nutritional support of the burned patient has resulted in increased
survival, improved immune status and improved rehabilitation. Recent innovations
in dietary components such as o 3 fatty acids, specific trauma essential amino
acids and vitamin and mineral supplements have contributed to this. In children,
therapies such as growth hormone which have been shown to improve growth fol-
lowing severe burns should be continued following discharge from hospital. Future
advances in hormonal manipulation of post burn hypermetabolism will further
improve outcome.
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147. Mjaaland M, Unneberg K, Larsson J et al. Growth hormone after abdominal sur-
gery attenuated forearm glutamine, alanine, 3-methyhistidine and total parenteral
nutrition. Ann Surg 1993; 217:413-22.
148. Herndon DN, Barrow RE, Kunkel KR et al. Effects of recombinant human growth
hormone on donor-site healing in severely burned children. Ann Surg 1990;
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149. Sherman SK, Demling RH, Lalonde C et al. Growth hormone enhances re-epi-
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156. Fryburg DA, Jahn LA, Hill SA et al. Insulin and insulin-like growth factor-1 en-
hance human skeletal muscle protein anabolism during hyperaminoacidemia by
different mechanisms. J Clin Invest 1995; 96:1722-1729.
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157. Ferrando AA, Chinkes DL, Wolf SE et al. A submaximal dose of insulin promotes
net skeletal muscle protein synthesis in patients with severe burns. Ann Surg 1999;
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162. Hart DW, Wolf SE, Ramzy PI et al. Anabolic effects of oxandrolone following
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CHAPTER 27
Nutritional Support
after Small Bowel Transplantation
S. Janes, S.V. Beath
Introduction
Small bowel transplantation has been attempted since the 1950s but with sur-
vival times of less than two weeks in dogs and human subjects. It did not become
established until the development of more effective immunosuppression regimes in
the 1980s and 1990s.
1-6
In the meantime, patients with chronic intestinal failure
have been managed with parenteral nutrition (PN) which has developed to the point
where 75% of patients can expect to survive 10 years.
7
There are 33 centers carrying
out small bowel transplantation world wide (communication Dr. D Grant, 5th In-
ternational Symposium on Intestinal Transplantation, Cambridge 1997), but only
patients who are experiencing complications with parenteral nutrition or feel that
their quality of life is intolerable are selected as candidates for intestinal transplanta-
tion.
8-10
In the UK, around 250 patients are identified as being on home PN which
equates to 4 per million and 50% of these could be considered potential recipients
for intestinal transplantation.
11-13
The reason successful intestinal transplantation has been hard to achieve is be-
cause of several unique characteristics: the great mass of lymphoid tissue in the gut
renders it highly immunogenic; accurate identification of rejection episodes in the
gut is difficult because of the presence of large numbers of lymphocytes under nor-
mal circumstances and the patchy nature of rejection; and the gut is continually
exposed to bacteria, fungi and food antigens resulting in high rates of sepsis when
gut integrity is damaged (as during rejection).
14
Furthermore, the newly engrafted
bowel seems to take longer than other organs to recover from the effects of ischemia
and hypoxia incurred during harvesting and preservation, and intestinal function
may take many months to stabilize (compared with an average of 2-3 weeks after
liver transplantation). The current 5-year survival after intestinal transplantation is
50%, although there is a center effect with the large North American centers achiev-
ing better figures than this and smaller centers with less than 10 patients achieving
less (personal communication Dr. David Grant, 5th International Symposium on
Intestinal Transplantation, Cambridge 1997).
The postoperative care of intestinal transplant recipients centers on fluid bal-
ance, meticulous attention to immunosuppression and a transfer from parenteral to
enteral feeding.
15
The fact that only patients experiencing significant morbidity are
selected for transplantation means that nutritional support after transplantation must
ensure good patient rehabilitation and stimulate graft adaptation simultaneously.
The goal of small bowel transplantation is to achieve independence of parenteral
419
Nutritional Support after Small Bowel Transplantation
27
nutrition and enhance quality of life for the patient and normal growth velocity for
pediatric patients.
16
This chapter will concentrate on nutritional support for small
bowel transplantation which can be split into three phases:
1. Recovery from the effects of ischemia, preservation and implantation.
2. Weaning from parenteral nutrition and establishment of enteral nutrition.
3. Establishment of oral intake of a wide range of foods including whole pro-
tein, lactose and long chain triglyceride.
Recovery from Ischemia and Preservation
4 (Post-Op Day 0-14)
The technique used for harvesting small bowel is similar to other abdominal
organs in that the graft is mobilized ready for excision and then perfused with a
preservation solution at 4
o
C which flushes out all blood.
17
The graft is kept on ice
until re-implantation 6-12 hours later. Even with rapid cooling and the use of a
preservation solution high in glucose and lactate, changes secondary to ischemia
occur. The production of free radicals from hypoxic tissue induces polymorph mar-
gination from capillaries into the lamina propria which becomes congested with a
mixed inflammatory infiltrate which produces yet more biochemical changes in-
cluding elevated phospholipase A2.
18
This process occurs slowly at 4C, but after 12
hours there is a risk that excessive inflammation may be associated with severe graft
dysfunction, sloughing of the mucosa and hyperacute rejection. This is in contrast
to liver and kidney tissue which are stable in preservation solution at 4
o
C for 24 and
48 hours, respectively. Therefore, transplant teams arrange to harvest the intestinal
graft and reimplant as soon as possible, even so some loss of villi occurs especially at
the apices where the effects of hypoxia are initially manifested. Preservation solu-
tions are an area of very active research with solutions being developed which neu-
tralize chemotactic molecules produced in hypoxic tissue. However, the solution
currently used in human intestinal transplantation is generally University of Wis-
consin solution which is able to preserve small bowel allografts isolated from the
circulation for up to 12 hours maximum.
Early intestinal dysfunction is, therefore, inevitable and takes the form of a para-
lytic ileus as a result of the surgical handling, lasting 2-5 days. From day 5-15 a
secretory diarrhea related to mucosal damage regeneration, develops. The secretory
diarrhea is usually mild (10-30 ml/kg/day) and self-limiting.
5,6
Occasionally, espe-
cially with end ileostomies a severe secretory diarrhea develops (greater than 100 ml/
kg/day) which requires treatment with octreotide (e.g., Sandostatin Sandoz, 1-3 g
per kg per hour intravenously or 50 g subcutaneously 2-4 times a day), although
long-term treatment should be avoided because of reports of hepatic dysfunction.
As soon as bowel sounds are heard or the ileostomy is seen to peristalse, dioralyte
solution 10-20 mls/hour is introduced. It is not usually possible to introduce feed
until there is evidence of absorption of dioralyte (i.e., ileostomy output is less than
enteral intake) which may occur anytime from day 5 postoperatively depending on
the speed of recovery from graft preservation and implantation. The principles used
in initiating enteral feeding after small bowel transplantation are similar to those in
rehabilitation of patients after major intestinal resection.
19
Nutrients are introduced
separately and in small increments so that tolerance and adequate absorption are
confirmed before adding more nutrients to the feed. This approach, which is called
modular feeding, has been useful in enhancing rapid adaptation of the newly en-
grafted bowel and is also important in enabling quicker identification of rejection
420
27
episodes which are manifested by malabsorption of the feed, which might otherwise
be attributed to changes in the feed. Table 27.1 shows details of the introduction of
enteral feeding for pediatric patients at our unit. Our initial modular feed provided
0.2 kcal/ml and 233 mosmol/kg, containing protein, carbohydrate and electrolytes,
with lipid omitted. The concentration is increased by adjusting one ingredient at a
time, adding fat during the third week of feeding and gradually progressing towards
an energy density of 1 kcal/ml and osmolality of 440 mosmol/kg (Fig. 27.1).
Weaning off Parenteral Nutrition
(Post-Op Day 15-40)
From day 15, the calorie density of the enteral feed is steadily increased to ap-
proximately 0.8 kcal/ml. In order to achieve this, medium chain triglyceride
20
and
disacharides are introduced individually with increments every 24-48 hours.
19
The
volume of the feed is usually kept low (i.e., 10-20 ml/kg per day) whilst the feed is
gradually built up. However, once the energy density of the feed is comparable to
the energy density of the PN, the latter is reduced while the feed is increased by the
same volume. This allows a smooth change over from PN and maintains the patients
nutritional parameters.
16
Fluid balance usually remains a problem especially with
end ileostomies and intravenous dextrose saline (i.e., 25-50 ml/kg/day) may still be
required at night for some months.
21
This system allows total flexibility and enables
the addition of chosen nutrients at the optimal time with respect to evolving recov-
ery and function of the graft. For details of the types of nutrients used please see
Table 27.2.
Components of Postoperative Enteral Feed
Protein
The initial protein source used in our unit is hydrolysed whey (hydrolysed whey
protein maltodextrin mixtureHWPMM, SHS), which is well absorbed even
in the presence of exocrine pancreatic dysfunction (common in enteral
understimulation
22
). The HWPMM provides 55 g protein per 100 g and some
carbohydrate. Increased intestinal permeability is also common in the first few weeks
after transplantation, so the hydrolysed protein is useful, with 28% of the peptides
having a molecular weight of greater than 1000 Daltons.
23
Hydrolysed protein is as
trophic to gut mucosa as whole protein,
24
which is an advantage after intestinal
transplant. In pediatric cases, we aim to provide greater than the reference nutrient
intake for protein, based on estimated requirements for sick children,
25
i.e., 3 g/kg
for infants and 2 g/kg for children.
Carbohydrate
Glucose polymer (Super Soluble Maxijul, SHS) is the principal source of carbo-
hydrate, as it is well tolerated due to its ease of absorption and low osmolality. When
the limit of tolerance of glucose polymer is reached (usually between 8-12 g per 100
ml feed), disaccharides (i.e., sucrose and lactose) may be incorporated to utilize al-
ternative channels of absorption which increases energy density of the feed.
19
Lipid
During retrieval and re-implantation, the lacteals are interrupted so that long
chain triglyceride (LCT) malabsorption is inevitable postoperatively. In the rat model
421
27
reconnection of lacteals can be demonstrated after 4 weeks,
26
but this appears to be
delayed for at least 3 months in humans,
27
where the coefficient of fat absorption on
a mixed diet is rarely greater than 80% before six months postoperatively. Thus,
medium chain triglyceride (MCT) emulsion (Liquigen, SHS) is the main lipid used
in initial feeds because it is absorbed directly into the portal vein and provides an
excellent alternative energy source.
28
Three to five grams of fat per 100 mls of feed
was introduced from the third week. However, restricting long chain triglyceride
(LCT) is likely to induce essential fatty acid deficiency which are important bioactive
molecules especially in the central nervous system and intercellular signalling in the
immune system.
29
Intralipid contains high concentrations of linoleic and linolenic
acid which can be given intermittently (i.e., 500 mg/kg intralipid once per
week) intravenously, until lacteal drainage is reestablished at about six months
postoperatively.
Substances Promoting Adaptation
Two novel substances were included in the feed used in our Unit: glutamine and
pectin. Glutamine is a preferred fuel source for enterocytes and is important in
maintaining mucosal integrity and preventing bacterial translocation.
22,30,31
Ani-
mal models with short bowel have shown increased mucosal weight and length of
villi when fed glutamine. Glutamine provided 25% of the protein within our modular
feed.
Ornithine alpha-ketoglutarate is a precursor of glutamine and may also have a
useful role in promoting adaptation of the intestinal graft. Rats fed enterally for 7
days with feed enriched with ornithine alpha-ketoglutarate demonstrated an in-
crease villus height and protein turnover in the tibialis muscle after extensive small
bowel resection (poster presentation Dr. F. Dumas et al, 5th International Sympo-
sium on Intestinal Transplantation, Cambridge 1997). A human study evaluating
the effect of 15 g ornithine alpha-ketoglutarate added to parenteral nutrition and
Table 27.1. Nutrient content of enteral feeds in early post-operative period
Post-Op Day
Gram per 100 ml of Feed 9 12 15 18 21 24
Carbohydrate (Total) 4.0 5.0 6.0 7.0 7.0 10.0
As glucose polymer 4.0 5.0 6.0 6.0 6.0 8.0
As lactose 0 0 0 0 0 0
As sucrose 0 0 0 1.0 1.0 2.0
Protein (Total) 1.1 1.1 1.1 2.2 2.2 2.2
As hydrolysed whey (75%) 0.83 0.83 0.83 1.65 1.65 1.65
As glutamine (25%) 0.28 0.28 0.28 0.55 0.55 0.55
Fat 0 0 0 1.0 3.0 3.0
As medium chain 0 0 0 1.0 3.0 3.0
triglyceride
As long chain triglyceride 0 0 0 0 0 0
Energy (kilocalories per ml) 0.21 0.25 0.29 0.46 0.64 0.77
422
27
administered to children with growth failure, showed an increase in glutamine,
glutamate, IGF-1 and height velocity (3.8 cm/yr to 6.5 cm/yr).
32
Pectin is a source of fermentable dietary fiber, which is thought to increase mu-
cosal hyperplasia and increase height of villi through the trophic action of the short
chain fatty acids derived from bacterial metabolism of pectin.
33,34
An additional
role of pectin is to prolong intestinal transit time, which enhances nutrient absorp-
tion in a similar way to loperamide.
35
One gram of powdered pectin was added per
100 ml of feed.
Electrolytes
To optimize feed absorption, electrolytes are included at similar concentrations
as in oral rehydration solutions
36
and are then adjusted to meet individual require-
ments. Sodium requirements may be as high as 10 mmol/kg/day at first when the
ileostomy output is high and sodium enriched. A comprehensive vitamin and min-
eral supplement (Pediatric Seravit, SHS) is added to the feed to meet the dietary
reference values for each patient.
37
Proprietary Feeds
There is no suitable single feed which meets all these requirements; however
examples of proprietary feeds that are used in children post small bowel transplant
are Pregestimil (Mead Johnson) and Neocate (Scientific Hospital Supplies UK Lim-
ited). Pregestimil is a semi-elemental infant formula, comprised of hydrolysed casein,
glucose polymer and both medium- and long-chain fats (55%MCT: 45%LCT).
Neocate is an elemental formula comprised of amino acids glucose polymer and
long chain fat. Whichever feed is chosen, it is commenced at low concentration and
osmolality, e.g., half strength (0.33 kcal/ml) and the density gradually increased,
according to tolerance, before advancing the volume of feed given. It is our practice
Fig. 27.1. Sequential additions of nutrients to enteral feed for child under 5 years of age
weeks 1-6 post small bowel transplant.
423
27
to change from a modular feed to MCT Pepdite between two and six months as
most children remain dependent on tube feeding for at least six months, and a
proprietary feed is easier to manage in the home environment. Adults are usually
able to progress onto a normal diet within 6 months if graft function is good, be-
cause they do not usually exhibit food aversion. However, adults who require calorie
supplementation may receive Nutrison (Nutricia Clinical Foods Limited) or some
other complete feed overnight.
Motility
The gut smooth muscle normally functions as an electrical syncytium with spe-
cialized cells in the stomach and proximal duodenum acting as a pacemaker for the
migrating myoelectric complexes (MMC) which sweep through the length of the
gastrointestinal tract. Since extrinsic denervation of the transplanted bowel is inevi-
table, motility depends on the intrinsic nervous system of the gut
38
and the trans-
planted gut develops its own contractile pattern which is independent of the native
gut. There have been few studies in man, but MMC activity appears to be absent,
and the transit of intestinal content seems to depend on local intestinal contractions
which are peristaltic for 10 cm or less.
39
There is some evidence in the canine model,
that reconnection of the native enteric nervous system with the donor enteric ner-
vous system occurs after 12-20 months and that MMCs reappear, but it is not
known if this occurs in man.
40
Thus motility of the transplanted intestine is sensi-
tive to local factors such as luminal distension and nutrient content, rather than
vagally mediated postprandial patterns of inhibition. Clinically, we have found that
patients have satisfactory gastric emptying followed by rapid transit (1-2 hours) as
the chyme passes along the transplanted intestine to the distal stoma. In our center,
this pattern of motility appears to be established two weeks postoperatively.
The transit time can be slowed using loperamide (50 mg/kg per dose
35
), but
care must be taken in the dose regimen to avoid inducing a paralytic ileus
Table 27.2. Types of nutrients used in nutritional support after small bowel
transplantation
Component Name Supplier
Carbohydrate
glucose polymer Maxijul super soluble SHS*
lactose Lactose BP Thornton & Ross
sucrose sugar supermarket
Protein
hydrolysed whey Hydrolysed whey protein SHS*
maltodextrin mixture
glutamine L-Glutamine SHS*
Fat
medium chain triglyceride Liquigen SHS*
long chain triglyceride Calogen SHS*
Vitamins & Minerals Pediatric seravit SHS*
Pectin Citrus pectin powder Citrus Colloid Limited
*Scientific Hospital Supplies
424
27
(unpublished observations). Transit time is conveniently measured using carmine
red dye taken orally, and transit times of less than 4 hours are treated with increasing
doses of loperamide to a maximum of 200 mg/kg/day.
Establishment of Normal Diet
4 (Post-Op 2-12 Months)
A low fat, cows milk protein free diet is allowed as soon as the patient requests it
(in practice usually at least one week postoperatively), but the majority of calories
will be derived from the modular feed. A cows milk protein diet is adopted as there
is increased intestinal permeability within the first few weeks posttransplantation. A
feed using protein hydrolysates is somewhat unpalatable and older children and
adults usually require administration nasogastrically, but babies will often drink it.
Many small bowel transplant recipients have poorly developed feeding skills and
may be afraid to swallow food.
14
These children may take 12-18 months to learn to
be confident about eating and the input of a multi-disciplinary including dietitian,
speech therapist and clinical psychologist is crucial,
41
beginning even before trans-
plantation.
12,20
Of 30 pediatric patients from Pittsburgh, 22% required tube feeds
at 1-3 years post-transplant, 20% at 3-5 years and two of three patients at 5-7 years
posttransplant (poster presentation B Kosmach et al, 5th International Symposium
on Intestinal Transplantation, Cambridge 1997). The speed at which a normal diet
is adopted is dependent on several factors: patient preference, graft function includ-
ing motility, fat absorption and type of ileostomy. Patients with a history of
pseudo-obstruction and infants tend to remain on specialized feeds longer. How-
ever, older children and adults may be able to take a normal diet from three months,
although fat malabsorption may cause high stomal output, which has to be com-
pensated for by increased oral intake or overnight intravenous dextrose and saline.
By six months the coefficient fat absorption is much improved with approximately
85-90% of conventional long chain fat being absorbed in dogs,
42
but there are only
limited studies in man.
27
Some patients, particularly those with an end ileostomy,
have a continuing requirement for intravenous fluids, after PN has been stopped,
owing to large volumes of fluid and electrolytes lost from the ileostomy. Of 22
patients from Pittsburgh, one third required intravenous fluid overnight at one year
posttransplant.
21
However, even end ileostomies achieve better sodium and water
reabsorption after 1-2 years.
43
Monitoring
Even before the patient is fully weaned from PN, close monitoring of graft func-
tion and nutritional support is essential. The daily volume of ileostomy output and
presence or not of reducing substances is extremely useful in early detection of rejec-
tion and other complications such as cytomegalovirus (CMV) enteritis and other
systemic infections, as well as determining changes to the feed
21
(see Fig. 27.2).
Provided good graft function is present (defined as when the ileostomy output does
not exceed input and there are no more than 1% reducing substances
16
), then the
energy density and volume of the feed can be increased.
In addition to anthropometric indices, biochemical markers of intestinal func-
tion such as albumin, essential fatty acids and trace elements should be assessed
regularly (see Table 27.3). At one year post transplant, 22 pediatric patients from
Pittsburgh, who were off PN, had increased their height centiles, were appropriate
weight for height and had maintained both muscle and fat stores (poster presentation
425
27
Dr. GM Rovera et al, 5
th
International Symposium on Intestinal Transplantation,
Cambridge 1997). Specific markers of intestinal function such as permeability may
be assessed by the differential absorption of lactulose and mannitol
44
or chromium
labelled EDTA
45
and differential fat absorption by extraction of lipids from ileal
output.
46
Disaccharidase activity in the transplanted small bowel is normal with two
weeks of operation (unpublished observations) although during severe rejection
disacharidase activity may be reduced.
47
Endoscopy and mucosal biopsies are taken
frequently (once or twice a week) to monitor for rejection which occurs at some
stage in over 75% patients.
3,5,14
Eosinophilic infiltration of the small bowel lamina
propria has also been reported to occur in over 50% of patients in the first four months
after transplant and in the absence of rejection may represent food sensitization.
48
Complications after Intestinal Transplant and Implications
for Nutritional Support
The main complications of small bowel transplantation are rejection and the
consequences of heavy immune suppression required to prevent it (see Table 27.4).
Rejection is most likely to occur in the first month and is manifested by malabsorp-
tion of enteral feeding. Patients are usually still receiving some PN which can be
increased to prevent weight loss, while the rejection episode is treated with methyl-
prednisolone.
15
Severe secretory diarrhea is uncommon fortunately, because it is life
threatening and may require octreotide to control it. However, a low grade secretory
state may be present at first manifested by sodium rich ileal output (sodium >100
mmol/L), which is important to recognize as the patient will require sodium supple-
ments. Cytomegalovirus (CMV) enteritis has been a major problem especially in
adult small bowel transplant recipients that some transplant centers will not use
CMV positive donors. CMV produces multiple ulcers in the graft which often bleed
Fig 27.2. Diagram illustrating major complications and effect on absorption of enteral feed in
a pediatric patient.
426
27
and may perforate. Although, CMV responds to hyperimmune globulin and
ganciclovir, it is liable to recur and a temporary return to PN may be needed for a
few weeks during treatment. The frequency of infections after intestinal transplan-
tation is directly related to the intensity of immune suppression and high levels of
tacrolimus (trough level greater than 30 ng/mL) are associated with opportunist
infections such as pneumocystis, and ultimately lymphoma triggered by Epstein-
Barr virus (EBV).
49,50
With increasing experience it has been realized that satisfac-
tory gut function can be achieved using lower exposure to tacrolimus (trough levels
of approximately 15 ng/mL after 3 months). Paradoxically, insufficient immune
suppression is also associated with infection in the form of septicaemia related to
translocation of enteric organisms through the leaky mucosa of rejecting bowel.
Conclusion
Small bowel transplantation is an alternative to patients on parenteral nutrition
with irreversible intestinal failure, but the necessity to use intense immune suppres-
sion and the susceptibility of the transplanted intestine to functional instability causing
malabsorption of drugs, fluids and food means that this is far from being a routine
operation and requires sophisticated nutritional support. However, in well prepared
patients supported by an experienced multidisciplinary team of surgeons, physi-
cians, nurses, dietitians, play specialists, feeding psychologist and liason staff this
operation achieves around 65% four-year survival
51
and is now a viable option for
patients with chronic intestinal failure.
Acknowledgment
We are grateful to colleagues in the Liver Unit and Gastroenterology Depart-
ment especially Dr. D.A. Kelly and Prof. I.W. Booth for their support, to Mrs. Rosie
Jones for much of the original dietetic protocol, and to Mrs. Anita MacDonald for
reviewing the manuscript.
Table 27.3. Nutritional monitoring after small bowel transplantation
Daily Weekly Monthly
plasma electrolytes zinc copper, selenium, manganese
ileostomy output (mls) magnesium essential fatty acids
reducing substances liver function viral serology, polymerase
in ileal fluid chain reaction e.g. EBV [44]
enteral intake (mls) coagulation
intestinal permeability
e.g. lactulose:mannitol
coefficient of fat absorption
weight triceps skin-fold
mid-arm circumference
height
ileoscopy*
* gastroscopy and ileoscopy are done every three months to screen for
lymphoproliferative disease.
427
27
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2. Kelly DA, Buckels JAC. The future of small bowel transplantation. Arch Dis Child
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3. Grant D. Current results of intestinal transplantation. Lancet 1996; 347:1801-3.
4. Beath SV and Mayer AD. Small bowel transplantation. Hospital Update
1996:27-31.
5. Kocoshis SA. Small bowel transplantation in infants and children. Gastroenterol-
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6. Goulet O, Jan D, Brousse N et al. Intestinal transplantation. J Ped Gastroenterol
Nutr 1997; 25:1-11.
7. Messing B, Crenn P, Beau P et al. Long-term survival and parenteral
nutrition-dependency of adult patients with nonmalignant short bowel. Trans-
plant Proc 1998; in Press.
8. Colomb V, Goulet O, De Potter S et al. Liver disease associated with long-term
parenteral nutrition in children. Transplant Proc1 1994; 26:1467.
9. Dollery CM, Sullivan ID, Bauraind O et al. Thrombosis and embolism in long
term central venous access for parenteral nutrition. Lancet 1994; 344:1043-45.
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12. Beath SV, Booth IW, Murphy MS et al. Nutritional care and candidates for
small-bowel transplantation. Arch Dis in Child 1995; 73:348-50.
13. Beath SV, Brook GA, Buckels JAC et al. Demand for paediatric small bowel trans-
plantation in the United Kingdom. Transplant Proc 1998; in press.
14. Tzakis AG, Todo S, Reyes J et al. Clinical intestinal transplantation: focus on com-
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15. Beath SV, Kelly DA, Booth IWB et al. Post operative care of children undergoing
combined small bowel and liver transplantation. Brit J Int Care 1994; 4:302-8.
16. Janes S, Beath SV, Jones R et al. Enteral feeding after intestinal transplantation: the
Birmingham experience. Transplant Proc 1997; 29:1855-6.
17. Casavilla A, Selby R, Abu-Elmagd K et al. Logistics and technique for combined
hepatic-intestinal retrieval. Ann Surg 1992; 216:605-9.
18. Sonnino RE, Wong L, Franson RC. Early secretory events during intestinal graft
preservation. Transplant Proc 1998; in press.
Table 27.4. Complications after intestinal transplantation
Typical Time of
Complication Onset Post-Op Day
Rejection 7-10
Secretory diarrhea 5-20
CMV enteritis 40
GI infections* e.g.rotavirus any time, often adenovirus after discharge
Lymphoproliferative disease 180 days
* may be severe leading to loss of graft
428
27
19. Warner BW, Ziegler MM. Management of the Short Bowel Syndrome in the Pedi-
atric Population. Pediatric Clinics of North America 1993; 40(6):1335-1350.
20. Gracey M, Burke V, Anderson CM. Medium chain triglycerides in pediatric prac-
tice. Arch Dis Child 1970; 45:445-52.
21. Rovera GM, Graham TO, Hutson WR et al. Nutritional management of intesti-
nal allograft recipients. Transplant Proc 1998; in press.
22. Vanderhoof JA, Langnas AN, Pinch LW et al. Short Bowel SyndromeA Review.
J Pediatr Gastroenterol Nutr 1992; 14:359-370.
23. MacDonald A. Which formula in cows milk protein intolerance? The dietitians
dilemma. Euro J Clin Nutr 1995; 49,Suppl 1:S56-S63.
24. Vanderhoof JA, Grandjean CJ, Burkley KT et al. Effect of casein versus casein
hydrolysate on mucosal adaptation following massive bowel resection in growing
rats. J Pediatr Gastroenterol Nutr 1983; 2:617-21.
25. Shaw V, Lawson M. Principles of paediatric dietetics. In: Shaw V and Lawson M,
eds. Clinical Paediatric Dietetics. 1st ed.Oxford:Blackwell Science Lim-
ited,1994:3-12.
26. Liu H, Teraoka S, Ota K et al. Successful lymphangiographic investigation of me-
senteric lymphatic regeneration after orthoptopic intestinal transplantation in the
rat. Transplant Proc 1992; 24:1113-14.
27. Mousa H, Bueno J, Griffith J et al. Intestinal motility in children after small bowel
transplantation. Transplant Proc 1998; in press.
28. Senior JR. Medium chain triglycerides. Philadelphia: University Pennsylva-
nia Press, 1968.
29. Sanders TAB. Essential and Trans-fatty acids in nutrition. Nutrition Research Re-
views. 1988; 1:57-78.
30. Hambridge KM, Krebs NF, Sokol RJ. Energy and Nutrient Requirements. In: Roy
CR, Silverman A and Alagille D, eds. Pediatric Clinical Gastroenterology. 4th ed.
Missouri: MosbyYear Book, Inc., 1995; 1005-1019.
31. McAnena OJ, Moore FA, Moore EE et al. Selective Uptake of Glutamine in the
Gastrointestinal Tract: Confirmation in a Human Study. Brit J Surgery 1991;
78:480-2.
32. Moukarzel AA, Goulet O, Salas JS et al. Growth retardation in children receiving
long-term parenteral nutrition: Effects of ornithine alpha-ketoglutrate. Am J Clin
Nutrition 1994; 60:408-13.
33. Allard JP, Jeejeebhoy KN. Nutritional Support and Therapy in the Short Bowel
Syndrome. Gastroenterology Clinics of North America 1989; 18:3,589-601.
34. Thompson JS. Management of the Short Bowel Syndrome. Gastroenterology Clin-
ics of North America 1994; 23(2):403-420.
35. Sandhu BK, Tripp JH, Milla PJ et al. Loperamide in severe protracted diarrhea.
Arch Dis Child 1983; 58:39-43.
36. Greenough III WB. Oral rehydration therapy: An epithelial transport success story.
Arch Dis Child 1989; 64:419-22.
37. Department of Health Report on Health and Social Subjects No 41. Dietary
reference values for food energy and nutrients for the United Kingdom. Lon-
don: HMSO, 1991.
38. Sarr MG, Kelly KA. Myoelectric activity of the autotransplanted canine
jejuno-ileum. Gastroenterol 1981; 81:303-10.
39. Sarr M, Hakim N. Motility of the transplanted gut. In: Enteric Physiology of the
transplanted intestine. Austin: RG Landes, 1994; 5:28-54.
40. Quigley EMM, Spanta AD, Rose SG et al. Long-term effects of jejunoileal au-
totransplantation on myoelectric activity in canine small intestine. Dig Dis Sci
1990; 35:1505-17.
41. Harris G, Booth IW. Feeding problems and eating disorders in children and ado-
lescents. In: Cooper PJ and Stein A, eds. Monographs in clinical pediatrics. 1st ed.
Reading: Harwood Academic Publishers, 1992; 5:61-84.
429
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42. Thompson JS, Rose SG, Spanta Ad et al. The long-term effect of jejunoileal au-
totransplantation on intestinal function. Surgery 1991; 111:62-8.
43. Ein SH. The pediatric ostomy. In: Walker WA, Durie PR, Hamilton JR et al, eds.
Pediatric Gastrointestinal Disease. Philadelphia/Toronto: BC Decker Inc,
1991:1767-78.
44. Lim et al. HIV and permeability. Scand J Gastroenterology 1993; 28:573-80.
45. Grant D, Hurlbut D, Zhong R et al. Intestinal permeability and bacterial translo-
cation following small bowel transplantation in the rat. Transplantation 1992;
52:221-224.
46. Beath SV, Willis KD, Hooley I et al. New method for determining faecal fat excre-
tion in infancy. Arch Dis Child 1993; 69:138-40.
47. Akhtar K, Deardon D, Pemberton PW et al. Study of mucosal brush border en-
zyme activity in porcine small bowel transplantation. Transplant Proc 1996;
28:2556-7.
48. Putnam PE, Bueno J, Kocoshis SA et al. Tissue eosinophilia after small bowel
transplantation in children. Transplant Proc 1998; in press.
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miology and Public Health, University of Leicester.
50. Green M, Reyes J, Jabbour N et al. Use of quantitative PCR to predict onset of
Epstein-Barr viral infection and post-transplant lymphoproliferative disease after
intestinal transplantation in children. Transplant Proc 1996; 28:2759-60.
51. Langnas AN, Antonson DL, Kaufman SS et al. Preliminary experience with intes-
tinal transplantation in infants and children. Transplant Proc 1996; 28:2752.
CHAPTER 28
Nutritional Support in Patients
with Head and Neck Cancer
Matthew E. Cohen, Rosemarie L. Fisher
Introduction
Patients with head and neck cancer share many nutritional support issues en-
countered in most patients with cancer, yet possess unique nutritional challenges
due to the location of their cancers in the proximal digestive tract. In this chapter,
the following topics are reviewed:
1. risk factors for malnutrition;
2. the relationship between malnutrition and clinical outcome;
3. the impact of enteral and parenteral nutritional support around the time of
surgery, radiotherapy or chemotherapy; and
4. methods of delivering enteral nutritional support.
Most studies of nutritional support have been retrospective, and many have suf-
fered from inadequate experimental design, heterogeneous or small groups of pa-
tients, or inappropriate endpoints.
1
In addition, many nutritional studies performed
in patients with head and neck cancer were descriptive without statistical analyses.
Thus, comparisons of studies are, at times, limited.
Risk Factors for Malnutrition
Forty-
2
to sixty-percent
3
of patients with head and neck cancer are malnourished
at presentation. There are many possible reasons for this high prevalence of malnu-
trition, including advanced age, alcohol or tobacco abuse, or dysphagia from the
tumor site, as well as psychosocial factors such as concomitant depression or inad-
equate social support. Data in patients with head and neck cancer are mixed, how-
ever, regarding the contribution of these characteristics to the risk of developing
malnutrition (Table 28.1).
While some researchers have found a trend toward age being an independent
risk factor for malnutrition,
4
others have not.
3,5
Despite the widely held assumption
that many patients maintain a marginal nutritional status at baseline because of
their unhealthy habits, smoking and alcohol consumption failed to correlate with
worse nutritional status in at least two studies.
3,4
A third study found a correlation
between pack-years of smoking and better nutritional status, but the implications of
this relationship are not known.
5
Psychosocial factors may play a role in the nutritional status of patients with
head and neck cancer. For example, depression may be more common in patients
with malnutrition than in those without malnutrition. Westin
6
performed nutri-
tional assessments and psychopathological ratings on 53 patients with various head
431
Nutrition Support in Patients with Head and Neck Cancer
28
and neck tumor sites, stages, therapeutic modalities and points in oncologic therapy.
While no well-nourished patient was depressed, 30% of the 16 malnourished pa-
tients were depressed, which was a statistically significant difference. The five de-
pressed patients had completed their therapies more than one year previously and
were admitted because of suspected or known cancer recurrence. The presence or
absence of a spouse is another psychosocial variable that may influence the nutri-
tional status of patients with head and neck cancer. In patients less than 60 years old
with head and neck cancer, being married decreased the risk of malnutrition, while
in those over 60 years of age, being married increased the risk of malnutrition.
5
The
source of this discrepancy was not discussed.
Another possible reason for malnutrition in patients with head and neck cancer
is the location of the tumor. Oropharyngeal cancer may cause anorexia, nausea,
inadequate mastication, xerostomia, dysgeusia, dysphagia or odynophagia.
7
Dimin-
ished oral intake and avoidance of firm solids correlated with malnutrition.
4
Main-
tained oral intake, however, did not prevent weight loss in all cases,
4
perhaps due to
tumor-induced metabolic alterations which favor tumor growth at the hosts ex-
pense.
8
Some studies of patients with head and neck cancer noted that tumors lo-
cated within the upper digestive tract (but not in the upper respiratory tract) pre-
dicted malnutrition (Table 28.1). As with tumor site, tumor stage may correlate
with malnutrition (Table 28.1). Other studies, in contrast, found that neither tu-
mor site nor stage predicted nutritional status.
9
Matthews, however, did find a cor-
relation between tumor stage and weight loss, which has predicted poor nutritional
status in some
5
(but not other
10
) studies.
Depressed cellular immune response is often attributed at least in part to malnu-
trition in patients with cancer. However, age (which affects immune response
5
) and
nutritional status were not investigated in most studies. In one study which did
compare well-nourished to malnourished patients with head and neck cancer, an-
ergy to all seven skin tests and a suppressed in vitro purified lymphocyte response to
Table 28.1. Possible risk factors for malnutrition in patients with head and
neck cancer
Variable Risk Factor?
Age Trend
4
No
3, 5
Depression Yes
6
Marriage Yes (if patient >= 60 years old)
5
No (if patient < 60 years old)
5
Smoking No
3-5
Tobacco No
3-5
Tumor Site Yes Oral cavity/oropharynx/hypopharynx
cervical esophagus >larynx/
nasopharynx/paranasal sinuses
2
Yes Oropharynx/hypopharynx > larynx
3
No
9
Tumor stage Yes
4
Trend
3
No
9
432
28
one of the stimulants (concanavalin A) correlated with malnutrition.
5
In another
study, patients with localized head and neck cancer were skin-tested sequentially
with DNCB and four common antigens.
11
DNCB reactivity correlated significantly
with disease-free survival at six months, one year and four years. In contrast, skin
test antigen reactivity did not correlate with clinical course. Any impairment in the
immune response was thought to be from deficits other than nutritional, however,
since all of the study subjects were outpatients and none had extreme cachexia.
11
In conclusion, about one-half of patients with head and neck cancer present
malnourished, which likely results more from tumor-induced metabolic alterations
than from any preexisting malnutrition from tobacco or alcohol abuse. In general,
both advanced head and neck cancer and location of tumor within the digestive
(versus respiratory) tract appear to increase the risk of malnutrition. Depressed de-
layed hypersensitivity responses reflect poor nutritional status, but may be as depen-
dent on advanced tumor burden. It is unclear if depression among patients with
head and neck cancer causes malnutrition or simply correlates with recurrent disease.
Malnutrition and Clinical Outcome
Some studies of patients with head and neck cancer have found correlations
between malnutrition and increased postoperative morbidity,
5,12,13
mortality,
5,13
length of hospitalization,
5
and decreased survival at two years.
2
Others have found
no independent correlation between any nutritional parameter and incidence of
postoperative complications or death.
9
Hooley
12
prospectively calculated the Prognostic Nutritional Index (Table 28.2)
in 29 patients with head and neck cancer 48 hours before surgery. All patients had
completed preoperative high-dose radiotherapy. The more malnourished patients
had a greater apparent risk of a major postoperative complications. No consider-
ation was given to the site of the head and neck cancer or to patient comorbidity.
Linn
5
prospectively evaluated 79 men who had surgery for head and neck can-
cer, using his Protein Energy Malnutrition Scale (Table 28.2).
14
Malnourished eld-
erly patients had the worst surgical outcomes. Potential reservations about the study
included the existence of significant differences between the cancer types in the
malnourished versus well-nourished groups and uncontrolled preoperative nutri-
tional support (given in 60% of younger malnourished patients and 20% of older
malnourished patients).
Goodwin
13
retrospectively studied 50 consecutive patients with stage III, IV or
recurrent squamous cell carcinoma of the head and neck, 47 of whom had a variety
of treatments, including induction chemotherapy, surgery, and/or radiation.
Treatment-related complications in the 14 patients with severe malnutrition based
on the Prognostic Nutritional Index were always major and more frequent, com-
pared to the 36 patients with no or mild malnutrition. Statistical analysis was re-
ported only for the 38 patients having surgery, nine of whom were severely mal-
nourished and suffered significantly more morbidity and mortality. There was no
attempt, however, to demonstrate a risk of malnutrition independent of tumor or
treatment variables.
Brookes
2
prospectively followed 114 patients with untreated squamous cell can-
cer of the head and neck, and found that a General Nutritional Status (Table 28.2)
of less than -10% (undernutrition) correlated with poorer survival, where a life table
analysis excluding those patients who received intensive nutritional support showed
a 58% survival rate of the adequately nourished patients at two years compared to
433
28
Table 28.2. Nutritional indexes used to assess patients with head and neck cancer
Protein Energy Malnutrition Scale
14
Note that the score of each item ranges along a geometric scale.
Score 1 2 4 8
Clinical History
Inadequate nutrient intake None Mild Moderate Severe
Excessive nutrient losses None Mild Moderate Severe
Increased metabolic needs None Mild Moderate Severe
Anti-nutrient or catabolic None Mild Moderate Severe
medications
Physical Examination
Cachexia None Mild Moderate Severe
Hair easily pluckable or None Mild Moderate Severe
nails brittle/ridged
Hepatomegaly or ascites None Mild Moderate Severe
Muscle atrophy None Mild Moderate Severe
Generalized edema None Mild Moderate Severe
Dry skin, scaling skin, or None Mild Moderate Severe
skin lesions
Anthropometric
Relation to ideal body weight (%) >=90 85-89 80-84 <80
Weight loss from usual weight (%) <=5 6-12 13-19 >=20
Triceps skin fold (mm)
MEN >=9.0 7.0-8.9 5.0-6.9 <5.0
WOMEN >=16.0 11.0-15.9 6.0-10.9 <6
Mid-arm muscle circumference (mm)
MEN >=243 216-242.9 189-215.9 <189
WOMEN >=192 170-191.9 148-169.9 <148
Laboratory
Albumin (gm/dL) >=3.5 2.8-3.4 2.1-2.7 <2.1
Hemoglobin (gm/dL) >=14.0 13.9-12.0 11.9-10.0 <10.0
Delayed hypersensitivity >=2>5mm 1>5mm 1<5mm Anergy
skin tests (of four)
Lymphocytes (cells/mL) >=1500 1200-1500 1000-1200 <1000
Creatinine excretion >=80 60-79 40-59 <40
index (%standard)
Transferrin (mg/dL) >=200 150-199 100-149 <100
Retinol-binding protein (mg/dL) >=3.0 2.5-2.9 2.0-2.4 <2.0
Pre-albumin (mg/dl) >=15 12.5-14.9 10.0-12.4 <10.0
Negative nitrogen balance (g/day) <=5.0 5.1-10.0 10.1-15.0 >15.0
Prognostic Nutritional Index (PNI)
12
PNI% = 158% - 16.6(ALB) - 0.78 (TSF) - 0.2(TFN) -5.8(DH)
ALB = albumin (g/dL); TSF = average of three triceps skin fold measurements (mm); TFN =
serum transferrin (mg/dL); DH = number of positive delayed hypersensitivity responses
measured at 24 and 48 hours after intradermal injection of five antigens (Candida albicans,
mumps, tuberculin purified protein derivative, Trichophyton, and streptokinase-strep-
todornase). Major post-operative complications occurred in patients with a PNI > 20.
12
In
another study, a PNI > 40 indicated a high risk of developing a post-operative infection.
64
434
28
an 8% survival rate among the undernourished patients. The authors claimed that
this correlation was irrespective of tumor site, stage, histology or age, although sta-
tistical analyses of these data were not presented.
Matthews
9
prospectively studied 42 patients with newly diagnosed upper
aerodigestive squamous cell carcinoma (31 of whom had cancer of the oral cavity,
oropharynx, or hypopharynx) who subsequently had surgery with or without radia-
tion therapy. There was a 38% incidence of minor complications, and a 10% inci-
dence of major complications. The study was limited by incomplete compilation of
data in the Subjective Global Assessment of Nutritional Status (Table 28.2), varied
tumor sites and non-standardized surgical procedures.
In summary, although data conflict and analyses are imperfect, most studies
support the conclusion that malnutrition predicts increased perioperaive morbidity
and mortality, and decreased long-term survival.
Surgery, Nutritional Support and Clinical Outcome
Data on the effect of preoperative enteral supplementation on postoperative
outcome in malnourished patients with head and neck cancer are mixed.
13,15
Flynn
15
prospectively studied 61 patients with squamous cell cancer of the upper aerodigestive
tract who were candidates for operative resection (Fig. 28.1). Malnourished patients
receiving nutritional supplementation were provided with specific recommenda-
tions to meet their individual nutrient requirements and an unspecified number
were given nutritional supplements. Additionally, these patients were contacted as
necessary during the 10-21 days between counseling and hospital admission to
Table 28.2. (cont'd)
General Nutrition Status (GNS)
2
GNS = P% + I% + A
3
P% = percentage weight change from pre-morbid weight; I% = percentage of ideal weight;
A% = percentage arm muscle circumference (AMC) change; AMC = mid-point non-dominant
upper arm circumference - ( x triceps skin fold {mm})
GNS > -10% Adequate nutrition
< -10% to 20% Under-nutrition
< -20% to 30% Malnutrition
<-30% Severe malnutrition
Subjective Global Assessment of Nutritional Status (SGA)
65
A routine history and physical examination is utilized for clinical assessment.
History includes Physical examination
inquiry about weight loss includes inspection for
Edema Cheilosis
Anorexia Glossitis
Vomiting Subcutaneous fat loss
Diarrhea Muscle wasting
Decreased or unusual food intake Edema
Chronic illness
Based on a global assessment of nutritional status, the examiner classifies a patient as:
A = NORMAL NUTRITIONAL STATUS B = MILD MALNUTRITION C = SEVERE MALNUTRITION
The SGA had a better combination of sensitivity (0.82) and specificity (0.72) in predicting post-
operative infection than the PNI or individual measures of creatinine-height index, percentage
body fat, serum transferrin, serum albumin, or delayed cutaneous hypersensitivity.
64
435
28
determine their nutritional status and to encourage them to comply with their nu-
tritional programs. The malnourished unsupplemented group received only nutri-
tional counseling, suggestions on ways to cope with eating problems, and no follow-up
until hospital admission. Seven of the 25 well-nourished patients (26%) and 23 of
F
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436
28
the 36 malnourished patients (63%) had received prior radiotherapy. Postopera-
tively, patients received oral, tube and/or parenteral nutrition. Compared to the
malnourished unsupplemented group, the malnourished supplemented patients were
younger, had a greater prevalance of advanced disease (68% prevalence versus 35%,
respectively), a greater likelihood of prior radiotherapy and a higher rate of extensive
resection (26% versus 0%). Yet, the supplemented group had fewer complications
and a shorter average hospital stay. The three-day decrease in average hospital stay
saved an average of $2,298 per patient. Limitations of the study included small
study size, nonstandardized treatment within the supplemented group, differences
of stage, prior irradiation and extent of surgery between compared groups, and de-
scriptive nonstatistical analysis.
Goodwin
13
included in their study six patients with severe malnutrition who
had an average of 14 days of preoperative enteral and parenteral nutrition, of whom
five had major complications. The three severely malnourished patients who under-
went surgery without preoperative nutritional support all suffered major complica-
tions. Despite the disappointing results, albeit on a small number of patients,
Goodwin advocated nearly a decade later one to two weeks of preoperative nutri-
tional support in those patients who have a 15% weight loss, decreased general
strength, or low serum proteins.
16
Data pertaining to altered clinical outcome with perioperative parenteral nutri-
tion are as rare as those addressing the role of enteral nutrition. Shortly after parenteral
nutrition became widely available in the 1970s, researchers noted that perioperative
parenteral nutrition improved some nutritional parameters. Yet, the majority of pa-
tients appeared to possess sufficient nutrient reserves to survive the catabolic and
semistarvation recovery period without the need for parenteral nutritional support.
Although researchers have argued against its use in the majority of patients due to its
high cost,
8
parenteral nutrition has been advocated for selected patients with head
and neck cancer, such as those who cannot tolerate enteral nutrition or require rapid
repletion of nutritional stores in order to qualify for timely oncologic therapy.
17
Copeland
17
reported an uncontrolled trial of perioperative (as well as
periradiotherapy and convalescent) parenteral nutrition in 23 patients with head
and neck cancer who had lost at least 20 pounds and who were severely cachectic or
intolerant of nasogastric feeding. Seven of the eight patients who received preopera-
tive parenteral nutrition suffered no postoperative complications. Weight gain, wound
healing and recovery were achieved in 20 patients, while only three patients suffered
intravenous catheter-related complications. Many patients who previously were in-
tolerant of enteral feeding regained their ability to tolerate enteral nutrition follow-
ing parenteral nutritional support.
Sako
18
studied 69 patients with head and neck cancer who had no better than a
moderate prognosis, stratified them based on nutritional status and prognosis, and
randomized them to receive either parenteral or enteral postoperative nutrition (Fig.
28.2). Eight of the 35 patients in the parenteral group received preoperative parenteral
nutrition for at least eight days as well. Thirty of the 35 patients received the postop-
erative parenteral nutrition for at least 12 days. Postoperative wound complications
and recurrence of cancer were similar in the two groups. Survival curves were signifi-
cantly worse in the patients receiving postoperative parenteral versus enteral nutri-
tion in all strata of malnutrition. Parenteral nutrition was superior to enteral nutri-
tion only in maintaining nitrogen balance and weight, and the stable weight was
thought to be secondary to fluid retention rather than from preserved tissue mass.
4
3
7
N
u
t
r
i
t
i
o
n

S
u
p
p
o
r
t

i
n

P
a
t
i
e
n
t
s

w
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t
h

H
e
a
d

a
n
d

N
e
c
k

C
a
n
c
e
r
2
8
Fig. 28.2. Effect of parenteral hyperlimentation in surgical patients with head and neck cancer. Adapted from Sako and colleagues.
18
438
28
Although the decreased survival among those patients receiving parenteral nutri-
tion in Sakos
18
study was not a result of catheter-related sepsis, this complication is
more common in patients treated for head and neck cancer than in patients with
any other site of cancer.
19
Contamination of central venous catheters in patients
with head and neck cancer may be more frequent due to pharyngostomy or tracheo-
stomy secretions, or from skin compromise secondary to local radiotherapy.
19
Changes in reimbursement policies may limit flexibility in providing periopera-
tive nutritional support. When 61 patients who were admitted for radical resections
of head and neck cancer after the implementation of diagnosis-related group
(DRG)-based reimbursement were compared with 59 similar patients admitted be-
fore DRGs were used, complications rates had more than doubled in malnourished
patients.
20
Comparing the post-DRG with the pre-DRG groups, nutritional status
determined by the Protein Energy Malnutrition Scale was similar at admission, but
the time from admission to surgery and nutritional status at surgery both decreased
in the post-DRG group. Linn
20
concluded that the higher complication rate in the
post-DRG patients was attributed to the DRG-driven pressure to limit preoperative
hospital stay and nutritional interventions. Although comparisons using historical
controls must be interpreted with caution, the study design usually favors the popu-
lation treated most recently (not the historical control).
In patients undergoing immediate mandibular reconstruction for oral cavity or
oropharyngeal cancer, decreased length of hospital stay was achieved by using a
coordinated care plan including oral feeding with speech and swallowing therapy
beginning on the first or second postoperative day. The ultimate ability to tolerate
regular food was influenced positively by the presence of teeth and tumor originat-
ing from the gingiva or retromolar trigone as opposed to the floor of the mouth or
the tongue.
21
In a study of 44 patients with dysphagia following head and neck
surgery who were enrolled in a comprehensive swallowing rehabilitation program,
the severity of impairment was related to the extent of surgical resection, and the
number of swallowing phases that were impaired (oral, pharyngeal or esophageal).
Severity of the residual swallowing impairment correlated with the magnitude of
initial impairment. The ability to compensate for residual impairment varied widely.
22
Copeland
19
advocated the use of parenteral nutrition during swallowing reha-
bilitation, after concluding that the lack of a nasogastric tube psychologically facili-
tated jaw function rehabilitation in five poorly motivated patients and after witness-
ing a return of competent swallowing function in three patients on parenteral nutrition
as general strength returned. Alternative routes of enteral nutrition delivery were
not considered, and it is unclear to what degree, if any, the positive outcome in these
patients was due to the parenteral nutrition. In the absence of a controlled trial,
parenteral nutrition cannot be recommended routinely for swallowing rehabilitation.
Although parenteral nutrition has not been demonstrated to be better than en-
teral nutrition (and may be worse
18
), relative indications for parenteral nutritional
support include a persistent pharyngocutaneous fistula
17
or chylous fistula.
23
Sus-
pending enteral nutrition decreases salivary and mucosal secretions. If the fistula
fails to heal spontaneously, surgical closure may be successful after parenteral
nutritional support even if a prior attempt at surgical correction was unsuccessful.
19
It appears reasonable to advocate preoperative coordinated nutritional counsel-
ing, enteral nutritional supplementation in severely malnourished patients, and avoid-
ance of preoperative parenteral nutrition. Following surgery, aggressive speech and
swallowing therapy should be implemented, as well as enteral tube feeding in those
439
28
patients with a protracted recovery of deglutition. If one wishes to avoid a nasogastric
tube, enteral feeding via a gastrostomy tube (placed prior to surgical resection) is
preferable to parenteral nutrition. Parenteral nutrition can be recommended only in
patients who cannot tolerate enteral feeding or who have persistent enteric fistulas.
Radiotherapy, Nutritional Support and Clinical Outcome
Radiotherapy is provided commonly to patients with head and neck cancer, but
may adversely affect nutritional status by causing mucositis, stomatitis, increased
xerostomia, dysgeusia, anorexia or dental defects. Radiotherapy may also affect nu-
tritional status by causing a preference for carbohydrates at the expense of protein,
24,25
perhaps as a result of relative sparing of sweet taste perception.
26
Radiotherapy-
induced dental lesions similar to caries may appear as early as one month after the
initiation of radiotherapy when the salivary glands are in the radiation field, likely
due to alterations in the oral milieu resulting from inadequate salivation.
27
Some
degree of anorexia, dysphagia, or dysgeusia may persist for several months.
28
Of note, zinc may prevent hypogeusia when administered at varying doses prior
to the initiation of radiotherapy.
29
Additionally, zinc therapy may improve hypogeusia
in patients receiving radiotherapy to the head and neck.
26
One recommended regi-
men is zinc sulfate 110 mg (elemental zinc 25 mg) orally four times a day during or
after meals (to decrease gastrointestinal toxicity).
29
To address the risk of malnutrition, 31 patients with newly-diagnosed localized
head and neck cancer treated with radical external beam radiotherapy for cure were
followed for six months.
10
In this descriptive study, weight loss averaging 10% cor-
related with the size of the radiation field when the oral cavity or oropharynx was
included within the field (assuming that the table correlating weight loss with the
radiation field only when located outside of the oral cavity was the result of a typo-
graphical error). Weight loss did not correlate with pretreatment dietary habits, an-
thropometric or biochemical measures. Two patients received enteral tube feeding
during the last week of four weeks of therapy, and none received parenteral nutrition.
In order to investigate the potential impact of nutritional supplements on nutri-
tional status, Nayel
25
prospectively randomized 11 patients to receive enteral supple-
mentation (Ensure
providing 1,500 to 2,000 kcal/day for 10-31 days) during ra-

diotherapy, and compared them to 12 patients who received radiotherapy without
nutritional support. Among the patients receiving enteral supplementation, there
were significant improvements in mid-arm circumference, triceps skin-fold thick-
ness and body weight, plus trends toward decreased dysphagia and mucositis. Addi-
tionally, there were no interruptions of radiotherapy in the cohort receiving enteral
supplements, while 5 of 12 patients (42%) receiving no nutritional support tempo-
rarily suspended radiotherapy due to poor performance status or severe mucositis.
Although enteral nutritional support improved some anthropometric nutritional
parameters and prevented therapy interruption in patients with advanced head and
neck cancer having radiotherapy, it was unclear if morbidity was altered, and mor-
tality was not investigated.
25
Parenteral nutrition has also been used to rehabilitate or maintain patients with
head and neck cancer undergoing radiotherapy.
19
Two severely malnourished pa-
tients had parenteral nutrition initiated seven to ten days before radiotherapy, while
seven patients received it after developing severe stomatitis or pharyngitis which
threatened the continuation of their treatment. Parenteral nutrition was delivered
for an average of 35 days, and produced weight gain averaging seven pounds. No
440
28
radiotherapy regimen had to be halted, and all patients completed the protocol
except for one who died prematurely of aspiration pneumonia.
Several studies have documented sequelae relevant to nutritional support in pa-
tients with head and neck cancer who have had prior radiotherapy. Twenty-four
patients with subjective and objective dry mouth at least four months after radio-
therapy to the head and neck with curative intent for carcinoma or lymphoma were
studied. Energy intake among the patients who had radiotherapy averaged 1,925
kilocalories, versus 2,219 kilocalories in age- and sex-matched controls. This de-
creased energy intake (nearly statistically significant) was independent of stimulated
saliva secretion rate. The patients who had radiotherapy had a significantly lower
intake of carbohydrate, sugar, fiber, and most micronutrients compared to controls,
despite all but one of the irradiated patients eating food of normal consistency.
30
In contrast to Bckstrms
30
findings, others have found that a majority of pa-
tients with oropharyngeal cancer having radiotherapy alone or radiotherapy com-
bined with surgery required long-term diet restrictions which decreased quality of
life somewhat and limited protein and calorie intake. Beeken
31
retrospectively re-
ported 25 disease-free patients who had completed treatment for oropharyngeal
cancer at least one year previously. Eighteen patients needed dietary modifications,
which limited caloric and protein intake. The four highest ranked side-effects all
related to eating (dry mouth, prolonged meals, dysphagia and dysgeusia). Although
quality of life scores were high (perhaps reflecting a bias of the retrospective design),
all seven patients who scored at or below seven (out of ten) required dietary modifi-
cations. As Beeken
31
did not specify how many had surgery, it is impossible to deter-
mine if this was the variable that explains why his group, but not Bckstrms,
30
required dietary restrictions.
Harrison
32
analyzed 30 patients with squamous cell cancer of the base of the
tongue having primary radiation therapy (local external beam and implant plus
external beam to the neck) plus neck dissection if nodes were palpable, compared to
ten patients having primary surgery (tumor resection and neck dissection) followed
by radiation therapy. Historically, both treatment methods gained local control in
more than 80% of patients. Posttreatment performance status in patients having
primary radiation was independent of cancer stage, while in patients having pri-
mary surgery it was inversely proportional to cancer stage. Subjective performance
and quality of life status at least six months after the primary therapy were superior
in the patients having primary radiation compared to the those having primary
surgery. Nutritional status was not measured, but one criterion of the performance
status was normalcy of diet.
To recapitulate, there likely is a role for enteral supplementation during radio-
therapy to decrease the risk of intolerable side effects and treatment suspensions.
Although performance status may not be jeopardized to the same degree as with
surgical resection, radiotherapy-induced side effects also create long-term risk of
malnutrition which may be lessened by coordinated nutritional counseling and con-
sideration of enteral supplements. As data are limited regarding the role of parenteral
nutrition in patients having radiotherapy, parenteral nutrition cannot be recom-
mended routinely in this population.
Chemotherapy, Nutritional Support and Clinical Outcome
Chemotherapy is less widely used than surgery or radiotherapy for treatment of
patients with head and neck cancer. Many of the agents used are emetigenic acutely,
441
28
and may cause mucositis about one week after being administered. Although che-
motherapy may adversely affect nutritional status, there are no data addressing this
issue specifically in patients with head and neck cancer. No studies have examined
the role of enteral nutrition in this patient population. The same is true for parenteral
nutrition, except for one uncontrolled description of 16 severely malnourished pa-
tients who were given parenteral nutrition an average of 27 days in order to increase
their previously poor chances of tolerating chemotherapy.
19
All the patients toler-
ated the chemotherapy, and gained an average of 10 pounds during the chemo-
therapy. Average survival was six months in the five patients who responded to the
chemotherapy, compared to one month in the eleven patients who did not respond.
Enteral Nutrition Delivery
Multiple avenues for enteral access are available to patients with head and neck
cancer, even for those suffering from relative obstruction of the upper alimentary
canal. With advanced planning in patients expected to require preoperative or pro-
longed postoperative nutritional support, tolerable enteral access can be established.
With rare exception, delivery of enteral nutrition is preferable to more costly and
potentially less efficacious parenteral nutrition, since patients almost invariably pos-
sess a functional gastrointestinal tract distal to the proximal esophagus.
Nasogastric Tubes
Access is usually established using a narrow-bore feeding tube, ideally placed
into the jejunum to allow immediate postsurgical feeding,
16
and may be used for
many months with long-term complication rates similar to those from percutane-
ous endoscopic gastrostomy.
33
If nasogastric tubes of sufficient caliber to allow gas-
tric decompression are used, they should remain in place for no more than one to
two weeks since they are relatively uncomfortable and predispose the patient to
necrosis of the nasal alae, pharyngoesophageal ulceration, postcricoid perichondri-
tis, sinusitis, otitis media and pneumonia due to pooling of secretions.
23,34-36
If the
nasogastric tube is dislodged in the early postoperative period, some advocate im-
mediate replacement to take advantage of the initial tensile strength of the suture
line, while others prefer to wait several days to allow some healing of the suture
line.
34
In one study, 18 of 46 patients needed reinsertion of their nasogastric tubes at
least once, and in two of the four patients who accidentally displaced or clogged
their tubes at least twice, a tube could not be reintroduced safely.
36
Given the lack of
data addressing the timing of nasogastric feeding tube reinsertion, institutional policy
is guided by anecdotal experience.
Also based on anecdotal experience, an opinion exists that prolonged nasogastric
intubation leads to delayed healing of suture lines, increased risk of fistulization and
impaired restoration of normal deglutition.
34
In one study, 10 of 46 patients being
fed with nasogastric tubes did develop dysphagia which resolved after removal of the
tube, but the incidence of pharyngocutaneous fistulas was similar in patients fed via
nasogastric versus percutaneous gastrostomy tubes.
36
Given the discomfort of
nasogastric feeding tubes, their frequent suboptimal delivery of nutrition (at least in
patients two weeks after acute cerebrovascular accident),
37
cosmetic detraction, and
general nuisance in ambulatory patients,
35
alternatives should be considered in pa-
tients requiring prolonged enteral nutritional support. Risk factors for needing post-
operative nutritional support for more than 30 days are listed in Table 28.3, derived
from a descriptive retrospective review of 109 patients with squamous cell carcinoma
442
28
of the oral cavity, pharynx or larynx treated with surgical resection. Of the 92 who
received postoperative enteral feeding, 41 (45%) required prolonged enteral sup-
port. Delayed wound healing was the indication for one-half of the patients requir-
ing prolonged enteral feeding.
38
Cervical Esophagostomy or Pharyngostomy
Percutaneous cervical esophagostomy or pharyngostomy tubes placed via the
pyriform sinus may be used as a route for temporary or prolonged enteral nutritional
support. If the tube is being placed to improve nutritional status preoperatively,
local cutaneous and topical oropharyngeal anesthesia may be sufficient to complete
the procedure,
39
although others have preferred general anesthesia.
35
Percutaneous
pharyngostomy tubes were placed in 42 patients without significant complication
and with much better tolerance than historically witnessed with nasogastric tubes.
35
In another study, however, the complication rate of 60% in the 17 patients with
esophagostomy tubes was higher than the 9% complication rate in 21 patients with
nasogastric tubes.
38
The most frequent delayed concern is accidental dislodgment of
the tube.
39
If the tube has been in place for at least a week prior to being removed, it
is usually easy to replace if done so promptly through the established track. If the
tube is not replaced, the track has been shown to close spontaneously within four
days.
35
Percutaneous Endoscopic Gastrostomy or Jejunostomy
A percutaneous endoscopic gastrostomy (PEG) or jejunostomy tube is another
reasonable alternative in patients who are expected to require protracted enteral
supplementation (e.g., at least four weeks), and has been recommended over
esophagostomy tubes due to a possible lower risk of major complication.
38
The
postoperative course in 43 patients with stage II, III or IV head and neck cancer
who received a PEG one day prior to surgery was compared retrospectively to 46
site- and stage-matched patients who received postoperative nutrition via a nasogastric
tube.
36
In the patients with the PEG tubes, length of hospital stay was decreased
Table 28.3. Risk factors for requiring prolonged postoperative enteral nutritional
support in patients with head and neck cancer
Individual Risk Factors Risk of Requiring
Support > 30 Days
Primary pharyngeal tumors 60%
Preoperative weight loss of more than ten pounds 56%
Stage IV cancer 55%
Combined surgery and radiotherapy 50%
Pooled risk factors
No risk factor 16%
One risk factor 26%
Two risk factors 52%
Three risk factors 56%
All four risk factors 86%
Adapted from Gardine, Kokal, Beatty and colleagues.
38
443
28
about 60% in patients with cancer of the larynx, pharynx, or tongue base from
about 50 days to about 20 days. Patients with cancer of the anterior tongue or floor
of mouth (in whom swallowing function is usually relatively preserved) stayed about
one month in both groups. When analyzed by stage, patients with stage III or IV
disease who had PEGs also left the hospital earlier. Patients with stage II diseases
stayed about the same length of time in both groups. In those patients with PEGs,
63% were discharged with plans for home tube feeding, compared to only 15% of
the patients with nasogastric tubes. This discrepancy in outpatient enteral feeding
frequencies may explain why PEG tubes allowed more timely discharges.
Patients with head and neck cancer who are likely to require prolonged enteral
nutritional support include those who are expected to suffer severe mucositis during
radiation therapy preceding surgery. An endoscopic gastrostomy tube placed prior
to or at the beginning of radiotherapy may prevent malnutrition from developing.
Other patients who may benefit from a prophylactically-placed percutaneous endo-
scopic gastrostomy tube include those expected to have difficulty establishing safe
swallowing postoperatively, such as those with cancer of the tongue or pharyngeal
walls.
16
Such patients can have the endoscopic gastrostomy tube placed preopera-
tively under conscious sedation or in the operating suite after administration of
general anesthesia but before resection of the cancer begins.
40
PEG placement in 114 patients with head and neck cancer was retrospectively
compared to PEG placement in 220 patients with neurological impairment.
41
The
PEG attempt failed due to pharyngeal or esophageal obstruction in 3% versus 0.5%
of patients, respectively. The post-PEG overall complication rate was only 5% in the
head and neck cancer compared to 14% in the neurological group. It was unclear if
any differences were statistically significant. Of the three patients who received che-
motherapy before the PEG and the 12 patients who underwent full-course chemo-
therapy immediately after PEG placement, only one developed wound breakdown.
Although no mention was made of periprocedure antibiotic use, the PEG site
cellulitis or wound breakdown incidences were only 3.5% and 4.5%, respectively,
41
below that observed in patients who received prophylactic doses of antibiotics be-
fore PEG placement.
42
In the randomized controlled trial by Jain,
42
the incidence of
peristomal wound infection was zero in the 52 patients already on antibiotics, 7%
(2 of 27) in patients not already on antibiotics who received cefazolin one gram
intravenously 30 minutes prior to the PEG procedure, and 32% (9 of 28) in the
control group who received no antibiotics. Based on these findings, the American
Society for Gastrointestinal Endoscopy recommended a prophylactic dose of a cepha-
losporin before PEG procedures.
43
The reported incidence of respiratory distress during PEG placement in patients
with head and neck cancer and an unsecured airway has ranged from 1-10%.
41,44
With judicious use of sedation, airway obstruction was only 0.9% (identical to the
control group with neurological impairment), despite inclusion of 19 patients with
stage IV pharyngeal cancer and 13 patients with Stage III or IV pyriform cancer.
41
In combining two smaller series (each from the same institutions), however, the risk
of respiratory arrest was 14%, occurring in 6 of 44 patients. In 5 of the 6 patients,
the airway obstruction occurred after sedation but before endoscopy.
44
If tumor bulk in head and neck cancer allows passage of the endoscope but is
unlikely to allow easy peroral passage of the feeding tube and bumper using either
the push (Sacks-Vine) technique
45
or pull (Ponsky) techniques
46
percutaneous
placement under endoscopic guidance can be achieved using the introducer
444
28
(Russell) technique.
47
However, being of smaller diameter and anchored by an in-
flated balloon rather than a solid bumper, tubes placed by the introducer method
are more prone to clogging and premature extrusion. If an endoscopic attempt at
gastrostomy placement is halted due to inability to pass even a pediatric fiberoptic
endoscope, poor tissue apposition or other technical limitation, an alternative is
fluoroscopically-guided percutaneous placement of a gastrostomy tube using the
introducer technique, although this method does require passage of an orogastric
tube to insufflate the stomach.
When providing nutrition into the stomach, aspiration pneumonia might be
decreased by using continuous feeding or slowly delivered intermittent boluses (e.g.,
480 mL over one hour).
48,49
Both delivery methods may decrease the risk of induc-
ing gastroesophageal reflux compared to rapidly delivered boluses. Rapid bolus feeding
(e.g., 250 mL of formula followed by 100 mL of water, all within 20 seconds) caused
marked relaxation of the lower esophageal sphincter on manometry and allowed
esophageal reflux to the sternal notch on scintigraphy despite elevation of the head
of the bed.
49,50
Jejunostomy extensions can be added to PEGs and guided through the pylorus
endoscopically or fluoroscopically. However, given the extensions risk for clogging,
migration into the stomach, and failure to decrease the risk of aspiration (as most
aspiration pneumonia appears to result from aspiration of oropharyngeal secretions
rather than gastroesophageal reflux
51
), the routine use of jejunostomy extensions
cannot be recommended. Rather, direct percutaneous endoscopic jejunostomy
52
should be considered in patients at risk for aspiration of gastric contents who would
not be inconvenienced by prolonged pump-driven feedings.
Surgical Gastrostomy or Jejunostomy
Another option is surgical gastrostomy, which is usually a separate procedure but
can be performed at the time of cancer resection.
53
When performed in patients
under intravenous conscious sedation, open gastrostomy has morbidity, mortality
and overall costs comparable to PEG.
54
In a retrospective study comparing
laparoscopic to open gastrostomy (performed under general anesthesia in 96% and
67% of the cases, respectively), laparoscopic gastrostomy offered significantly re-
duced operative time with similar morbidity, mortality, and procedural costs (in the
laparoscopic group, additional equipment charges offset reduced room charges).
53
The laparoscopic jejunostomy remains another consideration.
Gastrostomy Site Metastasis
One rare risk of gastrostomy tubes in patients with head and neck cancer is that
of gastrostomy site metastases. Most instances occurred after placing PEGs using
the pull technique
55-60
(preceded by bougienage of the esophagus only in the first
reported case
61
). These and other reports of pull PEG site metastases suggest that
after advancing through the head or neck cancer, the tube may seed the stoma with
cancer cells as it emerges from the stomach through the abdominal wall. The ab-
sence of reported cases in association with the push technique probably reflects the
greater popularity of pull PEGs, not any difference in risk.
There is evidence, however, that the source of PEG site metastases may be from
circulating cancer cells rather than those traveling on the feeding tube. In one case,
the PEG was placed six weeks after surgical resection of the laryngeal cancer, without
445
28
evidence for local or regional cancer at the time of PEG placement or 18 months
later when metastases were diagnosed in the lung and on the skin at both a prior
PEG site and a location several centimeters away.
55
Additionally, a metastasis to the
site of an operatively placed gastrostomy tube has been reported.
62
In these cases,
development of metastases at the gastrostomy sites presumably was the result of
hematogenous inoculation of traumatized tissue having a greater susceptibility to
implantation of cancer cells.
63
The incidence of gastrostomy site metastases is un-
known, but is presumably low. Also unknown is to what degree, if any, risk of gas-
trostomy site metastasis is reduced by using introducer or operative placement tech-
niques which avoid contamination of the gastrostomy tube with cancer cells.
Conclusion
Evidence-based guidelines regarding the appropriate nutritional support of sur-
gical, radiotherapy or chemotherapy candidates with head and neck cancer can only
be developed after the completion of prospective, randomized studies of sufficient
sample size to ensure adequate power.
9
Although such studies in patients with head
and neck cancer are lacking, nutritional support guidelines are offered in Table 28.4
based on the available data. These guidelines parallel recent general recommenda-
tions for nutritional support.
1
Malnourished patients with head and neck cancer may improve their nutritional
parameters after nutritional support. However, most data suggest that the majority
of patients do not improve their outcome with nutritional support. Severely mal-
nourished patients are the exception, in whom enteral nutritional support around
the time of therapeutic interventions decreases morbidity and mortality. Several
proven methods exist to provide enteral nutrition through a tube placed into the
stomach or proximal intestine of appropriate patients. In contrast to enteral nutri-
tion, there is little evidence to support the use of parenteral nutrition in patients
with head and neck cancer (the majority of whom can tolerate enteral nutrition).
Table 28.4. Guidelines for nutritional support in patients with head and
neck cancer
1) If the gut works, use it.
2) In severely malnourished patients anticipating major elective surgery, preopera-
tive nutritional support should be provided for ten days.
3) In surgical patients with malnutrition or postoperative complications, postopera-
tive nutritional support should be initiated immediately.
4) In surgical patients who are unable to resume oral feedings by postoperative
day ten, postoperative nutritional support should be initiated.
5) In malnourished patients anticipating radiation or chemotherapy, nutritional
support may improve toleration of the therapy, but is unlikely to alter morbidity
or mortality.
6) In patients requiring nutritional support in whom a nasogastric tube is
undesirable, a gastrostomy or jejunostomy is preferable to parenteral nutrition.
7) In patients with a persistent pharyngocutaneous or chylous fistula, parenteral
nutritional may improve the likelihood of healing.
446
28
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61. Preyer S, Thul P. Gastric metastasis of squamous cell carcinoma of the head and
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62. Alagaratnam T, Ong G. Wound implantation: A surgical hazard. Br J Surg 1977;
64:872-875.
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experimental metastasis. Cancer 1989; 64:2035-2044.
CHAPTER 1
CHAPTER 29
Nutritional Support in Patients
with Gastrointestinal, Pancreatic
and Liver Cancer
Matthew E. Cohen
Patients with gastrointestinal cancer who lose weight have poorer survival, with the
exception of those with advanced gastric cancer or pancreatic cancer.
1
Malnutrition
may compound preexisting immunosuppression, risk of infection, and poor wound
healing. Malnutrition may develop secondary to mechanical complications (e.g.,
obstruction) metabolic derangements (e.g., the catabolic state known as cancer
cachexia), functional disorders (e.g., postoperative ileus) or psychological reactions
(e.g., reactive depression). Although the cause of malnutrition in patients with gas-
trointestinal cancer may be multifactorial (see Table 29.1), negative energy balance
appears to be more closely linked to decreased intake than to increased expendi-
ture.
2
It has been impossible to verify that nutritional status is independent from
disease severity.
3
Therefore, it has been difficult to distinguish whether malnutrition
associated with gastrointestinal cancer is a cause of, or a result of, the illness.
Multiple studies have demonstrated that nutritional support improves nutri-
tional indices,
4
although anorectic and malnourished patients with advanced gas-
trointestinal cancer may be an exception.
5
Few studies have demonstrated that im-
proving nutritional parameters translates into improved clinical outcome in cancer
patients. One early example is a study of 50 patients with either gastroduodenal or
pancreatobiliary malignancy who were unable to maintain adequate enteral nutri-
tion in any form and who had parenteral nutrition for an average of 26 days (range
5-109 days). Discharge with improved physical status and plans for continued therapy
were predicted by increasing transferrin levels, total lymphocyte count, and to a
lesser extent, arm muscle circumference at two weeks, but not changes in albumin
level or skin test reactivity.
6
Otherwise healthy patients subjected to starvation benefit from nutritional reha-
bilitation. It is unclear what benefit patients with cancer receive from intensive
parenteral or enteral nutritional support, despite studies suggesting that reversing a
catabolic state predicted postoperative survival.
7
While basal carbohydrate and fat
metabolism in patients with early gastrointestinal cancer (and usually stable weight)
parallels healthy people,
8,9
those patients with advanced cancer (and usually weight
loss) have elevated rates of protein catabolism,
9
glycolysis,
9
lipolysis,
8
gluconeogen-
esis
9
(none of which is inhibited by glucose infusion), and lipogenesis,
10
plus im-
paired free fatty acid oxidation,
8,10
and, in contrast to malnourished patients with-
out cancer, fail to increase muscle strength despite two weeks of parenteral nutrition.
10
450
29
In addition to altered metabolism in gastrointestinal cancer, the physical stress of
surgical resection may further contribute to the risk of malnutrition.
11-14
One of the
first randomized trials of nutritional support studied its use in the perioperative
period of 30 patients with upper gastrointestinal cancer and recent weight loss. Major
complications were less in the group that received parenteral nutrition for three days
before and ten days after surgery compared to those who did not, although mortal-
ity was the same.
15
In a study of 100 patients undergoing gastrointestinal resection,
the majority of whom had cancer, parenteral supplementation of oral diets for at
least one week before surgery decreased infectious complications among the mal-
nourished only.
16
In 74 patients given intensive oral feeding and who underwent
laparotomy with anticipated surgical resection of esophageal or gastric cancer, those
who had 7-10 days of preoperative parenteral nutrition had a reduced incidence of
wound infection, despite no improvement in immunological parameters. Of those
patients with admission albumin below 3.5 g/dL, 5 of 9 in the control group devel-
oped wound infections, while none of the 8 patients who fell in this category from
the treated group developed a wound infection. The authors concluded that the
limited benefit did not justify the routine use of parenteral nutrition in this popula-
tion, given the complications from the central venous access and formula, and added
expense.
17
In a similar group of 125 patients, those who received 10 days of preop-
erative parenteral nutrition had fewer anastomotic leaks and reduced mortality (3%
versus 11%).
18
With the replacement of suturing by stapling to secure anastomoses,
it is quite possible that anastomotic breakdown, and its resultant morbidity and
mortality, has become a less significant issue.
19
Additionally, this study has been
criticized for failing to stratify for degree of malnutrition and for having been a
subgroup analysis, and therefore being at increased risk of type I error (erroneously
concluding that a difference exists between similar groups).
20
In a prospectively study of patients with cancer of the esophagus, stomach, co-
lon, pancreas or biliary system who had lost at least 10 pounds over 3 months, 30
patients were randomized to receive parenteral nutrition for 72 hours prior to surgery
Table 29.1. Potential causes of weight loss and malnutrition in patients with
gastrointestinal cancer
1. Anorexia of cancer cachexia
2. Obstruction
3. Malabsorption
a. Metastatic infiltration of small bowel or mesentery
b. Pancreatic duct obstruction or insufficiency
c. Small bowel fistulas
d. Biliary obstruction or bile salt insufficiency
e. Bacterial overgrowth
f. Megaloblastic changes from nutritional deficiencies
4. Fluid and electrolyte imbalance
a. Hypovolemia from inadequate intake
b. Emesis from obstruction
c. Osmotic diarrhea from malabsorption
d. Secretory diarrhea from hormone-secreting tumors
e. Fluid loss through fistulas
5. Increased tumor-induced energy expenditure
451
Nutrition Support in Gastrointestinal and Pancreas Cancer
29
and up to 10 days postoperatively until eating at least 1,500 kilocalories a day.
Twenty-six patients were randomized to receive no parenteral nutrition. Patient di-
ets were advanced as tolerated. In patients receiving parenteral nutrition, the post-
operative albumin level improved significantly over the preoperative value, 53%
gained more than 10 pounds, and only 7% lost more than 10 pounds. In contrast,
patients who received no parenteral nutrition had no improvement in albumin,
none gained more than 10 pounds, and 15% lost more than 10 pounds. Minor
complications and mortality (23% and 7%, respectively) were no different between
groups. Major complications were 13% in the parenteral nutrition group, and 19%
in the unsupplemented group, which was a statistically insignificant difference. The
statistical methods were not described.
15
Other studies have found that despite weight gain in those patients given parenteral
nutrition, there were no improvements in morbidity or mortality.
21
A meta-analysis
pooling 10 trials (9 of which focused on patients with gastrointestinal cancer) which
investigated the impact of preoperative parenteral nutrition on surgical resection of
cancer, however, favored parenteral nutrition when assessing endpoints of major
complication (95% confidence interval 0.30-0.84) and mortality (95% confidence
interval 0.21-0.90).
22
There are fewer data regarding the role of perioperative en-
teral nutrition. In malnourished patients with gastric or colorectal cancer, preopera-
tive enteral nutrition appeared to protect against infectious complications as well as
did parenteral nutrition.
23
Compared to 16 control patients, 16 patients randomized to receive immediate
nasojejunal feeding after small or large bowel resection had improved wound heal-
ing, trends toward earlier passage of flatus and feces, and fewer bowel obstructions,
despite their failure to meet nutritional requirements until after the introduction of
a normal oral diet. Muscle strength, fatigue, and length of stay were similar.
Three-quarters of the patients had no problems with the tube or the feedings, and
none had diarrhea or complications related to the feeding.
24
Similarly, in a random-
ized study comparing 14 patients who received immediate jejunal feeding after elec-
tive intestinal resection for quiescent, chronic gastrointestinal disease with 14 pa-
tients who received only intravenous fluids for an average of 6 days, the feeding
prevented transient postoperative negative nitrogen balance, attenuated gut perme-
ability, and may have decreased nausea, vomiting, weight loss, and infections (dif-
ferences between the small groups in these four outcomes did not achieve statistical
significance). Baseline nutritional status was not reported.
25
Other studies have also found benefit to immediate enteral feeding following
bowel resection
24,26
which compared favorably to parenteral nutrition at decreased
cost.
27
The only randomized study explicitly limited to patients with gastrointesti-
nal cancer (gastric adeno-carcinoma) found that postoperative jejunostomy feeding
was comparable to parenteral nutrition at one-half the cost, but caused more diar-
rhea (which was usually controlled by altering the infusion rate and adding
loperamide).
28
Parenteral nutrition in those patients with high caloric demands may
be appropriate, because patients fed via needle jejunostomy require gradual advance-
ment which delays positive nitrogen balance until the fifth postoperative day, on
average.
29
Enteral feeding via jejunostomy has been reported to cause pneumatosis
intestinalis and to be associated with small bowel infarction.
30,31
However, in a re-
view of 217 consecutive patients the incidence of the former complication was 1%
and the latter complication was not encountered.
32
452
29
In addition to bearing the stress of surgery, patients with gastrointestinal cancer
often receive additional therapy which jeopardizes their nutritional status, namely
chemotherapy,
33,34
and/or radiation therapy.
33,35
In malnourished patients given
parenteral nutrition, up to one-half will improve their indices of immunological
function.
36
There has been concern, however, that parenteral nutrition may favor
protein synthesis to a greater degree in the tumor than in the host,
14
although this
same effect has the potential to increase tumor susceptibility to therapy.
37,38
Most
studies have found parenteral nutrition to be associated with more infection,
22,39
poorer tumor response,
22,39
or shorter survival.
39
In a meta-analysis, no protective
effect of parenteral nutrition on the gastrointestinal toxicity of chemotherapy was
found,
40
although parenteral nutrition may decrease radiation enteritis by suppress-
ing pancreas exocrine function.
41
Reviews have concluded that there is little evi-
dence supporting a role for parenteral nutrition during chemotherapy.
19
Similarly,
enteral support has failed to improve nutritional or clinical outcomes following ra-
diation therapy for gastrointestinal malignancies,
42
although a low residue, low-fat
diet free of gluten and milk products was reported to prevent acute or delayed radia-
tion enteritis.
35
The American College of Physicians (ACP) concluded that in pa-
tients undergoing chemotherapy or combined chemotherapy and radiotherapy,
parenteral nutrition was associated with net harm, but conceded that the interven-
tion may be beneficial in patients who are severely malnourished
39
based on a
meta-analysis.
43
Although parenteral nutrition is more expensive than enteral nutrition, is associ-
ated with more infectious complications, and may produce limited if any nutri-
tional gains,
5
it may be the only alternative in patients without an intact gastrointes-
tinal tract, or the best alternative in special circumstances. For example, in 25 cancer
patients with gastrointestinal fistulas treated with parenteral nutrition, 44% closed
spontaneously after an average of one month (including those with cancer involving
the fistula) and an additional 28% were closed surgically.
44
(In contrast, patients
with enteric fistulas arising in irradiated bowel do not achieve sustained spontane-
ous closure.) For another example, of eight patients with esophageal anastomotic
leaks, only one recovered after emergency surgery. The next eight patients with this
complication were treated with parenteral nutrition and fasting, and six recovered.
45
There may be multiple reasons for the lack of consensus regarding the role of
nutritional support around the time of therapy in patients with gastrointestinal can-
cer. In studies addressing the role of nutritional support in this patient population,
methodological shortcomings have included:
1. enrolling patients with heterogeneous sites of disease or stage;
2. failing to stratify patients based on nutritional status;
3. neglecting to account for co-morbid illnesses;
4. providing nutritional support of variable composition, route of delivery,
rate or duration;
5. assessing nutritional repletion using unclear criteria;
6. defining post-therapeutic morbidity and mortality inconsistently;
7. neglecting to distinguish malnutrition-related complications from other
complications; and
8. using methods to assess malnutrition which are cumbersome and which
may not have clear clinical relevance.
46
453
29
No trial has met the ideal of including patients who:
1. share the identical diagnosis;
2. have the same degree of malnutrition;
3. receive consistent nutritional support;
4. undergo a standardized therapeutic intervention performed by equally ex-
perienced teams; and
5. are enrolled in sufficient numbers to confirm that quantitative differences
between groups are statistically significant.
This chapter reviews the literature addressing the problem of malnutrition and
the impact of nutritional support specifically in patients with gastrointestinal can-
cer, divided into sections on esophageal, gastric, colon, pancreatic, and liver cancer.
Esophageal Cancer
Despite suffering from dysphagia, patients with esophageal cancer may have sur-
prisingly infrequent weight loss (2%, 53% of the time, in one early study
47
). How-
ever, patients frequently have decreased indices of cell-mediated immunity, includ-
ing attenuated reaction to primary and recall antigens, impaired blastogenesis, and
decreased T-lymphocyte number, which has correlated with lower survival.
48
This
immune dysfunction, however, may be related to the presence of a cancer, per se,
rather than to malnutrition, since the changes were independent of albumin level or
body weight. Also, three weeks of enteral therapy improved T-lymphocyte num-
bers, but not anergy or depressed blastogenesis.
49
It is possible that parenteral nutri-
tion would have had an equivalent result. In a study assessing metabolic state, the
effects of jejunal feeding and parenteral nutrition were similar, such as the suppres-
sion of gluconeogenesis and the conservation of protein stores.
50
In the immediate
postoperative period, administering clonidine by continuous infusion (given for
prophylaxis against alcohol withdrawal) prevented the negative nitrogen balance
seen in nonalcoholic controls.
51
Providing at least 0.2 g N/kg body weight per
twenty-four hours can maintain positive nitrogen balance,
52
but it is unknown
to what degree, if any, short-term improvements in nitrogen balance influence
outcome.
Although surgical resection removes the obstruction and, therefore, at least one
barrier to adequate nutrition, it can create new nutritional challenges. In addition to
worsening reflux disease due to loss of the lower esophageal sphincter, esophagectomy
can cause gastric stasis and isolated fat malabsorption. Both phenomena have been
attributed to the effects of vagotomy, although the mechanism for fat malabsorption
is unclear.
53
(Substitution of medium-chain triglycerides [which can be absorbed by
the small intestine directly] for long-chain fatty acids has led to reduced fecal fat
loss.)
54
Anastomotic leaks which are often treated with prolonged parenteral nutri-
tion, are another threat to nutritional repletion. In a study of 617 patients who had
esophageal resection and esophagogastric anastomosis, 39 suffered an anastomotic
leak (over half of whom died from the complication). Albumin concentration below
3 gm/dL (along with a surgical margin being positive for cancer and use of a cervical
anastomosis) was predictive of anastomotic leak.
55
In another study of patients who
developed fistulas, those whose leak persisted were more likely to have had either
residual tumor after palliative operations or low presurgical albumin levels.
56
Given
the poor healing ability of these patients when malnourished, immediate surgical
repair of anastomotic leaks should be considered in patients with low preoperative
albumin levels.
454
29
Not surprisingly, the stage of esophageal cancer has correlated with the degree of
negative nitrogen balance and weight loss,
52
and protein-calorie malnutrition has
been identified as a risk factor for operative mortality.
57
One group of researchers
developed a Host Defense Index which included nutritional parameters of arm
muscle circumference, albumin, and transferrin to help discriminate between pa-
tients who were at high risk from those who were at low risk for perioperative mor-
tality. It was used to identify patients who could benefit from modification of the
proposed surgical procedure and more vigilant management of perioperative infec-
tions. Prospective implementation of the Host Defense Index may have been among
the reasons that fatal complications dropped from 80% to zero.
58
Despite enteral feedings, those patients who were not able to eat at all after
treatment (surgery, radiotherapy, and/or chemotherapy) were less likely to survive,
based on univariate analysis. In multivariable analysis, however, the mode of nutri-
tion delivery did not persist as a predictor of survival.
59
Survival differences were
better explained by retained variables such as persistent disease, which likely corre-
lated with an inability to eat. For patients with lesions obstructing the esophagus,
pyriformostomy tube feeding may maintain enough of an esophageal lumen to al-
low swallowing of oral secretions,
60
while being more comfortable and cosmetically
appealing than nasogastric tubes. In patients who have dysphagia from recurrence
of carcinoma after esophagectomy, a feeding tube can be placed percutaneously via
direct endoscopic jejunal puncture.
61
Beneficial effects of parenteral nutrition have been claimed in patients with esoph-
ageal cancer as early as 1965 (although in a nonrandomized analysis using historical
controls).
62
One early study included 15 patients with esophageal cancer undergo-
ing thoracotomy who were randomized to receive parenteral nutrition for about one
week before and one week after surgery. Although patients had similar weight loss
compared to the five control patients, wound healing appeared to be better in those
who received parenteral nutrition.
63
Another compared 12 patients randomized to
4 weeks of preoperative nutrition via a gastrostomy to 12 patients randomized to
parenteral nutrition. The latter group achieved an earlier positive nitrogen balance
and greater weight gain, despite the gastrostomy patients receiving a greater nitro-
gen delivery (although the weight gain may not have been from anabolismalbu-
min levels were similar between groups). The number of perioperative complica-
tions or death was twice as large in the gastrostomy group (14 in 10 patients) compared
to the parenteral nutrition group, but the number of observations was too small for
any statistical conclusions. The gastrostomy patients were, however, more content
with their care. Their hunger was relieved with the feedings, none developed diar-
rhea, and they were ambulatory. The patients receiving parenteral nutrition, in con-
trast, were reluctant to walk around despite encouragement for fear of accidents
occurring with the intravenous pole, often had hunger for the first week of therapy,
and had formulary expenses 15-17 times higher than the enteral formula.
64
In a study of patients with localized, distal esophageal squamous cell carcinoma
who lost more than 20% of their body weight or were unable to swallow liquids,
parenteral nutrition administered over two weeks (without any other therapy or
interventions) improved nitrogen balance and weight gain better than jejunostomy
feedings.
65
However, the improved nitrogen balance may have been solely a reflec-
tion of the greater amount of protein delivered in the parenteral product, and the
weight gain may have been from the accumulation of fat or water rather than muscle.
In one retrospective review of surgical patients treated between 1973 and 1980,
455
29
malnourished patients who received parenteral nutrition (most beginning two weeks
before surgery) lost less weight, had fewer major and minor complications, but had
higher perioperative mortality and similar five-year survival compared to
well-nourished patients who had no parenteral nutrition.
66
In a more recent review of 64 patients admitted to the hospital for the first time
with cancer of the esophagus, the 37 who received parenteral nutrition had a re-
duced incidence of weight loss (although not necessarily muscle loss) but an in-
creased incidence of pulmonary sepsis, with a resultant increase in length of hospi-
talization or death and an average increase of $6,000 in hospital fees (in 1984
dollars).
67
However, a greater proportion of the patients who received parenteral
nutrition had surgical resections, and the retrospective design raises the likely possi-
bility of selection bias, where patients considered to be at highest risk for complica-
tions were the same patients most likely to be given parenteral nutrition. It has been
proposed that in patients with esophageal cancer, nutrition should be delivered en-
terally whenever possible.
68
Gastric Cancer
Patients with gastric cancer appear to be particularly susceptible to malnutrition,
which may be multifactorial. In one study, 60% of patients with gastric cancer had
anorexia, compared with 37% of those with colorectal cancer.
69
Weight loss was
seen in 84% of patients with gastric cancer,
70
which was unmatched by patients
with esophagus, pancreas or primary liver cancer.
71
Anorexia from functional or
mechanical derangements is probably responsible for the majority of malnutrition
developing in patients with cancers of the upper versus lower gastrointestinal tract,
since energy expenditures appear similar.
72
Patients treated with surgical resection
are at risk for esophageal reflux disease and dumping syndrome. In a study of surgi-
cal technique, the pouch and Roux-en-Y approach for creating an enteric reservoir
after total gastrectomy was associated with toleration for greater meal volumes and
better weight recovery, when compared to simple Roux-en-Y and pouch and
interposition techniques.
73
Relatively little has been written on the application of
enteral or parenteral nutritional support in patients with gastric cancer. Use of post-
operative parenteral nutrition in patients with stage III or IV gastric cancer has been
claimed to restore cell-mediated immunocompetence, increase tolerance for 5-fluo-
rouracil, and improve three-year survival (54% versus zero). There was no descrip-
tion, however, of how patients were selected to be in the group receiving parenteral
nutrition, and hence, any differences could merely have reflected selection bias.
74
A study of preoperative nutritional assessment of 169 patients with stage IV
gastric cancer found that those who were able to undergo gastrectomy had signifi-
cantly higher albumin, prealbumin, retinol binding protein, transferrin, and vita-
min A levels compared to those who received only bypass or exploratory laparo-
tomy. No nutritional parameters in the group were significantly different between
those who suffered postoperative complications and those who did not. Thirty-four
of the patients received two weeks of preoperative parenteral nutrition for an albu-
min less than 3.5 g/dl. If albumin rose above 3.5 g/dl, then patients were twice as
likely to receive a gastrectomy. In predicting postoperative complications in this
subgroup after parenteral nutrition, an albumin of at least 3.0 g/dl, prealbumin of
20 mg/dl, or lymphocyte count of 1,000/mm
3
each possessed specificity in excess of
96%, but being at the terminus of the receiver operating characteristic curves, suf-
fered from low sensitivity. The prealbumin suggested discrete values which possessed
456
29
both sensitivity and specificity above 80%, but these relevant points on the curve
were neither commented upon in the text nor labeled in the figure. Of greater con-
cern, there was no description of the clinical relevance of gastrectomy versus enteral
bypass in this population with advanced cancer.
75
Given the lack of compelling evidence in favor of parenteral nutrition in patients
with gastric cancer, enteral access remains the preferred route, although gastric out-
let obstruction may require endoscopic stenting, surgical bypass, or decompression
gastrostomy and feeding jejunostomy tubes. In patients who are not surgical candi-
dates but in whom nutritional support is desired, inventive routes such as the biliary
tree may be used for establishing enteral access.
76
If parenteral nutrition must be
used, there is some evidence that specialized formulations may improve nutritional
parameters in patients with gastric cancer, although there is no evidence that these
compositions improve outcome.
In a randomized multi-center study of 173 patients having surgery for gastric
cancer, postoperative parenteral nutrition supplemented with branched-chain amino
acids led to decreased 3-methyl-histidine levels (an indication of skeletal muscle
catabolism) in patients having subtotal or total gastrectomy, and to improved nitro-
gen balance in patients having total gastrectomy. There were no differences in albu-
min or other serum protein levels. There did not appear to be any adverse side
effects of higher circulating branched-chain amino acids. Those with complicated
postoperative courses, however, were excluded from analysis.
77
In a smaller study,
seven patients given methionine-depleting parenteral nutrition and continuous in-
fusion of 5-fluorouracil for seven days before surgery for advanced gastric cancer
had marked degeneration of the tumor at the time of resection, compared to little
direct impact on the tumor in the seven control patients who received conventional
parenteral nutrition with 5-fluorouracil. The proposed mechanism is that the tu-
mor is unable to proliferate without L-methionine, which is essential for methyla-
tion in the synthesis of DNA, RNA, and protein. Additionally, the methionine
depletion appeared to further increase 5-fluorouracils inhibition of thymidylate syn-
thase activity.
78
The role for specialized parenteral nutrition in patients with gastric
cancer remains to be determined.
Colon Cancer
Patients with cancer of the colon are less likely to have malnutrition compared to
patients with cancers of the upper gastrointestinal tract. This observation may be
due to less frequent anorexia,
69
nausea, and inanition. Patients with colon cancer
may not develop gastrointestinal complaints until late in their disease when they
present with colonic obstruction. Colon cancer may also exhibit little effect on en-
ergy expenditure. Basal energy expenditure in patients with disease metastatic to the
liver did not differ from patients without metastases, and energy expenditure did
not change following potentially curative surgical resection.
79
Indicators of poor
prognosis on univariate analysis included weight loss, low albumin, and low caloric
intake. The best prognostic indicator on multivariate analysis was albumin. Low
caloric intake was preserved as a prognostic indicator in the multivariate analysis,
but weight loss was discarded (suggesting that it correlated better with albumin or
caloric intake than with prognosis).
80
Patients who are malnourished may be more
likely to remain malnourished following therapeutic interventions. More than half
of 68 patients who were well-nourished before surgery for colorectal cancer estab-
lished oral intake of at least 60% of their caloric needs by the tenth postoperative
457
29
day, whereas only one-quarter of the 33 patients who were malnourished had achieved
this goal by ten days.
81
Conventional management of patients after bowel resection includes support
with intravenous fluids and nothing by mouth until flatus is passed, heralding the
resolution of the postoperative ileus. Although postoperative gastroparesis is com-
mon, the small intestine remains functional in the postoperative period.
82
Despite
the potential for postoperative gastroparesis, eight consecutive elderly, high-risk pa-
tients were allowed immediate regular supplemented meals and cisapride 20 mg
twice a day after elective laparoscopic colonic resection for neoplastic disease. Pain
was controlled with epidural anesthesia and oral narcotics. Two had mild nausea on
one occasion, none vomited, six patients passed feces on postoperative day one, and
all were able to be discharged on the second postoperative day. When surveyed one
month later, none felt that they had been discharged prematurely.
83
A less aggressive approach to postoperative enteral nutrition in patients having a
bowel resection is to provide immediate jejunal feeding. The clinical value of post-
operative maintenance of nitrogen balance and weight is, however, unclear. For ex-
ample, in a study of parenteral nutrition following major surgery, temporary under-
nutrition and weight loss in the control group had no impact on recovery.
84
enteral
nutrition may decrease gut permeability, but, further study in humans is needed
before increased gut permeability can be linked with increased susceptibility to sep-
sis from bacteria originating in the gut.
85
Patients receiving chemotherapy or radiation therapy present nutritional chal-
lenges as well. Not only do the therapies cause side effects which lead to reduced
intake, but the treatment causes increased nutritional losses. For example, patients
with Dukes D colon cancer receiving chemotherapy had increased nitrogen losses,
likely due to decreased protein synthesis.
86
Although nutritional interventions have
allowed some patients to receive therapy who otherwise would have been too de-
pleted to tolerate the intervention, outcomes have remained disappointing. Fifty-one
patients randomized to receive oral nutritional support during the first 12 weeks of
chemotherapy for colorectal cancer had higher caloric intake than the 33 control
patients, but fared no better in weight change, tumor response, tolerance to chemo-
therapy, time to progression, or survival. Nutritional counseling had no impact on
toleration of chemotherapy, progression of tumor, or survival. Enteral tube feedings
were refused by the majority of patients who were failing to meet their targeted
caloric intake.
80
Randomized trials of parenteral versus oral nutrition during chemotherapy for
colorectal cancer have been disappointing, as well. In a study of 45 patients receiv-
ing identical chemotherapy for metastatic colon cancer, 14 days of pretreatment
parenteral nutrition continued throughout chemotherapy was well-tolerated, asso-
ciated with improved mood, and did not stimulate tumor growth, but survival was
significantly decreased (79 versus 308 days).
87
The impact of specialized amino acid formulations and lipids in parenteral
nutrition have been investigated in patients with colon cancer. In a study of 12
patients, glutamine-supplemented parenteral nutrition limited negative nitrogen
balance and maintained intramuscular glutamine concentrations, but outcomes of
the patients were not reported.
88
In addition to benefiting skeletal muscle metabo-
lism, glutamine may be essential for lymphocyte metabolism in times of stress,
as well. In a study of 22 patients who had a colorectal resection for a preoperative
diagnosis of carcinoma, postoperative glutamine-supplemented parenteral nutrition
458
29
enhanced in vitro T-lymphocyte response to stimulation, but reduced neither nega-
tive nitrogen balance nor infections.
89
Arginine, which also possesses anabolic and
immune stimulatory properties, did not enhance mitogen-stimulated lymphocyte
stimulation in postoperative colorectal cancer patients treated with parenteral argin-
ine given as the sole protein source.
90
There has been concern that infusion of lipids
might cause relative immunosuppression. Parenteral lipids, however, did not affect
neutrophil chemotaxis when administered to patients with colon cancer.
91
The concern for preferential tumor stimulation by parenteral nutrition has been
investigated to some extent in patients with colon cancer. In a study of 18 patients
with localized colorectal cancer, the nine patients randomized to receive parenteral
nutrition for 24 hours before surgery had tumor protein synthesis almost twice as
high as those patients who fasted.
92
Potential markers of tumor proliferation in-
clude polyamines. Putrescine levels increased significantly after parenteral nutrition
in 16 patients with colorectal cancer, while the same nutritional therapy caused no
change in levels in control patients without cancer.
93
Others, however, found that
such changes probably reflected increased whole-body, rather than tumor-specific,
metabolic activity.
94
The more amino acids administered parenterally, regardless of
the composition, the more protein synthesis occurred, while the rate of muscle break-
down remained constant.
95
Metabolic expenditures increased when calories admin-
istered via parenteral nutrition exceeded basal resting metabolic expenditure.
96
Branched chain amino acid-supplemented parenteral nutrition stimulated in vivo
colorectal cancer protein synthesis less than conventional parenteral nutrition, but
the effect was not selective. The same trend was seen in skeletal muscle protein
synthesis.
97
Even if parenteral nutrition cannot be recommended routinely, its use must be
individualized to patient circumstances. A Jehovahs Witness with an obstructing
sigmoid colon cancer had a profound anemia prohibiting surgery. After she failed to
respond to oral iron, institution of parenteral nutrition, human erythropoietin and
parenteral iron produced enough of a correction in her anemia for her to tolerate
surgery.
98
The nutritional support could have improved levels of iron-binding and
transport proteins such as ferritin and transferrin, and may play an integral role in
treating patients who are profound anemic, unwilling or unable to receive transfu-
sions, and incapable of tolerating enteral nutrition.
Home parenteral nutrition is an option being exercised for many patients with
colorectal cancer who have contraindications to enteral nutrition. The OASIS North
American Home Nutrition Support Patient Registry followed 1,362 active cancer
patients between 1984 and 1989, 20% of whom were those with colorectal cancer,
comprising the largest subgroup.
99
The 20% who were able to resume full oral feed-
ing likely were those who survived aggressive therapy which temporarily caused gas-
trointestinal dysfunction. Home parenteral nutrition for this subgroup of cancer
patients appears justified, as it is well tolerated and associated with only a 1% inci-
dence of parenteral nutrition-related mortality. The benefits of home parenteral
nutrition remain unclear when being used to extend life a small increment in pa-
tients with advanced colorectal cancer. In a retrospective uncontrolled review, pa-
tients with advanced colon cancer who received home parenteral nutrition survived
longer than those who did not,
100
but the difference could have been due to
selection bias.
Home parenteral nutrition is probably inappropriate for the majority of cancer
patients who initiate home parenteral nutrition but who are expected to die within
459
29
six to nine months. Forces encouraging this increasing trend may include a fascina-
tion with technology, expanded availability of services, pressure from families, in-
surers preference for substituting parenteral nutrition at home for that in the hospi-
tal
101
(since despite being $75,000 to $150,000/year [in 1992 dollars] home parenteral
nutrition was still one-third the cost of hospital care
102
), Medicares reimbursement
for home parenteral nutrition but not for home parenteral hydration, and the op-
portunity for hospitals to profit from joint ventures with infusion companies whereas
inpatient parenteral nutrition is not profitable.
99
Pancreatic Cancer
As in patients with esophageal cancer, weight loss may be significant in patients
with pancreatic cancer, although it is frequently secondary to anorexia rather than
dysphagia. One cause of anorexia may be depression, which was noted more than
60 years ago to be a frequent presenting symptom of patients with pancreatic can-
cer.
103
In a review of 52 patients with pancreatic cancer reported between 1923 and
1991, 71% had a depression-related disorder, one-third of whom developed the
psychiatric symptoms prior to any physical symptoms.
104
Depression appears to be
less frequent in patients with other gastrointestinal malignancies. For example, while
depression was diagnosed in 50% of patients who ultimately were diagnosed with
pancreatic cancer, none of the patients diagnosed with gastric cancer met criteria.
105
It is unclear what psychobiological mechanism causes patients with pancreatic can-
cer to be at particularly high risk for depression,
104
but it may place patients with
pancreatic cancer at particularly high risk for malnutrition. Although a combina-
tion of psychotherapy, cognitive-behavioral techniques, and antidepressant medica-
tion has been recommended to treat patients with pancreatic cancer and depres-
sion,
106
the impact of such treatment on malnutrition remains unknown.
Surgery may relieve the biliary, pancreatic or duodenal obstruction, but may not
immediately alleviate signs of gastric outlet obstruction. Following pylorus-preserving
pancreatico-duodenectomy (modified Whipple procedure), up to 50% of patients
may have delayed gastric emptying and require gastric decompression for a median
of 8-14 days. Introduced during the surgical procedure, an apparatus consisting of a
12 French jejunal feeding tube placed through a Y-connector fitted to a modified 32
French malecot catheter can be used both to decompress the stomach (obviating the
need for a nasogastric tube) and to provide jejunal feeding. The apparatus can be
removed in the outpatient setting when adequate gastric emptying function returns.
107
Another alternative for establishing jejunal feeding is to convert biliary-enteric anas-
tomotic stents to jejunal feeding tubes in the early postoperative period.
108
Although several studies have identified indicators of malnutrition which pre-
dicted postoperative complications, including weight loss greater than 10%, albu-
min less than 3.0 g/dL, and anergy,
109-111
studies investigating the role of nutri-
tional intervention in the perioperative period have had mixed results. One study
investigated preoperative nutrition. Sixty patients with obstructive jaundice (most
of whom had pancreatic cancer) who received preoperative enteral or (less often)
parenteral nutrition for at least 12 days (and a mean of 20 days) between percutane-
ous transhepatic biliary drainage and pancreatobiliary surgery reduced their mor-
bidity from 47-18% and their mortality from 13-4%.
112
A study of postoperative
nutritional support, however, came to opposite conclusions. In a recent prospective
randomized trial of 117 patients undergoing pancreatic resections, the group receiv-
ing routine postoperative total parenteral nutrition suffered a statistically significant
460
29
higher rate of major complications (45% vs. 23%). This relationship remained sig-
nificant even when complications thought to be reduced by bowel rest were ana-
lyzed separately (such as fistulas, abscess, obstruction, and anastomotic leak). Mor-
tality was similar between groups.
113
The authors postulated that the higher rate of
infectious complications in the patients receiving parenteral nutrition, in particular
abscess formation, may have resulted from increased translocation of bacteria across
the intestinal wall occurring in the absence of enteral feeding.
114
If patients survive for an extended time, their prospects for nutritional reple-
tion are excellent. In 25 patients who were free of recurrent disease at least six
months out from either conventional or pylorus-preserving pancreaticoduo-
denectomy, quality-of-life assessments demonstrated nearly normal well being
and little or no impairment in gastrointestinal function. These results were
similar to the matched cholecystectomy control group. Compared to the py-
lorus-preserving pancreaticoduodenectomy group, the group having a conven-
tional pancreaticoduodenectomy were more likely to complain of fullness and re-
stricted food intake, but were less likely to suffer heartburn. Although ten patients
required dietary or pharmacological intervention for diabetes, and five patients re-
ported greasy stool, no patients were malnourished and mean weight was greater
than mean preoperative weight and ideal weight.
115
In 23 patients with pancreatic cancer who were not surgical candidates (only one
of whom allegedly had disease confined to the pancreas) and who modified their
oral intake at least a moderate extent toward a macrobiotic diet for at least 3
months, survival averaged 17 months, compared to patients with similar disease and
time period in the Surveillance Epidemiology and End Results (SEER) National
Tumor Registry who lived only an average of 6 months.
116
The authors pointed out
the potential bias in the selection of cases and the limitations of a retrospective
study, but their observations remain intriguing, especially when considered with
evidence in experimental models that diets high in fat increased the incidence
of pancreatic neoplasms, while diets with a 10% reduction of calories pro-
tected against neoplasms.
117
Liver Cancer
In patients with liver disease, nutritional status cannot be determined reliably
using traditional methods.
118
For example, a low albumin may reflect limitations in
hepatic synthesis rather than depletion of visceral proteins, while protein balance
may be overestimated due to impaired urea synthesis and accumulation of ammo-
nia.
119
Edema may cause underestimation of protein or fat loss when determined by
mid-arm muscle circumference or skinfold thickness, and, combined with ascites,
may produce a falsely reassuring normal body weight. Not surprisingly, prognos-
tic nutritional indices have failed to predict complications in patients having liver
transplantation.
120
The majority of patients with primary liver cancer have underlying cirrhosis,
which may limit hepatic regenerative capacity or functional reserve, at least one of
which is needed to survive liver resection. Adequate nutrition increases liver regen-
eration in humans
121
and in the rat model.
122
Given that the liver demonstrates a
depressed metabolic capacity immediately following liver resection,
123
it is likely
that reestablishing functional reserve requires adequate nutrition, as well. Despite
having average energy requirements (unless under acute metabolic stress),
124
pa-
tients with cirrhosis may have nutritional deficiencies from a combination of poor
461
29
intake combined with some impairment of digestion, absorption, or metabolism.
125
Digestion, absorption, and metabolism of amino acids from routine protein sources,
however, appears to be maintained.
126
Hence, protein should be unrestricted unless
there has been prior or current encephalopathy, and patients should be encouraged
to eat. When diets were supplemented, patients had improved nutritional intake.
127
Due to depressed hepatic glycogen stores, patients with cirrhosis may sacrifice amino
acids for gluconeogenesis even after a short interval of fasting. Including a late evening
meal improved nitrogen metabolism in an uncontrolled study.
128
At least in patients
preparing for liver transplantation, preoperative ingestion of 120% of the calories
calculated by the Harris-Benedict basal level for ideal body weight slightly exceeded
resting energy expenditure throughout the perioperative period, and placed more
than 40% in a positive nitrogen balance preoperatively.
129
For liver cancer patients
with cholestasis and steatorrhea, supplementation of enteral diets with medium chain
triglycerides is appropriate, since they are absorbed into the portal circulation with-
out being transformed or transported in chylomicrons.
130
Sixty milliliters of me-
dium chain triglycerides delivered in divided doses in dressings or shakes provide
450 kilocalories per day. If medium chain triglycerides are used as an exclusive
fat source, linoleic acid will need to be delivered, as well, to prevent essential
fatty acid deficiency.
118
In patients who are unable to maintain adequate oral intake, enteral feeding via
tube may improve clinical condition and outcome.
131
As variceal hemorrhage ap-
pears to be a function of the magnitude of portal hypertension rather than of mu-
cosal trauma, enteral feeding via a soft, small-bore feeding tube is acceptable if oral
feedings are not feasible.
118
Standard protein delivery has been well tolerated in
selected patients.
132
Percutaneous placement of feeding tubes, however, should be
avoided due to the risk of hemorrhage from piercing gastric collateral vessels.
Ascites is another contraindication to percutaneous technique, although it may
not be absolute.
133
If parenteral nutrition is needed, standard amino acid solutions have been used
without precipitating encephalopathy,
134
even in those patients who were previ-
ously intolerant of smaller amounts of ingested protein.
118
In some patients with
liver disease, choline, cystine and tyrosine may be essential,
135,136
and their inclu-
sion in the formulation of amino acids should be confirmed. Glutamine might also
be a beneficial constituent of parenteral nutrition for patients with liver cancer. Free
glutamine constitutes 61% of the total intracellular pool of amino acids,
137
and
becomes depleted in states of physical stress.
138
While glutamine may be an essential
amino acid for intestinal mucosa, it is also a principal fuel for rapidly dividing can-
cers. Thus, while glutamine-supplemented parenteral nutrition might be more likely
to preserve intestinal mucosal integrity and overall protein synthesis, it might also
stimulate tumor growth. However, at least in rats inoculated with hepatoma cells,
glutamine improved nitrogen balance without enhancing tumor growth,
139
paral-
leling results in hepatoma-inoculated rats administered standard parenteral nutri-
tion.
140
Additionally, by stimulating the release of glucagon from the pancreas,
glutamine-supplemented parenteral nutrition normalized the portal vein insulin to
glucagon ratio in rats and protected the liver against steatosis
141
and cholestasis.
142
Another potentially beneficial intervention when using parenteral nutrition is
the inclusion of branched-chain amino acids. They are fuel for skeletal muscle and
increase protein synthesis in liver and muscle. They also inhibit muscle protein ca-
tabolism, which may be most important, given that the pool of plasma amino acids
462
29
derived from endogenous protein breakdown is five times greater than the pool
derived from the diet in patients with cirrhosis, and 12 times higher in patients with
fulminant hepatic failure.
143
In addition to reducing hepatic encephalopathy
144
and
possibly improving neurological function even in those patients without
encephalopathy,
145
branched-chain amino acids also could treat the protein-calorie
malnutrition of some patients with liver cancer. Most trials of branched-chain amino
acids focused on encephalopathy and had, at best, inadequate assessments of nutri-
tional status. The only large study with reasonable assessments of nutritional status
found improved nitrogen balance compared to casein supplement at three months,
but equivalent nitrogen balance at six months.
146
Branched-chain amino acid supple-
mentation did not improve postoperative outcomes in patients with liver dysfunc-
tion or cirrhosis having transplantation.
147,148
Since branched-chain amino acid
supplements in solution or powder cost at least ten times that of standard amino
acids, provide only marginal benefits to nutritional status, and do not improve
outcome in liver transplant patients, their routine use in liver cancer patients
cannot be supported.
118
Most investigators have studied nutritional interventions in patients who have
hepatic encephalopathy or are having liver transplantation. However, there is a study
of 150 patients undergoing potentially curative hepatic resection for hepatocellular
carcinoma who were randomized to receive either parenteral nutrition enriched with
branched-chain amino acids for one week before and one week after surgery or
parenteral crystalloid solution postoperatively. After excluding those patients who
had intra-abdominal metastases discovered during surgical exploration, the patients
receiving the parenteral nutrition had a statistically significant lower morbidity than
the control group (34% vs. 55%), and a trend toward lower mortality (8% vs.
15%).
149
It is possible, however, that the higher morbidity in the control group
was a result of the liberal definition of pneumonia (positive culture in association
with pneumonic or atelectatic changes on chest radiograph) combined with this
groups significantly greater incidence of ascites (and thus atelectasis).
150
Duration
of hospitalization was similar.
Immediately following liver resection, the ratio of arterial acetoacetate to
3-hydroxybutyrate falls, reflecting a reduced hepatic redox potential of the liver.
Because of depressed Krebs cycle activity in this scenario, adenosine triphosphate is
generated preferentially by beta oxidation of fatty acids. In the immediate postop-
erative period, intravenous administration of high concentrations of glucose or doses
of insulin should be restricted, since a hyperglycemic and hyperinsulinemic state
inhibits fatty acid liberation from adipocytes and hepatic ketone production. In
rats, infusion of lipids
151
or monoacetoacetate
152
increased the rate of liver regenera-
tion following liver resection, and lipids remain a safe source of nonprotein calories
in patients with liver disease requiring parenteral nutrition.
118
Extrapolating data from the transplant literature, a randomized study of 24 liver
transplantation patients compared parenteral nutrition with nasojejunal feeding
started during the first postoperative day. Both groups maintained anthropometric
indices of nutritional status, had equivalent incidence of infections (including
gut-related infections) and diarrhea, preserved intestinal absorptive capacity and
impermeability to macromolecules, and had similar length of stays. By postopera-
tive day ten, 87% of patients had achieved an adequate oral intake. The nasojejunal
tube with an integral gastric decompression port was easily positioned in 11 of 14
patients and remained patent in all patients, none of whom suffered pulmonary
463
29
aspiration. The enteral feeding was one-tenth the cost of parenteral nutrition.
153
Despite the high cost of parenteral nutrition, in another study of liver transplant
patients those who received postoperative parenteral nutrition had a mean reduc-
tion in hospital costs of $21,000.
147
A similar study in patients with liver cancer has
not been performed.
Patients with liver cancer undergoing hepatobiliary surgery or chemotherapy
can almost always be fed exclusively, or at least partially, by enteral means.
123
The
role of parenteral nutrition in the management of patients with liver cancer remains
to be determined.
154
In malnourished patients with gastrointestinal cancer and pre-
sumably normal livers, three days of preoperative parenteral nutrition supplement-
ing a hospital diet increased hepatic glycogen content and protein synthesis,
155
al-
though seven days of parenteral nutrition was needed to restore plasma concentrations
of several hepatically-synthesized proteins.
156
It is unknown if cirrhotic liver
would respond similarly. Also unknown is the clinical impact of this response,
when it occurs.
Cost Effectiveness
A cost-effectiveness analysis based on the results of Heatley and colleagues
17
and
Mller and colleagues,
18
expressed in 1982 dollars, calculated a net savings of $1,720
per patient given 10 days of preoperative parenteral nutrition.
157
Another cost effec-
tiveness analysis addressing the same question in people having gastrointestinal sur-
gery (for unspecified indications) assumed that when either the risk of postoperative
complications or the effectiveness of nutritional support in preventing these com-
plications was high, a strategy of providing nutritional support to all patients was
most appropriate. When either variable was lower, the most appropriate strategy
was to provide nutritional support only to a high-risk subpopulation, identified
using a nutritional assessment technique. For populations in whom the postopera-
tive incidence of nutrition-associated complications is 20%, using the Subjective
Global Assessment (SGA) which had the best combination of sensitivity and speci-
ficity (82% and 72%, respectively), the incremental cost per complication avoided
was $11,515 (in 1980-1981 Canadian dollars).
158
In the subsequent Veterans Administration Total parenteral nutrition Coopera-
tive Study Group conducted in the 1980s (which, granted, did not focus specifically
on patients with gastrointestinal cancer), incremental costs in 1992 dollars attrib-
uted to perioperative parenteral nutrition were above $3,000, which translated to
$13,959 per complication avoided in severely malnourished patients. The costs would
have been higher in a major urban teaching hospital.
159
In the mid-1980s, an esti-
mate of the cost of a ten-day course of parenteral nutrition for patients anticipating
surgery for gastrointestinal malignancy was $3,340, yielding an increased life ex-
pectancy of nine weeks.
19
There are less data available regarding the costs of enteral nutrition. In a study of
111 postoperative patients enterally supported for at least ten days via needle jejun-
ostomy, net savings totaled $33,000 (in the 1970s) compared to the expenses which
would have been incurred using parenteral nutrition.
160
enteral nutrition via tube
feeding, if reducing morbidity and mortality to the same degree assumed for parenteral
nutrition, would have saved well over $5,000 per patient using one model, leading
the authors to conclude that in patients able to tolerate enteral feeding, the adage of
if the gut works, use it recognizes principles of both physiology and economics.
157
464
29
Conclusion
Limitation of oral intake in response to illness is a behavior that may have evolved
because it protects the host, albeit by an unknown mechanism.
150
Efforts to
force-feed patients with gastrointestinal cancer, while well-intentioned, may not
always be in their best interest. At least one-third of parenteral nutrition adminis-
tered to patients with cancer is likely inappropriate.
161
Although parenteral nutri-
tion has been shown to improve some indicators of nutritional status in patients
with cancer (like body weight, serum proteins, nitrogen balance, and in vitro immune
function), its impact on morbidity and mortality has been mixed.
162
It is likely that
the effects of parenteral nutrition in patients with gastrointestinal, pancreatic, and
liver cancer anticipating surgery parallel those found in the Veterans Affairs Total
parenteral nutrition Cooperative Study Group. In this landmark study of preopera-
tive parenteral nutrition in malnourished patients scheduled to have major abdomi-
nal or noncardiac thoracic surgery, parenteral nutrition was found to be helpful only
in the patients who were severely malnourished.
163
A need to reverse the physiologi-
cal state of starvation in order to effect improved surgical outcomes may explain
why randomized trials of two to seven days of preoperative parenteral nutrition in
patients with gastrointestinal cancer failed to improve outcome,
15,63
while tri-
als providing 7-10 days of therapy resulted in decreased wound infections
17
and decreased mortality.
18
Continued research into manipulating the composition of enteral nutrition
164-167
and parenteral nutrition
168
might improve immunologic, metabolic, and clinical
outcomes. Some day, nutritional interventions might become adjuvant therapy in
the treatment of gastrointestinal cancer. In a study of 44 patients with primary gas-
trointestinal cancers given 15 days of parenteral nutrition, the cell kinetics of tu-
mors from those who had been on a lipid-based regimen mirrored those from pa-
tients in other studies who had received chemotherapy or radiotherapy.
169
In the
meantime, the generic ASPEN practice guidelines for cancer and perioperative nu-
tritional therapy (see Table 29.2) and the ACP practice guidelines for chemotherapy
and parenteral nutrition (see text) apply equally well to the specific challenge of
nutritional support in patients with gastrointestinal, pancreatic and liver cancer.
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Table 29.2. ASPEN practice guidelines for cancer and perioperative nutritional
support
Cancer
1. Enteral tube feeding and parenteral nutrition support may benefit some severely mal-
nourished patients or those in whom oncologic treatment toxicity is expected to pre-
clude adequate oral nutritional intake for more than one week. Nutritional support
should be given in conjunction with the initiation of oncologic therapy.
2. Intensive nutritional support is not routinely indicated for well-nourished or mildly
malnourished patients undergoing surgery, chemotherapy, or radiotherapy who are
expected to maintain adequate oral intake.
3. Parenteral nutrition is unlikely to benefit patients with advanced cancer unresponsive
to chemotherapy or radiation therapy.
Perioperative
1. Preoperative nutritional support may benefit severely malnourished patients undergo-
ing major surgery, when given for seven to ten days.
2. Preoperative nutritional support is not routinely indicated for well-nourished, mildly
malnourished, or moderately malnourished patients undergoing major surgery.
3. Preoperative nutritional support should be provided to malnourished patients who are
expected to otherwise sustain a prolonged period of starvation while awaiting
major surgery.
4. Postoperative nutritional support should be provided to severely malnourished pa-
tients as soon as possible. Postoperative nutritional support may be indicated for mildly
malnourished patients expected to otherwise sustain a postoperative period of starva-
tion longer than one week. Enteral access should be established at the time of surgery.
Adapted from ASPEN Board of Directors. Clinical Guidelines for the Use of Parenteral
and enteral nutrition in Adults and Pediatrics, Section IV: Nutrition Support for Adults
with Specific Diseases and Conditions.
170
466
29
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CHAPTER 1
CHAPTER 30
The Treatment of Obesity
Souheil Abou-Assi, Rifat Latifi and Stephen J.D. OKeefe
Epidemiology
Obesity is the most common and costly nutritional problem in the western coun-
tries. The incidence of obesity is rising not only in the USA and Europe, but also in
parts of Africa, Australia, and the Far East.
1
Approximately 100 million Americans,
or almost three out of every five adults, are overweight or obese. Obesity is the
second leading cause of preventable death after tobacco in the United States.
2
The National Institutes of Health
2
and others,
3
have estimated that the cost of
obesity to society in the USA may exceed $100 billion annually, including the health
care costs and the money spent on weight reduction programs and specialized diets.
Amazingly, Americans spend 33 billion dollars on commercial weight-loss prod-
ucts, and yet the prevalence of obesity continues to increase, with obesity-related
medical problems resulting in 300,000 deaths each year in the United States.
4
A simple definition of obesity is the excess of fat stores. However, the reason why
only certain individuals become obese when food is abundant is unclear, and obesity
has been recently described as a complex multifactorial chronic disease that devel-
ops from an interaction of genotype and the environment.
5
Obesity involves more
than simply eating too much or exercising too little, although both are very impor-
tant. Familial predisposition also plays a role, as the child of one obese parent has a
40% likelihood of obesity. With two obese parents, the probability goes up to 80%.
2,6
Whether this is determined by genetic and/or environmental influences, it remains
to be elucidated.
Measurements of Obesity
The Body Mass Index
In clinical practice and in epidemiological studies, body fat is most commonly
estimated by using a formula that is based on weight and height. The underlying
assumption is that most of the variation in weight for persons of the same height is
due to fat mass. The formula is the body-mass index (BMI), also called the
Quetelet index:
BMI= weight (kg) / height (m
2
).
The principal limitation of the BMI is the potential to overestimate obesity in a
muscular individual and underestimate the severity of obesity in a patient with a
large amount of visceral adiposity.
6,7
The NIH committee defined overweight as a
BMI of 25 to 29.9 kg/m
2
and obesity as a BMI of 30 kg/m
2
or higher. Extreme or
morbid obesity is defined as a BMI higher than 40 kg/m
2
, and carries a much higher
474
30
health risk.
3,8,9
The optimal BMI to decrease the risk of obesity-related diseases is in
the range of 19 to 21 kg/m
2
for women and 20 to 22 kg/ m
2
for men.
7,8
Visceral Obesity
While the distribution of excess adipose tissue can vary greatly , visceral obesity
is associated with greater morbidity.
2,3
Waist circumference correlates well with the
abdominal fat distribution. Deposition of fat in the abdomen, particularly if it is out
of proportion to the fat distribution elsewhere, is associated with the greatest health
risk.
7
In an attempt to standardize this measurement, it is often expressed as the
waist to hip ratio. A ratio greater than 0.8 for women and 0.9 for men is associated
with a higher risk of morbidity and mortality than a more peripheral distribu-
tion of fat.
3,6
Health Risks Associated with Obesity
Morbid obesity it is not only a disease in itself that needs urgent care, but it is a
harbinger of multiple other diseases and disorders, affecting every organ and system
of the body and is associated with several significant clinical syndromes:
1. Cardiovascular-related problems such as coronary artery disease, heart
failure, and increased complications following coronary artery bypass,
2. Respiratory insufficiency due to obesity hypoventilation syndrome and
obstructive sleep apnea syndrome (multiple nocturnal awakenings, loud
snoring, falling asleep while driving, daytime somnolence),
3. Metabolic complications such as diabetes mellitus, hypertension, elevated
triglycerides, cholesterol and gallstones,
4. Increased intra-abdominal pressure that is manifested as stress overflow
urinary incontinence, gastroesophageal reflux, nephrotic syndrome, in-
creased intra-cranial pressure leading to pseudotumor cerebri, hernias,
venous stasis, probably hypertension and pre-eclampsia
5. Hypercoagulapathy,
6. Sexual hormone dysfunction such as amenorrhea, dysmenorrhea, infer-
tility, hypermenorrhea,
7. Stein-Leventhal syndrome,
8. Increased incidence of breast cancer, uterine, colon, prostate and other
cancers and
9. Debilitating joint disease involving hips, knees, ankles, feet and lower
back.
The above obesity related comorbidities are thought to be consequences of both
the metabolic syndrome secondaries to increased visceral fat metabolism and to
chronically increased intra-abdominal pressure in centrally, obese patients or an-
droid obesity. In addition, obese people, clearly experience a multitude of difficul-
ties related to social acceptance in the society, work related problems, body image,
reduced mobility, sexual dysfunction and other psychosocial problems that add more
pathology to this chronic and deadly disorder.
There is a curvilinear relationship between body weight and mortality .The risk
is higher among the very heavy and the very lean. However, several prospective
studies that excluded smokers, and those with existing disease, have challenged the
notion of a curvilinear relation, suggesting that, overall, death rates increase linearly
with increasing BMI, with no excess risk among the very lean.
8,9
In a recent 14-year
follow-up prospective study of over 1 million healthy non-smoking adults in the
475
30
United States, the nadir of the curve for BMI and mortality was found at a BMI of
23.5 to 24.9 in men and 22.0 to 23.4 in women.
8
Obesity was most strongly associ-
ated with an increased risk of death among those who had never smoked and who
had no history of disease, whereas leanness was most strongly associated with an
increased risk of death among current or former smokers with a history of disease.
The risk of death from all causes, including cardiovascular disease, and cancer, in-
creased throughout the range of moderate to severe overweight for both men and
women in all age groups. Furthermore, the risk associated with a high BMI was
lower for blacks, in particular for black women, than for whites.
8
The American Cancer Society has concluded that:
1. men and women with a BMI of 30 or more had a 50 to 100% higher
mortality than those with a BMI below about 25, and
2. that the mortality for people with BMI values between 25 and 30 was
increased by about 10 to 25%.
9
Currently, about one-fifth of U.S. adults
have a BMI of 30 or more.
Cardiovascular disease, diabetes, and gallbladder disease account for most of the
increased mortality, but obesity is also strongly associated with hypertension, Hy-
perlipidemia, diabetes, and left ventricular heart failure. There is a significant but
weaker correlation with colon, uterine, ovarian, breast, and prostatic cancers.
2,7
When
a BMI is greater than 28 the risk of stroke, ischemic heart disease, and diabetes
mellitus increases by three to four times.
10
Can Obesity and Its Co-Morbid Diseases Be Reversed?
The answer is yes. There is substantial evidence that much of the risk is reversed
with weight loss. For example, hyperglycemia, hyperlipidemia, and hypertension
are ameliorated by a loss of as little as 10 to 15 % of body weight in obese subjects.
11
There is some information that childhood obesity may form an exception, as mor-
bidity may persist despite adequate weight loss.
5
Nearly all specialized hypocaloric diets when administered by a strict weight-loss
program result in some weight loss. Furthermore, even moderate losses in weight are
associated with improvements in glucose and fat metabolism, with reductions in
diabetic and cardiovascular disease risks. Unfortunately, over 90% of individuals
who successfully lose weight by non-surgical treatment regain all of the weight lost
(and often more) within two to five years.
3
For there to be any chance of success, weight-loss programs must not only con-
centrate on dietary restriction, but also patient psychology, behavior modification,
and exercise training. This necessitates the formation of a team to include a physi-
cian, registered dietitian, fitness counselor, pharmacist, and clinical psychologist.
3,5
If weight regain continues, drug therapy may be needed to suppress appetite. If that
fails, surgery is indicated.
Summary of Interventions, and Results of Randomized
Controlled Trials
While the causes of severe obesity are multifactorial and the pathophysiology of
morbid obesity syndrome is complex, the published success rate for all medical ap-
proaches including pharmacotherapy and behavioral modification for morbid obe-
sity is very poor. It has been estimated that over 95% of morbidly obese patients
subjected to medical weight-reduction programs regain all of their lost weight, as
well as additional excess weight, within two years of the onset of therapy.
4,5
476
30
Conventional Diet
Diet is the cornerstone of any weight-loss program. The standard dietary ap-
proach to weight loss has been a balanced, calorie-restricted diet; 1200 to 1500 kcal
in women and 1500 to 1800 kcal in men. Weight loss is often rapid due to fluid loss
in the first week of hypocaloric feeding, but should then level off to 1 to 2 pounds
per week, not exceeding 1 % of body weight per week.
3,12,13
It is recommended that
20 to 30% of calories be derived from fat, 55 to 60% from carbohydrate, and 15 to
20% from protein. Although all macronutrients contribute to caloric balance, a
reduction of dietary fat intake to below 40 g/d has been shown to be most predictive
of successful weight loss in patients on low calorie diets.
13
Conversely, on the other
hand caloric restriction (1000-1200 kcal/d) is more effective than fat restriction
(22-26 g/d) (-11.2 vs. -6.1 kg, p<0.001), in 80 obese adults studied for 24 weeks.
14
In a recent 100 patients with BMI >25 and <40, were randomized for three
months of conventional energy restricted diet (1200-1500 kcal/d or 5.2-6.3 MJ/d)
or an isocaloric diet in which two meals and two snacks were replaced with shakes,
soups or hot chocolate with essential vitamins and minerals supplementation.
15
Weight loss was significantly higher in the replacement group (7.1(3.5) kg vs. 1.3(2.2)
kg) and associated with reductions in blood glucose, triglyceride and insulin con-
centrations. All patients then entered a case-control Phase II for 24 months where
the cases were given a maintenance diet in which one meal and one snack was again
replaced with the liquid supplement. At the end of the study, 42% of the cases, but
not the controls, had reduced their body weight by >10% of their initial weight.
There was also significant improvement in biomarkers of disease risk (blood sugar,
blood pressure, and cholesterol).
The suggestion that a high fiber diet may result in lower caloric intake and there-
fore maintenance of weight loss, was unfortunately not supported by a controlled
trial on 31 obese women following weight loss from a VLCD.
16
Low- or Very-Low Caloric Diets (LCD/VLCD)
VLCD contain between 400 and 800 kilocalories per day. As fasting is associ-
ated with losses of not only body fat but also protein, they generally contain ad-
equate protein but inadequate energy to meet normal metabolic requirements. Most
come as a powder that is mixed with water or another noncaloric liquid, plus RDA
quantities of all vitamins and minerals. Food-based VLCD containing lean meat
and fish are also available. These diets are indicated in individuals who have a medi-
cal need to lose fat rapidly and have a BMI greater than 30 kg/m
2
. Serious arrhythmias
have been more frequently reported in patients with BMIs less than 30.
3,5,6
When
monitored properly, VLCD are safe and effective. The length of treatment is usually
from 12 to 16 weeks, the average weight losses are around 20 kg and amount to 1.5
to 2.5 kg per week, which is three to five times that seen with low-calorie dieting.
3,15
As the rate of weight loss is often more rapid with this diet than with conventional
diets, fluid, electrolyte and metabolic upset is more common. Frequent complica-
tions include dizziness, fatigue, muscle cramping, headache, cold intolerance, dehy-
dration, orthostatic hypotension, hypokalemia, hypomagnesemia, elevated uric acid
levels, and cholesterol gallstone formation.
6,18
Consequently patients with recent
histories of myocardial infarction, prolonged QT intervals, serious arrhythmias, ad-
vanced renal or hepatic diseases, cerebrovascular disease, Type I diabetes or signifi-
cant psychiatric disorders should be excluded.
477
30
In one study 59 obese patients were treated for five years with either VLCD and
behavior therapy (BT) or behavior therapy alone. The mean five-year weight loss
with this treatment patients who completed the study was 16.9 kg in the VLCD+
BT group and 4.9 kg in the BT group, but the dropout from the VLCD+BT and
BT was very high (56% and 28% respectively). When VLCD was compared to
LCDs in a one-year evaluation of diets containing either 420, 530 or 880 kcal/d in
93 obese (BMI 38.7) patients weight loss varied between 8 and 15% with no signifi-
cant difference between the 3 arms.
20
However, fewer adverse events were noted in
the LCD (800kcal/d) group. Attrition rates were high (30-45%). Unfortunately,
long-term results with these diets are no better than those with other obesity diet
treatment. After six months, weight loss slows and then plateaus, and further weight
loss becomes difficult to achieve. Although patients will by then have completed
behavioral modification training, weight regain is common when they are restarted
on a balanced maintenance diet.
3,17
Behavioral Modification
Behavioral modification(BM) sessions are usually conducted by a psychology
therapist in-groups of patients in order to enhance self-expression, assertion,
and confidence.
BM on its own can be useful and was recently reported as effective in improving
glycemic control in a group of obese NIDDM women.
21
In another study of 247
overweight elderly subjects that underwent an intensive 10-week psychoeducational
approach focused on lifestyle-change was effective in reducing BMI by 1.2 and
glucose levels by 0.8 mmol/l after two years of follow-up.
22
Unfortunately, there
was a high attrition rate with 30% dropping out of the study. Furthermore, weight
losses are generally small, and the true value of BM is when only it is incorporated
into a structured weight-loss program with diet and exercise interventions.
23
Exercise
Aerobic exercise has significant benefit for the cardiovascular system and for good
health in general, but is not very effective in weight reduction. To expend enough
calories to lose just one pound, a person would have to walk, jog, or run a distance
of 30 miles.
24
Exercise on its own can, however, reduce some of the obesity-related
complications. For example, it was found that exercise reduced the risk of obese
persons with impaired glucose tolerance developing diabetes by 46% during a six-
year period of follow-up.
25
Ideally, exercise should form part of a diet and lifestyle program. Studies have
shown that exercise is a good predictor of eventual maintenance of weight loss.
3
Recent data indicate that weight-resistance training seems to be the most beneficial
form of exercise for successful weight management. In a study of 65 obese patients
were assigned to strength training and diet, aerobic diet training and diet, or diet
(70% RME) only, it was found that body fat was significantly reduced to a similar
degree in all three groups. However, lean body mass was better preserved in the
group given strength training by inducing muscle hypertrophy without increasing
resting metabolic rate.
26
Pharmacological Therapy
The pharmacological management of obesity is developing rapidly as our under-
standing of the hormonal and metabolic control of fat storage and utilization advances.
478
30
Current pharmacological therapy is recommended for persons with an initial BMI
>30, or >27 with co-morbidities such as hypertension, diabetes mellitus or
dyslipidemia, who failed to lose weight using dietary and other manipulations.
6
Appetite Suppressants
Noradrenergic Agents
The first example to be used was amphetamine. Amphetamines work by en-
hancing the release of catecholamines in the brain, and thereby suppressing appe-
tite. Attempts to reduce addiction and cardiac side effects have lead to the development
of a variety of new products. Phenylpropanolamine (PPA), a sympathomimetic drug
and a synthetic derivative of ephedrine, is available as an over-the-counter appetite
suppressant and decongestant, PPA has shown some efficacy for short-term weight
loss, but long-term results have been inconclusive.
27
Phentermine is similar to am-
phetamine and modulates noradrenergic neurotransmission to decrease appetite,
but has little or no effect on dopaminergic neurotransmission and therefore reduces
the risk of addiction. It is currently used in dosages ranging from 30 to 37.5 mg/d as
a short-term (a few weeks) adjunct in a regimen of weight reduction based on ca-
loric restriction. The most common side effects include headache, insomnia, ner-
vousness, and irritability. Tachycardia and elevation in blood pressure may also occur.
The co-administration of fenfluramine enhances phentermines action.
28,29
Serotonergic Agents
Serotonergic agents are thought to affect food intake by reducing food-seeking
behavior, by decreasing the amount of food consumed at a particular time, and by
increasing basal metabolic rates.
28
The drug enhances the release of serotonin into
the synaptic cleft and partially inhibits its reuptake, thereby acting on the hypo-
thalamus to decrease food intake. The first popular drugs in this class, fenfluramine,
and dexfenfluramine, were withdrawn from the USA market by the FDA in 1997
following reports of valvular heart disease.
30
Valvular heart disease occurred on 24
women who were given the phentermine-fenfluramine combination for a mean of
11 6.9 months.
31
Echocardiogram demonstrated unusual valvular morphology
and regurgitation. Eight of the women developed pulmonary hypertension, and 5
women needed cardiac surgery for the valvular dysfunction.
Adrenergic/Serotonergic Agents
Sibutramine, a beta phenethylamine, is a potent reuptake inhibitor of norad-
renaline and serotonin that has recently been approved for the long-term manage-
ment of obesity. It has two mechanisms of action. First, by inhibiting monoamine
uptake, it suppresses appetite in a fashion similar to other selective serotonine reuptake
inhibitors. Secondly, sibutramine stimulates thermogenesis indirectly by activating
the beta 3 system in brown adipose tissue. Surprisingly there was no effect on BMI
after eight weeks therapy in 44 obese patients randomized to 10mg or 30mg/d in
comparison to placebo.
32
The reduction in weight is dose dependent. In a multi-center randomized trial
686 obese patients were randomized to placebo, 1, 5, 10, 15, 20 or 30 mg
silbutramine. The weight loss at 24 weeks was 1.3, 2.7, 3.9, 6.1, 7.4, 8.8, and 9.4%
respectively.
33
In another dose-ranging MCT, it was found the high dose to be most
effective with an average weight loss of 4.9 kg after 12 weeks therapy.
34
In most
479
30
studies 5 mg/ day dosage of sibutramine was not significantly different from pla-
cebo, but at 10 mg/d there was 5% weight loss in one year.
35
In a long-term study of sibutramine, 485 individuals were randomized to receive
placebo or sibutramine 10 or 15 mg/day. After 12 months, the persons in the pla-
cebo group lost an average of 1.8 kg while the persons in the sibutramine 10 and 15
mg/day groups lost an average of 4.8 and 6.1 kg, respectively.
36
The recommended starting dose is 10 mg/day. If there is inadequate weight loss
after four weeks, the dosage may be increased to 15 mg daily. Adverse effects such as
dry mouth, anorexia, constipation, increased pulse and blood pressure, and insom-
nia have been reported in over 70% of subjects in large controlled trials, with drop-
out rates of 10-17%.
31,34,37
Fears that sibutramine may be addictive like the
amphetamines, were not supported by blinded comparison studies.
38
In an attempt to prevent the initial weight regain in-patients successfully treated
with VLCD, 159 obese patients were randomized to one-year treatment with
sibutramine (10 mg) or placebo. At month 12, 75% of subjects in the sibutramine
group maintained at least 100 % of the weight loss achieved with a VLCD, com-
pared with 42% in the placebo group.
39
In a direct comparison study between silbutramine 10mg/d and dexfenfluramine
15 mg bid for 12 weeks in 226 obese (BMI>27) adults a significantly higher weight
loss with silbutramine (4.5(0.4) vs. 3.2(0.3) kg) has been reported.
37
Minor adverse
effects were common with both drugs (77%) with 6 and 11 withdrawals, respectively.
Digestion Inhibitors
Orlistat is a potent and irreversible inhibitor of gastric and pancreatic lipases,
inhibiting the digestion of dietary fat, and therefore decreasing the absorption of
fatty acids, cholesterol and, unfortunately, lipid soluble vitamins. At a dosage of
120mg tds, orlistat decreases the absorption of approximately 30% ingested dietary
fat. The reduction in energy absorption is usually associated with a loss of approxi-
mately 10% of body weight, and significant reductions in plasma cholesterol levels
after one year of treatment.
40
Side effects include steatorrhoea and fat soluble vita-
min deficiencies.
In a recent MCS study,
41
892 pts were randomized to placebo or 120mg-tid
orlistat for 52 weeks. During the study period orlistat-treated subjects lost more
weight (mean 8.76 0.37 kg) than placebo-treated subjects (5.81 0.67 kg). At the
end of 52 weeks, the placebo group continued on placebo, but the orlistat group
were re-randomized to placebo (n=138), orlistat 60mg (n=152) or 120mg (n=153)
3x/day. Only those randomized to high-dose therapy regained less weight than those
on placebo during the second year of study (3.2 0.45 kg; 35.2% regain vs. 5.63
0.42 kg; 63.4% regain, p<0.001). High-dose treatment was associated with im-
provements in fasting low-density lipoprotein, cholesterol, and insulin levels. Seven
types of GI events were seen more often in the orlistat group; flatus with discharge
(40.1%), oily spotting (32.7%), fecal urgency (29.7%), fatty/oily stool (19.8%),
oily evacuation (14.3%), fecal incontinence (11.8%), and increased defecation (11.1
%). Despite these GI side effects, less than 2% of patients withdrew from the study.
In a similar multi-center study, 1313 subjects who had managed to loose 8% of
their body weight on a hypocaloric diet over six months to a one-year were enrolled
on a controlled study to evaluate the ability of orlistat to prevent weight regain.
40
Once again, only the high dose of 120 mg tds was more effective than placebo in
inhibiting weight regain (wt regain 32.8% vs. 58.7%) and reducing blood lipids.
480
30
In a placebo controlled RMCT study involving 391 adult obese (BMI 28-40)
patients with Type II diabetes, treated with 120mg tds plus a hypocaloric diet, plus
oral sulfonylureas,
42
although weight loss was not greater with orlistat than placebo
at one year (6.2(0.45)% vs. 4.3(0.49)%), drug treatment was associated with sig-
nificantly lower fasting blood sugars, HbA1cs, and lipids. There is concern about a
possible increased incidence of breast cancer in users; nine cases of breast cancer
were found in patients taking orlistat 120 mg 3 times daily, one case in the 60 mg 3
times daily, and one case in the placebo group. Five of the nine cases were detected
within six months of initiating the treatment. The fact that orlistat has minimal
systemic absorption suggests an indirect mechanism, but further careful monitoring
and experimental investigation is clearly needed.
43
Fifteen European centers participated in a MCRCT study where 743 patients
(BMI 28-47) were first placed on a 400 kcal diet for four weeks, then randomized to
orlistat 120mg tid, or placebo for one year, while on a hypocaloric diet.
44
The drug-
treated group lost more weight (10.3 kg, or 10.2%) than those receiving placebo
(6.1 kg, or 6.1 kg). In the second year, patients were reassigned to drug or placebo,
plus maintenance eucaloric diet. The patients continuing on the drug only regained
half as much weight as those switched to placebo. Patients switched from placebo to
orlistat lost 0.9 kg whilst those who continued on placebo gained 2.5 kg. Drug
therapy was associated with significant reductions in blood lipids and glucose: insu-
lin ratio, but more GI side effects.
Hormonal Manipulation
The search for peptides that control appetite has begun to make progress. It
appears that there are two hypothalamic centers that exert opposing effects on food
intake. In the ventromedial hypothalamus is the satiety center which contains the
leptin-regulated neuropeptide network, and in the lateral hypothalamus is the feeding
center containing the orexin neuropeptides.
45
It is now well established that leptin
deficiency is the primary cause of obesity in the Obob mouse. Although leptin defi-
ciency does not appear to be the cause in humans, there is good evidence that leptin
resistance may be. The leptin levels are higher in the obesity secondary to a state of
leptin resistance,
46
which may be caused by a decreased capacity to transport leptin
into brain.
47
In a recent study., obese persons were either treated with daily subcutaneous
injections of leptin at four different doses, or placebo for six months.
48
A dose-
response was found, with the average weight loss ranging from 1.5 lbs. for those on
the lowest dose, to nearly 16 lbs. for those taking the highest dose of leptin. No
clinically significant adverse effects were observed.
There is evidence that recombinant growth hormone may be useful in prevent-
ing the usual loss of lean body mass during (LBM) hypocaloric fasting. In a ran-
domized double-blind, placebo controlled study GH reversed the loss of LBM and
nitrogen in obese subjects fed a hypocaloric diet, and at the same time caused a 1.6-
fold increase in the fraction of weight lost as fat, and particularly, as visceral fat.
49
Hormone administration may prove particularly useful in reducing visceral obesity.
When 30 men with abdominal/visceral obesity were randomized to recombinant
HGH injections (9.5 mcg/kg) or placebo for nine months.
50
Significant reductions
in body fat (9.2(2.4)%), abdominal subcutaneous fat (6.1(3.2)%), visceral fat
(18.1(7.6)%), blood lipids and glucose disposal were noted only in the HGH group.
481
30
Growth hormone secretogogues also appear to be able to increase fat-free mass and
energy expenditure in obese subjects.
51
In a more complex study, 33 moderately obese women were randomized to pla-
cebo or a combination of human GH and insulin-like growth factor injections plus
exercise for 12 weeks. Diet was kept constant at 500 kcal/day. The injections were
associated with significantly greater losses of weight, fat mass, whilst LBM and strength
were maintained.
52
Dropouts were unfortunately high (five subjects) because of in-
tolerable side effects.
Bariatric Surgery
Because of extremely high-failure of all non-surgical attempts to correct morbid
obesity including diet, behavior modification, hypnosis, voluntary incarceration,
jaw wiring and intragastric balloons, the presence of morbid obesity by itself is an
indication for surgical correction. Based on current medical evidence, the surgical
treatment of patients with BMI >40 kg/m
2
or BMI> 35 kg/m
2
with co-morbid con-
ditions, has emerged as definitive therapy.
53
Bariatric surgery has gained acceptance
among surgeons, physicians and the public. No non-operative program has had a
long-term weight loss efficacy in morbidly obese patients and as such remains the
most effective way of reversing morbid obesity.
The presence of any endocrine disorder that may be responsible for obesity, al-
beit extremely rare, should be treated first. Most insurance companies require that
patients have attempted but failed with non-surgical attempts to reduce the weight.
Following surgery patient needs to make significant lifestyle changes that include
increased exercise and dietary education.
Current Operations
Over the last decade the safety and effectiveness of many surgical procedures has
evolved.
54
Currently, most bariatric surgical centers in North America and Europe
perform Roux-en-Y gastric bypass (RYGB), vertical banded gastroplasty (VBG) or
adjusted gastric banding (AGB).
Gastroplasty
Gastroplasty was introduced
55
as an attempt to avoid adverse long-term nutri-
tional and ulcerogenic consequences of gastric bypass. In gastroplasty the upper
stomach is stapled near the gastroesophageal junction, and creates a small upper
gastric pouch, which communicates with the rest of the stomach and gastro-intesti-
nal tract through a small outlet. The concept and the technique of gastroplasty were
suggested as a safer and relatively easier method for restricting food intake, with
virtually no reported metabolic complications, as the gastrointestinal tract is in con-
tinuity. The main failures of gastroplasty procedures are mechanical in nature, such
as stomal or proximal dilatation or both. Gastroplasties are performed with either
horizontal or vertical placement of the staples. Horizontal gastroplasty usually re-
quires ligation and division of the short gastric vessels between the stomach and
spleen and carries the risk of devascularization of the gastric pouch or splenic injury
and has been associated with very high failure rates (42%-70%). The vertical banded
gastroplasty (VBG), on the other hand, is a procedure in which a stapled open-
ing is made in the stomach with an EEA stapling device 5 cm from the cardio
esophageal junction.
482
30
VBG can be associated with severe gastro-esophageal reflux. VBG is more effec-
tive than horizontal gastroplasty, but significantly less effective then RYGBP, as dem-
onstrated in randomized, prospective trials, in which several centers have reported
inferior weight reduction with this operation, as compared with a standard RYGBP
and need to convert VBG to RYGBP due to failure or complications.
56-59
Gastric Banding
Gastric banding was introduced as a treatment for morbid obesity, in which a
Dacron tube or silicone band is used to compartmentalize the stomach into small
proximal and large distal segments. This approach had the advantage of producing a
pure restrictive operation using a very simple, reversible technique, in which sta-
pling, with its inherent risk of staple-line disruption, was avoided. More recent de-
velopments include the introduction of an adjustable silicone gastric banding device,
originally described by Kuzmak,
60
which can be placed laparoscopically. This band
has a subcutaneous or subfascial reservoir. If weight loss is meager or if vomiting is
excessive the outlet diameter of the upper gastric segment can be adjusted.
Roux-en-Y Gastric Bypass
In recent years Roux-en-Y gastric bypass (RYGBP) (has become the most com-
mon bariatric operation performed by American bariatric surgeons.
54
The change
toward this operation is based mainly on superior long-term weight loss effects of
RYGBP when compared with VBG. In randomized, prospective trials, and retro-
spective studies RYGBP was found to induce significantly greater weight loss than
VBGP. This was particularly true for patients addicted to sweets. It was found that
sweet eaters loose less weight after VBG than after RYGBP because they develop
dumping syndrome symptoms following the ingestion of foods rich in sugar follow-
ing RYGBP.
61
The RYGBP is associated with significantly higher levels of
enteroglucagon than VBGP. Furthermore, many patients who have undergone VBG
often fail to loose enough weight to correct their obesity related co-morbidity.
Because of the high incidence of staple line disruption and ulcer formation some
surgeons recommend transecting the stomach for gastric bypass patients,
62
espe-
cially in those over 400 pounds. Others have performed resectional gastric bypass as
a new alternative in morbid obesity,
63
as a primary weight control operation. Cur-
rently most bariatric groups perform gastric bypass by constructing a small gastric
pouch (15-ml) with a 45cm Roux-en-Y limb and stoma restricted to 1 cm. Superobese
patients (BMI of 50 kg/m
2
or greater), achieve a significantly better weight loss with
a 150-cm Roux limb (long-limb gastric bypass).
64
The small gastric pouch has a
limited volume of acid secretion and is associated with a low incidence of marginal
ulcer. The GBP is associated with long lasting weight loss in the vast majority of
patients. The average weight loss at two years is 66% of excess weight, 60% at five
years and mid-50s at five years following surgery.
Laparoscopic Gastric Bypass
Laparoscopic bariatric surgery is still in its early phases of development. Although,
long-term results of laparoscopic bariatric surgery are not known, it is hoped that
the advantages should include a decreased length of hospital stay, less pain, and a
lower risk of incisional hernia, which currently exceeds 20% following open obesity
surgery. In addition, as with other laparoscopic surgeries, it is hoped for fewer and
less severe adhesions, with the potential for fewer subsequent small bowel obstructions.
483
30
The bariatric procedures currently performed laparoscopically include VBG, gastric
banding (with adjustable bands) and RYGBP.
The success of laparoscopic bariatric surgery should be compared to standard
open bariatric surgery. The initial experience with 75 patients, who have undergone
laparoscopic RYGBP (LRYGBP) using a 21-mm EEA, was reported to be compa-
rable to open GBP. Furthermore, follow- up from 3 to 60 months on 500 patients
who underwent LRYGBP has been reported with the incidence of major complica-
tions 11%, anastomotic leak 5%, and no mortality.
65
As experience is gained with the laparoscopic RYGBD, complications related to
the complex technical nature of the procedure that would probably decrease. As of
this writing, most surgeons perform LRYGBP in-patients with BMI of less then 50
kg/m
2
, although a few groups have reported on successful LRYGBP procedure in-
patients with a BMI up to 70 kg/m
2
. For the most part, the results are comparable to
the open technique.
In a most recent paper laparoscopic RYGBP was found to be safe and with very
low mortality and morbidity.
66
Furthermore, the recovery time was short and the
operative complications were overall comparable with the open technique. The con-
version rate from laparoscopic to an open technique in 275 consecutive patients was
1%, and median hospital stay was two days, while the return to work was 21 days.
The incidence of early major and minor complications was 3.3% and 27%, respec-
tively. There was only one death reported due to pulmonary embolus, and minor
wound infections were only 5%. The excess weight loss was comparable with the
open technique with 83% and 77% weight excess weight loss at 24 and 30 months
respectively. In addition, most of the comorbidities improved or resolved, and 95%
of patients reported significant improvement in their quality of life.
66
Laparoscopic Adjustable Gastric Banding
The adjustable silicone gastric band has been developed to be placed
laparoscopically. The device contains a balloon that is adjusted by injecting saline
into a subcutaneously implanted port. Although this procedure has become very
popular in Europe and other parts of the world, there are no long-term studies
validating its safety and efficacy. The results of an FDA approved trial in the United
States are not yet available. Problems with band slippage leading to gastric obstruc-
tion and the need for re-operation, esophageal dilatation, band erosion into the
lumen of the stomach, port infections and inadequate weight loss have been re-
ported. The presences of hiatal hernia and esophageal dysmotility were identified as
independent risk factors for lap-band slippage.
67
Other complications of gastric band-
ing include food intolerance, reflux esophagitis, pouch dilatation and stoma occlu-
sion. In a prospective, randomized trial of open versus laparoscopic adjustable silicone
gastric banding, there were no differences in weight loss, or post operative complica-
tions, for the first year of follow-up.
68
However, the laparoscopic procedure was
associated with a shorter initial hospital stay (5.9 days versus 7.2 days) for LASGBP
(P<. 0.05) and fewer admissions during one- year follow-up. On the other hand the
operative time was significantly longer in the laparoscopic procedure. The total num-
ber of readmissions (6 vs. 15) and overall hospital stay for the first year (7.8 vs. 11.8
days) were lower for LASGBP (P<0.05). The analysis of multicenter study
69
of 361
patients who underwent LASGB and 120 patients who underwent laparoscopic
VBG demonstrated that operative time and hospital stay were shorter in LASGBP.
In addition LASGB was associated with fewer complications. The weight loss,
484
30
however, was significantly less in the LASGB group. However the follow-up in this
study was very short. 35% of patients who underwent adjustable silicone gastric
banding in our center have had removal of the gastric band, and conversion to
gastric bypass. In some patients removal of the gastric band and conversion to RYGBP
can be performed laparoscopically; however, these operations are technically chal-
lenging with increased risks of complications.
70
Nutritional Complications Following Bariatric Surgery
Following gastric bypass for morbid obesity, significant nutritional complica-
tions such as acute protein calorie malnutrition may develop as well as iron calcium,
and liposoluble vitamin deficiencies. A rare syndrome of polyneuropathy can occur
after any bariatric procedure. This usually occurs in association with intractable
vomiting, and severe-protein calorie malnutrition with subsequent acute thia-
mine deficiency.
Although protein deficiency is the most serious deficiency following the malab-
sorption procedures, its true prevalence is unknown. The length of functional ab-
sorptive gut and the compromised role of pancreas and stomach in biliopancreatic
bypass are the main factors. Biliopancreatic bypass is associated with significant loss
of endogenous nitrogen and decreased protein absorption and, if persistent and
resistant to medical treatment, requires revision.
Iron deficiency is a frequent complication of gastric bypass in menstruating women
and requires vigilant monitoring and supplementation if severe consequences are to
be avoided. Iron-induced anemia can be refractory to supplemental ferrous sulfate,
because iron absorption takes place primarily in the duodenum and upper jejunum.
Occasionally, iron-dextran injections may be necessary. Hysterectomy may be re-
quired in a woman with heavy menses and recurrent iron deficiency anemia. All
menstruating women should take two iron sulfate tablets (325 mg/d) by mouth
after gastric bypass as long as they continue to menstruate.
The risk of vitamin B
12
deficiency mandates long-term follow-up with annual
measurement of the vitamin B
12
level. B
12
deficiency is probably due to decreased
acid digestion of vitamin B
12
from food with subsequent failure of coupling to in-
trinsic factor. Postoperatively patients need to take 500 mcg of oral vitamin B
12
daily
or 1 mg I.M. Vitamin B
12
per month. Calcium is a serious consequence of morbid
obesity surgery, because decreased calcium and vitamin absorption will disturb nor-
mal calcium physiology and effect the bone structure. To this end supplementation
is often necessary after any gastric bypass procedure. Patients with either a long-limb
gastric or partial biliopancreatic bypass with or without duodenal switch can de-
velop calcium and fat-soluble vitamin deficiencies that need to be monitored and
treated. Magnesium deficiency may also occur and require supplementation.
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489
I
n
d
e
x
Index
A
1-acid glycoprotein 104, 110-112
2-macroglobulin 104, 110
Actin 55, 89, 118, 119
Acute pancreatitis 168, 210, 214, 215,
320-331, 337
Acute phase protein 9, 63-66,
103-106, 108-112, 117, 120,
121, 133
Acute phase response (APR) 9, 63-65,
68, 70, 103, 104, 106-112
Acute respiratory failure (ARF) 384,
385, 389, 390
Adenosine diphosphate (ADP) 364,
373
Adenosine monophosphate (AMP)
372, 373, 397
Adenosine triphosphate (ATP) 13, 33,
54, 174, 353, 354, 373-375,
398, 462
Aerodigestive squamous cell carcinoma
434, 435
Alanine 2, 3, 56-58, 60-62, 81, 220,
329, 371, 375, 397, 398
Albumin 3, 8-12, 14, 42, 63-67, 69,
70, 83, 91, 104, 106, 108, 110,
111, 133-136, 140, 163, 164,
173, 175, 208, 211, 213-215,
266, 267, 269, 306, 307, 314,
326, 350, 355, 361, 370, 372,
378, 388, 406, 424, 433, 434,
449-451, 453-456, 459, 460
Alcohol 14, 92, 96, 129, 134, 136,
153, 167, 216, 254, 320-322,
325, 328, 335, 338, 340, 343,
397, 430, 432, 453
Alitraq 32
Alpha-1 acid glycoprotein (AAG) 2,
65, 68-70
Alpha-1 antitrypsin 9, 307, 346
Alpha-1 protease inhibitor 68
Amikacin 291, 293, 295
Amitriptyline 281, 288, 289
Ammonia 18, 32, 58, 60-62, 72, 75,
212, 398, 460
Amphogel 266
Amphotericin 14, 291-295
Amyloid 65, 68
Anemia 13, 59, 97, 128, 134, 162,
210, 269, 306, 307, 324, 379,
458, 484
Anthropometry 127, 131, 132, 181,
182, 184
APACHE II 41, 215, 376
Appetite suppressant 478
Arachidonic acid 6, 35-37, 390, 391
Arginase 72, 74-76, 79, 402
Arginine 17, 24-27, 34, 35, 40, 42, 43,
55-62, 72-83, 92-95, 113, 223,
252, 254, 255, 329, 369, 371,
374-379, 401, 402, 405, 458
Aromatic amino acids (AAA) 17-19,
169, 212, 213, 324, 325, 329,
349-351
Arterial blood ketone body ratio
(AKBR) 213, 214, 351, 353
Aspiration 37, 165, 176, 194-197,
199, 200, 203, 206, 282, 339,
385, 386, 405, 440, 444, 463
B
-blockade 407, 408
Bacterial translocation 24, 25, 27-29,
59, 95, 113, 145, 168, 278, 310,
371, 373, 405, 421
Bariatric surgery 481-484
Basal energy expenditure (BEE) 136,
139, 399, 401, 409, 456
Behavioral modification (BM) 477
Bile salt 210, 263, 264, 269, 277,
307, 309, 341, 451
Body mass index (BMI) 128, 131,
133, 137, 473
Bone mineral density (BMD) 365,
366
Branched-chain amino acids (BCAAs)
17-19, 21, 23, 24, 42, 43, 213,
214, 324, 325, 329, 339,
349-351, 355, 372, 378, 379,
398, 405, 456, 461, 462
Burn injury 24, 25, 65, 103, 106,
371, 395, 397, 398, 404-406
INDEX
490 The Biology and Practice of Current Nutritional Support
I
n
d
e
x
C
14C-triolein breath 337
C-reactive protein (CRP) 2, 9, 12, 65,
67, 68, 104, 105, 110, 112
C. albicans 292
C. krusei 292
C/EBP family 64
Cachexia 176, 210, 216, 306, 432,
433, 449, 451
Calcitonin gene-related peptide 224
Calcitonin gene-related polypeptide
(CGRP) 224-226
Calcium 6, 7, 13, 42, 55, 97, 131,
133, 146, 147, 149, 150, 153,
161, 164, 173-177, 211, 227,
263, 264, 267-269, 276, 278,
280, 307, 309, 326, 328, 366,
406, 484
Camalox 266
Carbamazepine 148-150, 153, 289
Carbohydrates 2, 4-6, 12, 18, 33, 41,
42, 96, 136, 158-160, 168, 169,
175, 176, 197, 212, 223, 227,
263-266, 268-270, 307, 311,
329, 338, 347, 349, 373, 385,
387, 389, 390, 392, 398, 401,
405, 420, 421, 423, 439, 440,
449, 476
Carbon dioxide production (VCO
2
) 5,
136, 387, 392, 390, 399
Catecholamines 2, 63, 64, 111, 197,
348, 350, 397, 405, 406, 478
Catheter embolization 165, 166
Catheter occlusion 167
Catheter sepsis 165, 167
Catheter tip dislocation 166
CD4 see Helper T-cells
CD8 see Suppressor T-cells
Cefazolin 293, 295, 443
Cefoxitin 293, 295
Ceftazidime 293, 295
Ceftriaxone 293, 295
Ceruloplasmin 9, 65, 68
Cervical esophagostomy 442
Chemotherapy 210, 216, 255, 371,
430, 432, 440, 441, 443, 445,
452, 454, 457, 463, 464
Chloride 6, 14, 147, 149, 153, 155,
161, 172, 173, 175, 176, 267,
269, 276
Cholecystokinin (CCK) 59, 224-226,
228, 230, 233, 234, 264, 328,
331, 334, 338, 341, 342
Cholelithiasis 168, 210, 263
Cholerrhea 263
Cholesterol 3, 11, 36, 37, 164, 295,
336, 337, 363, 406, 474, 476,
479
Cholestyramine 146, 266, 267, 269,
307, 309, 363-365
Chromium 7, 160, 161, 307, 425
Chronic obstructive pulmonary disease
(COPD) 176, 384, 385,
387-389, 391, 392
Chronic pancreatitis 210, 325, 326,
334-343
Chymotrypsin 60, 337, 341, 342
Cimetidine 153, 155, 266, 267, 280,
284, 289, 291, 295, 329
Ciprofloxacin 148, 150, 293, 295
Cis-Golgi network (CGN) 109, 110
Clindamycin 293, 295
Codeine 153, 155, 266, 267, 289
Collagen 52, 54-56, 59, 89, 90,
92-98, 233, 401-404
Colon cancer 456-458
Complement factor C-3 65
Conconavalin A (ConA) 25, 26
Copper 7, 55, 68, 97, 131, 160, 161,
211, 269, 307, 335, 336, 426
Cortisol 2, 3, 55, 63, 197, 349, 370,
397, 401, 405, 406
Cortisol-binding globulin (CBG) 3
Creatinine height index (CHI) 128,
132, 182
Crohns disease 126, 211, 212, 253,
276, 306-314, 321, 330, 335
Crypt fission 220, 251
Curreri formula 400, 401, 410
Cyclic adenine monophosphate
(cAMP) 108, 109, 397
Cyclosporine 280, 281, 283, 295,
362, 363, 365-367
Cytomegalovirus (CMV) 95, 424-427
491
I
n
d
e
x
Index
D
Delayed cutaneous hypersensitivity
skin testing (DHST) 135
Dextrose 18, 19, 21, 23, 26, 36, 92,
158, 159, 162, 163, 168, 169,
174, 176, 211, 265, 266, 268,
294, 327-330, 339, 340, 405,
420, 424
Diabetes 96, 149, 168, 170, 211, 267,
334-336, 362, 401, 460,
474-478, 480
Diagnosis-related group (DRG) 438
Dicyclomine hydrochloride 270
Digoxin 153, 155, 281-283, 289, 295
Docosahexaenoic acid (DHA) 37-39,
376
Dragstedt 201
Dual energy x-ray absorptiometry
(DEXA) 132, 406
Duodenectomy 263, 282, 459
Duodenum 60, 113, 115, 203, 224,
230, 233, 254, 262, 263, 269,
276, 280, 282, 321, 324, 327,
331, 337, 338, 342, 404, 423,
484
Dyslipidemia 360, 362, 478
E
E-mycin (Erythromycin) 149, 152,
155, 295
Eicosanoids 35-38, 43, 88, 98, 232,
390, 391
Eicosapentaenoic acid (EPA) 36-39,
41, 376, 391
Elastase 60, 68, 320, 325, 326
Elongation factor 54
End stage pulmonary disease (ESPD)
388, 392
Endoclose 206
Endostitch 206
Endothelial cells 80, 106, 108, 112,
115, 134, 326, 365
Endotoxin 25, 37, 41, 75-81, 83, 107,
108, 110, 112, 113, 115, 117,
118, 120, 405
Enrich 146
Ensure 145, 150, 153, 439
Ensure Plus 145, 153
Enteral hyperalimentation 91
Enteral nutrition 21, 27, 31, 61, 65,
91, 145, 149, 150, 152, 153,
168, 192, 193, 195, 198, 203,
205, 211, 215, 223, 306, 308,
315, 356, 376-378, 404, 419,
435, 436, 438, 441, 445, 449,
451, 452, 457, 458, 463, 464
Entero-enteral fistula 313
Entero-vesical fistula 313
Enterocutaneous fistula 205, 211,
212, 313, 315
Enteroglucagon 225, 226, 229, 230,
234, 235, 482
Epidermal growth factor (EGF) 224,
229-231, 233, 235, 250-253,
255
Erythrocyte 41, 88, 269
Esophageal cancer 126, 453-455, 459
Exercise 388, 475, 477, 481
Extracellular matrix (ECM) 88, 89, 96
F
Famotidine 266, 267, 284, 291, 295
Fatty acid 2, 4, 6, 35-39, 42, 43, 88,
98, 131, 133, 159, 164, 169,
187, 210-212, 223, 229, 235,
251, 252, 255, 261, 263, 264,
268, 269, 322, 326, 330, 347,
353, 356, 369, 370, 374-379,
389, 390, 398, 402-406, 408,
410, 421, 422, 424, 426, 449,
453, 461, 462, 479
Fentanyl 288, 291, 292, 294, 295
Fibrin 52, 68, 88, 108, 110-112, 167
Fibrinogen 65, 68, 108, 110-112, 213
Fibronectin (Fn) 9, 133, 134, 403
Fish oil 26, 27, 34, 35, 37-39, 41, 43,
98, 364, 365, 376, 390, 391,
403
FLEXIFLO LAP J 206
Fluconazole 292, 295
Fluvastatin 363, 365
Folic acid 160, 214, 263, 266, 268,
341, 364, 365, 367
Fulminant hepatitis 18, 19
I
n
d
e
x
G
-linolenic acid 35-37, 41, 43, 390, 391
Gallbladders 264, 270, 328, 334, 475
Gallstone 270, 322, 335, 474, 476
Galveston formula 401
Gastric banding 481-484
Gastric cancer 203, 449, 450, 455,
456, 459
Gastric inhibitory polypeptide (GIP)
225-227, 264, 342
Gastric tubes 150, 194, 442, 443, 454
Gastrin 225-227, 229, 230, 233, 235,
264, 271, 342
Gastrojejunostomy 282
Gastroplasty 481, 482
Gastrostomy 146, 150, 151, 194, 196,
199, 200-203, 205, 206, 321,
439, 441-445, 454, 456
Gastrostomy site metastasis 444, 445
Gastrostomy tubes 146, 196, 203,
441, 444
Gatifloxacin 293, 295
Gelusil 266
General Nutritional Status 432
Gentamicin 291, 293, 295
Glicentin 225
Glucagon 2, 63, 64, 111, 153, 197,
212, 225, 226, 229, 230,
233-235, 290, 328, 329, 349,
397, 401, 402, 405, 406, 461,
482
Glucagon-like peptide-1 (GLP-1) 225
Glucagon-like peptide-2 (GLP-2)
225-227, 230, 235, 251
Glucase 211, 212, 214, 215
Glucocortioid blockers 409
Gluconeogenesis 2-4, 8, 103, 158,
159, 349, 350, 371, 397, 398,
408, 453, 461
Glucorticoids 64
Glucose 2, 4, 6, 7, 12-14, 27, 39, 56,
58, 59, 111, 159, 161, 164, 169,
171, 177, 183, 195, 197, 220,
223, 225, 227, 231, 232, 252,
267, 325, 326, 330, 336,
338-340, 343, 347-351,
353-355, 370, 371, 389, 390,
397-399, 401, 402, 405,
419-423, 449, 462, 475-477, 480
GLUT2 336
Glutamine 17, 27-35, 42, 43, 55,
57-59, 61, 62, 78-80, 83, 95,
103, 104, 106, 114, 213, 220,
223, 231-233, 235, 252, 255,
266, 270, 271, 278, 310, 329,
339, 348, 349, 353, 369, 371,
372, 374-379, 398, 402, 405,
421-423, 457, 461
Glycine 23, 25, 26, 28, 52, 56-58, 60,
349, 372
GMP 372
Golgi complex 109, 110
Groshong catheter 278
Growth failure 307, 308, 311, 312,
315, 422
Growth hormone 2, 9, 55, 58, 64, 65,
134, 197, 229, 231, 232, 235,
255, 266, 270, 271, 278, 312,
371, 375, 402, 406, 407, 410,
480, 481
Guanosine triphosphate (GTP) 53, 54
Gut-liver axis 113, 114, 117
H
5-HIAA 350
H2 receptor blocker 267
Haptoglobulin 65
Harris-Benedict equation 5, 136, 163,
308, 352, 396, 399, 400
Helper T-cells (CD4) 26, 29-31, 38
Hepatic encephalopathy 17-19, 21,
169, 213, 214, 347, 348,
349-351, 353, 356, 462
Hepatocyte 63, 64, 103, 106-112,
134, 397
Hepatorenal syndrome 18, 19, 350
Hickman catheter 167, 204, 278
High density lipoprotein (HDL)
362-365
Histidine 3, 8, 56-60, 62, 181, 213,
349, 352, 370, 375, 456
HMG CoA reductase inhibitor 363,
367
Home TPN 162, 177, 265, 266, 278,
309, 314
Homocysteine (HCY) 364, 365
Human umbilical vein epithelial cells
(HUVEC) 82
493
I
n
d
e
x
Index
Hyaluronan (HA) 89, 98
Hydromorphone 291, 294, 295
Hydroxyproline 54, 56, 60, 89-91,
93, 94, 402
Hyoscyamine sulfate 266, 270, 288
Hypercalcemia 174, 321
Hyperchloremia 173
Hypercoagulapathy 474
Hyperglycemia 2, 4, 12, 14, 158, 168,
169, 171, 173, 197, 324, 329,
330, 349, 395, 397, 398, 401,
407, 475
Hyperhomocysteinemia 360, 362,
364, 365, 367
Hyperkalemia 172, 361
Hyperlipidemia 6, 169, 171, 173,
335, 340, 362, 365, 475
Hypermagnesemia 175
Hypermetabolism 2, 3, 8, 325, 346,
352, 353, 385, 395-397, 405,
406, 409, 410
Hypernatremia 171
Hyperoxaluria 261, 264, 269
Hyperphosphatemia 174, 175
Hypertriglyceridemia 164, 322, 324,
340
Hypoalbuminemia 173, 175
Hypocalcemia 171, 174, 210, 261,
269, 324, 326, 329
Hypochloremia 173
Hypocupticemia 261
Hypoglycemia 169, 171, 294, 347,
407
Hypokalemia 12, 172, 176, 210, 261,
476
Hypomagnesemia 175, 261, 324, 476
Hyponatremia 171, 173, 353
Hypophosphatemia 12, 13, 174
Hypozincemia 261
I
IFN- 25, 75, 78, 112
IkB 120-122
Ileocecal valve 261-264, 276, 277
Ileum 82, 83, 114, 115, 221-224,
226, 228-232, 262-264, 276,
277, 279, 281, 282, 307
Ileus 211, 215, 216, 324, 329, 331,
339, 356, 404, 405, 419, 423,
449, 457
Immun-Aid 32, 40, 42
Immune enhancing diet (IEF) 369,
377
Immuno-nutrition 377
Immunoglobulin A 29
Impact 40-42, 377
Inflammatory bowel disease (IBD)
183, 193, 204, 210-212, 253,
263, 306-314
Initiation factor 53
Inosine monophosphate (IMP) 372
Insulin 2-4, 7, 9, 13, 14, 55, 63, 64,
90, 95, 111, 134, 162, 168, 169,
172, 197, 212, 215, 225, 227,
229, 231, 232, 267, 288-291,
295, 296, 330, 336, 340, 349,
354, 362, 370, 371, 375, 395,
397, 401, 402, 406, 407, 461,
462, 476, 479-481
Insulin growth factor 1 (IGF-1) 2, 3,
9, 12, 13, 231, 232, 235, 250,
406, 422
Interleukin-1 (IL-1) 25, 119, 120
Interleukin-2 (IL-2) 25, 34, 233, 374
Interleukin-6 (IL-6) 2, 9, 25, 38, 64,
68, 109-112, 117-122, 233, 325,
405
Interleukin-11 (IL-11) 111
Intestinal adaptation 210, 213, 219,
220, 222-224, 226, 227,
229-235, 255, 263, 268, 272,
276, 277, 287
Intestinal motility 103, 117, 221, 224,
225, 228, 256, 279
Iron 7, 9, 10, 55, 67, 68, 131, 133,
134, 146, 150, 155, 162, 263,
268, 276, 295, 296, 307, 336,
341, 404, 458, 484
Ischemia/reperfusion (I/R) 80-82
Ischemia/reperfusion injury 81
Islets of Langerhans 336
Isoleucine 17, 23, 56-58, 60, 61, 329,
349, 398, 405
Ito cell 106-108
I
n
d
e
x
J
Janeway 201, 202
Jejunal tubes 195, 355
Jejunostomy tubes 150, 196, 456
Jejunum 61, 114-116, 120, 195, 199,
203-206, 220, 221, 223, 224,
226-230, 233, 262-264, 276,
281, 282, 328, 441, 484
K
Keratinocyte growth factor (KGF) 255
Ketoconazole 151, 155, 280, 409
Krebs cycle 3, 404, 462
Kupffer cells 64, 106-108, 110-112
Kwashiorkor 1
L
L-NAME 81, 82, 94
Lactate 4, 37, 264, 269, 398, 419
Lactic acid 37, 175, 210, 264, 356
Lactose intolerance 264, 269, 307
Laparoscopic adjustable gastric
banding 483
Laparoscopic gastric bypass 482
Laparoscopic gastrostomy 444
Leukemia inhibiting factor 111
Levofloxacin 280, 293, 295
Lipase 212, 326, 335-337, 340-342
Lipids 2, 3, 5, 6, 12, 17, 18, 21, 33,
35, 36, 37, 39, 41-43, 83, 158,
159, 162-164, 167-170, 175,
222, 223, 255, 277, 286, 322,
330, 336, 339, 340, 347, 356,
362-364, 367, 373, 389, 390,
398, 402, 403, 405, 408, 420,
421, 425, 457, 458, 462, 464,
479, 480
Liver cancer 453, 455, 460-464
Liver failure 210, 212-214, 347, 349,
350, 356
Liver transplantation (LT) 346, 347,
352-356, 418, 460-462
Lomotil 266
Long-chain triglyceride (LCT) 6, 35,
36, 39, 42, 43, 159, 170, 223,
390, 419-423
Loperamide 197, 266, 267, 284, 422-
424, 451
Lovastatin 363, 365
Lung 14, 25, 36, 75, 76, 81, 103,
104, 163, 165, 176, 323, 326,
330, 371, 373, 384-386,
389-391, 403-445
Lymphocytes 2, 8, 9, 25-27, 30, 33,
34, 40, 41, 55, 58, 68, 78, 88,
94, 107, 115, 135, 140, 208,
213, 214, 222, 334, 351, 372,
373, 402, 403, 405, 418, 431,
433, 449, 453, 455, 457, 458
Lysosomes 109, 322
M
3-methyl histidine 3, 8, 59, 352
Macrophages 2, 25, 34, 36, 38, 55,
58, 64, 68, 75, 76, 80, 88, 92,
98, 107, 112, 115, 134, 391,
402-404
Magnesium 6, 7, 13, 14, 133, 150,
153, 155, 161, 164, 169, 175,
176, 195, 197, 211, 264, 267,
269, 276, 293, 307, 326, 328,
336, 370, 426, 484
Malabsorption 14, 98, 128, 151, 210,
213, 219, 221, 255, 261-263,
269, 270, 275, 306, 307, 309,
313, 334-337, 342, 347, 400,
420, 424-426, 451, 453, 484
Malnutrition 1-3, 7-11, 13-15, 34,
61, 66, 89- 91, 93, 126, 128,
130-133, 135, 139, 168, 183,
184, 190, 192, 193, 208,
210-216, 223, 255, 261, 275,
306-309, 312-315, 325-327,
329, 331, 334, 342, 346, 347,
350-356, 360, 361, 366, 367,
378, 384, 385, 388, 389, 401,
406, 430-434, 436, 438-440,
443, 445, 449-456, 459, 484
Manganese 7, 98, 160, 161, 426
Marasmus 1, 66
Mean arm muscle mass (MAMA) 182
Medium-chain triglyceride (MCT)
35, 39, 42, 43, 147, 223, 268,
269, 338, 390, 420-423, 453,
461, 478
495
I
n
d
e
x
Index
Meperidine 291, 294, 295
Metabolic acidosis 128, 173, 175,
177, 261, 268
Metabolic alkalosis 172, 173, 176
Metoclopramide 152, 153, 155, 196,
284, 289, 295
Mid-arm fat area (MAFA) 182
Migrating motor (myoelectric)
complex (MMC) 221, 423
Milk product 269, 452
Mineral deficiencies 141, 197, 347
Monounsaturated fatty acid 35
Motilin 225, 226, 228, 229
mRNA 25, 53, 54, 64, 66, 75, 76,
108-111, 117-119, 225-229,
231, 232, 234
Mylanta 153, 266
Myofibroblast 89, 115
N
N-nitro-L-arginine methyl ester 94
Nafcillin 292, 293, 295
Nasal tubes 194
Nasoenteric tubes 196
Needle catheter jejunostomy 204
Neocate 422
Neuropeptide Y (NPY) 225, 226,
228, 230
Neurotensin 225, 226, 228, 230, 234
Neutrophils 58, 82, 88, 106-108, 112,
458
Nitric oxide (NO) 58, 73-78, 80-83,
92-95, 107-109, 112, 113, 386,
389
Nitric oxide synthase (NOS) 73-77,
81-83, 94
Nitrogen 2-8, 12, 15, 19, 21, 23, 24,
26-30, 33, 42, 59, 60, 62, 63,
65-67, 69, 70, 94, 130, 137-140,
158, 164, 195, 209, 211, 212,
214, 215, 308, 325, 327, 329,
330, 338, 339, 351, 352, 355,
356, 360, 361, 366, 369-372,
374-376, 387-389, 391, 392,
395, 398, 399, 401, 406, 407,
433, 436, 451, 453, 454,
456-458, 461, 462, 464, 480,
484
Nitrogen balance 2, 4, 6, 7, 12, 19,
21, 23, 24, 26, 28, 30, 33, 42,
59, 65, 66, 67, 69, 70, 130,
137-140, 164, 195, 209, 212,
214, 215, 329, 330, 338, 351,
352, 355, 356, 360, 361, 366,
369-371, 374-376, 387, 391,
392, 398, 401, 406, 407, 433,
436, 451, 453, 454, 456-458,
461, 462, 464
Nizoral 151
Nortriptyline 281
Nuclear factor-kappa B (NF-B) 109,
120-122
Nucleic acid 33, 97, 160, 234,
372-374, 406
Nucleotide 7, 13, 17, 33-35, 43, 53,
54, 83, 95, 353, 354, 369,
371-379
Nutritionally-dependent adaptive
dichotomy (NDAD) 2, 3, 12
O
-3 polyunsaturated fatty acid 35, 37
-6 polyunsaturated fatty acid 35
Obesity 61, 131, 168, 176, 201, 276,
362, 473-475, 477, 478,
480-482, 484
Omega 3-fatty acid 369, 374-376,
379, 389
Omeprazole 149, 152, 155, 266, 270,
289
Oncostatin 111
Orlistat 479, 480
Ornithine 56, 72-76, 78-80, 82, 83,
234, 376, 402
Oropharyngeal cancer 431, 438, 440
Osmolite 40, 41, 145
Osteoporosis 210, 360, 365, 366
Ostomy 201, 265, 267, 269, 278
Oxacillin 292, 293, 296
Oxandrolone 406, 407
Oxygen consumption (VO
2
) 5, 136,
309, 390, 392, 399
Oxygen-derived free radicals 320, 322
Oxyntomodulin 225
I
n
d
e
x
P
Pancreatic cancer 326, 337, 449, 459,
460
Pancreatic endopetidase 60
Pancreatic polypeptide (PP) 225, 226,
228, 229
Pancrelipase 147, 149, 340
Pantoprazole 266, 267
Parenteral nutrition 27, 31, 36, 37,
59, 65, 78, 91, 92, 114, 136,
137, 139, 145, 158-165, 167,
171, 177, 183, 192, 198,
208-210, 214, 216, 262, 265,
266, 270-272, 275, 294, 306,
309, 312, 320, 327, 330, 331,
337, 339, 342, 369, 372, 373,
376, 378, 390, 405, 418-421,
426, 436, 438-441, 445,
449-464
Peptide YY (PYY) 103, 115, 117, 122,
225, 226, 229, 230, 234
Percutaneous endoscopic gastrostomy
(PEG) 82, 200-203, 206,
441-445
Percutaneous endoscopic jejunostomy
(PEJ) 203, 206
Pharyngostomy 438, 442
Phenylalanine 17, 31, 56-61, 348,
349, 398
Phenytoin 148, 149, 155, 280
Phlebitis 149, 163, 166, 167, 288,
293, 405
Phospholipase A 320, 326
Phospholipase A2 326, 419
Phosphorus 6, 7, 13, 14, 146, 164,
174, 175, 211, 370
Phytohemagglutinin 26
Pit cells 106, 107
Platelets 35-37, 55, 68, 82, 88, 98,
108, 113, 211, 253, 364, 365
Platelet derived growth factor (PDGF)
88, 253, 254
Pneumonia 1, 13, 31, 37, 135, 176,
195, 293, 378, 384-386, 405,
440, 441, 444, 462
Pneumothorax 165, 166, 176
Polyamines 72, 73, 82, 234, 251, 254,
255, 458
Potassium 6, 7, 14, 147, 149, 153,
155, 161, 164, 169, 171-176,
181, 195, 197, 267, 269, 276,
278, 293, 370
Prealbumin 3, 9, 11, 12, 14, 63,
65-67, 133-135, 140, 163, 164,
213, 351, 378, 388, 405, 406,
455
Pregestimil 422
Procainamide 149, 280, 281, 283,
321
Procrit 379
Prognostic Nutritional Index (PNI)
135, 136, 351, 432, 433
Propantheline bromide 270
Prostaglandin E1 (PGE1) 36, 390,
403
Prostaglandin E2 (PGE2) 35, 38, 40,
41, 120, 403
Protein 1-12, 14, 15, 17, 19, 21, 23,
24, 26, 28, 31-34, 41-43, 52-57,
59-70, 75, 78, 81, 82, 89-97,
103-106, 108-122, 127, 128,
131-140, 146, 147, 151, 158-
160, 163, 164, 169, 171, 173,
175, 177, 181, 182, 183, 187,
195, 204, 209-217, 220, 223,
224, 227, 231, 232, 234, 252,
263-266, 268, 271, 307-309,
312, 313, 315, 322, 325, 326,
328, 330, 331, 335, 336, 338-
340, 346, 347, 349-356, 360,
361, 363, 366, 369-377, 384,
385, 387-392, 395, 398,
401-408, 410, 419-421, 423,
424, 432, 433, 436, 438-440,
449, 452-458, 460-464, 476,
484
Protein energy malnutrition (PEM) 9,
432, 433, 438
Protein Energy Malnutrition Scale
432, 433, 438
PTFE grafts 91
Pyloroplasty 271
Pytuvate 4, 56, 61, 62, 398
497
I
n
d
e
x
Index
R
Radiotherapy 97, 216, 430, 432, 436,
438-440, 442, 443, 452, 454,
464
Ranitidine 266, 267, 285, 291, 296
Ransons criteria 215, 320
Recombinant human growth hormone
(rhGH) 65
Refeeding syndrome 12, 164, 169,
172, 174, 195, 197
Reglan 152
Renal stone 210, 264
Renal transplantation 360, 361
Respiratory acidosis 168, 175, 176
Respiratory alkalosis 14, 176
Respiratory quotient (RQ) 5, 136,
164, 387, 399
Resting energy expenditure (REE) 5,
6, 136, 137, 399-401, 406, 409
Retinol-binding protein (RBP) 3, 9,
12, 66, 67, 133, 134, 163, 351,
372, 388, 405, 433, 455
Roux-en-Y gastric bypass (RYGBP)
205, 481-484
S
S. aureus 292, 293
Safflower oil 35, 159, 266, 268
Sandostatin 419
Secretin 59, 115, 229, 264, 322, 327,
328, 337, 340
Selenium 7, 98, 160, 162, 335, 336,
342, 379, 404, 426
Sepsis 1, 4, 7-9, 13, 21, 24, 27, 31,
33, 36-38, 40, 58, 65, 69, 72-75,
81, 90, 103-118, 120-122, 127,
135, 139, 165, 167, 168, 176,
196, 205, 208-211, 215, 278,
292, 308, 310, 322, 325, 330,
339, 356, 369-372, 374-376,
378, 379, 384-386, 389, 391,
396, 402, 405, 418, 438, 455,
457
Serotonin 348, 350, 478
Serum amyloid A 65, 68
Short bowel syndrome 221, 222, 225,
227, 261-266, 268-272, 275,
276, 278
Short chain fatty acids (SCFA) 223,
235, 251, 252, 255, 264, 422
Small bowel transplantation 418, 419,
423, 425, 426
Sodium 6, 14, 42, 60, 83, 94, 147,
149, 152, 153, 155, 161, 164,
170-176, 268, 269, 276, 277,
289, 291, 323, 422, 424, 425
Somatomedin C 9, 90
Somatostatin 211, 224-227, 229, 230,
251, 267, 290, 328, 329
Sorbitol 153
Sphincter of Oddi 328, 335
Stamm 199-201
Steatorrhea 277
Stein-Leventhal syndrome 474
Subclavian artery 165, 166
Subjective Global Assessment of
Nutritional Status 434
Sucralfate 151, 155, 266, 267, 280
Super Soluble Maxijul 420
Suppressor T-cells (CD8) 29, 31
Systemic inflammatory response
syndrome (SIRS) 1, 376, 377
T
T-lymphocytes 25, 26, 40, 68, 403,
453, 458
T. glabrata 292
Tacrolimus 281, 283, 291, 296, 426
Termination codons 54
Therapeutic intervention score (TIS)
376
Thromboxane A1 36
Thyroid hormone 2, 67, 233, 312,
397
Thyroxine-binding globulin (TBG) 3
Thyroxine-binding prealbumin (TTR)
3, 9-15, 134, 140
Ticarcillin-clavulanate 293, 296
Tobramycin 291, 293, 296
Total energy expenditure (TEE) 5,
136, 399, 400, 409
Total lymphocyte count (TLC) 9,
135, 140, 208, 213, 214, 405,
449
I
n
d
e
x
Total parenteral nutrition (TPN) 6, 7,
10, 28-32, 37, 65, 73, 78, 79,
91, 92, 114, 145, 158, 159,
161-165, 167-177, 183,
208-212, 214-217, 225, 255,
262, 265-268, 270, 271, 275,
278, 279, 288, 294-296, 306,
309, 310, 312-315, 320,
327-331, 337-340, 342,
354-356, 369, 371-375, 405,
459, 463, 464
TPN
Medication administration with
TPN 295, 296
Perioperative TPN 91, 312
Trans-Golgi network (TGN) 109, 110
Transferrin 3, 9, 10, 55, 63, 66, 67,
69, 70, 133-136, 140, 163, 213,
314, 351, 361, 372, 378, 388,
401, 406, 433, 434, 449, 454,
455, 458
Transforming growth factor-
(TGF-) 88, 111, 251
Transthyretin 3, 9, 11, 12, 14, 67, 163
Triceps skinfold (TSF) 131, 136, 182,
184, 213
tRNA 53, 54
Trypsin 9, 60, 65, 112, 307, 320, 322,
323, 326, 328, 335-337, 341,
342, 346
Tryptophan 17, 56-58, 60, 61,
348-350
Tumor necrosis factor (TNF) 2, 9, 25,
31, 38, 64, 75, 83, 98, 111-113,
117, 118, 120, 122, 231, 233,
325, 375, 341, 375, 397, 405
Tumor necrosis factor-alpha (TNF)
390
TwoCal HN 146
Tyrosine 17, 56-62, 235, 348-350
U
Ulcerative colitis 126, 212, 306, 307,
311, 313, 314
Urea cycle 3, 56, 58, 62, 72-74, 401
Urea kinetic modeling 138
Urinary infection 1
Urinary nitrogen appearance (UNA)
138, 139
V
Vagotomy 271, 453
Valine 17, 23, 57, 58, 329, 349, 398,
405
Vancomycin 292-294, 296
Vascular smooth muscle cells (VSMC)
78
Vasoactive intestinal polypeptide (VIP)
103, 115, 117, 225, 226,
228-230, 264
Venous air embolism 166
Venous thrombosis 166, 262, 279,
282
Viokase 147
Vitamin A 3, 7, 9, 67, 107, 134, 223,
403, 455
Vitamin B 7, 96, 264, 404
Vitamin B
12
7, 131, 264, 268, 269,
276, 277, 307, 336, 484
Vitamin C 95, 96, 131, 269, 403
Vitamin D 97, 177, 366
Vitamin E 97, 365, 403
Vitamin K 97, 151, 153, 214, 268,
290
Vitamins 159, 164, 197, 261,
263-269, 277
Vivonex 32, 40, 41, 146, 153
W
Warfarin 150, 151, 167, 279,
281-283
Witzel 201, 203, 204
Z
Zinc 7, 67, 97, 98, 131, 133, 146,
150, 160, 211, 223, 255, 267,
269, 276, 307, 335, 336, 379,
404, 426, 439
Zymogen granules 322, 326
V m
Rifat Latifi
Stanley J. Dudrick
a d e m e c u V a d e m e c u m
Table of contents
1. Clinical Implications
of Carbohydrate, Proteins,
Lipids, Vitamins and Trace
2. Current Nutrient Substrates
4. Acute Phase Proteins
5. Arginine Metabolism
in Critical Care and Sepsis
6. Wound Healing and the Role
The Vademecum series includes subjects generally not covered in other handbook
series, especially many technology-driven topics that reflect the increasing
influence of technology in clinical medicine.
The name chosen for this comprehensive medical handbook series is
Vademecum, a Latin word that roughly means to carry along. In the Middle
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The Landes Bioscience Vademecum books are intended to be used both in the
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www.landesbioscience.com
LANDES
B I OS C I E NC E
I SBN 1- 57059- 595- X
LANDES
B I OS C I E NC E
of Current Nutritional
Support
2nd edition
7. Protein Metabolism in Liver
and Intestine During Sepsis:
Mediators, Molecular Regulation,
and Clinical Implications
8. Biochemical Assessment and
Monitoring of Nutritional Status
9. Optimizing Drug Therapy
10. Techniques and Monitoring
of Total Parenteral Nutrition
11. Radiologic Assessment
of Nutritional and Metabolic
Status
12. Enteral Nutrition: Indications,
Monitoring and Complications
(excerpt)

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V m

version 4.0 (Abacus Concepts, Inc., Berkley,

), a nutrient-dense formula (TwoCal HN

), and an free amino

) when mixed with 39 common pharmaceutical prepa-

) and one tablet of sodium bicarbonate (324 mg) were

Special formulation for NG or J-tube administration

when compared to water. The Ensure

), an imidazole antifungal agent, requires an acidic pH to be

) are used to increase gastric emptying. Although dis-

suspension, codeine phosphate solution, theophyl-

providing 1,500 to 2,000 kcal/day for 10-31 days) during ra-

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