The Biology And Practice Of Current Nutritional Support 2nd Edition (Vademecum)

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Table of contents

7. Protein Metabolism in Liver and Intestine During Sepsis: Mediators, Molecular Regulation, and Clinical Implications

2. Current Nutrient Substrates

8. Biochemical Assessment and Monitoring of Nutritional Status

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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(excerpt)

1. Clinical Implications of Carbohydrate, Proteins, Lipids, Vitamins and Trace Elements in Nutrition Support

3. Biochemistry of Amino Acids: Clinical Implications

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9. Optimizing Drug Therapy and Enteral Nutrition: Detecting Drug-Nutrient Interactions

The Biology and Practice of Current Nutritional Support 2nd edition

10. Techniques and Monitoring of Total Parenteral Nutrition 11. Radiologic Assessment of Nutritional and Metabolic Status 12. Enteral Nutrition: Indications, Monitoring and Complications

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Rifat Latifi Stanley J. Dudrick

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The Biology and Practice of Current Nutritional Support 2nd Edition 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. Mary’s Hospital/Yale Affiliate Waterbury, Connecticut, U.S.A.

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GEORGETOWN, TEXAS U.S.A.

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. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publisher: Landes Bioscience, 810 S. Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 ISBN: 1-57059-595-X

Library of Congress Cataloging-in-Publication Data CIP applied for, but not received at time of printing.

While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Dedication Jonathan Evans Rhoads, M.D. 1907-2002 Dedicated to the surgeon of the century, whose extraordinary personal attributes 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

3. Biochemistry of Amino Acids: 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 Rifat Latifi, Stanley J. Dudrick 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 Uranües 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. O’Keefe 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 Department of Surgery University of Arizona Tucson, Arizona, U.S.A. Chapters 3, 6, 11, 17, 20, 24, 25, 30

Stanley J. Dudrick, M.D. Professor of Surgery Yale University School of Medicine St. Mary’s Hospital/Yale Affiliate Waterbury, Connecticut, U.S.A. Chapters 14, 17, 20, 21

Contributors Frizan Abdullah Department of Surgery Yale University New Haven, Connecticut, U.S.A. Chapter 17

S. V. Beath The Birmingham Children's Hospital and University of Birmingham Birmingham, U.K. Chapter 27

Souheil Abou-Assi Section of Nutrition Division of Gastroenterology Department of Internal Medicine Richmond, Virginia, U.S.A.

Larry H. Bernstein Yale University Pathology Bridgeport, Connecticut, U.S.A. Chapter 1

Chapter 30

Khawaja Azimuddin University of New Mexico Espanola Hospital Espanola, New Mexico, U.S.A. Chapters 3, 4

George L. Blackburn Division of Nutrition Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, U.S.A. Chapter 2

Timothy J. Babineau Minimally Invasive Surgery Boston Medical Center Boston University School of Medicine Boston, Massachusetts, U.S.A. Chapter 2

Wendy Swails Bollinger Department of Health Matters Pennsylvania State University University Park, Pennsylvania, U.S.A. Chapter 2

Marcia Brackbill Department of Pharmacy Shenandoah University Winchester, Virginia, U.S.A.

Rosemarie L. Fisher Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut, U.S.A.

Chapter 9

Chapter 28

Gretchen M. Brophy Department of Pharmacy and Neurosurgery Virginia Commonwealth University Medical College of Virginia Richmond, Virginia, U.S.A.

Richard Formica Section of Nephrology Yale University School of Medicine New Haven, Conneticut, U.S.A.

Chapter 9

Vanessa Fuchs Hospital General de México The American British Cowdray Medical Center México DF, Mexico

Antonio Cayco Section of Nephrology Yale University School of Medicine New Haven, Connecticut, U.S.A.

Chapter 23

Chapter 25

Chapter 23

Matthew E. Cohen Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut, U.S.A.

Bruce Grossie Department of Nutrition and Food Sciences Texas Woman's University Denton, Texas, U.S.A.

Chapters 28, 29

Chapter 5

Susan T. Crowley Section of Nephrology Yale University School of Medicine New Haven, Conneticut, U.S.A.

Per-Olof Hasselgren Department of Surgery Beth Israel Medical Center Harvard Medical School Boston, Massachusetts, U.S.A.

Chapter 23

Chapter 7

John M. Daly Department of Surgery Weill Medical College of Cornell University New York, New York, U.S.A.

David N. Herndon Galveston Shriners Hospital Blocker Burn Unit Galveston, Texas, U.S.A.

Forward

Chapter 26

Robert S. Dechicco The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A.

Diane R. Horowitz Radiologist Private Practice Orlando, Florida, U.S.A.

Chapter 8

Chapter 11

Eric Hungnness Department of Surgery University of Cincinnati Cincinnati, Ohio, U.S.A. Chapter 7

Rao R. Ivatury Virginia Commonwealth University Department of Surgery Medical College of Virginia Hospitals and Physicians Richmond, Virginia, U.S.A.

A. K. Malhotra Virginia Commonwealth University Department of Surgery Medical College of Virginia Hospitals and Physicians Richmond, Virginia, U.S.A. Chapter 25

Laura E. Matarese The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Chapters 8, 10

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 Section of Nutrition Medical College of Virginia Hospitals Richmond, Virginia, U.S.A. Chapter 18

David A. Lanning Children’s Hospital of Michigan Wayne State University Detroit, Michigan, U.S.A. Chapter 6

Gayle Minard Department of Surgery The University of Tennessee Memphis, Tennessee, U.S.A. Chapter 12

Michael M. J. Muller Department of Surgery South Auckland Burn Service Middlemore Hospital Otahuhu, Auckland, New Zealand Chapter 26

Stephen J. D. O'Keefe Section of Nutrition Division of Gastroenterology Department of Internal Medicine Richmond, Virginia, U.S.A. Chapter 30

Patricia Pecora Fulco Medical College of Virginia Hospitals Virginia Commonwealth University Richmond, Virginia, U.S.A. Chapter 18

Paul G. Perch Department of Surgery Virginia Commonwealth University Medical College of Virginia Hospitals and Physicans Richmond, Virginia, U.S.A. Chapter 21

Melissa F. Perkal Department of Surgery Yale University School of Medicine New Haven, Connecticut, U.S.A. Chapter 19

Renee Piazza-Barnett The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Chapter 10

John M. Porter Department of Surgery University of Arizonia Tucson, Arizona

John G. Sharp Department of Anatomy University of Nebraska Medical Center Surgical Services at the Omaha VA Medical Center Omaha, Nebraska, U.S.A. Chapters 15, 16

Jon S. Thompson Department of Surgery University of Nebraska Medical Center Omaha, Nebraska, U.S.A. Chapter 15, 16

Chapter 13

Timothy A. Pritts Department of Surgery University of Cincinnati Cincinnati, Ohio, U.S.A.

Selman Uranues Department of Surgery AustriaGraz University Graz, Austria Chapter 24

Chapter 7

Shailendra K. Sazena Department of Surgery University of Nebraska Medical Center Omaha, Nebraska, U.S.A. Chapters 15, 16

John H. Seashore Yale University School of Medicine New Haven, Connecticut, U.S.A. Chapter 19

Douglas L Seidner The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Chapters 8, 10

Ezra Steiger Cleveland Clinic Hospital Cleveland, Ohio, U.S.A. Chapter 8

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 achievement 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, cancer, 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 development of nutrition support teams and the development of the American Society of Parenteral and Enteral Nutrition were created by the concept of teaching proper nutritional support throughout the world. Teams of doctors, 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 1970’s 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 outcome. Prospective randomized trials were then begun and carried through into the 1980’s 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 emulsions 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 vitamin and mineral deficiencies. Early recognition of these problems led to their solution. The decades of the 1980’s and 1990’s 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. Prospective 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 hospitals 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 nutritional substrates, which can be administered in different clinical scenarios. Of particular importance, is the chapter on nutritional metabolic management 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 exemplifies the value of an inquisitive mind and the strength of working in partnership 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 Elements in Nutrition Support 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 adversely 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, particularly in the geriatric patient, because of the very strong association between malnutrition 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 interacting with a malnourished state.

The Malnutrition Risk The problem of unrecognized patient risk is tied to our conception and definition 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 don’t embody 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

Imperative for Nutritional Intervention

1

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 identify chronic losses and an acute stress state by both clinical and laboratory characteristics 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 substrates, 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 mediators 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 effects—hyperglycemia, 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 (T4) has an effect on target organs through the free hormone (FT4). 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 carbohydrate and fatty acid fuels, and necessary to support the repair of damaged tissue. The humoral events include the changes in and interactions between serum proteins in the inflammatory response. The systemic effects of fever, tachycardia, increased 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

Clinical Implications of Nutrition Elements

3

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 serum 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 adaptive 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 consider that this adaptive relationship in stress injury is affected by protein malnutrition 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 it’s binding to a lower plasma concentration of CBG. The liver is the repository for extrathyroidal T4. The extrathyroidal T4 is released with a decreased circulating TBG and TTR.9 The result is an increased thyroidal activity measured by an increased free T4 (FT4). 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. Vitamin 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 breakdown 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.

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Cuthbertson described the catabolic loss of nitrogen that cccurs with severe injury and is associated with skeletal muscle wasting, loss of strength, and attributed 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 CO2 production. 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 accretion 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 insulin, but with increased activities of counterregulatory hormones opposing the insulin 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. CO2 production is used to measure substrate oxidation and energy expenditure by indirect calorimetry from measurement of respiratory gas exchange rates. The method assumes the CO2 expired is proportional to the rate of respiration. The assumption depends on the O2 disappearing from the inspired air being used exclusively for biological oxidations so that all the CO2 expired is derived from

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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 substrate by oxidation, regardless of cycling that may occur along the way. The method of indirect calorimetry and the Fick principle both measure the oxygen consumption (VO2) and the carbon dioxide production (VCO2). Indirect calorimetry measures the oxygen consumption (VO2) and the transpulmonary O2 gradient from the respiratory gas exchange. Fick proposed to measure the VO2 and VCO2 from gas exchange and the transpulmonary O2 and CO2 gradient by heart catheterization. In this idealized model, the O2 input and CO2 output is measured, and the cardiac output (CO) provides the flow rate. The result is: VO2 = CO (arterial O2 – mixed venous O2) VCO2 = CO (arterial CO2 – mixed venous CO2) Assuming that ambient air is the only source for O2 and the only sink for metabolic CO2, the VO2 and the VCO2 are measured from the fractional concentrations of O2 and CO2 concentrations in the inspired (FI) and the expired (FE) air flows. The calculation is: VO2 = (FIO2 – FEO2)Ve VCO2 = (FICO2 – FECO2)Ve, where Ve is the ventilatory rate. The only significant difference between these is that the measures of VCO2 are 12% lower and less accurate with Fick than with indirect calorimetry.13

Energy of Fuels The respiratory quotient (RQ), defined as VCO 2/VO2, is the measure of efficiency of respiration.10 The calorimetric RQ is between 0.69 and 1.00. The energy expenditure being measured by the VO2, a value of less than 1.0 is incomplete combustion. RQ is important for calculating the nutritional requirements in providing assisted nutritional support. The RQ for fat is 0.7, whereas the RQ for carbohydrate 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 it’s low RQ. The effect of excessive carbohydrate calories is excessive CO2 production, which drives a hyperpnea, detrimental to the pulmonary compromized patient. Lipid has a rate of administration that is rate limited by it’s 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 estimated calorie and protein needs with reasonable agreement with actual needs. Males BEE = 66.47 + 13.75 W + 5.0 H—6.76 A Females BEE = 655.10 + 9.56 W + 1.85 H—4.68 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)

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Nutritional Requirements

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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 utilization 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 provision 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 compromised 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 nutrient intake, regardless of the route of administration. The major minerals—calcium, phosphorus, and magnesium, and electrolytes—sodium, 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 important 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;

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Table 1.1. Stress 0 1 2 3

Calorie and protein needs in stress Clinical Setting Simple starvation Elective Surgery Polytrauma Sepsis

CHO% 28 32 40 50

NPC:N 150:1 100:1 100:1 180:1

Stress 1.0 1.5 2.0 2.5

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 accounts 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 function, oxygen transfer systems, and neuromuscular function. The majority of phosphorus 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, phosphorus 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 regarding 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, manganese, iodide, selenium and molybdenum, and cobalt. These are required for metabolic function and their deficiency is associated with specific biochemical change and functional abnormality that is relieved by giving these nutrients. Of these, cobalt is associated with vitamin B12. 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 enzymes 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.

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Clinical vs. Laboratory Information

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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 themselves, contribute to over- and underutilization (malutilization) of nutritional support. 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 assessment is expected concordance between two types of observations. The sensitivity and one—specificity 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. Agreement 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 concept is the observation that a patient has an albumin of 2.7 g/dl AND and lymphocyte 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 variable, 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 proteolysis 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 catabolic phase more accurately than urinary urea nitrogen.

Clinical Implications of Nutrition Elements

Table 1.2.

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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/mm2 Pre-Albumin < 11 mg/dl Transferrin < 150 mg/dl Albumin < 3.0 g/dl

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 transferrin are also) even when other proteins are severely depressed. CRP is a particularly good indicator of bacterial infection. CRP and TNF-α 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 insensitive for measuring anabolism, and its volume distribution makes it a population 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 better 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 nephelometry. Insulin growth-factor 1 (IGF1) or somatomedin C is the best measure of anabolic 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 measuring fibronectin, which may have a role in wound healing. Fibronectin is decreased 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

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Table 1.4.

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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.

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

finding for a burn patient because the patient can’t 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 diverticulitis had a surgical resection and proximal diverting colostomy with a somewhat 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

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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 (correlation) 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, Rypka’s truth table comprehension,17 Rudolph’s 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 Bernstein18 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 interventions become inputs.

Improving Correction of Malnutrition Identify Malnutrition Risk and Intervene The ability to identify malnourished patients and to implement early intervention 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 obtaining 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 support. 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

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inadequate or that the patient is unresponsive. Serum TTR concentration is a prognostic indicator.

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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 nitrogen excretion is often used to assess the amount of protein deficit prior to feeding. Failure 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.

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 identifying serious risk. TTR is a measure of the NDAD, so the decrease in TTR is associated with changes in CRP, TNFalpha, 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 nitrogen 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) (SUNf—SUNi), 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 balance 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. Urinary 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 pCO2 production with CO2 retention. Carbohydrate also leads to fatty liver. This necessitates the close monitoring of pCO2 measurement for patients on nutritional support and less frequent evaluation of liver function, such as the alkaline phosphatase. 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 pCO2, the glucose, and the

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TTR. The K+, Mg2+ and H2PO32- 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 sudden 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 compounds 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 nucleotide production due to hypophosphatemia can result in hemolytic anemia, neuromuscular dysfunction, myocardial depression and respiratory failure. Adequate treatment of the severely malnourished patient requires adequate nutritional support 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 (Meguid’s IONIP), initial condition, unexpected complication (wound site infection, pneumonia), and malnutrition. The effect of nutritional status is independent and interacts with the other factors. The laboratory tests predict outcome by forming severity classes. Mozes et al22 recently classified surgical and nonsurgical major diagnostic categories into groups homogeneous with respect to LOS from seven laboratory values (wbc, Na, K, CO2, BUN, HCT, ALB) for 73,117 admissions at UCSF and Stanford. Studies have shown that Hb, cholesterol23 and insulin-like growth factor 1 (IGF1)24 are predictors of mortality. 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, intravenous and enteral, are uniquely identified input variables. In addition to the assignment 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 avoidance. Traditional cost accounting models are not adequate for the complexity of the issues.

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Table 1.6.

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The Biology and Practice of Current Nutritional Support

Problems of overfeeding

• excess CO2 production • fat deposition • hyperglycemia • pulmonary edema • worsening of existing congestive heart failure • hepatic complications

Table 1.7. Electrolyte

Etiology of common electrolyte deficiencies Cause of Deficiency

Sodium

Loss of skin, GI tract, lungs or kidney Kidney—diuretic 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

The ability to identify malnourished patients and to implement early intervention 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 admission 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 determination 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

Clinical Implications of Nutrition Elements

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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 reactant, 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. Failure 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. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

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. Bernstein LH, Shaw-Stiffel TA, Schorow M et al. Financial implications of malnutrition. In: Labbe R, ed. Clinics in laboratory medicine. Nutition support. Vol 13. Philadelphia: Saunders, June 1993:491-506. 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. Meguid MM, Campos ACL, Meguid V et al. IONIP: a criterion of surgical outcome and patient selection for preoperative nutritional support. Br J Clin Pract 1988; 42(suppl 63):8-14. Bernstein LH, Leukhardt-Fairfield CJ, Pleban W et al. Usefulness of data on albumin and prealbumin concentrations in determining effectiveness of nutritional support. Clin Chem 1989; 35:271-274. Bernstein LH. Utilizing laboratory parameters to monitor effectiveness of nutritional support. Nutr Int 1994; 10:58-60. 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. Wilmore DW, Black PR, Muhlbacher F. Injured Man: Trauma and Sepsis. Chapter 4. In: Winters RW, Greene HL, eds. Nutritional Support of the Seriously Ill Patient. New York: Academic Press, 1983:33-52. Ingenbleek Y, Bernstein L. The stressful condition as a nutritionally dependent adaptive dichotomy. Nutrition 1999; 15:305-320. 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. 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. Hill GL, King RFGJ, Smith RC et al. Multi-element analysis of the living body by neutron activaion analysis—application to critically ill patients receiving intravenous nutrition. Br J Surg 1979; 66:868-72. Ferrannini E. Equations and Assumptions of Indirect Calorimetry: Some Special Problems. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York: Raven Press, 1992:1-17. Young VR, Yong-Ming Y, Fukagawa NK. Whole Body Energy and Nitrogen (Protein) Relationships. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York: Raven Press, 1992:139-161.

1

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The Biology and Practice of Current Nutritional Support 15.

1

16. 17.

18. 19. 20. 21. 22. 23. 24.

Jeejeebhoy KN, Baker JP, Wolman SL et al. Critical evaluation of the role of clinical assessment and body composition studies in patients with malnutrition after total parenteral nutrition. Am J Clin Nutr 1982;35:1117-27. 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. 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. Rudolph RA, Bernstein LH, Babb J. Information-Induction for the diagnosis of myocardial infarction. Clin Chem 1988; 34:2031-2038. 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. Bernstein LH, Shaw-Stiffel T, Zarny L et al. An information approach to likelihood of malnutrition. Nutrition 1996; 12(9/10):772-776. Bernstein LH (Chairman). Prealbumin in Nutritional Care Consensus Group. Measurement of visceral protein status in assessing protein and energy malnutrition: Standard of care. Nutrition 1995; 11:169-171. 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. Verdery RB, Goldberg AP. Hypocholesterolemia as a predictor of death: a prospective study of 224 nursing home residents. J Gerontol:Med Sci 1991; 46:M84-M90. 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 concentrations seen in patients with hepatic encephalopathy. These plasma amino acid alterations 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 neurotransmitters” (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 The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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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 intermittent 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 correlation between the modifications in plasma amino acid levels and an improvement in the patient’s 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 al5 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 encephalopathy (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 encephalopathy. 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 encephalopathy (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

Current Nutrient Substrates

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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 enriched 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 -10% Adequate nutrition < -10% to 20% Under-nutrition < -20% to 30% Malnutrition 30 Days

Primary pharyngeal tumors Preoperative weight loss of more than ten pounds Stage IV cancer Combined surgery and radiotherapy

60% 56% 55% 50%

Pooled risk factors No risk factor One risk factor Two risk factors Three risk factors All four risk factors

16% 26% 52% 56% 86%

Adapted from Gardine, Kokal, Beatty and colleagues.38

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of the oral cavity, pharynx or larynx treated with surgical resection. Of the 92 who received postoperative enteral feeding, 41 (45%) required prolonged enteral support. Delayed wound healing was the indication for one-half of the patients requiring 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

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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 endoscopic 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 preoperatively 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 chemotherapy before the PEG and the 12 patients who underwent full-course chemotherapy 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 before 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 cephalosporin 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) technique45 or “pull” (Ponsky) techniques46 percutaneous placement under endoscopic guidance can be achieved using the “introducer”

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(Russell) technique.47 However, being of smaller diameter and anchored by an inflated 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 inducing 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 extension’s 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 reflux51), the routine use of jejunostomy extensions cannot be recommended. Rather, direct percutaneous endoscopic jejunostomy52 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 reduced 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 technique55-60 (preceded by bougienage of the esophagus only in the first reported case61). 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 absence 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

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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, preoperative nutritional support should be provided for ten days. 3) In surgical patients with malnutrition or postoperative complications, postoperative 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.

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 unknown, but is presumably low. Also unknown is to what degree, if any, risk of gastrostomy site metastasis is reduced by using introducer or operative placement techniques which avoid contamination of the gastrostomy tube with cancer cells.

Conclusion Evidence-based guidelines regarding the appropriate nutritional support of surgical, 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 recommendations 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 malnourished 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 nutrition, 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).

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Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

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12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Souba W. Nutritional support. N Engl J Med 1997; 336:41-48. Brookes GB. Nutritional status: A prognostic indicator in head and neck cancer. Otolaryngol Head Neck Surg 1985; 93:69-74. Bassett MR, Dobie RA. Patterns of nutritional deficiency in head and neck cancer. Otolaryngol Head Neck Surg 1983; 91:119-125. Guo C, Ma D, Zhang K. Nutritional status of patients with oral and maxillofacial malignancies. J Oral Maxillofac Surg 1994; 52:559-562. Linn BS, Robinson DS, Klimas NG. Effects of age and nutritional status on surgical outcomes in head and neck cancer. Ann Surg 1988; 207:267-273. Westin T, Jansson A, Zenckert C et al. Mental depression is associated with malnutrition in patients with head and neck cancer. Arch Otol Head Neck Surg 1988; 114:1449-1453. Sobol SM, Conoyer JM, Sessions DG. Enteral and parenteral nutrition in patients with head and neck cancer. Ann Otol 1979; 88:495-501. Sobol SM, Conoyer JM, Zill R et al. Nutritional concepts in the management of the head and neck cancer patient: I. Basic concepts. Laryngoscope 1979; 89:794-803. Matthews TW, Lampe HB, Dragosz K. Nutritional status in head and neck cancer patients. J Otolaryngol 1995; 24:87-91. Johnston CA, Keane TJ, Prudo SM. Weight loss in patients receiving radical radiation therapy for head and neck cancer: A prospective study. JPEN 1982; 6:399-402. Eilber FR, Morton DL, Ketcham AS. Immunologic abnormalities in head and neck cancer. Am J Surg 1974; 128:534-538. Hooley R, Levine H, Flores TC et al. Predicting postoperative head and neck complications using nutritional assessment: the prognostic nutritional index. Arch Otolaryngol 1983; 109:83-85. Goodwin WJ Jr, Torres J. The value of the prognostic nutritional index in the management of patients with advanced carcinoma of the head and neck. Head Neck Surg 1984; 6:932-937. Linn BS. A protein energy malnutrition scale (PEMS). Ann Surg 1984; 200:747-752. Flynn MB, Leightty FF. Preoperative outpatient nutritional support of patients with squamous cancer of the upper aerodigestive tract. Am J Surg 1987; 154:359-362. Goodwin WJ Jr, Byers PM. Nutritional management of the head and neck cancer patient. Med Clin N Am 1993; 77:597-610. Copeland EM, MacFadyen BV, MacComb WS et al. Intravenous hyperalimentation in patients with head and neck cancer. Cancer 1975; 35:606-611. Sako K, Loré JM, Kaufman S et al. Parenteral hyperalimentation in surgical patients with head and neck cancer: A randomized study. J Surg Oncol 1981; 16:391-402. Copeland EM III, Daly JM, Dudrick SJ. Nutritional concepts in the treatment of head and neck malignancies. Head Neck Surg 1979; 1:350-363. Linn BS, Robinson DS. The possible impact of DRGs on nutritional status of patients having surgery for cancer of the head and neck. JAMA 1988; 260:514-518. Heller KS, Dubner S, Keller A. Long-term evaluation of patients undergoing immediate mandibular reconstruction. Am J Surg 1995; 170:517-520. Aguilar NV, Olson ML, Shedd DP. Rehabilitation of deglutition problems in patients with head and neck cancer. Am J Surg 1979; 138:501-507. Williams EF III, Meguid MM. Nutritional concepts and considerations in head and neck surgery. Head and Neck 1989; 11:393-399. Chencharick JD, Mossman KL. Nutritional consequences of the radiotherapy of head and neck cancer. Cancer 1983; 51:811-815.

Nutrition Support in Patients with Head and Neck Cancer 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46.

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Nayel H, El-Ghoneimy E, El-Haddad S. Impact of nutritional supplementation on treatment delay and morbidity in patients with head and neck tumors treated with irradiation. Nutrition 1992; 8:13-18. Mossman KL, Henkin RI. Radiation-induced changes in taste acuity in cancer patients. Int J Rad Oncol Biol Phys 1978; 4:663-670. Frank RM, Herdly J, Philippe E. Acquired dental defects and salivary gland lesions after irradiation for carcinoma. J Amer Dent Assn 1965; 70:868-883. Mossman K, Scheer A. Complications of radiotherapy of head and neck cancer. ENT J 1977; 56:90-95. Henkin RI. Prevention and treatment of hypogeusia due to head and neck irradiation (letter). JAMA 1972; 220:870-871. Bäckström I, Funegärd U, Andersson I et al. Dietary intake in head and neck irradiated patients with permanent dry mouth symptoms. Eur J Cancer 1995; 31B:253-257. Beeken L, Calman F. A return to “normal eating” after curative treatment for oral cancer: What are the long-term prospects? Eur J Cancer 1994; 30B:387-392. Harrison LB, Zelefsky MJ, Armstrong JG et al. Performance status after treatment for squamous cell cancer of the base of the tongue: A comparison of primary radiation therapy versus primary surgery. Int J Radiat Oncol Biol Phys 1994; 30:953-957. Fay D, Poplausky M, Gruber M et al. Long-term enteral feeding: A retrospective comparison of delivery via percutaneous endoscopic gastrostomy and nasoenteric tubes. Am J Gastroenterol 1991; 86:1604-1609. Sobol SM, Conoyer JM, Zill R et al. Nutritional concepts in the management of the head and neck cancer patient: II. management concepts. Laryngoscope 1979; 89:962-979. Meehan SE, Wood RAB, Cuschieri A. Percutaneous cervical pharyngostomy: A comfortable and convenient alternative to protracted nasogastric intubation. Am J Surg 1984; 148:325-330. Gibson S, Wenig BL. Percutaneous endoscopic gastrostomy in the management of head and neck carcinoma. Laryngoscope 1992; 102:977-980. Norton B, Homer-Ward M, Donnelly MT et al. A randomized prospective comparison of percutaneous endoscopic gastrostomy and nasogastric tube feeding after acute dysphagic stroke. BMJ 1996; 312:13-16. Gardine RL, Kokal WA, Beatty JD. Predicting the need for prolonged enteral supplementation in the patient with head and neck cancer. Am J Surg 1988; 156:63-65. Noone RB, Graham WP III. Nutritional care after head and neck surgery. Postgrad Med 1973; 53:80-86. Selz PA, Santos PM. Percutaneous endoscopic gastrostomy. A useful tool for the otolaryngologist—head and neck surgeon. Arch Otolaryngol Head Neck Surg 1995; 121:1249-1252. Gibson SE, Wenig BL, Watkins JL. Complications of percutaneous endoscopic gastrostomy in head and neck cancer patients. Ann Otol Rhinol Laryngol 1992; 101:46-50. Jain NK, Larson DE, Schroeder KW et al. Antibiotic prophylaxis for percutaneous endoscopic gastrostomy: A prospective, randomized, double-blind clinical trial. Ann Intern Med 1987; 107:824-828. ASGE. Antibiotic prophylaxis for gastrointestinal endoscopy. Gastrointest Endosc 1995; 42:630-635. Riley DA, Strauss M. Airway and other complications of percutaneous endoscopic gastrostomy in head and neck cancer patients. Ann Otol Rhinol Laryngol 1992; 101:310-313. Sacks BA, Vine HS, Palestrant AM et al. A non-operative technique for establishment of a gastrostomy in the dog. Invest Radiol 1983; 18:485-489. Ponsky JL, Gauderer MWL. Percutaneous endoscopic gastrostomy: A nonoperative technique for feeding gastrostomy. Gastrointest Endosc 1981; 27:9-11.

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The Biology and Practice of Current Nutritional Support 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.

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58. 59. 60. 61. 62. 63.

Russell TR, Brotman M, Forbes N. Percutaneous gastrostomy: A new simplified and cost-effective technique. Am J Surg 1984; 148:132-137. Kocan MJ, Hickisch SM. A comparison of continuous and intermittent enteral nutrition in NICU patients. J Neurosci Nurs 1986; 18:333-337. Hamaoui E. Gastroesophageal reflux during gastrostomy feeding (commentary). JPEN 1995; 19:172-173. Silk DBA, Payne-James JJ. Complications of enteral nutrition. In: Rombeau J, Caldwell M, eds. Clinical Nutrition: Enteral and Tube Feeding. Philadelphia: WB Saunders Co, 1990. Kadakia SC, Sullivan HO, Starnes E. Percutaneous endoscopic gastrostomy or jejunostomy and the incidence of aspiration in 79 patients. Am J Surg 1992; 164:114-118. Shike M, Latkany L, Gerdes H et al. Direct percutaneous endoscopic jejunostomies for enteral feeding. Gastrointest Endosc 1996; 44:536-540. Lydiatt DD, Murayama KM, Hollins RR et al. Laparoscopic gastrostomy versus open gastrostomy in head and neck cancer patients. Laryngoscope 1996; 106:407-410. Stiegmann G, Goff J, Silas D et al. Endoscopic versus operative gastrostomy: Final results of a prospective randomized trial. Gastrointest Endosc 1990; 36:1-5. Bushnell L, White TW, Hunter JG. Metastatic implantation of laryngeal carcinoma at a PEG exit site. Gastrointest Endosc 1991; 37:480-482. Huang DT, Thomas G, Wilson WR. Stomal seeding by percutaneous endoscopic gastrostomy in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 1992; 118:658-659. Laccourreye O, Chabardes E, Merite-Drancy A et al. Implantation metastasis following percutaneous endoscopic gastrostomy. J Laryngol Otol 1993; 107:946-949. Meurer MF, Kenady DE. Metastatic head and neck carcinoma in a percutaneous gastrostomy site. Head Neck 1993; 15:70-73. Schiano TD, Pfister D, Harrison L et al. Neoplastic seeding as a complication of percutaneous endoscopic gastrostomy. Am J Gastroenterol 1994; 89:131-3. van Erpecum KJ, Akkersdijk WL, Warlam-Rodenhuis CC et al. Metastasis of hypopharyngeal carcinoma into the gastrostomy tract after placement of a percutaneous endoscopic gastrostomy catheter. Endoscopy 1995; 27:124-127. Preyer S, Thul P. Gastric metastasis of squamous cell carcinoma of the head and neck after percutaneous endoscopic gastrostomy: Report of a case. Endoscopy 1989; 21:295. Alagaratnam T, Ong G. Wound implantation: A surgical hazard. Br J Surg 1977; 64:872-875. Murthy SM, Goldschmidt RA, Rao LN et al. The influence of surgical trauma on 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 gastrointestinal cancer may be multifactorial (see Table 29.1), negative energy balance appears to be more closely linked to decreased intake than to increased expenditure.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 nutritional indices,4 although anorectic and malnourished patients with advanced gastrointestinal cancer may be an exception.5 Few studies have demonstrated that improving 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 nutrition 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 rehabilitation. 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 gluconeogenesis9 (none of which is inhibited by glucose infusion), and lipogenesis,10 plus impaired free fatty acid oxidation,8,10 and, in contrast to malnourished patients without cancer, fail to increase muscle strength despite two weeks of parenteral nutrition.10

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Table 29.1. Potential causes of weight loss and malnutrition in patients with gastrointestinal cancer 1. 2. 3. a. b. c. d. e. f. 4. a. b. c. d. e. 5.

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Anorexia of “cancer cachexia” Obstruction Malabsorption Metastatic infiltration of small bowel or mesentery Pancreatic duct obstruction or insufficiency Small bowel fistulas Biliary obstruction or bile salt insufficiency Bacterial overgrowth Megaloblastic changes from nutritional deficiencies Fluid and electrolyte imbalance Hypovolemia from inadequate intake Emesis from obstruction Osmotic diarrhea from malabsorption Secretory diarrhea from hormone-secreting tumors Fluid loss through fistulas Increased tumor-induced energy expenditure

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 mortality 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 malnourished 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 developed 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 population, 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 preoperative 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, colon, 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

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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 diets were advanced as tolerated. In patients receiving parenteral nutrition, the postoperative 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 enteral nutrition. In malnourished patients with gastric or colorectal cancer, preoperative 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 healing, 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 randomized study comparing 14 patients who received immediate jejunal feeding after elective intestinal resection for “quiescent, chronic gastrointestinal disease” with 14 patients who received only intravenous fluids for an average of 6 days, the feeding prevented transient postoperative negative nitrogen balance, attenuated gut permeability, and may have decreased nausea, vomiting, weight loss, and infections (differences 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 resection24,26 which compared favorably to parenteral nutrition at decreased cost.27 The only randomized study explicitly limited to patients with gastrointestinal cancer (gastric adeno-carcinoma) found that postoperative jejunostomy feeding was comparable to parenteral nutrition at one-half the cost, but caused more diarrhea (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 advancement 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 review of 217 consecutive patients the incidence of the former complication was 1% and the latter complication was not encountered.32

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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 suppressing pancreas exocrine function.41 Reviews have concluded that there is little evidence supporting a role for parenteral nutrition during chemotherapy.19 Similarly, enteral support has failed to improve nutritional or clinical outcomes following radiation 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 radiation enteritis.35 The American College of Physicians (ACP) concluded that in patients undergoing chemotherapy or combined chemotherapy and radiotherapy, parenteral nutrition was associated with net harm, but conceded that the intervention may be beneficial in patients who are severely malnourished39 based on a meta-analysis.43 Although parenteral nutrition is more expensive than enteral nutrition, is associated with more infectious complications, and may produce limited if any nutritional gains,5 it may be the only alternative in patients without an intact gastrointestinal 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 spontaneous 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 cancer. 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

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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 experienced 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 cancer, divided into sections on esophageal, gastric, colon, pancreatic, and liver cancer.

Esophageal Cancer Despite suffering from dysphagia, patients with esophageal cancer may have surprisingly infrequent weight loss (2%, 53% of the time, in one early study47). However, patients frequently have decreased indices of cell-mediated immunity, including 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 numbers, but not anergy or depressed blastogenesis.49 It is possible that parenteral nutrition 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 suppression 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 nutrition, 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.

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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 patients who were at high risk from those who were at low risk for perioperative mortality. It was used to identify patients who could benefit from modification of the proposed surgical procedure and more vigilant management of perioperative infections. 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 nutrition delivery did not persist as a predictor of survival.59 Survival differences were better explained by retained variables such as persistent disease, which likely correlated with an inability to eat. For patients with lesions obstructing the esophagus, pyriformostomy tube feeding may maintain enough of an esophageal lumen to allow 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 esophageal cancer as early as 1965 (although in a nonrandomized analysis using historical controls).62 One early study included 15 patients with esophageal cancer undergoing 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 nitrogen delivery (although the weight gain may not have been from anabolism—albumin levels were similar between groups). The number of perioperative complications 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 diarrhea, and they were ambulatory. The patients receiving parenteral nutrition, in contrast, 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 reflection 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,

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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 reduced incidence of weight loss (although not necessarily muscle loss) but an increased incidence of pulmonary sepsis, with a resultant increase in length of hospitalization 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 possibility of selection bias, where patients considered to be at highest risk for complications 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 enterally 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 surgical 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 postoperative parenteral nutrition in patients with stage III or IV gastric cancer has been claimed to restore cell-mediated immunocompetence, increase tolerance for 5-fluorouracil, and improve three-year survival (54% versus zero). There was no description, 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 significantly higher albumin, prealbumin, retinol binding protein, transferrin, and vitamin A levels compared to those who received only bypass or exploratory laparotomy. 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 albumin 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/mm3 each possessed specificity in excess of 96%, but being at the terminus of the receiver operating characteristic curves, suffered from low sensitivity. The prealbumin suggested discrete values which possessed

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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 concern, 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 outlet obstruction may require endoscopic stenting, surgical bypass, or decompression gastrostomy and feeding jejunostomy tubes. In patients who are not surgical candidates 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 nitrogen balance in patients having total gastrectomy. There were no differences in albumin 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 infusion 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 tumor is unable to proliferate without L-methionine, which is essential for methylation in the synthesis of DNA, RNA, and protein. Additionally, the methionine depletion appeared to further increase 5-fluorouracil’s inhibition of thymidylate synthase 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 energy 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 established oral intake of at least 60% of their caloric needs by the tenth postoperative

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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 common, the small intestine remains functional in the postoperative period.82 Despite the potential for postoperative gastroparesis, eight consecutive elderly, high-risk patients 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 postoperative maintenance of nitrogen balance and weight is, however, unclear. For example, in a study of parenteral nutrition following major surgery, temporary undernutrition 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 sepsis from bacteria originating in the gut.85 Patients receiving chemotherapy or radiation therapy present nutritional challenges 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 depleted 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 chemotherapy, 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 receiving identical chemotherapy for metastatic colon cancer, 14 days of pretreatment parenteral nutrition continued throughout chemotherapy was well-tolerated, associated 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 metabolism, 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

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enhanced in vitro T-lymphocyte response to stimulation, but reduced neither negative 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 arginine 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 include 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 breakdown remained constant.95 Metabolic expenditures increased when calories administered 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 Jehovah’s 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 transfusions, 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 feeding likely were those who survived aggressive therapy which temporarily caused gastrointestinal dysfunction. Home parenteral nutrition for this subgroup of cancer patients appears justified, as it is well tolerated and associated with only a 1% incidence of parenteral nutrition-related mortality. The benefits of home parenteral nutrition remain unclear when being used to extend life a small increment in patients with advanced colorectal cancer. In a retrospective uncontrolled review, patients 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

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six to nine months. Forces encouraging this increasing trend may include a fascination with technology, expanded availability of services, pressure from families, insurers’ preference for substituting parenteral nutrition at home for that in the hospital101 (since despite being $75,000 to $150,000/year [in 1992 dollars] home parenteral nutrition was still one-third the cost of hospital care102), Medicare’s reimbursement for home parenteral nutrition but not for home parenteral hydration, and the opportunity 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 cancer.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 cancer 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 combination of psychotherapy, cognitive-behavioral techniques, and antidepressant medication has been recommended to treat patients with pancreatic cancer and depression,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 anastomotic stents to jejunal feeding tubes in the early postoperative period.108 Although several studies have identified indicators of malnutrition which predicted postoperative complications, including weight loss greater than 10%, albumin less than 3.0 g/dL, and anergy,109-111 studies investigating the role of nutritional 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 percutaneous transhepatic biliary drainage and pancreatobiliary surgery reduced their morbidity 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 receiving routine postoperative total parenteral nutrition suffered a statistically significant

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higher rate of major complications (45% vs. 23%). This relationship remained significant even when complications thought to be reduced by bowel rest were analyzed separately (such as fistulas, abscess, obstruction, and anastomotic leak). Mortality 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 repletion are excellent. In 25 patients who were free of recurrent disease at least six months out from either conventional or pylorus-preserving pancreaticoduodenectomy, 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 pylorus-preserving pancreaticoduodenectomy group, the group having a conventional pancreaticoduodenectomy were more likely to complain of fullness and restricted food intake, but were less likely to suffer heartburn. Although ten patients required dietary or pharmacological intervention for diabetes, and five patients reported 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 protected 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 ammonia.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, prognostic 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 regeneration in humans121 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 patients with cirrhosis may have nutritional deficiencies from a combination of poor

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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 without being transformed or transported in chylomicrons.130 Sixty milliliters of medium 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 appears to be a function of the magnitude of portal hypertension rather than of mucosal 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 previously 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 inclusion 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 cancers. 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 paralleling results in hepatoma-inoculated rats administered standard parenteral nutrition.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 steatosis141 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 catabolism, which may be most important, given that the pool of plasma amino acids

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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 encephalopathy144 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 nutritional 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 supplementation did not improve postoperative outcomes in patients with liver dysfunction 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 group’s 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 postoperative 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 lipids151 or monoacetoacetate152 increased the rate of liver regeneration 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 postoperative 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

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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 reduction 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 presumably normal livers, three days of preoperative parenteral nutrition supplementing a hospital diet increased hepatic glycogen content and protein synthesis,155 although 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 colleagues17 and Müller 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 effectiveness analysis addressing the same question in people having gastrointestinal surgery (for unspecified indications) assumed that when either the risk of postoperative complications or the effectiveness of nutritional support in preventing these complications 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 postoperative incidence of nutrition-associated complications is 20%, using the Subjective Global Assessment (SGA) which had the best combination of sensitivity and specificity (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 Cooperative Study Group conducted in the 1980s (which, granted, did not focus specifically on patients with gastrointestinal cancer), incremental costs in 1992 dollars attributed 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 estimate 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 expectancy 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 jejunostomy, 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

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Conclusion

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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 administered to patients with cancer is likely inappropriate.161 Although parenteral nutrition 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 preoperative parenteral nutrition in malnourished patients scheduled to have major abdominal 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 physiological 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 trials providing 7-10 days of therapy resulted in decreased wound infections17 and decreased mortality.18 Continued research into manipulating the composition of enteral nutrition164-167 and parenteral nutrition168 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 gastrointestinal cancers given 15 days of parenteral nutrition, the cell kinetics of tumors from those who had been on a lipid-based regimen mirrored those from patients in other studies who had received chemotherapy or radiotherapy.169 In the meantime, the generic ASPEN practice guidelines for cancer and perioperative nutritional 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.

Selected References 1. 2. 3.

4. 5. 6.

Dewys W, Begg C, Lavin P et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 1980; 69:491-497. Lindmark L, Bennegard K, Eden E et al. Resting energy expenditure in malnourished patients with and without cancer. Gastroenterology 1984; 87:402-8. Buzby G, Willford W, Peterson O et al. A randomized clinical trial of total parenteral nutrition in malnourished surgical patients: the rationale and impact of previous clinical trials and pilot study on protocol design. Am J Clin Nutr 1988; 47(Suppl 2):366-381. Brennan M. Malnutrition in patients with gastrointestinal malignancy: Significance and management. Dig Dis Sci 1986; 31(Suppl):77S-90S. Lindh A, Cedermark B, Blomgren H et al. Enteral and parenteral nutrition in anorectic patients with advanced gastrointestinal cancer. J Surg Oncol 1986; 33:61-65. Eriksson B, Douglass H Jr. Intravenous hypealimentation: An adjunct to treatment of malignant disease of upper gastrointestinal tract. JAMA 1980; 243:2049-2052.

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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 malnourished patients or those in whom oncologic treatment toxicity is expected to preclude 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 undergoing 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 patients as soon as possible. Postoperative nutritional support may be indicated for mildly malnourished patients expected to otherwise sustain a postoperative period of starvation 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

7. 8. 9. 10. 11. 12. 13. 14. 15.

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Tayer J, Chlebowski R. Metabolic response to chemotherapy in colon cancer patients. JPEN 1992; 16 (Suppl):65S-71S. Nixon D, Moffitt S, Lawson D et al. Total parenteral nutrition as an adjunct to chemotherapy of metastatic colorectal cancer. Cancer Treat Rep 1981; 65(suppl 5):121-128. Stehle P, Zander J, Mertes N et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989; 1:231-233. O’Riordain M, Fearon K, Ross J et al. Glutamine-supplemented total parenteral nutrition enhances t-lymphocyte response in surgical patients undergoing colorectal resection. Ann Surg 1994; 220:212-221. Sigal R, Shou J, Daly J. Parenteral arginine infusion in humans: nutrient substrate or pharmacologic agent? JPEN 1992; 16:423-428. Escudier E, Escudier B, Henry-Amar M et al. Effects of infused intralipids on neutrophil chemotaxis during total parenteral nutrition. JPEN 1986; 10:596-598. Heys S, Park K, McNurlan M et al. Stimulation of protein synthesis in human tumors by parenteral nutrition: Evidence for modulation of tumor growth. Br J Surg 1991; 78:483-487. Ota D, Nishiok K, Grossie B et al. Erythrocyte polyamine levels during intravenous feeding of patients with colorectal carcinoma. Eur J Clin Oncol 1986; 22:837-842. Pöyhönen M, Takala J, Pitkänen O et al. Polyamine excretion in depleted patients with gastrointestinal malignancy: effect of perioperative nutrition and tumor removal. JPEN 1992; 16:226-231. Neuhäuser M, Bergström J, Chao L et al. Urinary excretion of 3-methylhistidine as an index of muscle protein catabolism in postoperative trauma: The effect of parenteral nutrition. Metabolism 1980; 29:1206-1213. Merrick H, Long C, Grecos G et al. Energy requirements for cancer patients and the effect of total parenteral nutrition. JPEN 1988; 12:8-14. McNurlan M, Heys S, Park K et al. Tumor and host tissue responses to branched-chain amino acid supplementation of patients with cancer. Clin Sci 1994; 86:339-345. Madura J. Use of erythropoietin and parenteral iron dextran in a severely anemic Jehovah’s Witness with colon cancer. Arch Surg 1993; 128:1168-1170. Howard L. Home parenteral nutrition in patients with a cancer diagnosis. JPEN 1992; 16 (Suppl):93S-99S. Levin R, Gordon J, Simonich W et al. Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium. J Clin Oncol 1991; 9:94-99. Wesley J, Khalidi N, Faubion W et al. Home parenteral nutrition: A hospital-based program with commercial logistic support. JPEN 1984; 8:585-588. Blackburn G, DiScala C, Miller M et al. Preliminary report on collaborative study for home parenteral nutrition patients. In: Johnson I, ed. Advances in Clinical Nutrition. Lancaster: MTP Press, Ltd., 1983:433-448. Yaskin J. Nervous symptoms as early manifestations of carcinoma of the pancreas. JAMA 1931; 96:1664-1668. Green A, Austin C. Psychopathology of pancreatic cancer: a psychobiological probe. Psychosomatics 1993; 34:208-221. Joffe R, Rubinow D, Demicoff K, Maher M, Sindelar W. Depression and carcinoma of the pancreas. Gen Hosp Psychiatry 1986; 8:241-245. Passik S, Breitbart W. Depression in patients with pancreatic carcinoma: diagnostic and treatment issues. Cancer 1996; 78:615-626. Hunter J, White T. Gastrostomy and jejunostomy using a transgastric tube for early enteral nutrition after pylorus-preserving pancreaticoduodenectomy. Surg Gyn Obstet 1991; 173:316-318.

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Burke D, MH T, McLean G et al. Conversion of choledochojejunostomy stents to jejunal feeding tubes for postoperative enteral alimentation. JPEN 1988; 12:225-226. Pitt H, Cameron J, Postier R et al. Factors affecting mortality in biliary tract surgery. Am J Surg 1981; 141:66-71. Dixon J, Armstrong C, Duffy S et al. Factors affecting morbidity and mortality after surgery for obstructive jaundice: A review of 373 patients. Gut 1983; 24:845-852. Halliday A, Benjamin I, Blumgart L. Nutritional risk factors in major hepatobiliary surgery. JPEN 1988; 12:43-48. Foschi D, Cavagna G, Callioni F et al. Hyperalimentation of jaundiced patients on percutaneous transhepatic biliary drainage. Br J Surg 1986; 73:716-719. Brennan M, Pisters P, Posner M et al. A prospective randomized trial of total parenteral nutrition after major pancreatic resection for malignancy. Ann Surg 1994; 220:436-444. Wells C, Rotstein O, Pruett T et al. Intestinal bacteria translocate into experimental intra-abdominal abscesses. Arch Surg 1986; 121:102-107. McLeod R, Taylor B, O’Connor B et al. Quality of life, nutritional status, and gastrointestinal hormone profile following the Whipple procedure. Am J Surg 1995; 169:179-185. Carter J, Saxe G, Newbold V et al. Hypothesis: Dietary management may improve survival from nutritionally linked cancers based on analysis of representative cases. J Am Coll Nutrition 1993; 12:209-226. Watanapa P, Williamson R. Experimental pancreatic hyperplasia and neoplasia: Effects of dietary and surgical manipulation. Br J Cancer 1993; 67:877-884. Muñoz S. Nutritional therapies in liver disease. Sem Liver Dis 1991; 11:278-291. Khatra B, Smith R, Millikan W. Activities of Krebs-Henseleit enzymes in normal and cirrhotic human liver. J Lab Clin Med 1974; 84:708-715. DiCecco S, Wieners E, Weisner R et al. Assessment of nutritional status in patients with end-stage liver disease undergoing liver transplantation. Mayo Clin Proc 1989; 65:95-102. Schmidt G, Tan P. Protein supplementation in a hepatic resection patient. Nutr Clin Pract 1990; 5:251-253. Sato N, Koyama Y, Oyamatsu M et al. Insulin-like growth factor-I (IGF-I) in malnourished rats following major hepatectomy. JPEN 1994; 18:25S. Helton W. Nutritional issues in hepatobiliary surgery. Sem Liver Dis 1994; 14:140-157. Krevsky B, Godley J. Nutritional support in advanced liver disease. Nutr Support Serv 1985; 5:8-17. Silk D, O’Keefe S, Wicks C. Nutritional support in liver disease. Gut 1991; (Suppl):S29-S33. Morgan M, Hawley K, Stambuk D. Amino acid tolerance in cirrhotic patients following oral protein and amino acid loads. Aliment Pharmacol Ther 1990; 4:183-200. Bunout D, Aicardi V, Hirsch S et al. Nutritional support in hospitalized patients with alcoholic liver disease. Eur J Clin Nutr 1989; 43:615-621. Swart G, Zillikens M, van Vuure J et al. Effect of a late evening meal on nitrogen balance in patients with cirrhosis of the liver. Br Med J 1989; 299:1202-1203. Plevak D, DiCecco S, Wiesner R et al. Nutritional support for liver transplantation: Identifying caloric and protein requirements. Mayo Clin Proc 1994; 69:225-230. Greenberger N, Skillman T. Medium-chain triglycerides: physiologic considerations and clinical implications. N Engl J Med 1969; 280:1045-1058.

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Cabre E, Gonzalez-Huiz F, Abad-Lacruz A et al. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics. Gastroenterol 1990; 98:715-720. Smith J, Horowitz J, Henderson J et al. Enteral hyperalimentation in undernourished patients with cirrhosis and ascites. Am J Clin Nutr 1982; 35:56-72. Herman L, Hoskins W, Shike M. Percutaneous endoscopic gastrostomy for decompression of the stomach and small bowel. Gastrointest Endosc 1992; 38:314-318. O’Keefe S, Abraham R, Davis M et al. Protein turnover in acute and chronic liver disease. Acta Chir Scand 1980; 507(Suppl):91-101. Chowla R, Wolf D, Kutner M et al. Choline may be an essential nutrient in malnourished patients with cirrhosis. Gastroenterol 1989; 97:1514-1520. Rudman D, Kutner M, Ainsley J et al. Hypotyrosinemia, hypocystinemia, and failure to retain nitrogen during total parenteral nutrition in cirrhotic patients. Gastroenterol 1981; 81:1025-1035. Bergström J, Fürst P, Norée L et al. Intracelluar free amino acid concentration in human muscle tissue. J Appl Physiol 1974; 36:693-697. Fürst P, Albers S, Stehle P. Evidence for a nutritional need for glutamine in catabolic patients. Kidney Internat 1989; 36 (Suppl 27):S287-S292. Kaibara A, Yoshida S, Yamasaki K et al. Effect of glutamine and chemotherapy on protein metabolism in tumor-bearing rats. J Surg Res 1994; 57:143-149. Daly J, Copeland III E, Dudrick S. Effects of intravenous nutrition on tumor growth and host immunocompetence in malnourished animals. Surgery 1978; 84:655-658. Li S, Nussbaum M, McFadden D et al. Addition of L-glutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis in rats. J Surg Res 1990; 48:421-426. Li J, Stahlgren L. Glutamine prevents the biliary lithogenic effect of total parenteral nutrition in rats. JPEN 1992; 17:28S. O’Keefe S, Abraham R, Zayadi A et al. Increased plasma tyrosine concentrations in patients with cirrhosis and fulminant hepatic failure associated with increased plasma tyrosine flux and reduced hepatic oxidation capacity. Gastroenterol 1981; 81:1017-1024. Naylor C, O’Rourke K, Detsky A et al. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy: a meta-analysis. Gastroenterology 1989; 97:1033-1042. Egbergts E, Schomerus H, Hamster W et al. Branched chain amino acids in the treatment of latent portal systemic encephalopathy: a double-blind placebo-controlled crossover study. Gastroenterol 1985; 88:887-895. Marchesini G, Dioguardi F, Bianchi G et al. Long-term oral branched chain amino acid treatment in chronic hepatic encephalopathy: a randomized double blind casein controlled trial. J Hepatol 1990; 11:92-101. Reilly J, Mehta R, Teperman L et al. Nutritional support after liver transplantation: A randomized prospective study. JPEN 1990; 14:386-391. Blackburn G, O’Keefe S. Nutrition in liver failure. Gastroenterol 1989; 97:1049-1051. Fan S, Lo C, Lai E et al. Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N Engl J Med 1994; 331:1547-1552. Koretz R. Perioperative nutritional support: A tale of two studies. Gastroenterol 1995; 109:628-630. Nishiguchi Y, Sowa M, Birkhahn R. Comparison of effects of long-chain and medium-chain triglyceride emulsions during hepatic regeneration in rats. Nutrition 1991; 7:23-27.

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Birkahn R, Awad S, Klaunig J et al. Interaction of ketosis and liver regeneration in the rat. J Surg Res 1989; 47:427-432. Wicks C, Somasundaram S, Bjarnason I et al. Comparison of enteral feeding and total parenteral nutrition after liver transplantation. Lancet 1994; 344:837-840. Haupt W, Husemann B, Sailer D. Postoperative parenteral nutrition following segmental liver resection: Are fat emulsions a risk? Infusion 1990; 17:94-98. Zeiderman M, King R, Young G et al. Metabolic changes in human liver associated with pre-operative intravenous nutrition. Clin Sci 1989; 77:343-349. Young G, Chem C, Zeiderman M et al. Influence of preoperative intravenous nutrition upon hepatic protein synthesis and plasma proteins and amino acids. JPEN 1989; 13:596-602. Twomey P, Patching S. Cost-effectiveness of nutritional support. JPEN 1985; 9:3-10. Detsky A, Jeejeebhoy K. Cost-effectiveness of preoperative parenteral nutrition in patients undergoing major gastrointestinal surgery. JPEN 1984; 8:632-637. Eisenberg J, Glick H, Buzby G et al. Does perioperative total parenteral nutrition reduce medical care costs? JPEN 1993; 17:201-209. Page C, Carlton P, Andrassy R et al. Safe cost-effective postoperative nutrition: defined formula diet via needle-catheter jejunostomy. Am J Surg 1979; 138:939-945. Katz S, Oye R. Parenteral nutrition use at a university hospital: factors associated with inappropriate use. West J Med 1990; 152:683-686. Daly J, Redmond H, Gallagher H. Perioperative nutrition in cancer patients. JPEN 1992; 16 (Suppl):100S-105S. Buzby G, Blouin G, Colling C et al. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991; 325:525-532. Kemen M, Senkal M, Homann H et al. Early postoperative enteral nutrition with arginine-ω-3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: An immunologic evaluation of Impact. Crit Care Med 1995; 23:652-659. Daly J, Lieberman M, Goldfine J et al. Enteral nutrition with supplemented arginine, RNA, and omega-3 fatty acids in patients after operation: Immunologic, metabolic, and clinical outcome. Surgery 1992; 112:56-67. Daly J, Weintraub F, Shou J et al. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg 1995; 221:327-338. Senkal M, Kemen M, Homann H et al. Modulation of postoperative immune response by enteral nutrition with a diet enriched with arginine, RNA, and omega-3 fatty acids in patients with upper gastrointestinal cancer. Eur J Surg 1995; 161:115-122. Heys S, Park K, Garlick P et al. Nutrition and malignant disease: implications for surgical practice. Br J Surg 1992; 79:614-623. Franchi F, Rossi-Fanelli F, Seminara P et al. Cell kinetics of gastrointestinal tumors after different nutritional regimens: A preliminary report. J Clin Gastroenterol 1991; 13:313-315. ASPEN. Clinical guidelines for the use of parenteral and enteral nutrition in adults and pediatrics: Perioperative therapy. JPEN 1993; 17(Suppl):21SA-22SA.

CHAPTER 1 CHAPTER 30

The Treatment of Obesity Souheil Abou-Assi, Rifat Latifi and Stephen J.D. O’Keefe

Epidemiology Obesity is the most common and costly nutritional problem in the western countries. 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 Health2 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 products, 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 develops 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 important. 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 (m2). 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/m2 and obesity as a BMI of 30 kg/m2 or higher. Extreme or morbid obesity is defined as a BMI higher than 40 kg/m2, and carries a much higher

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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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/m2 for women and 20 to 22 kg/ m2 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 distribution of fat.3,6

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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, increased 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, infertility, 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 android obesity. In addition, obese people, clearly experience a multitude of difficulties 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

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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 associated 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, increased 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, Hyperlipidemia, 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 morbidity 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 concentrate on dietary restriction, but also patient psychology, behavior modification, and exercise training. This necessitates the formation of a team to include a physician, 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 approaches including pharmacotherapy and behavioral modification for morbid obesity 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

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Conventional Diet Diet is the cornerstone of any weight-loss program. The standard dietary approach 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, p25 and 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 therefore maintenance of weight loss, was unfortunately not supported by a controlled trial on 31 obese women following weight loss from a VLCD.16

30

Low- or Very-Low Caloric Diets (LCD/VLCD) VLCD contain between 400 and 800 kilocalories per day. As fasting is associated with losses of not only body fat but also protein, they generally contain adequate 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 medical need to lose fat rapidly and have a BMI greater than 30 kg/m2. 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 complications include dizziness, fatigue, muscle cramping, headache, cold intolerance, dehydration, 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, advanced renal or hepatic diseases, cerebrovascular disease, Type I diabetes or significant psychiatric disorders should be excluded.

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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 significant 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 sixyear 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 understanding of the hormonal and metabolic control of fat storage and utilization advances.

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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 enhancing the release of catecholamines in the brain, and thereby suppressing appetite. 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 amphetamine 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 caloric restriction. The most common side effects include headache, insomnia, nervousness, and irritability. Tachycardia and elevation in blood pressure may also occur. The co-administration of fenfluramine enhances phentermine’s action.28,29

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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 hypothalamus 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 noradrenaline and serotonin that has recently been approved for the long-term management 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

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studies 5 mg/ day dosage of sibutramine was not significantly different from placebo, 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 placebo 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 insomnia have been reported in over 70% of subjects in large controlled trials, with dropout 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, compared 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 approximately 10% of body weight, and significant reductions in plasma cholesterol levels after one year of treatment.40 Side effects include steatorrhoea and fat soluble vitamin 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, p40 kg/m2 or BMI> 35 kg/m2 with co-morbid conditions, 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, albeit 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 introduced55 as an attempt to avoid adverse long-term nutritional and ulcerogenic consequences of gastric bypass. In gastroplasty the upper stomach is stapled near the gastro- esophageal junction, and creates a small upper gastric pouch, which communicates with the rest of the stomach and gastro-intestinal 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 continuity. 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 requires 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 opening is made in the stomach with an EEA stapling device 5 cm from the cardio esophageal junction.

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The Biology and Practice of Current Nutritional Support

VBG can be associated with severe gastro-esophageal reflux. VBG is more effective than horizontal gastroplasty, but significantly less effective then RYGBP, as demonstrated 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 stapling, with its inherent risk of staple-line disruption, was avoided. More recent developments 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

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In recent years Roux-en-Y gastric bypass (RYGBP) (has become the most common 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 retrospective 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 following 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 especially 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. Currently 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/m2 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.

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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 comparable 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 complications 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/m2, although a few groups have reported on successful LRYGBP procedure inpatients with a BMI up to 70 kg/m2. 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 conversion 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%, respectively. 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 obstruction and the need for re-operation, esophageal dilatation, band erosion into the lumen of the stomach, port infections and inadequate weight loss have been reported. The presences of hiatal hernia and esophageal dysmotility were identified as independent risk factors for lap-band slippage.67 Other complications of gastric banding include food intolerance, reflux esophagitis, pouch dilatation and stoma occlusion. In a prospective, randomized trial of open versus laparoscopic adjustable silicone gastric banding, there were no differences in weight loss, or post operative complications, 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